Smelting of Scandium by Microwave Irradiation.
Scandium is being explored as an alloying element for aluminum alloys, which are gaining importance as high-performance lightweight structural alloys in the transportation industry. A few years ago, Sc was also found to be suitable for use in electrical devices. High-Sc-content ScAlN thin films have attracted significant attention because of their strong piezoelectricity. The piezoelectric response of ScAlN suggests that ScAlN thin films formed on a hard substrate would be suitable surface acoustic wave wideband filters for next-generation wireless communication systems. However, it is often difficult to use ScAlN thin films in MEMS devices-including acoustic ones-because of the extremely high price of metallic Sc, given the difficulty associated with smelting it. Here, we propose a novel process for smelting Sc metal by microwave irradiation. Sc metal was able to be obtained successfully from ScF₃ through a microwave-irradiation-based carbon reduction reaction. The reaction temperature for this reduction process was approximately 880°C, which is half of that for the conventional smelting process involving reduction with Ca. Thus, the proposed microwave irradiation process has significant potential for use in the smelting of Sc metal.


[Growth pattern of the frontal bone primordium and involvement of Bmps in this process].
The mammalian skull vault consists of several membrane bones with different origins. A pair of frontal bones, which occupies the anterior part of the skull vault, is derived from cranial neural crest cells. The frontal bone primordium develops at the superciliary ridge region, then expands towards the top of the head. In this study, we investigated the growth pattern of the frontal bone primordium and the factors involved in this process. In situ hybridization of fibroblast growth factor receptor 2 and Runx2, which are markers of preosteoblast, revealed that the frontal bone primordium appears around embryonic day 12.5 (E 12.5) and actively grows between E 14 and E 16. We labelled the head mesenchyme of E 13 at the superciliary ridge with DiI by ex-utero surgery and found that the labelled cells were present at the apical edge of the developing frontal bone on E 18. To elucidate the molecular basis of this formation, we cultured E 15 calvarium in the presence of recombinant human bone morphogenetic proteins (rhBMPs); rhBMP-2 and rhBMP-7, but not rhBMP-4, accelerated the growth of the frontal bone domain. These results suggest that the frontal bone primordium grows intrinsically by expanding the primordium not by recruiting surrounding cells, and Bmp-2 and -7 play roles in stimulating the growth of the frontal bone primordium.


Apparent mineralocorticoid excess: time of manifestation and complications despite treatment.
Here we describe the case of a patient followed from birth because of a positive family history for apparent mineralocorticoid excess (AME) in an older brother. The patient, a girl, had normal serum electrolyte and blood pressure measurements in the first months after birth. Not until the age of 11 months did she develop anorexia and failure to thrive in combination with hypertension, hypokalemia, and metabolic alkalosis, which are consistent with the diagnosis of AME. This diagnosis was confirmed by mutation analysis of the HSD11B2 gene (C1228T). Treatment with amiloride and furosemide electrolyte disturbances normalized her blood pressure. At the age of 19 years she unexpectedly suffered a stroke. Additional investigations revealed no accepted risk factor for stroke. We discuss the possible underlying mechanisms for the delayed manifestation of hypertension and electrolyte disturbances in AME, propose an additional explanation for the stroke in this patient, and advise treatment with a mineralocorticoid receptor antagonist to reduce stroke risk in patients with AME.


Conditional ablation of astroglial CCL2 suppresses CNS accumulation of M1 macrophages and preserves axons in mice with MOG peptide EAE.
Current multiple sclerosis (MS) therapies only partially prevent chronically worsening neurological deficits, which are largely attributable to progressive loss of CNS axons. Prior studies of experimental autoimmune encephalomyelitis (EAE) induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG peptide), a model of MS, documented continued axon loss for months after acute CNS inflammatory infiltrates had subsided, and massive astroglial induction of CCL2 (MCP-1), a chemokine for CCR2(+) monocytes. We now report that conditional deletion of astroglial CCL2 significantly decreases CNS accumulation of classically activated (M1) monocyte-derived macrophages and microglial expression of M1 markers during the initial CNS inflammatory phase of MOG peptide EAE, reduces the acute and long-term severity of clinical deficits and slows the progression of spinal cord axon loss. In addition, lack of astroglial-derived CCL2 results in increased accumulation of Th17 cells within the CNS in these mice, but also in greater confinement of CD4(+) lymphocytes to CNS perivascular spaces. These findings suggest that therapies designed to inhibit astroglial CCL2-driven trafficking of monocyte-derived macrophages to the CNS during acute MS exacerbations have the potential to significantly reduce CNS axon loss and slow progression of neurological deficits.


Reoperations after repair of partial and complete atrioventricular septal defect.
The most common cause of reoperation following repair of atrioventricular septal defect (AVSD) is left atrioventricular valve regurgitation. However, reoperation for subaortic obstruction is required in some, especially after initial repair of partial AVSD. Etiology of reoperation and late outcome were evaluated. Between 1962 and 2007, 146 patients (59 male) underwent reoperation at the authors' institution after prior repair of partial (n = 96) and complete (n = 50) AVSD. Median age at reoperation after repair of partial AVSD was 26 years (range, 10 months to 71 years) and 4.5 years (range, 53 days to 38 years) after repair of complete AVSD. The 3 most common indications for reoperation included left atrioventricular (AV) valve regurgitation in 105 patients, subaortic stenosis in 29, and right AV valve regurgitation in 21. The most common procedures performed included left AV valve repair in 59 (40%) patients, left AV valve replacement in 56 (38%), subaortic fibrous resection/myectomy in 24 (16%), and right AV valve surgery in 19 (13%). Freedom from subsequent reoperation at 10 years was 48% after initial repair of complete AVSD and 84% after initial repair of partial AVSD. During late follow-up, 10-year actuarial survival was 91% and 77% after initial repair of complete and partial AVSD, respectively. The most common indication for reoperation after initial repair of partial or complete AVSD is left AV valve pathology; left ventricular outflow tract obstruction was more common in partial AVSD. Although freedom from subsequent reoperations is higher after initial repair of partial AVSD, these patients have reduced long-term survival when compared with complete AVSD.


Downregulated MCOLN1 Attenuates The Progression Of Non-Small-Cell Lung Cancer By Inhibiting Lysosome-Autophagy.
Autophagy plays various roles in non-small-cell lung cancer (NSCLC). MCOLN1, a reactive oxygen species sensor, can regulate autophagy via lysosomal Ca(2+); however, the role of MCOLN1 in NSCLC is largely unknown. This study aimed to explore the effects of MCOLN1 on proliferation, invasion and migration in NSCLC and the underling mechanisms. The tissues of NSCLC patients were collected, then MCOLN1 expression in tumor and adjacent tissues was measured and its relationship with pathological staging was analyzed. The Cell Counting Kit-8 (CCK-8) assay, wound healing assay and transwell migration assay were used to evaluate the proliferation, migration and invasion ability, respectively. Live-cell imaging and transmission electron microscopy (TEM) were used to observe autophagic flux and autolysosomes. It was found that MCOLN1 expression was significantly decreased in human NSCLC tissues compared with normal lung tissues while more MCOLN1 in stage III-IV was shown than stage I-II, indicating that MCOLN1 increased along with the progression of NSCLC. Furthermore, CCK-8 assay, wound healing assay and transwell migration assay confirmed that the inhibition of MCOLN1 suppressed NSCLC cells proliferation migration and invasion. Overexpression of MCOLN1 promoted autophagy in A549 and H1299 cells with increased LC3-II/I, lamp1 expression and autolysosomes as well as autophagic flux shown by live-cell imaging and TEM. Our study shows that downregulated MCOLN1 reduced lysosome-autophagy activity contributing to inhibited tumor progression, which reveals a novel role of MCOLN1 in NSCLC, and targeting MCOLN1 may be a therapeutic potential for NSCLC.


Improving the health of African Americans in the USA: an overdue opportunity for social justice.
Using a modified social ecological model, we conducted a review of the literature and nationwide statistics on African American health. We discuss the main social determinants of health and main health disparities, risk factors, the leading causes of morbidity and mortality, and access to health services for blacks in the USA. The mechanisms through which social determinants, including racism, exert their deleterious effects on black health are discussed at the macro and individual levels. Incarceration and mental health care issues are highlighted as priorities to be addressed. African Americans remain the least healthy ethnic group in the USA, a somber legacy of years of racial and social injustice and a formidable challenge to equitable health care for all. Systemic causes of suboptimal black health require equally systemic solutions; positive trends in black health indicators seem to be driven by social development programs, economic investment in education, participation of African Americans in policy, and decision-making and expansion of access to health care.


Validating gingival surface temperature as an alternative tool in the diagnosis of periodontal disease activity: An observational clinical trial.
Background. Elevated temperature has been recognized as an inflammatory sign. It is the only indication that can be both objectively and quantitatively evaluated and is considered as a potential indicator of periodontal disease. Assessing gingival surface temperature (GST) could be a diagnostic parameter to determine periodontal health. This pilot clinical study aimed to validate gingival surface temperature (GST) as a clinical diagnostic tool to measure periodontal disease activity by correlating with the periodontal inflamed surface area (PISA). Methods. A cross-sectional mono-center pilot study was conducted with a convenient sample of 50 participants with a mean age of 34.14±13.7 years. Clinical parameters such as probing pocket depth (PPD) clinical attachment loss (CAL) and bleeding on probing (BOP) were measured. GST was recorded with a single lead of the bedside patient monitor and correlated with PISA. Results. The results showed a positive correlation between PISA and GST (P=0.46). Conclusion. This study showed a rise in GST of inflamed sites, but the results did not support the hypothesis that increased GST is an indicator of periodontal disease. As this is a pilot study, further studies with more larger sample sizes need to be undertaken to confirm its use as a diagnostic tool in clinical trials.


Decreased susceptibility to cephalosporins among gonococci: data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales, 2007-2011.
Effective treatment of gonorrhoea is fundamental to public health control; however, the ability of Neisseria gonorrhoeae to successively develop resistance to different treatments has hampered control efforts. The extended-spectrum cephalosporins--cefixime and ceftriaxone--have been recommended in the UK for treatment of gonorrhoea since 2005. We looked at surveillance data from England and Wales to ascertain the current usefulness of these drugs and to inform changes to national treatment guidelines. We obtained data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) for patients attending 26 genitourinary medicine clinics in England and Wales between 2007 and 2011. We did analyses with univariate and multivariable logistic regression methods to identify trends in susceptibility to cephalosporins and risk factors associated with infection with isolates with decreased susceptibility to cefixime, and we assessed changes in prescribing practices. We did molecular typing to investigate genetic relatedness of non-susceptible isolates. The prevalence of decreased susceptibility to both cefixime and ceftriaxone rose between 2007 and 2010 but was more noticeable for cefixime (an increase from 1·5% in 2007 to 17·1% in 2010), with a bimodal distribution of minimum inhibitory concentration recorded between 2009 and 2010. By multivariable analysis, isolates with decreased susceptibility to cefixime were associated with infection in men who have sex with men (odds ratio 5·47, 95% CI 3·99-7·48; p<0·0001) and year of isolation (in 2010, 13·08, 7·49-22·8; p<0·0001). Such isolates had a largely clonal population, with most belonging to genogroup G1407 and harbouring the penA mosaic gene. Data from 2011 showed a significant decline in prevalence of isolates with decreased cefixime susceptibility, falling from 17·1% in 2010 to 10·8% in 2011 (p<0·0001), concomitant with the change in prescribing practice in 2010 from cefixime to ceftriaxone plus azithromycin. Guidance for treatment of gonorrhoea in England and Wales was changed in 2010 to prolong the use of cephalosporins. The decline in prevalence of isolates with decreased cefixime susceptibility cannot be attributed unequivocally to this change in prescribing practice; however, the association is striking. Department of Health (England), Public Health England.


Chloroquine interferes with lipopolysaccharide-induced TNF-alpha gene expression by a nonlysosomotropic mechanism.
Chloroquine (CQ) is a lysosomotropic weak base with over 60 years of clinical use for the treatment of malaria and rheumatologic disorders. Consistent with its anti-inflammatory properties, CQ has been shown to interfere with TNF-alpha release from mononuclear phagocytes. Because it is unclear how CQ mediates these immunomodulatory effects, we set out to elucidate its mechanism of action. CQ exhibited dose-dependent inhibition of LPS-induced TNF-alpha release from human PBMC at therapeutically attainable concentrations. Additional studies to determine the specificity of this effect showed that although CQ reduced IL-1beta and IL-6 release, secretion of RANTES was unaffected. CQ acted by reducing TNF-alpha mRNA accumulation without destabilizing its mRNA or interfering with NF-kappaB nuclear translocation or p50/p65 isoform composition of DNA-binding complexes. Intracellular cytokine staining indicated that CQ reduced TNF-alpha production pretranslationally without interfering with TNF-alpha processing or release. We utilized bafilomycin A1 pretreatment to block the pH-dependent trapping of CQ in endosomes and lysosomes. Although bafilomycin A1 alone did not interfere with TNF-alpha expression, preincubation augmented the ability of CQ to reduce TNF-alpha mRNA levels, suggesting that CQ did not act by a lysosomotropic mechanism. Using confocal microscopy, we showed that bafilomycin A1 pretreatment resulted in a dramatic redistribution of quinacrine, a fluorescent congener of CQ, from cytoplasmic vacuoles to the nucleus. These data indicate that CQ inhibits TNF-alpha gene expression without altering translocation of NF-kappaB p50/p65 heterodimers. This dose-dependent effect occurs over a pharmacologically relevant concentration range and does not require pH-dependent lysosomotropic accumulation of CQ.


Intrinsically disordered linkers determine the interplay between phase separation and gelation in multivalent proteins.
Phase transitions of linear multivalent proteins control the reversible formation of many intracellular membraneless bodies. Specific non-covalent crosslinks involving domains/motifs lead to system-spanning networks referred to as gels. Gelation transitions can occur with or without phase separation. In gelation driven by phase separation multivalent proteins and their ligands condense into dense droplets, and gels form within droplets. System spanning networks can also form without a condensation or demixing of proteins into droplets. Gelation driven by phase separation requires lower protein concentrations, and seems to be the biologically preferred mechanism for forming membraneless bodies. Here, we use coarse-grained computer simulations and the theory of associative polymers to uncover the physical properties of intrinsically disordered linkers that determine the extent to which gelation of linear multivalent proteins is driven by phase separation. Our findings are relevant for understanding how sequence-encoded information in disordered linkers influences phase transitions of multivalent proteins.


Bilateral leg edema in an older woman.
Bilateral leg edema is a frequent symptom in older people and an important concern in geriatric medicine. Further evaluation is frequently not performed and simple therapy with diuretics is prescribed. Particularly in older patients, long-term use of diuretics can lead to severe electrolyte imbalances, volume depletion, and falls. In this case report we want to focus the physicians' attention on the necessity to determine the cause and show a correspondingly effective treatment for bilateral leg edema in older people. A thorough approach is required to recognize diseases and to avoid adverse drug events as geriatric patients often show an atypical presentation or minor symptoms. The cause of swollen legs is often multifactorial; therefore, the patient's individual history and an appropriate physical examination are important. Depending on the clinical symptoms, evaluation including basic laboratory tests, urinalysis, chest radiography, and echocardiogram may be indicated. The most probable cause of bilateral edema in older patients is chronic venous insufficiency. Heart failure is also a common cause. Other systemic causes such as renal disease or liver disease are much rarer. Antihypertensive and anti-inflammatory drugs can frequently cause leg edema, but the incidence of drug-induced leg swelling is unknown. With the help of this special case we tried to develop an approach to the diagnosis of symmetric leg edema in older patients, a problem frequently neglected in geriatric medicine.


Microfluorometric monitoring of NAD redox state in isolated perfused renal tubules.
We report the successful application of microfluorometric techniques to monitor the redox state of mitochondrial nicotinamide adenine dinucleotide (NAD) in conjunction with measurements of transepithelial transport in intact isolated perfused tubules from the rabbit kidney. The determination of the redox state of NAD yields important information on the delivery of substrate to, and the energy demands on, the tubular mitochondria. These studies required only minor modifications of the basic perfusion apparatus. With this technique we detected net reductions of mitochondrial NAD upon the addition of metabolic substrates (succinate), the inhibition of active ion transport (ouabain), and the inhibition of mitochondrial electron flow (cyanide). Uncoupling of oxidative phosphorylation with 1799 caused an oxidation of NAD. These changes in NAD redox state are predictable from previous studies in isolated mitochondria, intact tissues, and from experiments on cortical tubule suspensions from the rabbit cortex.


Peri-Implant Plastic Surgical Approaches to Increasing Keratinized Mucosa Width.
The long-term efficacy of adequate keratinized mucosa (>2 mm) in dental implants is controversial. Peri-implant plastic surgeries are currently used because they increase keratinized mucosa width (KMW), helping to regain peri-implant health and maintaining it over the long-term. We present the clinical findings using free-gingival-graft (FGG) and free-periosteal-graft (FPG) techniques in peri-implant plastic surgery for implant rehabilitation patients. We included 20 patients with implant indications of inadequate KMW (KMW < 2 mm for postimplantation) in the maxilla and mandible. All underwent clinical and radiographic measurements and a treatment protocol was prepared for implant rehabilitation and subsequent peri-implant plastic surgery. A decision as to whether and when FGG or FPG techniques would be used was made. FGG/FPG was performed pre-implantation (before monocortical block-bone augmentation) or postimplantation (before/during/after stage 2 surgery). KMW was ≥ 2 mm after application of FGG/FPG pre- or post-implantation. Moreover, peri-implant tissue health was regained/maintained in all cases from 6 months to 4 years. Peri-implant plastic surgery techniques can prevent hard- and soft-tissue problems after implant rehabilitation and during treatment of developing problems. However, surgical design and timing, and an interdisciplinary perspective determine the success of peri-implant plastic surgery.


Drugs affecting the cell cycle via actions on the polyamine metabolic pathway.
Polyamines (putrescine, spermidine, and spermine) are ubiquitous cellular components that have multiple functions, including actions affecting the cell cycle. Polyamine biosynthesis and content is altered during the course of cell cycling via changes in two key biosynthetic enzymes, ornithine decarboxylase and S-adenosyl-methionine decarboxylase. Decreases in polyamine content and/or alterations in the relative amounts of polyamines can be achieved by treatment with inhibitors of these enzymes or by application of polyamine analogues, which subvert mechanisms for polyamine homeostasis and may interfere directly with polyamine-dependent processes. Such changes cause G1 and G2-M cell cycle blocks that can be brought about via induction of p21WAF1/CIP1.


Effect of a Web-Based Behavior Change Program on Weight Loss and Cardiovascular Risk Factors in Overweight and Obese Adults at High Risk of Developing Cardiovascular Disease: Randomized Controlled Trial.
Web-based programs are a potential medium for supporting weight loss because of their accessibility and wide reach. Research is warranted to determine the shorter- and longer-term effects of these programs in relation to weight loss and other health outcomes. The aim was to evaluate the effects of a Web-based component of a weight loss service (Imperative Health) in an overweight/obese population at risk of cardiovascular disease (CVD) using a randomized controlled design and a true control group. A total of 65 overweight/obese adults at high risk of CVD were randomly allocated to 1 of 2 groups. Group 1 (n=32) was provided with the Web-based program, which supported positive dietary and physical activity changes and assisted in managing weight. Group 2 continued with their usual self-care (n=33). Assessments were conducted face-to-face. The primary outcome was between-group change in weight at 3 months. Secondary outcomes included between-group change in anthropometric measurements, blood pressure, lipid measurements, physical activity, and energy intake at 3, 6, and 12 months. Interviews were conducted to explore participants' views of the Web-based program. Retention rates for the intervention and control groups at 3 months were 78% (25/32) vs 97% (32/33), at 6 months were 66% (21/32) vs 94% (31/33), and at 12 months were 53% (17/32) vs 88% (29/33). Intention-to-treat analysis, using baseline observation carried forward imputation method, revealed that the intervention group lost more weight relative to the control group at 3 months (mean -3.41, 95% CI -4.70 to -2.13 kg vs mean -0.52, 95% CI -1.55 to 0.52 kg, P<.001), at 6 months (mean -3.47, 95% CI -4.95 to -1.98 kg vs mean -0.81, 95% CI -2.23 to 0.61 kg, P=.02), but not at 12 months (mean -2.38, 95% CI -3.48 to -0.97 kg vs mean -1.80, 95% CI -3.15 to -0.44 kg, P=.77). More intervention group participants lost ≥5% of their baseline body weight at 3 months (34%, 11/32 vs 3%, 1/33, P<.001) and 6 months (41%, 13/32 vs 18%, 6/33, P=.047), but not at 12 months (22%, 7/32 vs 21%, 7/33, P=.95) versus control group. The intervention group showed improvements in total cholesterol, triglycerides, and adopted more positive dietary and physical activity behaviors for up to 3 months verus control; however, these improvements were not sustained. Although the intervention group had high attrition levels, this study provides evidence that this Web-based program can be used to initiate clinically relevant weight loss and lower CVD risk up to 3-6 months based on the proportion of intervention group participants losing ≥5% of their body weight versus control group. It also highlights a need for augmenting Web-based programs with further interventions, such as in-person support to enhance engagement and maintain these changes. ClinicalTrials.gov NCT01472276; http://clinicaltrials.gov/ct2/show/study/NCT01472276 (Archived by Webcite at http://www.webcitation.org/6Z9lfj8nD).


Melkersson-Rosenthal syndrome with isolated unilateral eyelid edema: an immunopathologic study.
Lymphedema is caused by defective drainage of the lymphatic system. In Melkersson-Rosenthal syndrome, involvement is predominantly of the lumens with blockage of lymphatic channels by histiocytic-epithelioid cell clusters accompanied by dermal granulomas and lymphocytes. It is a localized, painless, nonitching, and nonpitting form of lymphedema. Besides the eyelids, the disease can cause lip edema, facial palsy, and/or fissured tongue. It is rare and has received little attention in the ophthalmic literature, either in its complete triadic form, or more frequently, in its monosymptomatic forms. Pathogenesis is not well understood, and there is no effective therapy. The authors describe a case of Melkesson-Rosenthal syndrome in a 45-year-old Hispanic man with isolated unilateral upper eyelid edema. Histopathological and immunohistochemical evaluations of an eyelid biopsy specimen revealed intravascular and extravascular clusters of histiocytic-epithelioid cells that were CD68/163-positive. Variable numbers of mostly T-lymphocytes were found in the epidermis, dermis, and orbicularis muscle and by virtue of the associated granulomas established the diagnosis of Melkersson-Rosenthal syndrome. CD4 helper and CD8 suppressor T-lymphocytes were equally represented. CD20 B-lymphocytes were exceedingly sparse. Conspicuous CD1a-positive Langerhans' cells were present in the epidermis, sometimes formed subepithelial loose aggregates and were also incorporated in the granulomas. The differential diagnosis includes the far more common condition of acne rosacea. Management of Melkersson-Rosenthal syndrome, and of angioedema in general, is reviewed.


Beyond the myocardium? SGLT2 inhibitors target peripheral components of reduced oxygen flux in the diabetic patient with heart failure with preserved ejection fraction.
Recent cardiovascular outcome trials have highlighted the propensity of the antidiabetic agents, SGLT2 inhibitors (SGLT2is or -flozin drugs), to exert positive clinical outcomes in patients with cardiovascular disease at risk for major adverse cardiovascular events (MACEs). Of interest in cardiac diabetology is the physiological status of the patient with T2DM and heart failure with preserved ejection fraction (HFpEF), a well-examined association. Underlying this pathologic tandem are the effects that long-standing hyperglycemia has on the ability of the HFpEF heart to adequately deliver oxygen. It is believed that shortcomings in oxygen diffusion or utilization and the resulting hypoxia thereafter may play a role in underlying the clinical sequelae of patients with T2DM and HFpEF, with implications in the long-term decline of extra-cardiac tissue. Oxygen consumption is one of the most critical factors in indexing heart failure disease burden, warranting a probe into the role of SGLT2i on oxygen utility in HFpEF and T2DM. We investigated the role of oxygen flux in the patient with T2DM and HFpEF extending beyond the heart with focuses on cellular metabolism, perivascular fibrosis with endothelial dysfunction, hematologic changes, and renal effects with neurohormonal considerations in the patient with HFpEF and T2DM. Moreover, we give a commentary on potential therapeutic targets of these components with SGLT2i to gain insight into disease burden amelioration in patients with HFpEF and T2DM.


[Direct cost of cerebrovascular disease during the first year of follow-up].
There are not sufficient studies analyzing the health costs of ictus in Spain. We carried out a prospective study to evaluate the health costs incurred by a person with a stroke during the first postictal year. We included 118 patients from the Stroke Unit of the Hospital Universitario San Carlos in Madrid, admitted between 1 July and 31 December 1996. We studied 90 survivors, of an average age of 68 years, one year after having an stroke and specifically calculated the cost of an average period in hospital, neuroimaging tests, rehabilitation treatment, medical follow-up in the Outpatient Clinic, transport costs and the cost of medicines. The average cost patient/year was: hospital admission (418,203 ptas.), health transport (108,209 ptas.), cost of medicines (74,647 ptas.), follow-up visits (64,496 ptas.), neuroimaging (61,203 ptas.), rehabilitation (58,643 ptas.). The total cost was 79,930,719 ptas. and the average cost patient/year 888,119 ptas. during the first year following the ictus. The use of health resources depended on the variables: handicap (increased in patients with a score < 60 on the Barthel scale), average neurological deficit on the Scandinavian neurological scale and sex (cost greater in women). The clinical follow-up of total infarcts of the territory of the anterior circulation cost twice as much as follow-up in cases of lacunar infarcts. Cerebrovascular disease is expensive in terms of health-care. Fifty four percent of the health-care expenses are incurred during the acute phase of the ictus and the other 46% during the first year of follow-up.


Scapulothoracic arthrodesis in facioscapulohumeral muscular dystrophy.
Forty-nine scapulothoracic arthrodeses were done in 33 patients with facioscapulohumeral muscular dystrophy to improve upper limb performance during activities of daily living. Mean followup was 102 months (range, 12-257 months). An initial average increase in shoulder abduction of 25 degrees and forward elevation of 29 degrees was seen. Complications included pleural effusion in four patients, atelectasis in one patient, stress fractures in both scapulas in one patient, asymptomatic fractures of the two lower wired ribs in one patient, and spontaneously reversible neurologic complications in two patients. No effect on respiratory function was seen.


Golgi-associated GSK3beta regulates the sorting process of post-Golgi membrane trafficking.
Glycogen synthase kinase β (GSK3β) phosphorylates many substrates in mammalian cells, and functions in many physiological processes. We observed that GSK3β knockdown by siRNA perturbed both Golgi morphology in HeLa cells and the anterograde transport of cation-independent mannose 6-phosphate receptor (CI-M6PR) from the trans-Golgi network (TGN) to prelysosomal compartments (PLC), diverting it to the exocytic pathway. Moreover, we demonstrate that a portion of GSK3β was localized to the TGN through the Golgi peripheral protein p230 and that this localization regulated CLASP2 phosphorylation. Our results also show that GSK3β knockdown resulted in accumulation of CLASP2 at microtubule plus ends at the cell periphery. Our findings support the hypothesis that GSK3β at the TGN acts as a guide, activates exocytic transport, and redirects CI-M6PR from transport to the PLC into the exocytic pathway by regulating the affinity of CLASPs for microtubules.


Correction: Comparison of professionalism between emergency medicine resident physicians and faculty physicians: A multicenter cross-sectional study.
[This corrects the article DOI: 10.1371/journal.pone.0230186.].


A comparison between the new Low-profile Visualized Intraluminal Support (LVIS Blue) stent and the Flow Redirection Endoluminal Device (FRED) in bench-top and cadaver studies.
The aim of this study is to demonstrate the differences between the new Low-profile Visualized Intraluminal Support (LVIS Blue) stenting device and the Flow Redirection Endoluminal Device (FRED) using a series of bench-top evaluations and optical coherence tomography (OCT) images in a cadaveric preparation of the basilar artery. The first part of the evaluation was bench-top microscopic documentation of metal coverage for LVIS Blue and FRED stents. OCT images of the cerebral vessels and deployed stents were acquired using OCT intravascular imaging. The stents were deployed from the left posterior cerebral artery to the basilar artery in a fresh frozen cadaver. Wall apposition and the relationship to jailed perforators were evaluated. The metal coverage along the inner curves of the LVIS Blue stent was similar to that along the outer curves of the FRED stent. The LVIS Blue stent cell size was compatible for crossing with the tested microcatheters after deployment of the stent. The LVIS Blue stent showed better wall apposition and less coverage of the perforator than the FRED stent in the cadaver experiment. LVIS Blue has a good crossing profile for microcatheters, better wall apposition, and less perforator coverage than FRED. These are desirable features in territories with high densities of perforators such as the posterior circulation.


Accreditation and regulatory implications of electronic health records for laboratory reporting.
The Clinical Laboratory Improvement Amendments of 1988 include strict regulations for reporting content, and it falls on the named director to ensure that this content is available to the caregiver. With the electronic health record serving as the conduit to the end user of the laboratory data, the laboratory generally, and the director specifically, must verify accurate transmission of these content components. An understanding of regulatory and accreditation requirements is essential both to allow the proper discharge of these mandated responsibilities and to enforce the role and authority that the pathologist must have to ensure that these requirements are satisfied by the reporting system. The regulatory requirements will be discussed in the context of the Clinical Laboratory Improvement Amendments of 1988 standards; however, interpretation and expansion on these regulations exist both in Clinical Laboratory Improvement Amendments of 1988 inspection guidelines from the Centers for Medicare and Medicaid Services and in accreditation program requirements. This regulatory expectation both places the laboratory director in a position of risk and provides leverage to ensure meaningful and accurate communication of laboratory information.


CNS prophylaxis and treatment in non-Hodgkin's lymphoma: variation in practice and lessons from the literature.
Practices regarding central nervous system (CNS) prophylaxis and treatment for non-"high-grade" lymphomas are not standardized. We designed a survey to address the CNS surveillance, prophylaxis and treatment (S + P + T) habits of Ontario oncologists, to compare tertiary with community care and gauge interest in a randomized controlled trial (RCT). We mailed 145 questionnaires to oncologists/hematologists registered at the Royal College of Physicians and Surgeons of Ontario between 1980 and 1999. The questionnaire posed questions of S + P + T for a variety of histologies, locations and risk factors. Results showed that 49/77 respondents treated adult NHL, (19 community, 30 tertiary care). Surveillance LP's were commonly done in testicular, orbital, sinus and epidural sites of presentation (76, 69, 71, 80%, respectively), but these were less commonly prophylaxed (45, 33, 29 and 41%). HIV associated NHL received surveillance and prophylaxis by 51 and 33% of respondents. Stage IV disease, increased LDH and extranodal-sites warranted infrequent S + P. IT chemotherapy via LP was the most commonly used form of prophylaxis (74%) or treatment (84%). Twenty percent used systemic agents that cross the blood brain barrier for prophylaxis, and 45% for treatment. A vast heterogeneity of practice within and between tertiary care and community physicians' practices was documented. Ninety percent of physicians indicated willingness to participate in a RCT. In conclusion, CNS surveillance and prophylaxis in non-"high-grade" NHL is highly variable, probably because there are poorly defined risk factors, inconclusive prophylaxis efficacy and the inconvenience/toxicity of therapy. Patients at high risk by International prognostic index criteria are at an increased risk for CNS relapse. A RCT comparing standard chemotherapy with or without CNS prophylaxis in selected patients is needed.


Hydraulic Tomography: Continuity and Discontinuity of High-K and Low-K Zones.
Hydraulic tomography is an emerging field and modeling method that provides a continuous hydraulic conductivity (K) distribution for an investigated region. Characterization approaches that rely on interpolation between one-dimensional (1D) profiles have limited ability to accurately identify high-K channels, juxtapositions of lenses with high K contrast, and breaches in layers or channels between such profiles. However, locating these features is especially important for groundwater flow and transport modeling, and for design and operation of in situ remediation in complex hydrogeologic environments. We use transient hydraulic tomography to estimate 3D K in a volume of 15-m diameter by 20-m saturated thickness in a highly heterogeneous unconfined alluvial (clay to sand-and-gravel) aquifer with a K range of approximately seven orders of magnitude at an active industrial site in Assemini, Sardinia, Italy. A modified Levenberg-Marquardt algorithm was used for geostatistical inversion to deal with the nonlinear nature of the highly heterogeneous system. The imaging results are validated with pumping tests not used in the tomographic inversion. These tests were conducted from three of five clusters of continuous multichannel tubing (CMTs) installed for observation in the tomographic testing. Locations of high-K continuity and discontinuity, juxtaposition of very high-K and very low-K lenses, and low-K "plugs" are evident in regions of the investigated volume where they likely would not have been identified with interpolation from 1D profiles at the positions of the pumping well and five CMT clusters. Quality assessment methods identified a suspect high-K feature between the tested volume and a lateral boundary of the model.


Concordance between PCR-based extraction-free saliva and nasopharyngeal swabs for SARS-CoV-2 testing.
Introduction: Saliva represents a less invasive alternative to nasopharyngeal swab (NPS) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection. SalivaDirect is a nucleic acid extraction-free method for detecting SARS-CoV2 in saliva specimens. Studies evaluating the concordance of gold standard NPS and newly developed SalivaDirect protocols are limited. The aim of our study was to to assess SalivaDirect as an alternative method for COVID-19 testing. Methods: Matching NPS and saliva samples were analysed from a cohort of symptomatic (n=127) and asymptomatic (n=181) participants recruited from hospital and university settings, respectively. RNA was extracted from NPS while saliva samples were subjected to the SalivaDirect protocol before RT-qPCR analysis. The presence of SARS-Cov-2 was assessed using RdRP and N1 gene targets in NPS and saliva, respectively. Results: Overall we observed 94.3% sensitivity (95% CI 87.2-97.5%), and 95.9% specificity (95% CI 92.4-97.8%) in saliva when compared to matching NPS samples. Analysis of concordance demonstrated 95.5% accuracy overall for the saliva test relative to NPS, and a very high level of agreement (κ coefficient = 0.889, 95% CI 0.833-0.946) between the two sets of specimens. Fourteen of 308 samples were discordant, all from symptomatic patients. Ct values were >30 in 13/14 and >35 in 6/14 samples. No significant difference was found in the Ct values of matching NPS and saliva sample ( p=0.860). A highly significant correlation (r = 0.475, p<0.0001) was also found between the Ct values of the concordant positive saliva and NPS specimens. Conclusions: Use of saliva processed according to the SalivaDirect protocol represents a valid method to detect SARS-CoV-2. Accurate and less invasive saliva screening is an attractive alternative to current testing methods based on NPS and would afford greater capacity to test asymptomatic populations especially in the context of frequent testing.


Effectiveness of the P.A.R.T.Y. (Prevent Alcohol and Risk-related Trauma in Youth) program in preventing traumatic injuries: a 10-year analysis.
The P.A.R.T.Y. (Prevent Alcohol and Risk-Related Trauma in Youth) program is a 1-day injury awareness and prevention program for youth aged 15 years and older. The goal is to teach adolescents to recognize their injury risks and make informed decisions to reduce them. This study assessed the effectiveness of the P.A.R.T.Y. Program in preventing traumatic injuries during a period of 10 years (1992-2004). P.A.R.T.Y. participants (STUDY) were matched with subjects having the same age, gender, residential area, and initial year in database, who did not attend the P.A.R.T.Y. Program (CONTROL). Data from hospital discharge database, and provincial health claims, were searched to determine the incidence of traumatic injuries in both groups. Statistical comparisons were made for the two groups, gender, calendar year, and before and after the graduating driver licensing system was implemented, using the χ and conditional logistic regression analysis with a p<0.05 considered significant. Of 3,905 P.A.R.T.Y. participants, 1,281 were successfully randomly matched on the above 4 variables with 1,281 controls. The most frequent injury was injury by other or homicide 373 of 2,562 (14.8%). There were fewer traumatic injuries in the STUDY group than in the CONTROL group (43.3% vs. 47.4%; p=0.02; OR, 1.22; 95% CI, 1.03-1.45). This difference was stronger in females (44.4% vs. 49.0%; p=0.04) and before the graduating driver licensing system implementation (60.1% vs. 67.2%; p=0.04). The P.A.R.T.Y. Program effectively reduced the incidence of traumatic injuries among its participants. This effectiveness was stronger among females and before the driver licensing system was implemented.


Convenient preparation of tert-butyl beta-(protected amino)esters.
Refluxing an aldehyde 1 with benzotriazole and benzylcarbamate in the presence of a catalytic amount of p-TsOH gave the corresponding benzyloxycarbonylamino-1-(1-benzotriazolyl)alkane 2 in good yields. Compounds 2 treated with substituted tert-butyl acetates 3 using LDA as a base afford smoothly and under mild conditions the N-2-protected 3-aminoalkanoic esters 4.


Difficulties in diagnosing sexual abuse in children with condyloma acuminata in Turkey.
Human papillomavirus is responsible for anogenital warts and could be regarded as an indicator of possible sexual abuse in children. A genital wart was detected during an investigation of anti-hepatitis C virus positivity in a four-year-old male patient. No pathological findings of another sexually transmitted disease were found except complete cleft palate and circumferential lesions in the perianal region. No family member was anti-hepatitis C virus positive, but the patient's uncle and his wife had genital condylomata. Although detailed physical examination uncovered no other findings indicative of sexual abuse, suspicion of abuse could not be eliminated. Therefore, we wanted to draw the attention of health professionals to the association of anogenital warts and sexual abuse.


Transplantation in inborn errors of metabolism: current considerations and future perspectives.
Inborn errors of metabolism (IEM) comprise an assorted group of inherited diseases, some of which are due to disordered lysosomal or peroxisomal function and some of which might be improved following haemopoietic cell transplantation (HCT). In these disorders, the onset in infancy or early childhood is typically accompanied by rapid deterioration, resulting in early death in the more severe phenotypes. Timely diagnosis and immediate referral to an IEM specialist are essential steps in optimal management. Treatment recommendations are based on the diagnosis, its phenotype, rate of progression, prior extent of disease, family values and expectations and the risks and benefits associated with available therapies, including HCT. International collaborative efforts are of utmost importance in determining outcomes of therapy for these rare diseases, and have improved those outcomes significantly over recent decades. This discussion focuses on HCT in IEM, providing an international perspective on progress, limitations, and future directions.


Abundance or stress? Faunal exploitation patterns and subsistence strategies: The case study of Brush Hut 1 at Ohalo II, a submerged 23,000-year-old camp in the Sea of Galilee, Israel.
The submerged site of Ohalo II was occupied during the Last Glacial Maximum (LGM), between 23,500-22,500 cal BP, bridging the Upper Paleolithic/Epipaleolithic transition in the southern Levant. The site is known for the excellent preservation of its brush huts and botanical remains. This study examines the behavior of its past inhabitants through analysis of the entire faunal assemblage found on the three successive floors of Brush Hut 1. Furthermore, it provides an opportunity to test differing models of prey choice and assess whether the observed resource diversification is the result of resource depression (explained by Optimal Foraging Theory) or resource abundance (explained by Niche Construction Theory). We focused on a quantitative, qualitative and spatial investigation of the more than 20,000 faunal remains, combining traditional zooarchaeological methods with microwear analysis of teeth and Fourier Transform Infrared Spectroscopy (FTIR) of burnt bones. Identification of faunal remains to the most detailed level possible, combined with analysis of skeletal element frequencies allowed reconstruction of a profile of the desired prey, highlighting the importance of small, expedient prey compared to larger game (ungulates). FTIR was used to identify degrees of burning and to develop a key to identifying burnt bones from water-logged environments. Availability of multiple food sources within a rich habitat may have driven exploitation of those varied local resources, rather than targeting energetically-rich large prey. The choice of a littoral habitat that could be intensively exploited is an example of niche selection. Comparison with contemporaneous and later sites contributes to the ongoing discussion about Early Epipaleolithic prey choice, and the impact, if any, of the LGM in the Jordan Valley. Ohalo II is an example of diverse prey choice motivated by abundance rather than stress, at a 23,000-year-old fisher-hunter-gatherers camp.


Low Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) Ratio Associated with Increased Cardiovascular Disease and its Risk Factors in Healthy Japanese Population.
This study aimed to evaluate the association between aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio and cardiovascular disease, and risk factors in a healthy Japanese population. A retrospective cohort study was conducted at St. Luke's International Hospital, Tokyo, Japan, between 2005 and 2018. We included all participants who visited the hospital for voluntary health checkups. Our primary outcome was the development of cardiovascular disease, and the secondary outcomes were cardiovascular risk factors. We grouped the participants into quartiles (Qs) according to their baseline AST/ ALT ratios and examined the outcomes of patients in each group. 87,740 participants were included in this study. The mean age of the participants was 44.9 years [standard deviation (SD): 12.1], and 43,191 (49.2%) were men. The mean AST and ALT levels were 21.7 IU/L (SD 10.0) and 22.4 IU/L (SD 16.5), respectively, resulting in a mean AST/ALT ratio of 1.1 (0.4). During the median follow-up of 1,829 days (interquartile range 756-3,470), 1,493 (1.7%) participants developed cardiovascular disease, 831 (1%) experienced ischemic heart disease, and 723 (0.8%) experienced strokes. Those in the Q1 AST/ALT ratio group had significantly higher hazard ratios compared to those in the Q3 AST/ ALT ratio group [adjusted hazard ratio (HR)=1.32, 95% confidence interval (CI): 1.12-1.56 for cardiovascular disease; HR=1.36, 95%CI: 1.09-1.68 for ischemic heart disease; HR=1.28, 95%CI: 1.00-1.65 for stroke]. However, those belonging to the Q4 or Q5 AST/ALT ratio groups was not statistically different for primary outcomes compared to the Q3 AST/ALT ratio group. In contrast, the adjusted HRs for all secondary outcomes decreased in a dose-dependent manner as the AST/ALT ratio increased. A Q1 AST/ALT ratio was associated with an increased risk of cardiovascular disease compared to the Q3 AST/ALT ratio in the Japanese population, which is in contrast with the Western population. In our study, Q4 or Q5 AST/ALT ratios were not associated with cardiovascular disease compared to the Q3 AST/ ALT ratio. As for cardiovascular risk factors, the risk decreased as the AST/ALT ratio increased.


California serogroup virus infections in the Ryazan region of the USSR.
Serum samples from 60 people diagnosed in the summer of 1989 as having acute respiratory infections, meningitis or meningoencephalitis, acute pneumonia, Lyme disease, or other illnesses were tested by neutralization and hemagglutination-inhibition with Tahyna, Inkoo, and snowshoe hare viruses of the California serogroup (family Bunyaviridae, genus Bunyavirus). Demonstration of a diagnostic increase in antibody titers between paired serum samples from seven people showed that their illnesses were probably caused by Inkoo or Tahyna viruses. The clinical pictures were less specific. One patient had signs of meningoencephalitis, three had signs of meningitis, and three had influenza-like illnesses. These observations and other results suggest that California serogroup viruses are widespread in Russia and may account for an unexpectedly large number of presently undiagnosed febrile illnesses, some with central nervous system involvement.


Inherent Surface Activation of Laser-Scribed Graphene Decorated with Au and Ag Nanoparticles: Simultaneous Electrochemical Behavior toward Uric Acid and Dopamine.
Laser-scribed graphene electrodes (LSGEs) have attracted great attention for the development of electrochemical (bio)sensors due to their excellent electronic properties, large surface area, and high porosity, which enhances the electrons' transfer rate. An increasing active surface area and defect sites are the quickest way to amplify the electrochemical sensing attributes of the electrodes. Here, we have found that the activation procedure coupled to the electrodeposition of metal nanoparticles resulted in a significant amplification of the active area and the analytical performance. This preliminary study is supported by the demonstration of the simultaneous electrochemical sensing of dopamine (DA) and uric acid (UA) by the electrochemically activated LSGEs (LSGE*s). Furthermore, the electrodeposition of two different metal nanoparticles, gold (Au) and silver (Ag), was performed in multiple combinations on working and reference electrodes to investigate the enhancement in the electrochemical response of LSGE*s. Current enhancements of 32, 27, and 35% were observed from LSGE* with WE:Au/RE:LSG/CE:LSGE, WE:Au/RE:Au/CE:LSGE, and WE:Au/RE:Ag/CE:LSGE, compared to the same combinations of LSGEs without any surface activation. A homemade and practical potentiostat, KAUSTat, was used in these electrochemical depositions in this study. Among all of the combinations, the surface area was increased 1.6-, 2.0-, and 1.2-fold for WE:Au/RE:LSG/CE:LSGE, WE:Au/RE:Au/CE:LSGE, and WE:Au/RE:Ag/CE:LSGE prepared from LSGE*s, respectively. To evaluate the analytical performance, DA and UA were detected simultaneously in the presence of ascorbic acid. The LODs of DA and UA are calculated to be ∼0.8 and ∼0.6 μM, respectively. Hence, this study has the potential to open new insights into new surface activation strategies with a combination of one-step nanostructured metal depositions by a custom-made potentiostat. This novel strategy could be an excellent and straightforward method to enhance the electrochemical transducer sensitivity for various electrochemical sensing applications.


Open Abdomen and Fluid Instillation in the Septic Abdomen: Results from the IROA Study.
Open abdomen (OA) is a surgical option that can be used in patients with severe peritonitis. Few evidences exist to recommend the use of intraperitoneal fluid instillation associated with OA in managing septic abdomen. A prospective analysis of adult patients enrolled in the International Register of Open Abdomen (trial registration: NCT02382770) was performed. A total of 387 patients were enrolled in two groups: 84 with peritoneal fluid instillation (FI) and 303 without (NFI). The groups were homogeneous for baseline characteristics. Overall complications were 92.9% in FI and 86.3% in NFI (p = 0.106). Complications during OA were 72.6% in FI and 59.9% in NFI (p = 0.034). Complications after definitive closure were 70.8% in FI and 61.1% in NFI (p = 0.133). Entero-atmospheric fistula was 13.1% in FI and 12% in NFI (p = 0.828). Fascial closure was 78.6% in FI and 63.7% in NFI (p = 0.02). Analysis of FI in negative pressure wound therapy (NPWT) showed: Overall morbidity in NPWT was 94% and in non-NPWT 91.2% (p = 0.622) and morbidity during OA was 68% and 79.4% (p = 0.25), respectively. Definitive fascial closure in NPWT was 87.8% and 96.8% in non-NPWT (p = 0.173). Overall mortality was 40% in NPWT and 29.4% in non-NPWT (p = 0.32) and morality during OA period was 18% and 8.8% (p = 0.238), respectively. We found intraperitoneal fluid instillation during open abdomen in peritonitic patients to increase the complication rate during the open abdomen period, with no impact on mortality, entero-atmospheric fistula rate and opening time. Fascial closure rate is increased by instillation. Fluid instillation is feasible even when associated with nonnegative pressure temporary abdominal closure techniques.


Evidence That Brain-Controlled Functional Electrical Stimulation Could Elicit Targeted Corticospinal Facilitation of Hand Muscles in Healthy Young Adults.
Brain-computer interface (BCI)-controlled functional electrical stimulation (FES) has been used in rehabilitation for improving hand motor function. However, mechanisms of improvements are still not well understood. The objective of this study was to investigate how BCI-controlled FES affects hand muscle corticospinal excitability. A total of 12 healthy young adults were recruited in the study. During BCI calibration, a single electroencephalography channel from the motor cortex and a frequency band were chosen to detect event-related desynchronization (ERD) of cortical oscillatory activity during kinesthetic wrist motor imagery (MI). The MI-based BCI system was used to detect active states on the basis of ERD activity in real time and produce contralateral wrist extension movements through FES of the extensor carpi radialis (ECR) muscle. As a control condition, FES was used to generate wrist extension at random intervals. The two interventions were performed on separate days and lasted 25 minutes. Motor evoked potentials (MEPs) in ECR (intervention target) and flexor carpi radialis (FCR) muscles were elicited through single-pulse transcranial magnetic stimulation of the motor cortex to compare corticospinal excitability before (pre), immediately after (post0), and 30 minutes after (post30) the interventions. After the BCI-FES intervention, ECR muscle MEPs were significantly facilitated at post0 and post30 time points compared with before the intervention (pre), whereas there were no changes in the FCR muscle corticospinal excitability. Conversely, after the random FES intervention, both ECR and FCR muscle MEPs were unaffected compared with before the intervention (pre). Our results demonstrated evidence that BCI-FES intervention could elicit muscle-specific short-term corticospinal excitability facilitation of the intervention targeted (ECR) muscle only, whereas randomly applied FES was ineffective in eliciting any changes. Notably, these findings suggest that associative cortical and peripheral activations during BCI-FES can effectively elicit targeted muscle corticospinal excitability facilitation, implying possible rehabilitation mechanisms.


Epigenetic reprogramming of OCT4 and NANOG regulatory regions by embryonal carcinoma cell extract.
Analyses of molecular events associated with reprogramming somatic nuclei to pluripotency are scarce. We previously reported the reprogramming of epithelial cells by extract of undifferentiated embryonal carcinoma (EC) cells. We now demonstrate reprogramming of DNA methylation and histone modifications on regulatory regions of the developmentally regulated OCT4 and NANOG genes by exposure of 293T cells to EC cell extract. OCT4 and NANOG are transcriptionally up-regulated and undergo mosaic cytosine-phosphate-guanosine demethylation. OCT4 demethylation occurs as early as week 1, is enhanced by week 2, and is most prominent in the proximal promoter and distal enhancer. Targeted OCT4 and NANOG demethylation does not occur in 293T extract-treated cells. Retinoic acid-mediated differentiation of reprogrammed cells elicits OCT4 promoter remethylation and transcriptional repression. Chromatin immunoprecipitation analyses of lysines K4, K9, and K27 of histone H3 on OCT4 and NANOG indicate that primary chromatin remodeling determinants are acetylation of H3K9 and demethylation of dimethylated H3K9. H3K4 remains di- and trimethylated. Demethylation of trimethylated H3K9 and H3K27 also occurs; however, trimethylation seems more stable than dimethylation. We conclude that a central epigenetic reprogramming event is relaxation of chromatin at loci associated with pluripotency to create a conformation compatible with transcriptional activation.


Monitoring of sport participation and injury risk in young athletes.
Careful modulation of training characteristics in high-level sports optimizes performance and avoids inappropriate workloads and associated sports injury risk. The aims of this study were to compare sport participation characteristics in different youth sport categories and to investigate their relationship with injury. Prospective cohort follow-up. Young (12-19 years) high-level athletes (n=154) from a regional sport school were followed during 41 weeks regarding sport participation characteristics and traumatic and overuse sports injuries (time-loss definition). All data were self-recorded by the athletes in an electronic system "TIPPS" (Training and Injury Prevention Platform for Sports) and subject to a systematic data quality control. Volume and intensity (self-rated perceived exertion) of each sport session were used to compute weekly load, monotony and strain. Sport categories were defined as team, racket, and individual sports. All sport participation characteristics were dependent on sport category (p<0.05). Weekly intensity, load and strain were dependent on age (p<0.05). Racket and individual sports were associated with lower injury risk (HR=0.37 and 0.34, p=0.001 and p<0.001, respectively) compared to team sports. Average sport participation characteristics were not related to injury according to the survival analysis. However, intensity during the week prior to injury was significantly higher (p<0.01) compared to that of the 4 preceding weeks. This study investigated for the first time the relationship between sport participation pattern and injury risk in young athletes. The monitoring method was sensitive to variations according to pertinent variables and might help identify athletes with increased sports injury risk.


Prognostic significance of immunohistochemical biomarkers in diffuse large B-cell lymphoma: a study from the Lunenburg Lymphoma Biomarker Consortium.
The Lunenburg Lymphoma Biomarker Consortium (LLBC) evaluated the prognostic value of IHC biomarkers in a large series of patients with diffuse large B-cell lymphoma (DLBCL). Clinical data and tumor samples were retrieved from 12 studies from Europe and North America, with patients treated before or after the rituximab era. Using tissue microarrays from 1514 patients, IHC for BCL2, BCL6, CD5, CD10, MUM1, Ki67, and HLA-DR was performed and scored according to previously validated protocols. Optimal cut points predicting overall survival of patients treated in the rituximab era could only be determined for CD5 (P = .003) and Ki67 (P = .02), whereas such cut points for BCL2, BCL6, HLA-DR, and MUM1 could only be defined in patients not receiving rituximab. A prognostic model for patients treated in the rituximab era identified 4 risk groups using BCL2, Ki67, and International Prognostic Index (IPI) with improved discrimination of low-risk patients. Newly recognized correlations between specific biomarkers and IPI highlight the importance of carefully controlling for clinical and biologic factors in prognostic models. These data demonstrate that the IPI remains the best available index in patients with DLBCL treated with rituximab and chemotherapy.


Cancer and blood concentrations of the comutagen harmane in essential tremor.
Blood concentrations of harmane, a tremor-producing neurotoxin, are elevated in essential tremor (ET). Harmane is also a comutagen. Using a case-control design, we compared the prevalence of cancer in ET cases vs. controls, and determined whether blood harmane concentrations are elevated among ET cases with cancer. 66/267 (24.7%) ET cases vs. 55/331 (16.6%) controls had cancer (adjusted OR 1.52, 95% CI 1.01-2.30, P = 0.04). Among specific cancer types, colon cancer was more prevalent in ET cases than controls (2.6% vs. 0.6%, P = 0.04). Log blood harmane concentration was higher in ET cases vs. controls (P = 0.02) and in participants with vs. without cancer (P = 0.02). Log blood harmane concentration was highest in ET cases with cancer when compared with other groups (P = 0.009). These links between cancer and ET and between high blood harmane and cancer in ET deserve further study.


Approaching the transition state in the crystal structure of a phosphoribosyltransferase.
Hypoxanthine phosphoribosyltransferase (HPRT) salvages 6-oxopurine bases in the nucleotide metabolic pathway. The 1.8 A crystal structure of an asymmetric dimer of the HPRT from the protozoan parasite Trypanosoma cruzi was determined in a ternary complex with the primary substrate phosphoribosylpyrophosphate (PRPP) and an analogue of the substrate hypoxanthine, revealing both open and closed active site conformations. The ligands are positioned for in-line nucleophilic attack at the PRPP ribose C1' by two metal ions which straddle the pyrophosphate leaving group. The structure provides the first evidence for the involvement of two metal ions in the HPRT-catalyzed reaction, and structural details further suggest the mechanism may proceed via SN2-type chemistry. The closed conformation reveals the structural roles for invariant flexible loop residues Ser103 and Tyr104 and supports a role for the loop in the liberation of pyrophosphate. The pre-transition state structure is valuable for understanding the enzyme mechanism, as well as providing a foundation for antiparasite drug design efforts against T. cruzi, which causes Chagas' disease in humans. Additionally, the structure illuminates the molecular basis of three inherited mutations in the human HPRT leading to Lesch-Nyhan syndrome (D193N) or gout (S103R or S109L), as the homologous residues in the trypanosomal enzyme contribute to the previously unrecognized Mg2+ ion binding site and to the formation of the closed flexible loop, respectively.


Policy options to achieve culturally-aware and environmentally-sustainable tourism in Fiji.
Increased visitation rates are expected to further impact ecosystems and local communities depending on them to generate income from tourism. We measure how different sustainable tourism management options of such areas in ways that respect the concept of vanua, the Fijian understanding of the connectiveness of the natural environment, humans and traditions, are perceived by a representative sample of potential visitors of the UK population. We then consider some plausible management options and how these may impact welfare. Results show that prospective UK respondents are willing to donate approximately £73 for a management option that enforces medium restrictions by local communities to enter coastal and marine areas in Fiji, so that vanua is respected. A management option that instead denies access to local communities is not seen favourably by prospective UK visitors to Fiji. In terms of time preference, UK respondents, in particular those with previous experiences of tropical areas, prefer environmental projects that restore and protect coastal and marine ecosystems to be completed as soon as possible. Our findings seem to support the introduction of more sustainable and community-based management practices in Fiji as they appear to increase welfare of visitors respecting local traditions and customs, as long as some access is provided to tourists. Donations from tourists or a change in tourism management from a traditional to a more sustainable practice may support the sustainable development of the local coastal communities in Fiji.


Evaluation of the Association of Polymorphisms With Palbociclib-Induced Neutropenia: Pharmacogenetic Analysis of PALOMA-2/-3.
The most frequently reported treatment-related adverse event in clinical trials with the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib is neutropenia. Allelic variants in ABCB1 and ERCC1 might be associated with early occurrence (i.e., end of week 2 treatment) of grade 3/4 neutropenia. Pharmacogenetic analyses were performed to uncover associations between single nucleotide polymorphisms (SNPs) in these genes, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia. ABCB1 (rs1045642, rs1128503) and ERCC1 (rs3212986, rs11615) were analyzed in germline DNA from palbociclib-treated patients from PALOMA-2 (n = 584) and PALOMA-3 (n = 442). SNP, race, and cycle 1 day 15 (C1D15) absolute neutrophil count (ANC) data were available for 652 patients. Univariate and multivariable analyses evaluated associations between SNPs, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia. Analyses were stratified by Asian (n = 122) and non-Asian (n = 530) ethnicity. Median progression-free survival (mPFS) was estimated using the Kaplan-Meier method. The effect of genetic variants on palbociclib pharmacokinetics was analyzed. ABCB1 and ERCC1_rs11615 SNP frequencies differed between Asian and non-Asian patients. Multivariable analysis showed that low baseline ANC was a strong independent risk factor for C1D15 grade 3/4 neutropenia regardless of race (Asians: odds ratio [OR], 6.033, 95% confidence interval [CI], 2.615-13.922, p < .0001; Non-Asians: OR, 6.884, 95% CI, 4.138-11.451, p < .0001). ABCB1_rs1128503 (C/C vs. T/T: OR, 0.57, 95% CI, 0.311-1.047, p = .070) and ERCC1_rs11615 (A/A vs. G/G: OR, 1.75, 95% CI, 0.901-3.397, p = .098) were potential independent risk factors for C1D15 grade 3/4 neutropenia in non-Asian patients. Palbociclib mPFS was consistent across genetic variants; exposure was not associated with ABCB1 genotype. This is the first comprehensive assessment of pharmacogenetic data in relationship to exposure to a CDK4/6 inhibitor. Pharmacogenetic testing may inform about potentially increased likelihood of patients developing severe neutropenia (NCT01740427, NCT01942135). Palbociclib plus endocrine therapy improves hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer outcomes, but is commonly associated with neutropenia. Genetic variants in ABCB1 may influence palbociclib exposure, and in ERCC1 are associated with chemotherapy-induced severe neutropenia. Here, the associations of single nucleotide polymorphisms in these genes and baseline characteristics with neutropenia were assessed. Low baseline absolute neutrophil count was a strong risk factor (p < .0001) for grade 3/4 neutropenia. There was a trend indicating that ABCB1_rs1128503 and ERCC1_rs11615 were potential risk factors (p < .10) for grade 3/4 neutropenia in non-Asian patients. Pharmacogenetic testing could inform clinicians about the likelihood of severe neutropenia with palbociclib.


Identification of quantitative trait loci associated with bacterial spot race T4 resistance in intra-specific populations of tomato (Solanum lycopersicum L.).
Bacterial spot of tomato is a serious disease caused by at least four species and four races of Xanthomonas- X. euvesicatoria (race T1), X. vesicatoria (race T2), X. perforans (race T3 and T4), and X. gardneri, with X. perforans race T4 being predominant in the southeast USA. Practical management of this disease is challenging because of the need for more effective chemicals and commercially resistant cultivars. Identification of genetic resistance is the first step to developing a disease-resistant variety. The objective of this study was to identify quantitative trait loci (QTL) conferring resistance to race T4 in two independent recombinant inbred lines (RILs) populations NC 10204 (intra-specific) and NC 13666 (interspecific) developed by crossing NC 30P x NC22L-1(2008) and NC 1CELBR x PI 270443, respectively. Seven QTLs on chromosomes 2, 6, 7, 11, and 12 were identified in NC 10204. The QTL on chromosome 6 explained the highest percentage of phenotypic variance (up to 21.3%), followed by the QTL on chromosome 12 (up to 8.2%). On the other hand, the QTLs on chromosomes 1, 3, 4, 6, 7, 8, 9, and 11 were detected in NC 13666. The QTLs on chromosomes 6, 7, and 11 were co-located in NC 10204 and NC 13666 populations. The donor of the resistance associated with these QTL in NC 10204 is a released breeding line with superior horticultural traits. Therefore, both the donor parent and the QTL information will be useful in tomato breeding programs as there will be minimal linkage drag associated with the bacterial spot resistance.


Low oxygen levels can help to prevent the detrimental effect of acute warming on mitochondrial efficiency in fish.
Aerobic metabolism of aquatic ectotherms is highly sensitive to fluctuating climates. Many mitochondrial traits exhibit phenotypic plasticity in response to acute variations in temperature and oxygen availability. These responses are critical for understanding the effects of environmental variations on aquatic ectotherms' performance. Using the European seabass, Dicentrarchus labrax, we determined the effects of acute warming and deoxygenation in vitro on mitochondrial respiratory capacities and mitochondrial efficiency to produce ATP (ATP/O ratio). We show that acute warming reduced ATP/O ratio but deoxygenation marginally raised ATP/O ratio, leading to a compensatory effect of low oxygen availability on mitochondrial ATP/O ratio at high temperature. The acute effect of warming and deoxygenation on mitochondrial efficiency might be related to the leak of protons across the mitochondrial inner membrane, as the mitochondrial respiration required to counteract the proton leak increased with warming and decreased with deoxygenation. Our study underlines the importance of integrating the combined effects of temperature and oxygen availability on mitochondrial metabolism. Predictions on decline in performance of aquatic ectotherms owing to climate change may not be accurate, since these predictions typically look at respiratory capacity and ignore efficiency of ATP production.


Aberrant Dynamic Functional Network Connectivity and Graph Properties in Major Depressive Disorder.
Major depressive disorder (MDD) is a complex mood disorder characterized by persistent and overwhelming depression. Previous studies have identified abnormalities in large scale functional brain networks in MDD, yet most of them were based on static functional connectivity. In contrast, here we explored disrupted topological organization of dynamic functional network connectivity (dFNC) in MDD based on graph theory. One hundred and eighty-two MDD patients and 218 healthy controls were included in this study, all Chinese Han people. By applying group information guided independent component analysis (GIG-ICA) to resting-state functional magnetic resonance imaging (fMRI) data, the dFNCs of each subject were estimated using a sliding window method and k-means clustering. Network properties including global efficiency, local efficiency, node strength and harmonic centrality, were calculated for each subject. Five dynamic functional states were identified, three of which demonstrated significant group differences in their percentage of state occurrence. Interestingly, MDD patients spent much more time in a weakly-connected State 2, which includes regions previously associated with self-focused thinking, a representative feature of depression. In addition, the FNCs in MDD were connected differently in different states, especially among prefrontal, sensorimotor, and cerebellum networks. MDD patients exhibited significantly reduced harmonic centrality primarily involving parietal lobule, lingual gyrus and thalamus. Moreover, three dFNCs with disrupted node properties were commonly identified in different states, and also correlated with depressive symptom severity and cognitive performance. This study is the first attempt to investigate the dynamic functional abnormalities in MDD in a Chinese population using a relatively large sample size, which provides new evidence on aberrant time-varying brain activity and its network disruptions in MDD, which might underscore the impaired cognitive functions in this mental disorder.


Cannabinoid pharmacology/therapeutics in chronic degenerative disorders affecting the central nervous system.
The endocannabinoid system (ECS) exerts a modulatory effect of important functions such as neurotransmission, glial activation, oxidative stress, or protein homeostasis. Dysregulation of these cellular processes is a common neuropathological hallmark in aging and in neurodegenerative diseases of the central nervous system (CNS). The broad spectrum of actions of cannabinoids allows targeting different aspects of these multifactorial diseases. In this review, we examine the therapeutic potential of the ECS for the treatment of chronic neurodegenerative diseases of the CNS focusing on Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. First, we describe the localization of the molecular components of the ECS and how they are altered under neurodegenerative conditions, either contributing to or protecting cells from degeneration. Second, we address recent advances in the modulation of the ECS using experimental models through different strategies including the direct targeting of cannabinoid receptors with agonists or antagonists, increasing the endocannabinoid tone by the inhibition of endocannabinoid hydrolysis, and activation of cannabinoid receptor-independent effects. Preclinical evidence indicates that cannabinoid pharmacology is complex but supports the therapeutic potential of targeting the ECS. Third, we review the clinical evidence and discuss the future perspectives on how to bridge human and animal studies to develop cannabinoid-based therapies for each neurodegenerative disorder. Finally, we summarize the most relevant opportunities of cannabinoid pharmacology related to each disease and the multiple unexplored pathways in cannabinoid pharmacology that could be useful for the treatment of neurodegenerative diseases.


Mechanism of antitumor drug action: poisoning of mammalian DNA topoisomerase II on DNA by 4'-(9-acridinylamino)-methanesulfon-m-anisidide.
The intercalative acridine derivative 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), but not its isomer o-AMSA, is a potent antitumor drug that in mammalian cells stimulates the formation of DNA strand breaks that are characterized by tightly bound proteins. Using purified mammalian DNA topoisomerases, we have analyzed the effects of these antitumor drugs on topoisomerase-DNA interactions. The antitumor drug m-AMSA dramatically stimulates the formation of a topoisomerase II-DNA complex that is detected on protein-denaturant treatment: both single- and double-stranded DNA breaks are produced and a topoisomerase II subunit is linked covalently to each 5' end of the broken DNA strands. The noncytotoxic isomer, o-AMSA, which does not induce significant amounts of DNA breaks in cultured cells, exhibits a correspondingly smaller effect in stimulating formation of the complex in vitro. The agreement between in vitro and in vivo studies suggests that mammalian DNA topoisomerase II may be the primary target of m-AMSA and that the drug-induced complex formation between topoisomerase II and DNA may be the cause of cytotoxicity and other effects such as DNA sequence rearrangements and sister-chromatid exchange.


Antagonistic effect of bacteriocin against urinary catheter associated Pseudomonas aeruginosa biofilm.
Pseudomonas aeruginosa is a gram negative opportunistic bacteria causes several infections commonly colonize these devices and developing biofilms. Bacteria in biofilm can be up to 1,000 times more resistant to antibiotics than the same bacteria circulating in a planktonic state. A total of 10 isolates of Pseudomonas aeruginosa were isolated from catheter associated urinary tract infections. While carbenicillin was the most effective antibiotic, all isolates developed multidrug resistant. Both crude and purified bacteriocin showed marked inhibition activity against planktonic and biofilm of the highly resistant isolate P. aeruginosa P7. Bacteriocin extracted from a locally isolated L. acidophilus has an anti P. aeruginosa biofilm activity also it can be used as a therapeutic agent after adequate in vivo experimentation.


Perfusion and diffusion imaging in acute focal cerebral ischemia: temporal vs. spatial resolution.
High-resolution diffusion- (DWI) and perfusion-weighted (PWI) imaging may provide substantial benefits in accurate delineation of normal, ischemic, and at-risk tissue. We compared the capability of low (400 x 400 microm(2)) and high (200 x 200 microm(2)) spatial resolution imaging in characterizing the spatiotemporal evolution of the ischemic lesion in a permanent middle artery occlusion (MCAO) model in rats. Serial measurements of cerebral blood flow (CBF) and the apparent diffusion coefficient (ADC) were performed. Lesion volumes were calculated by using viability thresholds or by visual inspection, and correlated with infarct volume defined by TTC staining at 24 h after MCAO. At the very early phase of ischemia, high-resolution resulted in a significantly larger ADC-derived lesion volume and a smaller PWI/DWI mismatch. At 3 h after MCAO, ADC and CBF lesions showed similar robust correlations with TTC-defined infarct volumes for both groups using previously established thresholds. When lesions were determined visually, low-resolution resulted in a substantial overestimation of TTC-defined infarct volume and a lower inter-observer reliability (r = 0.75), whereas high-resolution produced an excellent correlation with TTC-defined infarct volume and inter-observer reliability (r = 0.96). In conclusion, high-resolution MRI resulted in substantial temporal averaging of the ischemic lesion during the early phase, but was clearly superior in visual determination of final infarct size. Low-resolution reasonably evaluated the temporal and spatial evolution of ischemia when thresholds were used.


Density- and size-dependent mortality of a settling coral-reef damselfish (Pomacentrus moluccensis Bleeker).
Density-dependent mortality may regulate many populations, but due to an offshore larval phase in benthic marine organisms, it is often difficult to quantify the effects of mortality of arriving individuals. We added approximately 600 recruit-sized individuals onto coral reef that parallels patterns in naturally settling fish. Strong, positive density-dependent mortality occurred 3 days, 1-2 weeks, and 4 months after release. Since our study species was patchily distributed, we estimated both mean group size and overall density in a transect. Mortality was more strongly related to mean group size than overall density in a transect, indicating that recruit patchiness was important. Cohesive groups may suffer higher mortality than those spread over larger areas, even if overall density of the latter is greater. Aggregative responses of predators may occur in response to larger groups, so may have contributed to positive density-dependent mortality. Increased conspicuousness to predators and congeneric aggression are additional factors that may vary positively with group size. Tagging of recruits showed migration within but not between transects, so persistence was tantamount to survival. Standard otolith back-calculation techniques employed to reconstruct original size of tagged recruits that persisted 4 months after additions indicated that mortality was also size-dependent. Size-dependent mortality was apparent at the site with the highest mortality but not at the site with the lowest mortality, resulting in different mean body sizes of recruits between sites. Size-dependent mortality may influence estimation of growth and lead to onset of size-based maturity in these fish. Strong, positive density-dependent mortality may regulate recruitment, and if coupled with size-dependent mortality, may increase maturity rate, adding to reproductive schedules of those that survive.


The importance of low control at work and home on depression and anxiety: do these effects vary by gender and social class?
In this study we consider both a gender model, a model that focuses on the stress associated with social roles and conditions in the home environment, and a job model, which addresses the stressful characteristics of the work environment, to investigate patterns of women's and men's psychological morbidity across different social positions. Using data from the Whitehall II Study, a longitudinal study of British civil servants, we hypothesise that a lack of control in the home and work environments affects depression and anxiety differently for women and men and across three social class groups. Both women and men with low control either at work or at home had an increased risk of developing depression and anxiety. We did not find an interaction between low control at home and work. We did, however, find that the risks associated with low control either at home or work were not evenly distributed across different social positions, measured by employment grade. Women in the lowest or middle employment grades who also reported low control at work or home were at most risk for depression and anxiety. Men in the middle grade with low work control were at risk for depression while those in the lowest grade were at risk for anxiety. Men in the middle and highest grades, however, were at greatest risk for both outcomes if they reported low control at home. We conclude that, in addition to social roles and characteristics of the work environment, future investigations of gender inequalities in health incorporate variables associated with control at home and social position.


Evaluating an interdisciplinary undergraduate training program in health promotion research.
The University of California at Irvine Interdisciplinary Summer Undergraduate Research Experience (ID-SURE) program had three objectives: (1) designing an interdisciplinary health promotion training curriculum for undergraduate research fellows; (2) developing measures for evaluating and assessing program-related educational processes and products; and (3) comparing these educational process and product measures between groups of students who did or did not receive the training. A total of 101 students participated in the ID-SURE program during 2005, 2006, and 2007. A longitudinal research design was employed whereby students' interdisciplinary attitudes and behaviors were assessed at the beginning and end of the training program. The interdisciplinary and intellectual qualities of students' academic and research products were assessed at the conclusion of the training activities. In addition, ID-SURE participants' interdisciplinary attitudes, behaviors, and research products were compared to those of 70 participants in another fellowship program that did not have an interdisciplinary training component. Exposing undergraduate research fellows to the interdisciplinary curriculum led to increased participation in, and positive attitudes about, interdisciplinary classroom and laboratory activities. Products, such as the integrative and interdisciplinary quality of student research projects, showed no differences when compared to those of undergraduates who were not exposed to the interdisciplinary curriculum. However, undergraduates exposed to the training engaged in more interdisciplinary behaviors at the end of the program than students who were not trained in interdisciplinary research techniques. The findings from this study offer evidence for the efficacy of the ID-SURE program for training undergraduate students in transdisciplinary concepts, methods, and skills that are needed for effective scientific collaboration. Additionally, this study makes two important contributions to the development and evaluation of interdisciplinary health research training programs: (1) It presents and evaluates a novel curriculum for training undergraduate students in interdisciplinary theories, concepts, and methods of health promotion that can be replicated in other settings and contexts; (2) It provides and tests the reliability of new measures for evaluating interdisciplinary collaborative processes and develops objective criteria for rating the integrative and intellectual quality of students' research products.


Outcomes of a Remote Cardiac Rehabilitation Program for Patients Undergoing Atrial Fibrillation Ablation: Pilot Study.
Risk factor modification, in particular exercise and weight loss, has been shown to improve outcomes for patients with atrial fibrillation (AF). However, access to structured supporting programs is limited. Barriers include the distance from appropriate facilities, insurance coverage, work or home responsibilities, and transportation. Digital health technology offers an opportunity to address this gap and offer scalable interventions for risk factor modification. This study aims to assess the feasibility and effectiveness of a 12-week asynchronous remotely supervised exercise and patient education program, modeled on cardiac rehabilitation programs, in patients with AF. A total of 12 patients undergoing catheter ablation of AF were enrolled in this pilot study. Participants met with an exercise physiologist for a supervised exercise session to generate a personalized exercise plan to be implemented over the subsequent 12-week program. Disease-specific education was also provided as well as instruction in areas such as blood pressure and weight measurement. A digital health toolkit for self-tracking was provided to facilitate monitoring of exercise time, blood pressure, weight, and cardiac rhythm. The exercise physiologist remotely monitored participants and completed weekly check-ins to titrate exercise targets and provide further education. The primary end point was program completion. Secondary end points included change in self-tracking adherence, weight, 6-minute walk test (6MWT), waist circumference, AF symptom score, and program satisfaction. The median participant age was 67.5 years, with a mean BMI of 33.8 kg/m2 and CHADs2VASC (Congestive Heart Failure, Hypertension, Age [≥75 years], Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age [65-74 years], Sex [Female]) of 1.5. A total of 11/12 (92%) participants completed the program, with 94% of expected check-ins completed and 2.9 exercise sessions per week. Adherence to electrocardiogram and blood pressure tracking was fair at 81% and 47%, respectively. Significant reductions in weight, waist circumference, and BMI were observed with improvements in 6MWT and AF symptom scores (P<.05) at the completion of the program. For program management, a mean of 2 hours per week or 0.5 hours per patient per week was required, inclusive of time for follow-up and intake visits. Participants rated the program highly (>8 on a 10-point Likert scale) in terms of the impact on health and wellness, educational value, and sustainability of the personal exercise program. An asynchronous remotely supervised exercise program augmented with AF-specific educational components for patients with AF was feasible and well received in this pilot study. While improvements in patient metrics like BMI and 6MWT are encouraging, they should be viewed as hypothesis generating. Based on insights gained, future program iterations will include particular attention to improved technology for data aggregation, adjustment of self-monitoring targets based on observed adherence, and protocol-driven exercise titration. The study design will need to incorporate strategies to facilitate the recruitment of a diverse and representative participant cohort.


Cytotoxic activity of selected Nigerian plants.
Cancer is one of the most prominent human diseases which has stimulated scientific and commercial interest in the discovery of new anticancer agents from natural sources. The current study investigates the cytotoxic activity of ethanolic extracts of sixteen Nigerian plants used locally for the treatment of cancer using the MTT assay on the HeLa cell line. Sapium ellipticum leaves showed activity comparable to the reference compound Cisplatin and greater cytotoxic activity than Combretum paniculatum, Celosia trigyna, Drymaria cordata, Cyathula achyranthoides and Cyathula prostata. Justica extensa, Pupalia lappacea, Hedranthera barteri leaves, Alternanthera sessilis, Ethulia conyzoides leaves, Combretum zenkeri root, Sapium ellipticum stembark and Lannea nigritana stembark showed very low activity while Combretum molle, Adenanthera parvoniana and Lannea acida showed no activity. The results justify the use of Sapium, Combretum, Celosia, Drymaria and Cyathula in traditional treatment of cancer.


Malignant fibrous histiocytoma of the trachea.
We experienced a rare case of malignant fibrous histiocytoma (MFH) arising in the trachea. A 24-year-old man with severe dyspnea had a well-defined mass in the cervical trachea on chest X-ray examination. Chest computed tomography showed a 2.0-cm diameter mass originating in the right-posterior wall of the trachea. The tumor occupied over 90% of the lumen. A radical excision of the tumor (tracheal resection) with tracheal plasty was performed. The microscopic diagnosis was MFH. The patient remains well, without evidence of recurrence, 3 months after surgery.


Idiom comprehension deficits in relation to corpus callosum agenesis and hypoplasia in children with spina bifida meningomyelocele.
Idioms are phrases with figurative meanings that are not directly derived from the literal meanings of the words in the phrase. Idiom comprehension varies with: literality, whether the idiom is literally plausible; compositionality, whether individual words contribute to a figurative meaning; and contextual bias. We studied idiom comprehension in children with spina bifida meningomyelocele (SBM), a neurodevelopmental disorder associated with problems in discourse comprehension and agenesis and hypoplasia of the corpus callosum. Compared to age peers, children with SBM understood decomposable idioms (which are processed more like literal language) but not non-decomposable idioms (which require contextual analyses for acquisition). The impairment in non-decomposable idioms was related to congenital agenesis of the corpus callosum, which suggests that the consequences of impaired interhemispheric communication, whether congenital or acquired in adulthood, are borne more by configurational than by compositional language.


[Transcription factors of the anterior pituitary and combined hypopituitarism].
In the recent years, spontaneous and experimental models of hypopituitarism have underlined the involvement of a number of homeodomain transcription factors in different forms of congenital anterior pituitary hormone deficiencies. Indeed, abnormalities of the transcription factor Pit-1 are responsible for combined deficiencies affecting thyrotroph, somatotroph and lactotroph cell lineages both in dwarf mouse strains (Snell, Jackson) and in human patients. More recently, alterations of the Prop-1 gene have been shown to induce a similar phenotype in the Ames mice, and alterations of the human homolog gene have been evidenced in patients with anterior pituitary deficiencies involving the same three lineages together with the gonadotrophs. Gene knock-out experiments have demonstrated the importance of other transcription factors such as Lhx3 and Lhx4 in the development of the normal pituitary gland. These findings illustrate the potential involvement of anomalies of these and many other factors in the various forms of multiple hypopituitarism.


TRIM28 variants and Wilms' tumour predisposition.
TRIM28 was recently identified as a Wilms' tumour (WT) predisposition gene, with germline pathogenic variants identified in around 1% of isolated and 8% of familial WT cases. TRIM28 variants are associated with epithelial WT, but the presence of other tumour components or anaplasia does not exclude the presence of a germline or somatic TRIM28 variant. In children with WT, TRIM28 acts as a classical tumour suppressor gene, with both alleles generally disrupted in the tumour. Therefore, loss of TRIM28 (KAP1/TIF1beta) protein expression in tumour tissue by immunohistochemistry is an effective strategy to identify patients carrying pathogenic TRIM28 variants. TRIM28 is a ubiquitously expressed corepressor that binds transcription factors in a context-, species-, and cell-type-specific manner to control the expression of genes and transposable elements during embryogenesis and cellular differentiation. In this review, we describe the inheritance patterns, histopathological and clinical features of TRIM28-associated WT, as well as potential underlying mechanisms of tumourigenesis during embryonic kidney development. Recognizing germline TRIM28 variants in patients with WT can enable counselling, genetic testing, and potential early detection of WT in other children in the family. A further exploration of TRIM28-associated WT will help to unravel the diverse and complex mechanisms underlying WT development. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.


Selection of reference genes for gene expression analysis by real-time qPCR in avian cells infected with infectious bronchitis virus.
Infectious bronchitis virus (IBV) causes infectious bronchitis in poultry, a respiratory disease that is a source of major economic loss to the poultry industry. Detection and the study of the molecular pathogenesis of the virus often involve the use of real-time quantitative PCR assays (qPCR). To account for error within the experiments, the levels of target gene transcription are normalized to that of suitable reference genes. Despite publication of the MIQE (Minimum Information for Publication of Quantitative Real-Time PCR Experiments) guidelines in 2009, single un-tested reference genes are often used for normalization of qPCR assays in avian research studies. Here, we use the geNorm algorithm to identify suitable reference genes in different avian cell types during infection with apathogenic and pathogenic strains of IBV. We discuss the importance of selecting an appropriate experimental sample subset for geNorm analysis, and show the effect that this selection can have on resultant reference gene selection. The effects of inappropriate normalization on the transcription pattern of a cellular signalling gene, AKT1, and the interferon-inducible, MX1, were studied. We identify the possibility of the misinterpretation of qPCR data when an inappropriate normalization strategy is employed. This is most notable when measuring the transcription of AKT1, where changes are minimal during infection.