Acute kidney injury after lung resection surgery: incidence and perioperative risk factors.
Postoperative acute kidney injury (AKI) is associated with increased perioperative morbidity and mortality in a variety of surgical settings, but has not been well studied after lung resection surgery. In the present study, we defined the incidence of postoperative AKI, identified risk factors, and clarified the relationship between postoperative AKI and outcome in patients undergoing lung resection surgery. A retrospective, observational study of patients who underwent lung resection surgery between January 2006 and March 2010 in a tertiary care academic center was conducted. Postoperative AKI was diagnosed within 72 hours after surgery based on the Acute Kidney Injury Network creatinine criteria. Logistic regression was used to model the association between perioperative factors and the risk of AKI within 72 hours after surgery. The relationship between postoperative AKI and patient outcome including mortality, days in hospital, and the requirement of reintubation was investigated. A total of 1129 patients (pneumonectomy n = 71, bilobectomy n = 30, lobectomy n = 580, segmentectomy n = 35, wedge resection/bullectomy n = 413) were included in the final analysis. Patients were an average of 61 years (SD 15) and 50% were female. AKI was diagnosed in 67 patients (5.9%) based on Acute Kidney Injury Network criteria (stage 1, n = 59; stage 2, n = 8; and stage 3, n = 0) within 72 hours after surgery, and only 1 patient required renal replacement therapy. Multivariate analysis demonstrated an independent association between postoperative AKI and hypertension (adjusted odds ratio [OR] 2.0, 95% confidence interval [CI]: 1.1-3.8), peripheral vascular disease (OR 4.4, 95% CI: 1.8-10), estimated glomerular filtration rate (OR 0.8, 95% CI: 0.69-0.93), preoperative use of angiotensin II receptor blockers (OR 2.2, 95% CI: 1.1-4.4), intraoperative hydroxyethyl starch administration (OR 1.5, 95% CI: 1.1-2.1), and thoracoscopic (versus open) procedures (OR 0.37, 95% CI: 0.15-0.90). Development of AKI was associated with increased rates of tracheal reintubation (12% vs 2%, P < 0.001), postoperative mechanical ventilation (15% vs 3%, P < 0.001), and prolonged hospital length of stay (10 vs 8 days, P < 0.001). There was no difference in mortality between the 2 groups (3% vs 1%, P = 0.12). Preoperative risk factors for AKI after lung resection surgery overlap with those established for other surgical procedures. Perioperative management seems to influence the risk of AKI after lung resection; in particular, the use of synthetic colloids may increase the risk, whereas thoracoscopic procedures may decrease the risk of AKI. Early postoperative AKI is associated with respiratory complications and prolonged hospitalization.


[Apical pleural fibrosis related to inhalation of asbestos fibers].
The involvement of the apical pleura is infrequent in diffuse pleural thickening secondary to asbestos exposure. Most often diffuse pleural thickening is accompanied by an obliteration of the costophrenic angle and the posterior and paraspinous pleural surfaces of the pleura are involved to the greatest extent. Unlike this typical form, we observed in five patients exposed to asbestos an apical pleural fibrosis, uni or bilateral, accompanied with lung retraction, hilar ascension and tracheal attraction. Apical pleural thickening with upper lobe changes in asbestos-exposed persons should be regarded as due to the asbestos exposure, after exclusion of other causes like tuberculosis and the apex tumors. Usually the evolution of the lesions is slowly progressive over several years or even decade, and results in mild restrictive defect.


miR-9 enhances the transactivation of nuclear factor of activated T cells by targeting KPNB1 and DYRK1B.
The fast response to stimuli and subsequent activation of the nuclear factor of activated T cells (NFAT) signaling pathway play an essential role in human T cell functions. MicroRNAs (miRNAs) are increasingly implicated in regulation of numerous biological and pathological processes. In this study we demonstrate a novel function of miRNA-9 (miR-9) in regulation of the NFAT signaling pathway. Upon PMA-ionomycin stimulation, miR-9 was markedly increased, consistent with NFAT activation. Overexpression of miR-9 significantly enhanced NFAT activity and accelerated NFAT dephosphorylation and its nuclear translocation in response to PMA-ionomycin. Karyopherin-β1 (KPNB1, a nucleocytoplasmic transporter) and dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) were identified as direct targets of miR-9. Functionally, miR-9 promoted IL-2 production in stimulated human lymphocyte Jurkat T cells. Collectively, our data reveal a novel role for miR-9 in regulation of the NFAT pathway by targeting KPNB1 and DYRK1B.


Laparoscopic Adjustable Gastric Banding (LAGB) Aftercare Attendance and Attrition.
Regular aftercare attendance following laparoscopic adjustable gastric banding (LAGB) is associated with greater weight loss and fewer post-surgical complications. Despite high reported rates of attrition from LAGB aftercare, the reasons for non-attendance have not been previously explored. The present study aimed to explore patient-reported barriers to LAGB aftercare attendance, and the perceived helpfulness of potential attrition-reducing strategies, in both regular attendees and non-attendees of aftercare. One hundred and seventy-nine participants (107 regular attendees and 72 non-attendees) completed a semi-structured questionnaire, assessing barriers to attrition (101 items) and usefulness of attrition prevention strategies (14 items). Findings indicate that both regular attendees and non-attendees experience multiple barriers to aftercare attendance. Non-attendees generally reported that barriers had a greater impact on their aftercare attendance. There was evidence for some level of acceptability for attrition-reducing strategies suggesting that LAGB patients may be receptive to such strategies. Current findings highlight the importance of assessing barriers to treatment in both attendees and non-attendees. It is proposed that addressing barriers that differentiate non-attendees from attendees may be most effective in reducing attrition from aftercare.


[5-fluorouracil in high doses. Principles and toxicity].
5 fluorouracil (5FU) is considered the most important chemotherapeutic agent for gastrointestinal cancer treatment. High dose 5FU (3 gr./m2), given together with allopurinol to prevent normal tissue toxicity may be used to get a better therapeutic index. Toxic effects are specially considered in this paper, where effects in 20 advanced gastrointestinal patients are evaluated. Taking into consideration the results obtained, we consider it can be safely used in this way.


[Cowden's disease: a new paediatric observation].
We report on a paediatric observation of Cowden's disease in a 6-year-old child. Familial steroid-resistant nephrotic syndrome was associated to papulous and papillomatous lesions of gingiva and oral mucosa, multiple hamartoma of the back and of upper limbs, facial dysmorphism and follicular thyroid cancer. Thyroid cancer evolved favorably after surgical treatment, radioactive iodine and L-thyroxin supplementation. Nephrotic syndrome evolved to chronic renal insufficiency after 11 years. The early diagnosis of Cowden's disease, or multiple hamartoma syndrome, allows a careful monitoring of the patients who are facing the risk of cancer transformation, which is the principal complication of the condition.


Identification and molecular characterization of the beta-ketoacyl-[acyl carrier protein] synthase component of the Arabidopsis mitochondrial fatty acid synthase.
Substrate specificity of condensing enzymes is a predominant factor determining the nature of fatty acyl chains synthesized by type II fatty acid synthase (FAS) enzyme complexes composed of discrete enzymes. The gene (mtKAS) encoding the condensing enzyme, beta-ketoacyl-[acyl carrier protein] (ACP) synthase (KAS), constituent of the mitochondrial FAS was cloned from Arabidopsis thaliana, and its product was purified and characterized. The mtKAS cDNA complemented the KAS II defect in the E. coli CY244 strain mutated in both fabB and fabF encoding KAS I and KAS II, respectively, demonstrating its ability to catalyze the condensation reaction in fatty acid synthesis. In vitro assays using extracts of CY244 containing all E. coli FAS components, except that KAS I and II were replaced by mtKAS, gave C(4)-C(18) fatty acids exhibiting a bimodal distribution with peaks at C(8) and C(14)-C(16). Previously observed bimodal distributions obtained using mitochondrial extracts appear attributable to the mtKAS enzyme in the extracts. Although the mtKAS sequence is most similar to that of bacterial KAS IIs, sensitivity of mtKAS to the antibiotic cerulenin resembles that of E. coli KAS I. In the first or priming condensation reaction of de novo fatty acid synthesis, purified His-tagged mtKAS efficiently utilized malonyl-ACP, but not acetyl-CoA as primer substrate. Intracellular targeting using green fluorescent protein, Western blot, and deletion analyses identified an N-terminal signal conveying mtKAS into mitochondria. Thus, mtKAS with its broad chain length specificity accomplishes all condensation steps in mitochondrial fatty acid synthesis, whereas in plastids three KAS enzymes are required.


[Epidemiology and inequality: notes on theory and history].
In this paper we present a historical analysis of the concept of inequality, and we also discuss how inequality has been viewed within the field of health. Natural and social inequalities are discussed, along with the concept of equity, theoretical explanations for inequality, and stratification in modern societies. Finally, we focus on the relationships between epidemiology and studies on social inequalities in health since epidemiology was established as a discipline, during the so-called bacteriological era, and at the present time, when there is a growing interest in social inequalities in health.


Transcriptional Active Parvovirus B19 Infection Predicts Adverse Long-Term Outcome in Patients with Non-Ischemic Cardiomyopathy.
Parvovirus B19 (B19V) is the predominant cardiotropic virus currently found in endomyocardial biopsies (EMBs). However, direct evidence showing a causal relationship between B19V and progression of inflammatory cardiomyopathy are still missing. The aim of this study was to analyze the impact of transcriptionally active cardiotropic B19V infection determined by viral RNA expression upon long-term outcomes in a large cohort of adult patients with non-ischemic cardiomyopathy in a retrospective analysis from a prospective observational cohort. In total, the analyzed study group comprised 871 consecutive B19V-positive patients (mean age 50.0 ± 15.0 years) with non-ischemic cardiomyopathy who underwent EMB. B19V-positivity was ascertained by routine diagnosis of viral genomes in EMBs. Molecular analysis of EMB revealed positive B19V transcriptional activity in n = 165 patients (18.9%). Primary endpoint was all-cause mortality in the overall cohort. The patients were followed up to 60 months. On the Cox regression analysis, B19V transcriptional activity was predictive of a worse prognosis compared to those without actively replicating B19V (p = 0.01). Moreover, multivariable analysis revealed transcriptional active B19V combined with inflammation [hazard ratio 4.013, 95% confidence interval 1.515-10.629 (p = 0.005)] as the strongest predictor of impaired survival even after adjustment for age and baseline LVEF (p = 0.005) and independently of viral load. The study demonstrates for the first time the pathogenic clinical importance of B19V with transcriptional activity in a large cohort of patients. Transcriptionally active B19V infection is an unfavourable prognostic trigger of adverse outcome. Our findings are of high clinical relevance, indicating that advanced diagnostic differentiation of B19V positive patients is of high prognostic importance.


Congenital myasthenic syndromes: multiple molecular targets at the neuromuscular junction.
Congenital myasthenic syndromes (CMS) stem from defects in presynaptic, synaptic, and postsynaptic proteins. The presynaptic CMS are associated with defects that curtail the evoked release of acetylcholine (ACh) quanta or ACh resynthesis. Defects in ACh resynthesis have now been traced to mutations in choline acetyltransferase. A synaptic CMS is caused by mutations in the collagenic tail subunit (ColQ) of the endplate species of acetylcholinesterase that prevent the tail subunit from associating with catalytic subunits or from becoming inserted into the synaptic basal lamina. Most postsynaptic CMS are caused by mutations in subunits of the acetylcholine receptor (AChR) that alter the kinetic properties or decrease the expression of AChR. The kinetic mutations increase or decrease the synaptic response to ACh and result in slow- and fast-channel syndromes, respectively. Most low-expressor mutations reside in the AChR epsilon subunit and are partially compensated by residual expression of the fetal-type gamma subunit. In a subset of CMS patients, endplate AChR deficiency is caused by mutations in rapsyn, a molecule that plays a critical role in concentrating AChR in the postsynaptic membrane.


Bioprinting and In Vitro Characterization of an Eggwhite-Based Cell-Laden Patch for Endothelialized Tissue Engineering Applications.
Three-dimensional (3D) bioprinting is an emerging fabrication technique to create 3D constructs with living cells. Notably, bioprinting bioinks are limited due to the mechanical weakness of natural biomaterials and the low bioactivity of synthetic peers. This paper presents the development of a natural bioink from chicken eggwhite and sodium alginate for bioprinting cell-laden patches to be used in endothelialized tissue engineering applications. Eggwhite was utilized for enhanced biological properties, while sodium alginate was used to improve bioink printability. The rheological properties of bioinks with varying amounts of sodium alginate were examined with the results illustrating that 2.0-3.0% (w/v) sodium alginate was suitable for printing patch constructs. The printed patches were then characterized mechanically and biologically, and the results showed that the printed patches exhibited elastic moduli close to that of natural heart tissue (20-27 kPa) and more than 94% of the vascular endothelial cells survived in the examination period of one week post 3D bioprinting. Our research also illustrated the printed patches appropriate water uptake ability (>1800%).


Drug-drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4.
Patients undergoing treatment with immunosuppressant drugs following solid organ or hematopoietic stem cell transplantation are at particular risk for development of serious infections such as invasive aspergillosis. Four triazole antifungal drugs, voriconazole, posaconazole, itraconazole, and isavuconazole, are approved to treat invasive aspergillosis either as first- or second-line therapy. All of these agents are inhibitors of cytochrome P450 3A4, which plays a key role in metabolizing immunosuppressant drugs such as cyclosporine, tacrolimus, and sirolimus. Thus, co-administration of a triazole antifungal drug with these immunosuppressant drugs can potentially increase plasma concentrations of the immunosuppressant drugs, thereby resulting in toxicity, or upon discontinuation, inadvertently decrease the respective concentrations with increased risk of rejection or graft-versus-host disease. In this article, we review the evidence for the extent of inhibition of cytochrome P450 3A4 by each of these triazole antifungal drugs and assess their effects on cyclosporine, tacrolimus, and sirolimus. We also consider other factors affecting interactions of these two classes of drugs. Finally, we examine recommendations and strategies to evaluate and address those potential drug-drug interactions in these patients.


Evolutionary expansion of the amidohydrolase superfamily in bacteria in response to the synthetic compounds molinate and diuron.
The amidohydrolase superfamily has remarkable functional diversity, with considerable structural and functional annotation of known sequences. In microbes, the recent evolution of several members of this family to catalyze the breakdown of environmental xenobiotics is not well understood. An evolutionary transition from binuclear to mononuclear metal ion coordination at the active sites of these enzymes could produce large functional changes such as those observed in nature, but there are few clear examples available to support this hypothesis. To investigate the role of binuclear-mononuclear active-site transitions in the evolution of new function in this superfamily, we have characterized two recently evolved enzymes that catalyze the hydrolysis of the synthetic herbicides molinate (MolA) and phenylurea (PuhB). In this work, the crystal structures, mutagenesis, metal ion analysis, and enzyme kinetics of both MolA and PuhB establish that these enzymes utilize a mononuclear active site. However, bioinformatics and structural comparisons reveal that the closest putative ancestor of these enzymes had a binuclear active site, indicating that a binuclear-mononuclear transition has occurred. These proteins may represent examples of evolution modifying the characteristics of existing catalysts to satisfy new requirements, specifically, metal ion rearrangement leading to large leaps in activity that would not otherwise be possible.


Fusion with a cell wall binding domain renders autolysin LytM a potent anti-Staphylococcus aureus agent.
Despite intense efforts by the medical and pharmaceutical communities, Staphylococcus aureus continues to be a pervasive pathogen that causes a myriad of diseases and a high level of morbidity and mortality among infected patients. Thus, discovering or designing novel therapeutics able to kill both drug-resistant and drug-sensitive S. aureus remains a top priority. Bacteriolytic enzymes, mostly from phage, have shown great promise in preclinical studies, but little consideration has been given to cis-acting autolytic enzymes derived from the pathogen itself. Here, we use the S. aureus autolysin LytM as a proof of principal to demonstrate the antibacterial potential of endogenous peptidoglycan-degrading enzymes. While native LytM is only marginally bactericidal, fusion of LytM to the lysostaphin cell wall binding domain enhances its anti-staphylococcal activity approximately 540-fold, placing it on par with many phage lysins currently in preclinical development. The potential to therapeutically co-opt a pathogen's endogenous peptidoglycan recycling machinery opens the door to a previously untapped reservoir of antibacterial drug candidates.


Wild bird trade at live poultry markets potentiates risks of avian influenza virus introductions in Iran.
Wild aquatic birds are the main natural host reservoir of avian influenza viruses (AIV). Migratory aquatic birds can translocate AI viruses over wide geographic distances. AIV may be transmitted reciprocally at the wild bird-poultry interface, increasing viral variability and potentially driving the zoonotic potential of these viruses. A cross-sectional study on AIV and several further avian viral pathogens conducted in 396 trapped migratory aquatic birds traded at live bird markets (LBM) in northern Iran identified 11 AIV-positive cases. The 10 identified H9N2 viral sequences fell into wild bird H9 lineage Y439; in addition, an H10N3 virus of Eurasian lineage was detected. Ten samples contained low viral loads of avian coronavirus but could not be further characterized. Although traditional trading of live-trapped wild birds provides income for hunters, particularly during fall migration periods, it increases the risk of introducing new AIV strains from the natural reservoir to poultry kept at LBMs and, potentially, to traders and customers. Banning these birds from poultry trading lines would lower such risks considerably.


Critical role of neutrophil extracellular traps (NETs) in patients with Behcet's disease.
Behçet's disease (BD) is a chronic systemic vasculitis. Thrombosis is a frequent and life-threatening complication. The pathogenesis of BD is poorly understood and evidence supporting a role for primed neutrophils in BD-associated thrombotic risk is scant. To respond to inflammatory insults, neutrophils release web-like structures, known as neutrophil extracellular traps (NETs), which are prothrombotic. We evaluated the role of NETs and markers of NETs in BD. Blood samples were collected from patients with BD, according to the International Study Group Criteria for Behçet's disease, and healthy donors (HD). NET components, including cell-free DNA (CfDNA) and neutrophil enzymes myeloperoxidase (MPO), were assessed in serum or in purified neutrophils from patients with BD and HD. Patients with active BD had elevated serum cfDNA levels and MPO-DNA complexes compared with patients with inactive BD and to HD. In addition, levels of cfDNA and MPO-DNA complexes were significantly higher in patients with BD with vascular involvement compared with those without vascular symptoms. Purified neutrophils from patients with BD exhibited spontaneous NETosis compared with HD. Thrombin generation in BD plasma was significantly increased and positively correlated with the levels of MPO-DNA complexes and cfDNA. Importantly, DNAse treatment significantly decreased thrombin generation in BD plasma but not in HD plasma. In addition, biopsy materials obtained from patients with BD showed NETs production in areas of vasculitic inflammation and thrombosis. Our data show that NETs and markers of NETS levels are elevated in patients with BD and contribute to the procoagulant state. Targeting NETs may represent a potential therapeutic target for the reduction or prevention of BD-associated thrombotic risk.


High spectral resolution x-ray optics with highly oriented pyrolytic graphite.
Thin films of highly oriented pyrolytic graphite (HOPG) give the opportunity to realize crystal optics with arbitrary geometry by mounting it on a mould of any shape. A specific feature of HOPG is its mosaicity accompanied by a high integral reflectivity, which is by an order of magnitude higher than that of all other known crystals in an energy range between 2 keV up to several 10 keV. These characteristics make it possible to realize highly efficient collecting optics, which could be also relevant for compact x-ray diagnostic tools and spectrometers. For these applications the achievable spectral resolution of the crystal optics is of interest. In this article measurements with a spectral resolution of E/DeltaE=2900 in the second order reflection and E/DeltaE=1800 in the first order reflection obtained with HOPG crystals are presented. These are by far the highest spectral resolutions reported for HOPG crystals. The integral reflectivity of these very thin films is still comparable with that of ideal Ge crystals. The trade-off between energy resolution and high integral reflectivity for HOPG is demonstrated by determining these parameters for HOPG films of different thickness.


Ontogeny of hepatic insulin and glucagon receptors and adenylate cyclase in rabbit.
In rabbit liver plasma membranes (LPM), specific binding of 125I-insulin rapidly increased in late gestation and peaked at birth, declining thereafter. In contrast, 125I-glucagon binding was lowest in late gestation, somewhat higher at birth, and increased by 48 h although only to 20-25% of adult. These changes in binding were due to changing numbers of receptors involving predominantly high affinity sites for insulin and low affinity sites for glucagon, with only minor changes in affinity. Despite measurable glucagon receptors by birth, fetal LPM produced no increment above basal in cAMP production with maximal doses of glucagon (10(-6) M), prostaglandin E1 (10(-4) M), or epinephrine (10(-4) M). Near birth only NaF (10 mM) produced a modest but significant increment in cAMP. By 2 h postbirth, all stimuli evoked significant increments in cAMP production that increased progressively but was still only 15-20% of adult at 48 h. Furthermore, although specific binding of cholera toxin was greater in fetal LPM (11 +/- 1 vs. 6 +/- 1%), cholera toxin-stimulated cAMP production increased by only 12-26% above basal in the fetus compared with 220% in adult. Markers of membrane purity including 5'-nucleotidase, phosphodiesterase, and insulin or glucagon degradation were not different in fetus and adult. We conclude that receptors and components of the adenylate cyclase complex mature independently; initial coupling occurs between the G/F regulatory protein and the catalytic unit (NaF but not hormonal activation) followed within hours of birth by coupling to the hormone receptor.


New concepts in Salmonella virulence: the importance of reducing the intracellular growth rate in the host.
The literature refers to Salmonella enterica as an intracellular bacterial pathogen that proliferates within vacuoles of mammalian cells. However, recent in vivo studies have revealed that the vast majority of infected cells contain very few intracellular bacteria (three to four organisms). Salmonella intracellular growth is also limited in cultured dendritic cells and fibroblasts, two cell types abundant in tissues located underneath the intestinal epithelium. Recently, a Salmonella factor previously known for its role as a negative regulator of intracellular growth has been shown to tightly repress certain pathogen functions upon host colonization and to be critical for virulence. The connection between virulence and the negative control of intracellular growth is further sustained by the fact that some attenuated mutants overgrow in non-phagocytic cells located in the intestinal lamina propria. These findings are changing our classical view of Salmonella as a fast growing intracellular pathogen and suggest that this pathogen may trigger responses directed to reduce the growth rate within the infected cell. These responses could play a critical role in modulating the delicate balance between disease and persistence.


STRUCTURAL-FUNCTIONAL CORRELATION IN PATIENTS WITH DIABETIC MACULAR EDEMA.
Previous studies have shown that patients with diabetic macular edema (DME) with relatively good visual acuity can have slow reading speed. The aim of this study was to evaluate the structural-functional correlation in a cohort of patients with DME and to assess whether the central four retinal points on microperimetry (MP4) could be used as a potentially faster and more reliable method of assessing retinal function in patients with DME than reading speed. The study was performed on patients with clinically significant DME. The best-corrected visual acuity (BCVA) was recorded with letter counting on a modified ETDRS chart, the maximal reading speed (MRS) was recorded with MNREAD, the retinal sensitivity (MP28 and MP4) was measured with Optos OCT/ Scanning Laser Ophthalmoscopy and the central subfield thickness was measured by Heidelberg Spectralis Spectral Domain Optical Coherent Topography. Of 100 eyes analyzed, 76 eyes were included in the study. The mean BCVA was 76.5 letters (Snellen equivalent 6/18), the mean MRS was 156.8 words per minute, the mean MP4 was 9.81 dB per point, and the mean central subfield thickness was 309.3 microns. It was found that faster MRS is correlated with younger age (P = 0.001), better BCVA (P < 0.0001), and better retinal sensitivity (P < 0.0001) for both MP28 and MP4, but not with central subfield thickness (P = 0.66). Central subfield thickness is correlated with MP28 (P = 0.05) but not with age (P = 0.812), BCVA (P = 0.113), or MP4 (P = 0.485). After correction for age and BCVA, MRS is still correlated with MP28 (P = 0.001) and MP4 (P = 0.015). Patients with DME can have reduced reading speed despite good visual acuity. Maximal reading speed is often reported to be difficult to perform, inconsistent, and affected by language and educational level. However, in this study, the authors found that the central MP4 points are quick and easy to test in most of the patients, and are highly correlated with MRS. Microperimetry might therefore represent a useful additional functional test that could be considered better than BCVA or reading speed in quantifying visual function in patients with DME.


Acenaphthenediimine complex-bridged porphyrin porous organic polymer with enriched active sites as a robust water splitting electrocatalyst.
To realize efficient water splitting, a highly promising hydrogen evolution reaction (HER) electrocatalyst is needed for the generation of hydrogen. Herein, we demonstrate a novel acenaphthenediimine complex-bridged porphyrin porous organic polymer (NiTAPP-NiACQ) with enriched active metal sites and hierarchical pores. The as-prepared NiTAPP-NiACQ exhibits good long-term durability and remarkable HER performance in 1.0 M KOH with a low overpotential of 117 mV at 10 mA cm-2, which is comparable to many previously reported electrocatalytic HER systems. Furthermore, a simple water-alkali electrolyzer using NiTAPP-NiACQ as the cathode requires a small cell voltage of 1.59 V to deliver a current density of 10 mA cm-2 at room temperature, along with outstanding durability. NiTAPP-NiACQ features not only a metal ion as the catalytic active center in the porphyrin core but also metal ion coordination on the anthraquinone component to promote HER performance, enabling multiple metal ions as the electrocatalytic active sites for the HER reaction. The excellent HER activity of NiTAPP-NiACQ is ascribed to a combination of mechanisms. These findings highlight the viability of porphyrin-derived porous organic polymers in energy conversion processes.


The 5'-flanking region of the human smooth muscle cell calponin gene contains a cis-acting domain for interaction with a methylated DNA-binding transcription repressor.
The human smooth muscle cell (SMC) calponin gene, which is composed of seven exons and six introns, spanning an approximately 11.2 kilobase (kb) genomic DNA, has been isolated and characterized by sequence analysis. As determined by primer extension mapping and rapid amplification of mRNA transcripts, a major transcription start site of the calponin gene is located at 101 base-pairs (bp) upstream of the ATG start codon. A striking feature of the 5'-flanking, 5'-untranslated, and amino-terminal protein coding regions is the presence of an Alu repetitive sequence and a stretch of DNA sequence identified using a methyl CpG-binding protein affinity column [Cross, S.H., Charlton, J.A., Nan, X., and Bird, A.P. (1994) Nature Genet, 6,236-244]. The results of this study provide a new insight into the molecular mechanism underlying regulation of SMC-lineage specific gene expression.


Whole soy, but not purified daidzein, had a favorable effect on improvement of cardiovascular risks: a 6-month randomized, double-blind, and placebo-controlled trial in equol-producing postmenopausal women.
Equol is produced by the intestinal bacteria from isoflavone daidzein. Studies have reported the health benefits of soy can only present or more pronounced in equol producers. This 6-month randomized controlled trial examined the effect of whole soy (soy flour) and purified daidzein on cardiovascular biomarkers and carotid intima-media thickness (CIMT) in prehypertensive postmenopausal women who were equol producers. Two hundred seventy eligible women were randomized to either one of the three treatments: 40 g soy flour (whole soy group), 40 g low-fat milk powder + 63 mg daidzein (daidzein group), or 40 g low-fat milk powder (placebo group) daily each for 6 months. Fasting venous samples were obtained at baseline and end of trial for testing glucose, lipids, high sensitivity C-reactive protein (hs-CRP), and free fatty acid. Changes in common CIMT were also assessed. Serum LDL-C decreased by 7.95% (95% CI: -15.09∼-0.81%) and 6.32% (95% CI: -13.45∼0.08%), and serum hs-CRP decreased by 0.164 (95% CI: -0.309∼-0.019) and 0.054 (95% CI: -0.199∼0.012) in the whole soy group compared with daidzein and milk placebo groups, respectively. No significant change in CIMT was found. Whole soy, but not purified daidzein, had a beneficial effect on reduction of LDL-C and hs-CRP among prehypertensive equol-producing postmenopausal women.


Genomic Justice and Imagined Communities.
In this issue of the Hastings Center Report, Maya Sabatello and Paul Appelbaum explore the assumptions about community embedded in the U.S. Precision Medicine Initiative, which aims to recruit donor-partners who reflect the United States' racial and ethnic diversity. As Sabatello and Appelbaum discuss, the initiative is like other national biobanking efforts in bringing to life an imagined genetic community in need of critical attention, and given the public-private forms of partnership at the heart of the PMI, such efforts could become avenues to deepen existing inequalities rather than to alleviate them. The notion of justice has underwritten debates about genomic medicine, informed consent, citizenship, benefit sharing, and profit making since the first national biobanking project emerged at the dawn of the twenty-first century. In a paradigmatic case, the creation, by an Icelandic company, of the deCODE genomic biobank opened up fierce debates about the proper relationship between public good and private gain and became the first global example of the economic and political implications that imagined genetic communities could have in our shared future. In Mexico, in 2001, the Icelandic case fueled a policy agenda to deal with global health justice and the prospects of a future market-based colonialism predicated on the intimate knowledge of DNA.


Vitamin E in neonatology.
It is difficult to maintain an objective attitude toward the use of vitamin E in neonatology. On the one hand, the desire to ameliorate iatrogenic diseases, such as BPD and ROP, makes one grasp hopefully at any theory or clinical trial that suggests a role for vitamin E in decreasing the handicaps that patients take with them from the intensive care nursery. On the other hand, when the question of toxicity arises, one tends to be negative, remembering the unfortunate experiences with oxygen, chloramphenicol, sulfisoxazole, and now, E-Ferol Aqueous Solution. We like to think that if this review had been written 2 years ago, our conclusions, based on the analysis of the data, would have been the same. But, probably, in the absence of data on the severe toxicity of one vitamin E preparation, we would have been more liberal in our recommendations for the use of vitamin E in neonatology. At this time, however, any use of supplemental vitamin E beyond the guidelines of the American Academy of Pediatrics cannot be recommended. Nor can the monitoring of blood Vitamin E levels be recommended as an assurance of nontoxic tissue concentrations in sick, premature infants. All physicians caring for premature infants are urged to review their nursery policies to make sure that excessive doses of vitamin E are not being administered. It is hoped that additional clinical trials will provide more definite answers to the questions about the efficacy of vitamin E in ROP and IVH.


Therapeutic efficacy and safety of dihydroartemisinin-piperaquine versus artesunate-mefloquine in uncomplicated Plasmodium falciparum malaria in India.
Resistance in Plasmodium falciparum to commonly used anti-malarial drugs, especially chloroquine, is being increasingly documented in India. By 2007, the first-line treatment for uncomplicated malaria has been revised to recommend artemisinin-based combination therapy (ACT) for all confirmed P. falciparum cases. The objective of this study was to compare the efficacy, safety and tolerability between dihydroartemisinin-piperaquine (DP) and artesunate plus mefloquine (A + M) drug combinations in the treatment of uncomplicated P. falciparum malaria in India. Between 2006 and 2007, 150 patients with acute uncomplicated P. falciparum malaria were enrolled, randomized to DP (101) or A + M (49) and followed up for 63 days as part of an open-label, non-inferiority, randomized, phase III multicenter trial in Asia. The heterogeneity analysis showed no statistically significant difference between India and the other countries involved in the phase III study, for both the PCR-corrected and uncorrected cure rates. As shown at the whole study level, both forms of ACT were highly efficacious in India. In fact, in the per protocol population, the 63-day cure rates were 100% for A + M and 98.8% for DP. The DP combination exerted a significant post-treatment prophylactic effect, and compared with A + M a significant reduction in the incidence of new infections for DP was observed (respectively 17.1% versus 7.5% of patients experienced new infection within follow up). Parasite and fever clearance was rapid in both treatment arms (median time to parasite clearance of one day for both groups). Both DP and A + M were well tolerated, with the majority of adverse events of mild or moderate severity. The frequencies of individual adverse events were generally similar between treatments, although the incidence of post treatment adverse events was slightly higher in patients who received A + M with respect to those treated with DP. DP is a new ACT displaying high efficacy and safety in the treatment of uncomplicated P. falciparum malaria and could potentially be considered for the first-line treatment of uncomplicated falciparum malaria in India. Current Controlled Trials ISRCTN 81306618.


Nitrogen Rate Effects on Cry3Bb1 and Cry3Bb1 + Cry34/35Ab1 Expression in Transgenic Corn Roots, Resulting Root Injury, and Corn Rootworm Beetle Emergence.
Nitrogen (N) application rates have been recommended historically for maximum economic yield of corn (Zea mays L.), but not for optimal expression or impacts of Bt (Bacillus thuringiensis Berliner) Cry protein(s) on target insects. This study explored the need to adjust N rates to optimize expression of corn rootworm-active Bt (Bt-RW) protein(s) in a single and a pyramided trait hybrid and resulting impacts on beetle emergence and root injury, under field conditions. The experiment featured a factorial treatment arrangement in a split-plot randomized complete block design with six N rates as the main plots and three hybrids (MON88017 expressing Cry3Bb1, MON88017 x DAS-59122 expressing Cry3Bb1 + Cry34/35Ab1, and a non-Bt-RW hybrid) as the subplots. Corn roots were sampled at the beginning of, and after, peak larval feeding to determine Bt-expression levels using an enzyme-linked immunosorbent assay. Beetles were collected every 2-3 d during emergence using cut-plant emergence cages. Cry3Bb1 expression was significantly reduced when little or no N was applied. Cry34Ab1 and Cry35Ab1 expression was highly variable and unaffected by N rate. Beetle emergence increased with N rate in the non-Bt-RW hybrid while root injury declined. Provided Bt-RW hybrids had sufficient applied N, root injury was relatively low. Results indicate that N management could affect Bt-RW expression and success of insect resistance management plans provided N is applied at rates that enhance production of susceptible beetles emerging from the non-Bt-RW (refuge) hybrid, and achieve optimal expression and efficacy of Bt traits.


Body mass index and mobility limitations: An analysis of middle-aged and older Black, Hispanic, and White women in the U.S.
While the Body Mass Index (BMI) did not change significantly for men from 2005 to 2014 in the United States, women exhibited an upward linear trend. Hispanic and Black women, in particular, showed a dramatic increase. Therefore, the objective of this study was to examine the association between BMI and mobility limitations for non-institutionalised middle-aged and older Black, Hispanic, and White women. The International Classification of Functioning, Disability, and Health model was applied to a sample of 2865 Black, 1846 Hispanic, and 9721 White women categorised as middle-aged and older (i.e., at least 50 years of age) from the 2010 and 2014 Rand Health and Retirement Study. A random effects ordered logit was employed. After accounting for personal/activity characteristics, the analyses revealed Black women with greater BMI were associated with a higher likelihood for mobility limitations with an odds ratio of 1.11 [1.06-1.16, 95% CI]. A significant association was also found for Hispanic women with an odds ratio of 1.16 [1.11-1.23, 95% CI] and White women with an odds ratio of 1.16 [1.13-1.19, 95% CI]. Even after accounting for the possibility of endogeneity, BMI remained robust. Higher-levels of BMI were associated with an increased probability for mobility limitations for Black, Hispanic, and White middle-aged and older women. Those with a vigorous exercise regimen were less likely to be in this category across all ranges of BMI. These results are useful for prioritising minority health policy, particularly given the limited amount of existing research in this specific area.


The mild® procedure: a systematic review of the current literature.
This study's objective was to determine if the literature supports use of the Minimally Invasive Lumbar Decompression (mild®) procedure (Vertos Medical, Aliso Viejo, CA, USA) to reduce pain and improve function in patients with symptomatic degenerative lumbar spinal stenosis. The study was designed as an evidence-based review of available data. Studies were identified from PubMed, Embase, and the Cochrane Library. Articles were evaluated using the Grading of Recommendations Assessment, Development and Evaluation Working Group system. Results were compiled assessing short- (4-6 weeks), medium- (3-6 months), and long-term (>1 year) outcomes. The primary outcomes evaluated were pain, measured by the visual analog scale (VAS), and function, measured by the Oswestry Disability Index (ODI). Secondary outcomes included pain and patient satisfaction, measured by the Zurich Claudication Questionnaire, adverse effects/complications, and changes in utilization of co-interventions. The literature search revealed one randomized controlled trial (RCT) and 12 other studies (seven prospective cohort, four retrospective, and one case series) that provided information on the use of mild® in patients with degenerative lumbar spinal stenosis. All studies showed statistically significant improvements in VAS and ODI scores at all time frames compared with preprocedure levels; the RCT showed improvement over controls. Categorical data were not provided; thus, the proportion of patients who experienced minimal clinically meaningful outcomes is unknown. The current body of evidence addressing mild® is of low quality. High-quality studies that are independent of industry funding and provide categorical data are needed to clarify the proportions of patients who benefit from mild® and the degree to which these patients benefit. Additional data at up to 2 years are needed to determine the overall utility of the procedure.


Industrial sources influence air concentrations of hydrogen sulfide and sulfur dioxide in rural areas of western Canada.
A survey of monthly average concentrations of sulfur dioxide (SO2) and hydrogen sulfide (H2S) at rural locations in western Canada (provinces of Alberta, British Columbia, and Saskatchewan) was conducted in 2001-2002, as part of an epidemiological study of the effects of oil and gas industry emissions on the health of cattle. Repeated measurements were obtained at some months and locations. We aimed to develop statistical models of the effect of oil and gas infrastructure on air concentrations. The regulatory authorities supplied the information on location of the different oil and gas facilities during the study period and, for Alberta, provided data on H2S content of wells and flaring volumes. Linear mixed effects models were used to relate observed concentrations to proximity and type of oil and gas infrastructure. Low concentrations were recorded; the monthly geometric mean was 0.1-0.2 ppb for H2S, and 0.3-1.3 ppb for SO2. Substantial variability between repeated measurements was observed. The precision of the measurement method was 0.005 ppb for both contaminants. There were seasonal trends in the concentrations, but the spatial variability was greater. This was explained, in part, by proximity to oil/gas/bitumen wells and (for SO2) gas plants. Wells within 2 km of monitoring stations had the greatest impact on measured concentrations. For H2S, 8% of between-location variability was explained by proximity to industrial sources of emissions; for SO2 this proportion was 18%. In Alberta, proximity to sour gas wells and flares was associated with elevated H2S concentrations; however, the estimate of the effect of sour gas wells in the immediate vicinity of monitoring stations was unstable. Our study was unable to control for all possible sources of the contaminants. However, the results suggest that oil and gas extraction activities contribute to air pollution in rural areas of western Canada.


A high-pressure single-crystal X-ray diffraction study of potassium guaninate hydrate, K+·C5H4N5O-·H2O.
The crystal structure of potassium guaninate hydrate, K+·C5H4N5O-·H2O, was studied in the pressure range of 1 atm to 7.3 GPa by single-crystal diffraction using synchrotron radiation and a laboratory X-ray diffraction source. Structural strain was compared to that of the same salt hydrate on cooling, and in 2Na+·C5H3N5O2-·7H2O under hydrostatic compression and on cooling. A polymorphic transition into a new, incommensurately modulated, phase was observed at ∼4-5 GPa. The transition was reversible with a hysteresis: the satellite reflections disappeared on decompression to ∼1.4 GPa.


Chronic peripheral neuropathy in workers with previous exposure to carbon disulphide.
Two groups of viscose rayon production workers were examined 10 years after discontinuation of exposure to CS2. Group A comprised 20 subjects exposed to high CS2 concentrations and group B 13 subjects with lower exposure. Clinical findings and the measurements of nerve conduction velocity of the slow fibres in the peripheral nerves were evaluated. Twelve subjects had both clinical and electromyographic evidence of neuropathy and 10 showed a diminution in motor conduction velocity. A relationship between the degrees of exposure to CS2 and prevalence of polyneuropathy was found. On re-examining 12 subjects with neuropathy who had been examined four years before no significant electromyographic improvement was observed. These findings are consistent with a permanent axonal neuropathy caused by carbon disulphide.


Methadone: a substrate and mechanism-based inhibitor of CYP19 (aromatase).
The peripheral conversion of testosterone to estradiol by aromatase is the primary source of endogenous estrogen in postmenopausal women. Studies indicating that placental aromatase is able to metabolize methadone to its primary metabolite, 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidin (EDDP), led us to test the hypothesis that methadone is able to act as an inhibitor of aromatase. Using recombinant human CYP19, we examined the ability of methadone to bring about either reversible or mechanism-based inhibition of the conversion of testosterone to estradiol. To test for reversible inhibition, racemic methadone or its metabolite EDDP or 2-ethyl-5-methyl-3, 3-diphenylpyrroline (EMDP) was incubated for 30 min with testosterone at the K(m) (4 microM). To test for mechanism-based inhibition, microsomal preincubations were performed for up to 30 min using racemic methadone (1-1000 microM), R- or S-methadone (0.5-500 microM), or EDDP or EMDP (10 and 100 microM) followed by incubation with testosterone at a V(max) concentration (50 microM). Racemic methadone, EDDP, and EMDP did not act as competitive inhibitors of CYP19. Preincubation of methadone, EDDP, or EMDP with CYP19 resulted in time- and concentration-dependent inhibition, indicating a mechanism-based reaction that destroys CYP19 activity. The K(I) and k(inact) values for racemic methadone were calculated to be 40.6 +/- 2.8 microM and 0.061 +/- 0.001 min(-1), respectively. No stereoselectivity was observed. Methadone is metabolized by CYP19 and may act as a potent inhibitor of CYP19 in vivo. These findings may contribute to variability in methadone clearance, to drug-drug interactions, and to side effects observed in individual patients.


The effects of membrane potential, extracellular potassium, and tetrodotoxin on the intracellular sodium ion activity of sheep cardiac muscle.
The intracellular sodium ion activity was measured using liquid ion-exchange microelectrodes with rapid response times in sheep Purkinje fibers and ventricular muscle under voltage control. The mean sodium ion activity in quiescent Purkinje fibers was 8.5 mM at a holding potential of -80 mV. With maintained hyperpolarizing (-110 mV) or depolarizing (-40 and 0 mV) voltage steps, sodium ion activity increased or decreased, respectively. At 0 mV, the mean steady state value for the sodium ion activity was 3.8 mM. Following a voltage step to 0 mV, or back to -80 mV, the time course of the sodium ion activity change could be fitted by single exponentials, with similar half-times. Increasing the extracellular potassium ion concentration from 5.4 to 15 mM did not alter the steady state value of the sodium ion activity at clamped voltages of -80 or 0 mV, which suggests that the external potassium ion activating site of the Na-K pump was saturated. With the extracellular potassium concentration 0 mM (holding potential -80 mV), the sodium ion activity increased. When maintained depolarizing steps to 0 mV were applied, the sodium ion activity decreased by up to 20 mM. This large fall in sodium ion activity is assumed to represent partial reactivation of the Na-K pump due to potassium ion accumulation in clefts. We also studied the stimulation-dependent change in sodium ion activity. Trains of action potentials or short duration depolarizing voltage clamp steps caused a frequency dependent rise in sodium ion activity. The magnitude of the rise of sodium ion activity was not altered by lengthening the duration of each voltage clamp step, but was inhibited by tetrodotoxin or by holding the membrane potential at -50 mV between depolarizing steps. These results show that sodium ion activity is a complex function of membrane voltage, depolarization frequency, and time. The rise in sodium ion activity with stimulation appears to depend on sodium ion entry regulated by the sodium channel, and may be important in the modulation of intracellular calcium and tension through the Na+-Ca++ exchange mechanism.


Standardization of two immunological HbA1c routine assays according to the new IFCC reference method.
The measurement of HbA1c is meanwhile well established as the most important parameter in clinical chemistry for monitoring the long term metabolic control of diabetic patients. However, the comparability of HbA1c values obtained by different methods in different laboratories and different countries is limited since there was no internationally agreed reference method available. Additionally the % HbA1c values, based on the most common DCCT values are too high due to well known non specificity of the DCCT standardization protocol. Recently a new reference method for the determination of HbA1c was developed and has been approved by the IFCC as the future basis for the worldwide standardization of HbA1c routine assays. The two routine methods from Roche Diagnostics (both based on the immunoturbidimetric determination of the stable glucose adduct to the N-terminal group of the hemoglobin beta chain, Roche-Hitachi/Tina-quant [a] and COBAS INTEGRA) are directly standardized against this new reference method. Both routine methods are based on a two step approach: in a first step the total Hb is quantified by a colorimetric method and in a second step the stable glucose adduct to the N-terminal group of the hemoglobin beta chain is quantified by immunoturbidity (HbA1c mass). Consequently, first the standardization of the total Hb assay was reconfirmed by method comparisons against the cyanomethemoglobin reference method. Second, the standardization of the HbA1c mass was done by running method comparisons against the new IFCC reference method. The resulting new calibrator values for HbA1c [mass] and total Hb [mass] allow a direct estimation of % HbA1c according to IFCC just by calculating the HbA1c [mass]/total Hb [mass] ratio. Good linear correlations were obtained when comparing the routine methods against the new IFCC reference, indicating the high specificity of these immunological approaches. The following correlations are obtained: Hitachi / Tina-quant [a] (Y) versus IFCC reference method (X): Y = -0.031 + 1.009 x X; r = 0.995. COBAS INTEGRA (Y) versus IFCC reference method (X): Y = -0.156 + 1.006 x X; r = 0.997. Hitachi / Tina-quant [a] (Y) versus Integra (X); (both standardized according to IFCC): Y = 0.057 + 1.003 x X; r = 0.997. The HbA1c values obtained with this new IFCC standardization are significantly lower than the well known DCCT values. Due to the specificity of the immunological approach which is very close to the analyte as defined by the IFCC reference method, no further corrections of the obtained % HbA1c values are necessary. A slope/intercept correction formula is derived which allows the transformation of IFCC values into the DCCT numbers if requested.


Active School Transport among Children from Canada, Colombia, Finland, South Africa, and the United States: A Tale of Two Journeys.
Walking and biking to school represent a source of regular daily physical activity (PA). The objectives of this paper are to determine the associations of distance to school, crime safety, and socioeconomic variables with active school transport (AST) among children from five culturally and socioeconomically different country sites and to describe the main policies related to AST in those country sites. The analytical sample included 2845 children aged 9-11 years from the International Study of Childhood Obesity, Lifestyle and the Environment. Multilevel generalized linear mixed models were used to estimate the associations between distance, safety and socioeconomic variables, and the odds of engaging in AST. Greater distance to school and vehicle ownership were associated with a lower likelihood of engaging in AST in sites in upper-middle- and high-income countries. Crime perception was negatively associated to AST only in sites in high-income countries. Our results suggest that distance to school is a consistent correlate of AST in different contexts. Our findings regarding crime perception support a need vs. choice framework, indicating that AST may be the only commuting choice for many children from the study sites in upper-middle-income countries, despite the high perception of crime.


Primary anaplastic pleomorphic xanthoastrocytoma in adults. Case report and review of literature.
Pleomorphic xanthoastrocytoma (PXA) classified as a low Grade (WHO II) astrocytic neoplasm. It is known for its relatively favorable prognosis. It most commonly occurs in young adults. Malignant progression in PXA has been frequently reported since its first description in 1979; however, the presentation of a primary anaplastic PXA tumor with an aggressive clinical course in adults is rare especially in the later age group. We present a case of primary anaplastic PXA in a 53 year old male that manifested with an early recurrence pattern at 9 weeks. Treatment performed was surgical excision and external beam radiotherapy. The aforementioned tumor followed an aggressive clinical course. Tumor cells exhibited the characteristic expression of GFAP (Glial fibrillary acidic protein), higher proliferative index (8-10%) on Ki-67 staining along with the presence of increased mitoses ( >5/10hpf). A review of previously reported primary anaplastic pleomorphic xanthoastrocytoma cases in adults with histological features was also done. Our review of all reported cases of APXA in adults concludes that the clinical behavior of this tumor varies considerably from its benign variant. Early disease recurrence in anaplastic pleomorphic xanthoastrocytomas is associated with fatal outcomes. As per our review of literature it is seen that anaplastic variant of PXA shows histological characteristics as well as clinical course comparable with Grade III astrocytomas. We recommend further evaluation of PXA with anaplastic features regarding their genetic characteristics to understand the origin as well as behavior of this tumor.


Improved house staff results with subclavian cannulation.
In the teaching hospital, insertion of subclavian lines is frequently the responsibility of the House Staff. This paper reviews 225 subclavian cannulations by the Surgical House Staff of St. Barnabas Medical Center over an eight-month period. Twenty-six complications were documented. The major complication rate was 1.8 per cent and minor complications, 9.8 per cent. No correlation could be found between age, sex, or side of the catheter insertion with regard to complications. The overall complication rate was highest in the postgraduate year I (PGY) and PGY II levels, and this decreased with the more experienced residents. These results were statistically significant (P less than 0.05). The literature is reviewed, and recommendations concerning subclavian cannulation techniques are made.


Pre-transmetalation intermediates in the Suzuki-Miyaura reaction revealed: The missing link.
Despite the widespread application of Suzuki-Miyaura cross-coupling to forge carbon-carbon bonds, the structure of the reactive intermediates underlying the key transmetalation step from the boron reagent to the palladium catalyst remains uncertain. Here we report the use of low-temperature rapid injection nuclear magnetic resonance spectroscopy and kinetic studies to generate, observe, and characterize these previously elusive complexes. Specifically, this work establishes the identity of three different species containing palladium-oxygen-boron linkages, a tricoordinate boronic acid complex, and two tetracoordinate boronate complexes with 2:1 and 1:1 stoichiometry with respect to palladium. All of these species transfer their boron-bearing aryl groups to a coordinatively unsaturated palladium center in the critical transmetalation event.


Muscarinic receptor regulation in the sympathetically innervated avian expansor secundariorum.
We sought to examine further the regulation of muscarinic receptors in the developing expansor secundariorum, a smooth muscle of the avian wing. [(3)H]Quinuclidinyl benzilate binding was used as a measure of muscarinic receptors present in the muscle, which gradually decline in density from hatch during the following few weeks. Receptor loss can be prevented by denervation of the muscle immediately after hatch, but receptor density is not recovered by denervation in older birds. As the major innervation is provided by sympathetic, noradrenergic fibres with no evidence of a cholinergic input, the action of several pharmacological agents known to affect noradrenergic transmission was examined. Reserpine partially prevented the early receptor decline but phenoxybenzamine and dimethylphenylpiperazinium did not significantly affect receptor density. The muscle was also immobilized by tenotomy, since this unique muscle is attached to the shoulder by a long, discrete tendon. Tenotomy significantly retarded the normal developmental receptor loss. It is suggested that in this muscle, muscarinic receptor density is regulated by noradrenergic nerves, possibly by a mechanism involving the transmitter, noradrenaline.


Effect of local density changes on the failure load of the proximal femur.
Hip fracture among the elderly is a large and growing public health issue. Presently, all therapies approved for treatment and prevention of osteoporosis involve pharmacological agents that act systemically. In this study, we evaluated the feasibility of preventing osteoporotic hip fractures with local, rather than systemic, therapy. Our hypothesis is that local therapy to increase bone density may be as effective as systemic therapy in reducing fracture risk. Thus, the goal of this investigation was to use finite element analyses to study the effect of a localized increase in bone density on the strength of an osteopenic, human femur. Finite element predictions of the failure load were made after increasing the bone density within small regions in the proximal femur. The outcome variable from these analyses was the predicted load required to break a femur in a simulated fall to the side with impact on the greater trochanter. Increasing the density by 25% relative to baseline values in a small region (0.86 cm3) of the femoral neck increased the predicted failure load by 6.2%. The same density increase in a much larger region (4.92 cm3) increased the failure load by 15%. Inclusion of more than one region of increased density provided little additional benefit. In comparison, when the density of the entire femur was increased by 5% relative to baseline values, the predicted failure load increased by 5.4%. These findings suggest that agents capable of inducing increased bone density in small regions of the proximal femur have the potential to reduce the risk of hip fracture.


Histological evaluation of sinus augmentation using platelet rich plasma (PRP): a case series.
The use of Platelet Rich Plasma (PRP) in conjunction with autogenous bone graft materials has recently been advocated for use in sinus augmentation surgery as a means of enhancing both quantity and quality of newly forming bone. The use of PRP is based on the premise that autogenous plasma, rich in platelets, contributes large quantities of mitogenic polypeptides such as Platelet Derived Growth Factor (PDGF), Transforming Growth Factor-b (TGF-b) and Insulin-like Growth Factor-I (IGF-I), thereby enhancing osteogenesis. The aim of this study was to evaluate the potential of PRP to enhance bone formation following sinus augmentation with different bone derivative/substitute materials (DFDBA, FDBA, Xenograft, Bioactive Glass). This study presents histology of trephine-obtained core samples from five clinical cases in which sinus augmentation was performed with PRP combined with bone derivatives/substitutes. Histological evaluation of this case series consistently revealed the presence of residual graft particles surrounded by loose connective tissue, with a limited amount of newly formed bone. The findings suggest that the addition of PRP to bone derivative/substitute materials may not significantly enhance bone formation in the maxillary sinus area.


New drugs in ovarian cancer and malignant melanoma: in vitro phase II screening with the human tumor stem cell assay.
The successful development of a soft agar clonogenic assay for human tumor stem cells provides an in vitro technique with a high degree of accuracy for predicting in vivo clinical response to standard anticancer drugs. We used this system to conduct an "in vitro phase II trial" in human ovarian cancer and melanoma. This approach can potentially identify active phase I--II drugs suitable for treatment of given tumor types for specific patients and eliminates the need to subject patients (who would be predicted not to respond) to toxic side effects. In vitro sensitivity for new agents was operationally defined as at least a 70% reduction of tumor colony-forming units (TCFU) at concentrations which are readily achievable pharmacologically. The new agents AMSA and vindesine (as well as vinblastine) appeared to have activity in melanoma, while PALA and thymidine were inactive. Pentamethylmelamine, mitomycin C, methyl-GAG, and AMSA were relatively ineffective in ovarian cancer. Vinblastine and vindesine had definite activity. The human tumor stem cell assay may thus provide the basis for a useful alternative to the current clinical phase II testing approach for identifying antitumor activity of new agents. Validation of this concept with correlative in vitro and in vivo phase II trials of new agents in patients with tumor types predicted to be sensitive is clearly warranted.


Reaction time distributions across normal forgetting: searching for markers of memory consolidation.
Volunteers studied pictures of objects and were then tested for yes/no recognition at 10 min and 1 week after learning (experiment 1), or at 10 min and 4 months after learning (experiment 2). Because the gradual consolidation of long-term memory is thought to occur across this time scale (weeks and months), the reaction time distributions of successfully retrieved items were analyzed in an attempt to detect markers of consolidation. At each retention interval, reaction times for items retrieved successfully were well fit by a model that assumed a single underlying distribution. No evidence for a bimodal distribution of reaction times was observed. Furthermore, there was no evidence that some small subset of items was actually retrieved faster after a long retention interval than after a short interval. The results are consistent with the idea that consolidation works not to increase memory trace strength but to change the nature of memory storage. This process occurs during the course of normal forgetting and may not be observable in the behavior of normal memory.


Racial and ethnic disparities in cardiovascular medication use among older adults in the United States.
Despite persistent racial/ethnic disparities in cardiovascular disease (CVD) among older adults, information on whether there are similar disparities in the use of prescription and over-the-counter medications to prevent such disease is limited. We examined racial and ethnic disparities in the use of statins and aspirin among older adults at low, moderate, and high risk for CVD. In-home interviews, including a medication inventory, were administered between June 2005 and March 2006 to 3005 community-residing individuals, ages 57-85 years, drawn from a cross-sectional, nationally-representative probability sample of the United States. Based on a modified version of the Adult Treatment Panel III (ATP III) risk stratification guidelines, 1066 respondents were at high cardiovascular risk, 977 were at moderate risk, and 812 were at low risk. Rates of use were highest among respondents at high cardiovascular risk. Racial differences were highest among respondents at high risk with blacks less likely than whites to use statins (38% vs. 50%, p = 0.007) and aspirin (29% vs. 44%, p = 0.008). After controlling for age, gender, comorbidity, and socioeconomic, and access to care factors, racial/ethnic disparities persisted. In particular, blacks at highest risk were less likely than their white counterparts to use statins (odds ratio (OR) 0.65, confidence interval (CI) 0.46-0.90) or aspirin (OR 0.61, CI 0.37-0.98). These results, based on an in-home survey of actual medication use, suggest widespread underuse of indicated preventive therapies among older adults at high cardiovascular risk in the United States. Racial/ethnic disparities in such use may contribute to documented disparities in cardiovascular outcomes.


Access to CD4 Testing for Rural HIV Patients: Findings from a Cohort Study in Zimbabwe.
CD4 cell count measurement remains an important diagnostic tool for HIV care in developing countries. Insufficient laboratory capacity in rural Sub-Saharan Africa is frequently mentioned but data on the impact at an individual patient level are lacking. Urban-rural discrepancies in CD4 testing have not been quantified to date. Such evidence is crucial for public health planning and to justify new yet more expensive diagnostic procedures that could circumvent access constraints in rural areas. To compare CD4 testing among rural and urban HIV patients during the first year of treatment. Records from 2,145 HIV positive adult patients from a Médecins sans Frontières (Doctors without Borders) HIV project in Beitbridge, Zimbabwe, during 2011 and 2012 were used for a retrospective cohort analysis. Covariate-adjusted risk ratios were calculated to estimate the effects of area of residence on CD4 testing at treatment initiation, six and 12 months among rural and urban patients. While the proportion of HIV patients returning for medical consultations at six and 12 months decreased at a similar rate in both patient groups, CD4 testing during consultations dropped to 21% and 8% for urban, and 2% and 1% for rural patients at six and 12 months, respectively. Risk ratios for missing CD4 testing were 0.8 (95% CI 0.7-0.9), 9.2 (95% CI 5.5-15.3), and 7.6 (95% 3.7-17.1) comparing rural versus urban patients at treatment initiation, six and 12 months, respectively. CD4 testing was low overall, and particularly poor in rural patients. Difficulties with specimen transportation were probably a major factor underlying this difference and requires new diagnostic approaches. Our findings point to severe health system constraints in providing CD4 testing overall that need to be addressed if effective monitoring of HIV patients is to be achieved, whether by alternative CD4 diagnostics or newly-recommended routine viral load testing.


A framework for healthcare interventions to address maternal morbidity.
The maternal health agenda is undergoing a paradigm shift from preventing maternal deaths to promoting women's health and wellness. A critical focus of this trajectory includes addressing maternal morbidity and the increasing burden of chronic and noncommunicable diseases (NCD) among pregnant women. The WHO convened the Maternal Morbidity Working Group (MMWG) to improve the scientific basis for defining, measuring, and monitoring maternal morbidity. Based on the MMWG's work, we propose paradigms for conceptualizing maternal health and related interventions, and call for greater integration between maternal health and NCD programs. This integration can be synergistic, given the links between chronic conditions, morbidity in pregnancy, and long-term health. Pregnancy should be viewed as a window of opportunity into the current and future health of women, and offers critical entry points for women who may otherwise not seek or have access to care for chronic conditions. Maternal health services should move beyond the focus on emergency obstetric care, to a broader approach that encompasses preventive and early interventions, and integration with existing services. Health systems need to respond by prioritizing funding for developing integrated health programs, and workforce strengthening. The MMWG's efforts have highlighted the changing landscape of maternal health, and the need to expand the narrow focus of maternal health, moving beyond surviving to thriving.


Splenic enlargement and hyperfunction as indications for splenectomy in chronic leukemia.
The chronic leukemias are associated with significant morbidity from splenic enlargement and hyperfunction. Although some patients with chronic leukemia benefit from splenectomy, the indications for operation are unclear. To identify those patients who benefit most from splenectomy, nine patients with chronic lymphocytic leukemia (CLL) and eight patients with chronic granulocytic leukemia (CGL) who had splenectomy to palliate the symptoms of massive splenic bulk or to improve the hematologic sequelae of splenic hyperfunction were studied. Splenectomy for bulk symptoms provided good palliation of symptoms, but the duration of the benefit was limited by the stage of the disease. Five of eight patients with CGL with bulk symptoms died within 6 months of operation. Splenectomy for hyperfunction was limited to a short-term hematologic response. In three of four patients with CLL who were Coombs positive, the presence of autoantibodies correlated with a recurrent transfusion requirement within 3 months of splenectomy. Thus, the benefit of splenectomy for bulk symptoms must be weighed against the risk of surgery and the patient's limited life expectancy. The benefit of splenectomy for treatment of splenic hyperfunction depends on the stimulus to hyperfunction and may not be beneficial for patients with refractory autoimmune anemias.


[Anxiety and depression among the epileptics in general population in Benin (Western Africa)].
In order to assess prevalence of depression and anxiety among epileptic patients and to compare it to a control population, a matched case-control survey was performed in 196 persons above 18 Year old (98 epileptics and 98 controls matched according to sex, age 10 and social environment) in Republic of Benin (West Africa), using Goldberg's Depression and Anxiety scale. Two main investigators helped by 5 sociology students were trained on a questionnaire by a psychiatrist skilled with public health matters. People taking part in the survey are epileptic patients who already used health services. Inclusions took place within 17 communes of four departments (Mono, Zou, Ouémé, Atlantique) located in Southern part of Benin. The questionnaire used an Identity sheet and the Goldberg Depression Scale. Results are shown as mean standard deviations, for quantitative values, and percents for qualitative ones. Comparisons of proportions in qualitative variables are carried out using c2 test or Fisher's exact test. Comparisons of means rates between subject's groups are carried out with a Student t test or variance analysis. The correlations between two quantitative variables were assessed by linear correlation coefficient. Significance threshold chosen for the whole set of statistics analysis is 0.05. The majority of interviewed epileptic patients is young (average 32.6 11.5 Years old). A male predominance exists (sex ratio 1.28). 93% of interviewed persons live within their family, are married or cohabit (controls: 98.2%; cases: 87.9%); 57.4% are married (controls: 70%; cases: 44%). The most represented professional categories are craftsmen and shopkeepers (29.2%) as well as farmers (19.5%). Most of recruited patients live in an urban setting (55.4%) and 63.6% of interviewed persons had been living in the area of survey for over 10 Years. The most represented religion within the sample is Christian religion (67.7%), Animists (23.3%) and Muslims (5.8%). 97% of epileptic patients reported they had one fit during the two Years before the survey; roughly one half (48%) had 2 to 5 fits and 41.5% of them had more than 10 fits; only 14% say they have had an EEG. Presence of an Anti Epileptic Drug (77.5%) reduces anxiety and depression. Considering a severity threshold of 5 for anxiety and 2 for depression (8), proportions of epileptic patients displaying a severe anxiety (79.8%) or a severe depression (89.6%) are significantly higher (p<0.0001) than in control subjects (12.3% and 46.9%). Comparison of average scores confirms the difference (p<0.0001) between cases (5.8 2.0 and 2.3 1.9) and controls (4.7 2.4 and 2.0 2.1) regarding anxiety and depression. Neither the sex, nor age, nor life environment (urban/rural), nor frequency of fits hold significant influence over an-xiety and depression. However, results in this survey include higher average rates of anxiety and depression for women (6.3 1.8) than men (5.5 1.8), though such statement is only nearly significant (p=0.06). Results of the survey confirm the other works on this topic about characteristics of depression for epileptic patients, though results here are higher than usual. Anxiety and depression are common troubles found in epileptic patient, both often occurring at the same time. Two distinct theories about this fact are opposed, first explain the connection of anxiety and depression with epilepsy because of the social and cultural burden upon an epileptic patient in those countries, the second theory is about depression and epilepsy sharing some neuroaminergical dysfunctions; these facts were not considered in this survey. When taking into account the thresholds of seriousness on Goldberg's scale, proportion of controls displaying a probably deeper depression is high (46.9%) compared to usual hospital prevalence rates (4 to 25%) found in Western Africa where survey in general population are scarce. It could either be a bias in the selection or the confirmation that family and relatives of an epileptic patient are enduring a great psychic pain too; finally, this high rate o, this high rate of severe depression within controls may suggest a need to adapt thresholds of Goldberg's scale to match African populations. This hypothesis is interesting regarding the results of some Authors who validated this scale in population of aged people; they highlighted the fewer precision of two items (lost of interest, focus difficulties) and also a slight discriminatory weight for other few items. However the psychometric characteristics of Goldberg's scale are accurate (for depression subscale, a sensitivity of 88% and a specificity of 68%; for the whole scale, a sensitivity of 84% and a specificity of 68%). It would be pertinent to carry out a study to validate Goldberg's scale within some African populations. This study also highlights the importance of psychological factors in epilepsy and suggests a specific global care of the disease.


Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway.
The Ras family of small GTPases constitutes a central node in the transmission of mitogenic stimuli to the cell cycle machinery. The ultimate receptor of these mitogenic signals is the retinoblastoma (Rb) family of pocket proteins, whose inactivation is a required step to license cell proliferation. However, little is known regarding the molecular events that connect Ras signaling with the cell cycle. Here, we provide genetic evidence to illustrate that the p53/p21 Cdk-interacting protein 1 (Cip1)/Rb axis is an essential component of the Ras signaling pathway. Indeed, knockdown of p53, p21Cip1, or Rb restores proliferative properties in cells arrested by ablation of the three Ras loci, H-, N- and K-Ras. Ras signaling selectively inactivates p53-mediated induction of p21Cip1 expression by inhibiting acetylation of specific lysine residues in the p53 DNA binding domain. Proliferation of cells lacking both Ras proteins and p53 can be prevented by reexpression of the human p53 ortholog, provided that it retains an active DNA binding domain and an intact lysine residue at position 164. These results unveil a previously unidentified role for p53 in preventing cell proliferation under unfavorable mitogenic conditions. Moreover, we provide evidence that cells lacking Ras and p53 proteins owe their proliferative properties to the unexpected retroactivation of the Raf/Mek/Erk cascade by a Ras-independent mechanism.


Impact of orthodontic treatment need and deviant occlusal traits on oral health-related quality of life in children: A cross-sectional study in the Generation R cohort.
Many studies have investigated the impact of orthodontic treatment need (OTN) on children's oral health-related quality of life (OHRQOL). However, few studies have explored the impact of deviant occlusal traits on OHRQOL regarding the severity of OTN. This cross-sectional study aims to address this gap in the literature. This study was conducted within the Generation R Study, a population-based prospective cohort study. We assessed OTN with the Index of Orthodontic Treatment Need and OHRQOL with a parental short-form of the Child Oral Health Impact Profile in 3048 children at a median age of 9.74 years (9.5-10.0). We also further assessed individual malocclusion traits in a subsample of 2714 children. We investigated the association between OTN, malocclusion traits, and OHRQOL using multiple regression analysis with weighted least squares. Children with definite (adjusted effect estimate = -0.81; 95% confidence interval -1.12 to -0.50) or borderline (adjusted effect estimate = -0.34; 95% confidence interval -0.61 to -0.08) OTN experienced significant decreases in their OHRQOL than those with no need. An impacted tooth, increased overjet, or crowding had significant negative impacts on children's OHRQOL. Children with an overjet experienced negative impacts on OHRQOL even when orthodontic treatment was not necessary. Progressively greater OTN has increasingly negative impacts on parent's perception of children's OHRQOL. In particular, children presenting with large overjets and impacted teeth have lower OHRQOL. These perspectives add to better patient-clinician communication and understanding of patient expectations around OTN, which may potentially lead to improvements in quality of care from the patient perspective.


Assessing the Risk of Respiratory-Related Healthcare Visits Associated with Wildfire Smoke Exposure in Children 0-18 Years Old: A Systematic Review.
Wildfires are increasing in frequency, size, and intensity, and increasingly affect highly populated areas. Wildfire smoke impacts cardiorespiratory health; children are at increased risk due to smaller airways, a higher metabolic rate and ongoing development. The objective of this systematic review was to describe the risk of pediatric respiratory symptoms and healthcare visits following exposure to wildfire smoke. Medical and scientific databases and the grey literature were searched from inception until December 2020. Included studies evaluated pediatric respiratory-related healthcare visits or symptoms associated with wildfire smoke exposure. Prescribed burns, non-respiratory symptoms and non-pediatric studies were excluded. Risk of bias was evaluated using the National Toxicology Program's Office of Health Assessment and Translation Risk of Bias Rating Tool. Data are presented narratively due to study heterogeneity. Of 2138 results, 1167 titles and abstracts were screened after duplicate removal; 65 full text screens identified 5 pre-post and 11 cross-sectional studies of rural, urban and mixed sites from the USA, Australia, Canada and Spain. There is a significant increase in respiratory emergency department visits and asthma hospitalizations within the first 3 days of exposure to wildfire smoke, particularly in children < 5 years old.


Drug-induced liver injury: a clinical update.
To gather new and important data published on idiosyncratic drug-induced liver injury (DILI) over the past 2 years in the peer-reviewed literature. Clinical studies focusing on mechanisms of injury, clinical evaluation and prognosis will be reviewed. The most common drugs leading to DILI in the United States are antibiotics, central nervous system agents, herbal/dietary supplements and immunomodulatory agents. Hepatocellular type of DILI is more common in younger patients, whereas cholestatic pattern increases with older age. Certain human leukocyte antigen genotype increases the likelihood of flucloxacillin-induced liver injury. Idiosyncratic DILI was shown to have an important dose-dependency and drugs with extensive hepatic metabolism are associated with higher frequency of DILI. Chronic DILI may occur, but development of clinically important liver injury after severe DILI is rare. N-acetylcysteine seems to be beneficial for patients with acute liver failure caused by medications or herbal agents.


Validity of Radiograph-Based Infrapatellar Fat Pad Opacity Grading for Assessing Knee Synovitis: Correlation With Contrast-Enhanced MRI.
The purpose of this study was to determine the validity of infrapatellar fat pad (IPFP) opacity grading based on lateral knee radiography for assessing knee synovitis using correlation with contrast-enhanced (CE) MRI. Retrospective reviews of radiographs and CE knee MR images from 79 patients were independently performed by two radiologists. They evaluated IPFP opacity alteration (IPFPCR) and joint effusion grades on lateral knee conventional radiographs, IPFP signal intensity alteration (IPFPMR) and joint effusion grades on CE MR images, and synovitis (SYNMR) grade in nine divided regions, three compartments (parapatellar, periligamentous, perimeniscal), and the whole knee on CE MR images. Correlations between radiographic grades and MRI assessments were evaluated using Spearman correlation tests, and the correlation coefficients (ρ) were compared. Interobserver agreement was evaluated using weighted kappa values. The IPFPCR grade was very highly correlated with the IPFPMR grade (ρ = 0.906, p < 0.001) and highly correlated with SYNMR grades from four regions (suprapatellar, infrapatellar, intercondylar, lateral parapatellar recess), the parapatellar compartment, and the whole knee (ρ = 0.614-0.740, all p < 0.001). The IPFPCR grade was moderately correlated with the SYNMR grades of the remaining five regions and two compartments (ρ = 0.457-0.547, all p < 0.001). The differences between correlation coefficients for SYNMR grades and the IPFPCR and IPFPMR grades were not statistically significant (p = 0.290-1.0). Interobserver reliabilities were excellent or good for IPFPCR, IPFPMR, and SYNMR grades (κ = 0.661-1.000). IPFPCR grade assessment enables valid evaluation and reporting of knee synovitis, especially in the parapatellar compartment and the whole knee.


Transcatheter valve-in-valve implantation in a degenerated very small Mitroflow prosthesis.
To assess the feasibility and results of 'valve-in-valve' implantation using the 23-mm CoreValve for the treatment of degenerated 19-mm and 21-mm Mitroflow bioprostheses. We retrospectively analysed all consecutive patients who underwent transcatheter aortic valve implantation for 19-mm and 21-mm Mitroflow bioprostheses. The height of implantation with respect to the ring of the Mitroflow prosthesis was targeted at -6 mm for the first 3 cases. In the following cases, the target was higher to promote free supra-annular movement of the leaflets. The procedure was successful in 17 of 18 patients (94%). For implantations above the limit of -6 mm, the mean gradient was 10.4 ± 2.6 mmHg compared with 28.1 ± 11.6 mmHg for implantations below the limit of -6 mm (P < 0.01). For patients with severe stenosis as main mechanism of failure of the bioprosthesis, the mean post-procedural gradient was 31.2 ± 11.8 mmHg compared with 12.7 ± 6 mmHg in the absence of severe stenosis (P < 0.01). Patient-prosthesis mismatch (indexed effective orifice area ≤ 0.85 cm2/m2) and severe mismatch (indexed effective orifice area ≤ 0.65 cm2/m2) were present in 83% (15 of 18) and 27% (5 of 18) of patients, respectively. We did not notice any complications following the procedures. Six months after the procedure, functional status was improved in all patients. Our short series demonstrates the ability to perform transcatheter 'valve-in-valve' implantation in 19-mm and 21-mm Mitroflow prostheses with satisfactory results, but high post-procedural gradients and patient-prosthesis mismatch remain a relatively frequent problem mostly when severe stenosis is the main mechanism of failure. Implantation in a high position is critical to decrease the rate of high postimplantation gradients.


Is there a biochemical basis for lower oesophageal sphincter (LOS) resting pressure?
Myosin plays a fundamental role in the contraction of muscle cells. Some structural differences of this protein are related to the different physical properties of muscle--that is, speed of shortening. The typical myosin protein has a molecular weight of 460 000 daltons and is made up of six subunits: two heavy chains (200 000 daltons each) and two pairs of light chains (LC) weighting 15 000-25 000 daltons each (LC1 and LC2). Myosin was extracted from six specimens of human oesophagus in order to find out whether any biochemical differences exist between the oesophageal body and the lower oesophageal sphincter, to account for their different properties. Myosin was examined by two dimensional gel electrophoresis. Peptide mapping of myosin heavy chains was obtained by carrying out enzymatic digestion during the electrophoretic run. A quantitative difference between LC1 of the oesophageal body and the lower oesophageal sphincter was found in the circular fibres, thereby suggesting that two populations of muscle fibres exist in the inner coat of the oesophagus. The presence of more than one type of myosin strongly implies functional differentiation of the two specialised zones.


Formation of hollow mesoporous silica nanoworm with two holes at the terminals.
A chiral low-molecular-weight amphiphile, L- 18Ala11PyPF(6), was synthesized from L-alanine. Hollow silica nanoworms with circular pore channels parallel to the shell surfaces and holes at the terminals were prepared using the self-assemblies of it as templates via a single-templating approach. The formation of this hierarchical structure was studied by taking TEM images after different reaction time and changing reaction conditions. It was found that the morphologies of the amphiphile-silica assemblies changed gradually during the sol-gel transcription process.


Hypochlorite-induced oxidation of thiols: formation of thiyl radicals and the role of sulfenyl chlorides as intermediates.
Activated phagocytic cells generate hypochlorite (HOCl) via release of hydrogen peroxide and the enzyme myeloperoxidase. HOCl plays an important role in bacterial cell killing, but excessive or misplaced production of HOCI is also known to cause tissue damage. Studies have shown that low-molecular-weight thiols such as reduced glutathione (GSH), and sulfur-containing amino acids in proteins, are major targets for HOCl. Radicals have not generally been implicated as intermediates in thiol oxidation by HOCl, though there is considerable literature evidence for the involvement of radicals in the metal ion-, thermal- or UV light-catalysed decomposition of sulfenyl or sulfonyl chlorides which are postulated intermediates in thiol oxidation. In this study we show that thiyl radicals are generated on reaction of a number of low-molecular-weight thiols with HOCl. With sub-stoichiometric amounts of HOCl, relative to the thiol, thiyl radicals are the major species detected by EPR spin trapping. When the HOCl is present in excess over the thiol, additional radicals are detected with compounds which contain amine functions; these additional radicals are assigned to nitrogen-centered species. Evidence is presented for the involvement of sulfenyl chlorides (RSCl) in the formation of these radicals, and studies with an authentic sulfenyl chloride have demonstrated that this compound readily decomposes in thermal-, metal-ion- or light-catalysed reactions to give thiyl radicals. The formation of thiyl radicals on oxidation of thiols with HOCl appears to compete with non-radical reactions. The circumstances under which radical formation may be important are discussed.


Clinical evaluation of local anaesthetic agents.
The precise evaluation of local anaesthetic drugs in clinical practice has many difficulties. The factors which may modify the clinical profile of these drugs are: (1) procedural in nature; (2) patient related; (3) drug related; and (4) investigator related. All these factors are discussed in relation to the proper design of clinical trials.


Inevitability and containment of replication errors for eukaryotic genome lengths spanning megabase to gigabase.
The replication of DNA is initiated at particular sites on the genome called replication origins (ROs). Understanding the constraints that regulate the distribution of ROs across different organisms is fundamental for quantifying the degree of replication errors and their downstream consequences. Using a simple probabilistic model, we generate a set of predictions on the extreme sensitivity of error rates to the distribution of ROs, and how this distribution must therefore be tuned for genomes of vastly different sizes. As genome size changes from megabases to gigabases, we predict that regularity of RO spacing is lost, that large gaps between ROs dominate error rates but are heavily constrained by the mean stalling distance of replication forks, and that, for genomes spanning ∼100 megabases to ∼10 gigabases, errors become increasingly inevitable but their number remains very small (three or less). Our theory predicts that the number of errors becomes significantly higher for genome sizes greater than ∼10 gigabases. We test these predictions against datasets in yeast, Arabidopsis, Drosophila, and human, and also through direct experimentation on two different human cell lines. Agreement of theoretical predictions with experiment and datasets is found in all cases, resulting in a picture of great simplicity, whereby the density and positioning of ROs explain the replication error rates for the entire range of eukaryotes for which data are available. The theory highlights three domains of error rates: negligible (yeast), tolerable (metazoan), and high (some plants), with the human genome at the extreme end of the middle domain.


The Effectiveness of an Intervention to Promote Awareness and Reduce Online Risk Behavior in Early Adolescence.
The current study explored the effect of a school-based intervention on online risk awareness and behavior in order to shed light on a relatively unexplored field with high practical relevance. More than 800 Belgium primary school children (grade 4 and 6) were assessed at two measurements (n T1 = 812, 51.2 % female; n T2 = 819, 51.3 % female) before and after the intervention. Half of them received a 10 min classroom intervention indicating online risks. Children in the control group received a 10 min presentation concerning online applications without any emphasis on risks. Children in the intervention group were more likely to be aware of online risks directly after the intervention; this effect was still noticeable 4 months after. Reporting of online risk behavior in the intervention group was also higher compared to the control group who did not receive the intervention. Overall online risk awareness and online risk behavior were negatively associated and the awareness did not modulate the association between the intervention and online risk behavior. Furthermore, individual differences were assessed. Girls were more likely to be aware of online risks and asserted less online risk behavior than boys were. In line with the imperative in adolescence to become more risk taking, children in a higher grade were more likely to behave in a risky manner when online. The current study provides a valuable starting point for further research on how to decrease online risk behavior in early adolescence.


Single cell analysis reveals the involvement of the long non-coding RNA Pvt1 in the modulation of muscle atrophy and mitochondrial network.
Long non-coding RNAs (lncRNAs) are emerging as important players in the regulation of several aspects of cellular biology. For a better comprehension of their function, it is fundamental to determine their tissue or cell specificity and to identify their subcellular localization. In fact, the activity of lncRNAs may vary according to cell and tissue specificity and subcellular compartmentalization. Myofibers are the smallest complete contractile system of skeletal muscle influencing its contraction velocity and metabolism. How lncRNAs are expressed in different myofibers, participate in metabolism regulation and muscle atrophy or how they are compartmentalized within a single myofiber is still unknown. We compiled a comprehensive catalog of lncRNAs expressed in skeletal muscle, associating the fiber-type specificity and subcellular location to each of them, and demonstrating that many lncRNAs can be involved in the biological processes de-regulated during muscle atrophy. We demonstrated that the lncRNA Pvt1, activated early during muscle atrophy, impacts mitochondrial respiration and morphology and affects mito/autophagy, apoptosis and myofiber size in vivo. This work corroborates the importance of lncRNAs in the regulation of metabolism and neuromuscular pathologies and offers a valuable resource to study the metabolism in single cells characterized by pronounced plasticity.


The response of the lens to trauma.
The results of a number of investigations into traumatic cataract and after-cataract are presented. The traumatic cataract has been studied both in human lenses and experimentally. Light and electron microscopy, quantitative microradiography and an extracellular tracer--procion dye, were used to follow the cellular changes during cataract progression. The influence of wound size and wound healing as well as the lens fibre response to trauma were followed. Furthermore, tissue culture was used to study the proliferation of lens epithelial cells on the lens capsule. The after-cataract formed in tissue culture as well as experimental traumatic cataracts in rats and rabbits were compared to different stages of human traumatic cataract. Traumatic cataract has a subcapsular distribution and the importance of an intact functioning epithelium for lens transparency is emphasized.