Bioactive glasses in wound healing: hope or hype?
Bioactive glasses have long been investigated in mineralized tissue regeneration, but recently their potential applications in soft tissue repair, and in particular wound healing, have demonstrated great promise. Commonly used glasses, such as the silicate-based Bioglass® 45S5 [(46.1)SiO2-(26.9)CaO-(24.4)Na2O-(2.6)P2O5 (mol%)] and borate-based 13-93B3 [(54)B2O3-(22)CaO-(6)Na2O-(8)K2O-(8)MgO-(2)P2O5 (mol%)] have been implicated in the stages of wound healing due to their ability to release ions that can stimulate processes, such as haemostasis, antibacterial efficacy, epithelial cell migration, angiogenesis, and fibroblastic cell proliferation, amongst others. More recently, a wound dressing composed of a borate-based glass received regulatory approval for use in the treatment of acute and chronic wounds. However, to date, there are no comprehensive reports on their specific mechanism of action in accelerating the wound healing processes. In this highlight, we will provide a brief overview of the wound healing stages, review the bioactive glass formulations that have been investigated for potential applications in wound healing and attempt to summarize the consensus on why these glasses may be successful in wound healing.


The inhibitory effects of lindane in batch and upflow anaerobic sludge blanket reactors.
In this study, the inhibitory effects of lindane (LIN) on originally unacclimated mixed anaerobic cultures were investigated by anaerobic toxicity assay (ATA) experiments. ATA experiments revealed that 10 mg/l LIN exerted inhibitory effects on anaerobic cultures, which was recoverable. Continuous reactor experiments conducted to determine the inhibitory effects of LIN and the maximum LIN loading rate achievable in two-stage upflow anaerobic sludge blanket (UASB) reactors indicated that anaerobic granular cultures were successfully acclimated to 30 mg/l LIN. The maximum LIN loading rate and minimum hydraulic retention time (HRT) possible for the UASB system were 10 mg/l day and 18 h, respectively, which resulted in the overall chemical oxygen demand (COD) removal efficiency of 89%.


Hypoxia promotes uveal melanoma invasion through enhanced Notch and MAPK activation.
The transcriptional response promoted by hypoxia-inducible factors has been associated with metastatic spread of uveal melanoma. We found expression of hypoxia-inducible factor 1α (HIF-1α) protein in well-vascularized tumor regions as well as in four cell lines grown in normoxia, thus this pathway may be important even in well-oxygenated uveal melanoma cells. HIF-1α protein accumulation in normoxia was inhibited by rapamycin. As expected, hypoxia (1% pO2) further induced HIF-1α protein levels along with its target genes VEGF and LOX. Growth in hypoxia significantly increased cellular invasion of all 5 uveal melanoma lines tested, as did the introduction of an oxygen-insensitive HIF-1α mutant into Mel285 cells with low HIF-1α baseline levels. In contrast, HIF-1α knockdown using shRNA significantly decreased growth in hypoxia, and reduced by more than 50% tumor invasion in four lines with high HIF-1α baseline levels. Pharmacologic blockade of HIF-1α protein expression using digoxin dramatically suppressed cellular invasion both in normoxia and in hypoxia. We found that Notch pathway components, including Jag1-2 ligands, Hes1-Hey1 targets and the intracellular domain of Notch1, were increased in hypoxia, as well as the phosphorylation levels of Erk1-2 and Akt. Pharmacologic and genetic inhibition of Notch largely blocked the hypoxic induction of invasion as did the pharmacologic suppression of Erk1-2 activity. In addition, the increase in Erk1-2 and Akt phosphorylation by hypoxia was partially reduced by inhibiting Notch signaling. Our findings support the functional importance of HIF-1α signaling in promoting the invasive capacity of uveal melanoma cells in both hypoxia and normoxia, and suggest that pharmacologically targeting HIF-1α pathway directly or through blockade of Notch or Erk1-2 pathways can slow tumor spread.


The vertical and extended rectus abdominis myocutaneous flap for irradiated thigh and groin defects.
Thigh and groin tumors are often treated with limb-sparing surgery and adjuvant preoperative irradiation, frequently resulting in complex soft-tissue defects and wounds. The authors evaluated outcomes after reconstruction of these difficult wounds with the vertical and extended rectus abdominis myocutaneous (RAM) flap. A retrospective chart review was performed of 50 consecutive patients who underwent inferiorly based RAM pedicle flaps to reconstruct thigh and groin defects after preoperative irradiation and oncologic resection. Timing of reconstruction, flap design, complications, metastasis/recurrence, and ambulation status were analyzed. Fifty patients (mean age, 56 years; range, 10 to 83 years) underwent 51 RAM flaps. Sixty-three percent of flaps were for immediate reconstruction and the remaining flaps were for secondary coverage after failure of initial closure. There were no perioperative deaths. The median length of hospital stay was 9 days. All flaps survived. The vertical RAM flap was used in 63 percent of cases; the extended RAM flap was used in 37 percent and permitted closure of larger, contralateral, and more distal defects. With a mean follow-up of 28 months, complications included partial flap necrosis [n = 2 (4 percent)], infection [n = 8 (16 percent)], seroma [n = 2 (4 percent)], dehiscence [n = 2 (4 percent)], and donor-site bulge [n = 6 (12 percent)]. Postoperative wound complications were significantly higher in patients who underwent delayed or secondary (47 percent) versus immediate reconstruction (9.4 percent, p < 0.005). Three patients required additional coverage. There was no significant difference in flap complications between the extended and nonextended flap designs. Independent ambulation was achieved in 82 percent of patients. The vertical and extended RAM flaps provide reliable coverage of irradiated thigh and groin oncologic wounds, with significantly improved results obtained with immediate versus delayed reconstruction.


Chloroquine and hydroxychloroquine as a repurposed agent against COVID-19: a narrative review.
The predicament arising from the coronavirus disease 2019 (COVID-19) pandemic has become one of the most significant modern public health challenges. Despite uncertainties in the viral determinants and pathogenesis, it is crucial to accurately inspect all available evidence to construct accurate clinical guidelines for optimised patient care. This study aims to discuss the available evidence for the use of chloroquine (CQ) and hydroxychloroquine (HCQ) against COVID-19. Early in vitro studies of CQ/HCQ against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are convincing. But contradictory evidence exists on the clinical use of CQ/HCQ, either alone or in combination with azithromycin. As of now, there is no compelling clinical evidence on CQ, HCQ, and azithromycin in COVID-19 and the available evidence is limited to methodologically inferior non-randomised studies. Studies have also shown detrimental drug reactions to CQ and 'HCQ plus azithromycin', mainly cardiac side effects in hospitalised patients with coexisting cardiovascular comorbidities. Therefore, we recommend that physicians avoid high doses and exercise extreme caution in the compassionate use of CQ/HCQ, either alone or in combination with other antiviral drugs.


Chronic fatigue and myalgia syndrome: mitochondrial and glycolytic studies in skeletal muscle.
Clinical and biochemical findings in skeletal muscle in 11 patients with chronic fatigue myalgia syndromes of unknown aetiology are reported. All patients had severe asthenia for from one to 10 years with greatly limited exercise capacity and protracted exhaustion after minor exercise. Diffuse myalgia was prominent and was exacerbated for hours to days after exercise. Assay of skeletal muscle carnitine, phosphorylase, all glycolytic enzymes and the mitochondrial marker enzymes monoamine oxidase, isocitrate dehydrogenase and cytochrome oxidase were normal. These findings lend no support to the presence of a major defect in muscle intermediary energy pathways in this syndrome.


Dermatologist and electrologist perspectives on laser procedures by nonphysicians.
As hair removal technology continues to evolve and new equipment comes to market, conflicts may develop between dermatologists and electrologists regarding the professional control and use of these devices. A total of 1004 Fellows of the American Academy of Dermatology and 719 electrologists from the southern United States were anonymously surveyed about clinical laser procedures (CLPs). Compared to electrologists, dermatologists were more likely to support clinical laser regulations that placed licensed physicians in control (P =.001) and preferred that a delegating physician be physically present on the premises when CLPs were performed (P =.001). If a laser device was invented for permanent hair removal that was identical to traditional needle/probe electrolysis in every respect except energy type ("laser fiberoptic probe," LFP), electrologists were more likely than dermatologists to support independent use of this device by electrologists (P =.001). A greater percentage of electrologists from Texas, a state without electrolysis licensing, were more likely to support the unlicensed use of the LFP and CLPs than electrologists from states requiring electrolysis licensing. These data are consistent with previously published literature and permit a greater understanding of the multiple attitudinal, regulatory, and ethical issues involved when considering delegated and independent CLPs by electrologists.


Deletion of ribosomal S6 kinases does not attenuate pathological, physiological, or insulin-like growth factor 1 receptor-phosphoinositide 3-kinase-induced cardiac hypertrophy.
Ribosomal S6 kinases (S6Ks) have been depicted as critical effectors downstream of growth factor pathways, which play an important role in the regulation of protein synthesis by phosphorylating the ribosomal protein, S6. The goal of this study was to determine whether S6Ks regulate heart size, are critical for the induction of cardiac hypertrophy in response to a pathological or physiological stimulus, and whether S6Ks are critical downstream effectors of the insulin-like growth factor 1 (IGF1)-phosphoinositide 3-kinase (PI3K) pathway. For this purpose, we generated and characterized cardiac-specific S6K1 and S6K2 transgenic mice and subjected S6K1(-/-), S6K2(-/-), and S6K1(-/-) S6K2(-/-) mice to a pathological stress (aortic banding) or a physiological stress (exercise training). To determine the genetic relationship between S6Ks and the IGF1-PI3K pathway, S6K transgenic and knockout mice were crossed with cardiac-specific transgenic mice overexpressing the IGF1 receptor (IGF1R) or PI3K mutants. Here we show that overexpression of S6K1 induced a modest degree of hypertrophy, whereas overexpression of S6K2 resulted in no obvious cardiac phenotype. Unexpectedly, deletion of S6K1 and S6K2 had no impact on the development of pathological, physiological, or IGF1R-PI3K-induced cardiac hypertrophy. These studies suggest that S6Ks alone are not essential for the development of cardiac hypertrophy.


Anti-Claudin Antibodies as a Concept for Development of Claudin-Directed Drugs.
Claudin (CLDN) proteins, a tetra-transmembrane family containing over 20 members, have been identified as key structural and functional components of intercellular seals, tight junctions (TJs). CLDNs are involved in the barrier and fence functions of TJs. Loosening the TJ barrier is one strategy for increasing drug absorption and delivery to the brain. Due to aberrant CLDN expression, the TJ fence function is frequently dysregulated in carcinogenesis. In addition, CLDN-1 is a co-receptor for the hepatitis C virus. Together these characteristics indicate CLDNs as promising targets for drug development, and CLDN binders are potential candidates for delivering drugs, treating cancer, and preventing viral infection. Before 2008, a receptor-binding fragment of Clostridium perfringens enterotoxin was the only CLDN binder available. Since then, several challenges regarding the generation of monoclonal antibodies against CLDNs have been surmounted, leading to breakthroughs in CLDN-targeted drug development. Here, we provide an overview of the recent progress in technology using created CLDN binders-anti-CLDN monoclonal antibodies.


Interpretation of knockout experiments: the congenic footprint.
In gene targeting experiments, the importance of genetic background is now widely appreciated, and knockout alleles are routinely backcrossed onto a standard inbred background. This produces a congenic strain with a substantial segment of embryonic stem (ES)-cell-derived chromosome still flanking the knockout allele, a phenomenon often neglected in knockout studies. In cholecystokynin 2 (Cckbr) knockout mice backcrossed with C57BL/6, we have found a clear 'congenic footprint' of expression differences in at least 10 genes across 40 Mb sequence flanking the Cckbr locus, each of which is potentially responsible for aspects of the 'knockout' phenotype. The expression differences are overwhelmingly in the knockout-low direction, which may point to a general phenomenon of background dependence. This finding emphasizes the need for caution in using gene knockouts to attribute phenotypic effects to genes. This is especially the case when the gene is of unknown function or the phenotype is unexpected, and is a particular concern for large-scale knockout and phenotypic screening programmes. However, the impact of genetic background should not be simply viewed as a potential confound, but as a unique opportunity to study the broader responses of a system to a specific (genetic) perturbation.


Physical capacity, not skeletal maturity, distinguishes competitive levels in male Norwegian U14 soccer players.
The main aim of the present study was to compare skeletal maturity level and physical capacities between male Norwegian soccer players playing at elite, sub-elite and non-elite level. Secondary, we aimed to investigate the association between skeletal maturity level and physical capacities. One hundred and two U14 soccer players (12.8-14.5 years old) recruited from four local clubs, and a regional team were tested for bone age and physical capacities. Bone age was estimated with x-ray of their left hand and used to indicate maturation of the skeleton. Players went through a comprehensive test battery to assess their physical capacities. Between-groups analysis revealed no difference in chronological age, skeletal maturity level, leg strength, body weight, or stature. However, elite players were superior to sub-elite and non-elite players on important functional characteristics as intermittent-endurance capacity (running distance: 1664 m ± 367 vs 1197 m ± 338 vs 693 m ± 235) and running speed (fastest 10 m split time: 1.27 seconds ± 0.06 vs 1.33 seconds ± 0.10 vs 1.39 seconds ± 0.11), in addition to maximal oxygen uptake ( V ˙ O 2 m a x ), standing long jump, and upper body strength (P < .05 for all comparisons). Medium-to-large correlations were found between skeletal maturity level and peak force (r = 695, P < .01), power (r = 684, P < .01), sprint (r = -.471, P<.001), and jump performance (r = .359, P < .01), but no correlation with upper body strength, V ˙ O 2 m a x , or intermittent-endurance capacity. These findings imply that skeletal maturity level does not bias the selection of players, although well-developed physical capacity clearly distinguishes competitive levels. The superior physical performance of the highest-ranked players seems related to an appropriate training environment.


Ber e 1 protein: the versatile major allergen from Brazil nut seeds.
Due mainly to its extremely high content of sulphur amino acids, Ber e 1 protein, the major allergen from Brazil nut, has attracted much scientific and press attention. Ber e 1 was the main target protein in early biotechnology transgenic work, in early processing studies of plant storage proteins, in plant vacuolar targeting studies and as the main protein in early nutritional supplementation experiments. Ber e 1 was also one of the first food allergens to be unintentionally transferred from one plant to another and was involved in the first reported case of systemic allergic reaction caused by a food allergen transferred in semen. In this review, many of the Ber e 1 unique biotechnological and structural functions are discussed with a particular emphasis on its use as model protein for studies of intrinsic allergenicity of food proteins.


Obesity and persistent organic pollutants: possible obesogenic effect of organochlorine pesticides and polychlorinated biphenyls.
Persistent organic pollutants (POPs) are endocrine-disrupting chemicals associated with the development of the metabolic syndrome and type 2 diabetes. In humans, little is known about their role in the potential origin of obesity. This study aims to assess the associations between serum levels of POPs and the prevalence of obesity in a cohort of obese and lean adult men and women. POP serum samples were investigated cross-sectionally in 98 obese and 47 lean participants, aged ≥18 years. Serum samples were analyzed for the presence of polychlorinated biphenyl (PCB) congeners 153, 138, 180, and 170 and for the organochlorine pesticides, dichloro-diphenyl-dichloroethylene (pp-DDE), and β-hexachlorocyclohexane (βHCH). We established a significant negative correlation between BMI, waist, fat mass percentage, total and subcutaneous abdominal adipose tissue, and serum levels of PCB 153, 180, 170, and the sumPCBs. For βHCH, we demonstrated a positive correlation with BMI, waist, fat mass percentage, and total and subcutaneous abdominal adipose tissue. PCBs 180, 170, and the sum of PCBs correlated significantly negative with homeostasis model assessment for insulin resistance (HOMA(IR)). βHCH correlated significantly positively with HOMA(IR). A strong correlation was established between all POP serum levels and age. We established a positive relationship between high serum levels of βHCH and BMI and HOMA(IR), whereas serum PCB levels were inversely correlated with BMI and HOMA(IR). Combined, these results suggest that the diabetogenic effect of low-dose exposure to POPs might be more complicated than a simple obesogenic effect.


Gene promoter and exon DNA methylation changes in colon cancer development - mRNA expression and tumor mutation alterations.
DNA mutations occur randomly and sporadically in growth-related genes, mostly on cytosines. Demethylation of cytosines may lead to genetic instability through spontaneous deamination. Aims were whole genome methylation and targeted mutation analysis of colorectal cancer (CRC)-related genes and mRNA expression analysis of TP53 pathway genes. Long interspersed nuclear element-1 (LINE-1) BS-PCR followed by pyrosequencing was performed for the estimation of global DNA metlyation levels along the colorectal normal-adenoma-carcinoma sequence. Methyl capture sequencing was done on 6 normal adjacent (NAT), 15 adenomatous (AD) and 9 CRC tissues. Overall quantitative methylation analysis, selection of top hyper/hypomethylated genes, methylation analysis on mutation regions and TP53 pathway gene promoters were performed. Mutations of 12 CRC-related genes (APC, BRAF, CTNNB1, EGFR, FBXW7, KRAS, NRAS, MSH6, PIK3CA, SMAD2, SMAD4, TP53) were evaluated. mRNA expression of TP53 pathway genes was also analyzed. According to the LINE-1 methylation results, overall hypomethylation was observed along the normal-adenoma-carcinoma sequence. Within top50 differential methylated regions (DMRs), in AD-N comparison TP73, NGFR, PDGFRA genes were hypermethylated, FMN1, SLC16A7 genes were hypomethylated. In CRC-N comparison DKK2, SDC2, SOX1 genes showed hypermethylation, while ERBB4, CREB5, CNTN1 genes were hypomethylated. In certain mutation hot spot regions significant DNA methylation alterations were detected. The TP53 gene body was addressed by hypermethylation in adenomas. APC, TP53 and KRAS mutations were found in 30, 15, 21% of adenomas, and in 29, 53, 29% of CRCs, respectively. mRNA expression changes were observed in several TP53 pathway genes showing promoter methylation alterations. DNA methylation with consecutive phenotypic effect can be observed in a high number of promoter and gene body regions through CRC development.


Chronic kidney disease as a predictor of coronary lesion morphology.
Coronary artery disease (CAD) is the main cause of death in patients with chronic kidney disease (CKD). We investigated whether CKD stage affected coronary lesion morphology in patients with established CAD. Coronary angiograms of 264 patients were evaluated. Chronic kidney disease was staged using the estimated glomerular filtration rate (eGFR) from the serum creatinine prior to coronary angiography. Patients were divided into 3 groups: dialysis or severe decrease in GFR <30 mL/min per 1.73 m(2) (group 1; n = 60), patients with moderate kidney failure (group 2; n = 116), and patients with normal renal function or mild decrease in GFR (group 3; n = 88). The likelihood of CAD and lesion complexity increased with decreasing eGFR (P = .001). Patients with CKD also had more significant CAD. The risk of significant coronary obstruction and lesion complexity increased progressively with decreasing eGFR. The eGFR may predict lesion complexity among patients with CKD undergoing coronary angiography.


Degradation Mechanism of Micro-Nanobubble Technology for Organic Pollutants in Aqueous Solutions.
Micro-nanobubbles (MNBs) technology has emerged as an effective means of sewage treatment, while the molecular mechanism for its pollutant degradation is still unknown. In this paper, the reactive molecular dynamics simulation technique is used to study the degradation mechanism of pollutants caused by shock-induced nanobubble collapse. We first demonstrate that the propagating shock wave can induce nanobubble collapse, and the collapsing nanobubble has the ability to focus mechanical energy via the converging motion of liquid in the interior of the bubble, leading to the formation of a high-speed jet with a much higher energy density. We also unveil the mechanical nature of long-chain pollutant degradation and the mechanism of free radical generation. Due to the impacting jet, the high-gradient flow has the ability to stretch the long-chain molecule and cause mechanical scission of the molecule in a homolytic manner. Finally, our simulation results reveal that adding ozone molecules to the collapsing bubble would introduce an additional dehydrogenation mechanism.


Sagittal synostosis.
This report concerns a 20-month-old boy, born at 31 weeks of gestation, being followed in the paediatric clinic because of prematurity. He was developing appropriately for his age and his head circumference was growing steadily (between the 75th and 90th centile), with weight and height on the 25th centile. An x-ray of his skull was performed at this stage because of his head shape, which was long and narrow (scaphocephalic)-in itself suggestive of sagittal synostosis. The x-ray confirmed the diagnosis. He was referred to a regional neurosurgical unit for further management. He had a successful surgical correction without major problems. It is to be emphasised that there is a higher morbidity and mortality if reconstructive surgery is not carried out at an early age, and therefore early diagnosis is vital in this congenital condition.


Plant carbonic anhydrase-like enzymes in neuroactive alkaloid biosynthesis.
Plants synthesize numerous alkaloids that mimic animal neurotransmitters1. The diversity of alkaloid structures is achieved through the generation and tailoring of unique carbon scaffolds2,3, yet many neuroactive alkaloids belong to a scaffold class for which no biosynthetic route or enzyme catalyst is known. By studying highly coordinated, tissue-specific gene expression in plants that produce neuroactive Lycopodium alkaloids4, we identified an unexpected enzyme class for alkaloid biosynthesis: neofunctionalized α-carbonic anhydrases (CAHs). We show that three CAH-like (CAL) proteins are required in the biosynthetic route to a key precursor of the Lycopodium alkaloids by catalysing a stereospecific Mannich-like condensation and subsequent bicyclic scaffold generation. Also, we describe a series of scaffold tailoring steps that generate the optimized acetylcholinesterase inhibition activity of huperzine A5. Our findings suggest a broader involvement of CAH-like enzymes in specialized metabolism and demonstrate how successive scaffold tailoring can drive potency against a neurological protein target.


Ziziphus Jujube: a review study of its anticancer effects in various tumor models invitro and invivo.
The growing rate of cancer incidences and inefficiency of current therapies have made scientists to find novel agents such as medicinal plants. Ziziphus jujube is one of these plants whose pharmaceutical effects have been studied for a long time. Recent investigations have proved that bioactive compounds of Ziziphus jujube including triterpenic acids, flavonoids, cerebrosides, phenolic acids, α tocopherol, β carotene, and polysaccharides have anti-proliferative effects on several cancerous cell lines and animals. The present study aimed to cover all previous invitro and invivo findings and some of molecular mechanisms of its anticancer property.


Antigenic structure of cell surfaces. An immunoferritin study of the occurrence and topography of H-2' theta, and TL alloantigens on mouse cells.
The representation of mouse alloantigens belonging to three systems, H-2, theta and TL, on the surface of cells from thymus, spleen, lymph nodes, and peritoneal cavity, was studied by electron microscopy with ferritin-labeled antibody. As expected from earlier serological data, TL was confined to thymocytes, theta was found on thymocytes and lymphocytes, and H-2 occurred to some extent on all cell types observed. On reticular cells, lymphocytes, plasma cells, and eosinophils, the majority of the cell surface was occupied by H-2; thymocytes had considerably less H-2, and erythrocytes and peritoneal macrophages least of all. In every instance the representation of antigen was discontinuous, the fraction of the cell surface covered being characteristic both of the antigen and of the type of cell. H-2 and theta provide a striking example of this; H-2 is present in far higher amounts on lymphocytes than on thymocytes, whereas the converse is true of theta. Within areas positive for H-2 or theta, protuberances of the surface membrane were often antigen-negative. A better definition of cell surface structure, gained from studies such as this, is necessary for further inquiry into how the cell surface is assembled, and into selective gene action in relation to cellular differentiation.


[Variability in Act. circulatus var. monomycini induced by N-5-nitroso-N-methylbiuret].
The effect of N-5-nitrozo-N-methylbiuret (NMB) on various features of Act. circulatus var. monomycini, an organism producing monomycin was studied. It was found that the lethal effect of NMB depended on the exposure time, prolongation of which resulted in increased numbers of the plus variants, morphological and auxotrophic mutations and reverses into the populations of the monomycin-producing organism. An increase in the temperature of the treatment had an effect on the frequency of morphological and auxotrophic mutations inducing an increase in the number of the first and some decrease in the number of the second. The fact of specificity in formation of the vitamin B6-deficient auxotrophic mutants of the same type was of special interest. This was probably associated with genetic peculiar properties of the culture. It was supposed that the genes controlling biosynthesis of vitamin B6 were localized on the actinomycete plasmids, elimination of which under the effect of NMB resulted in blocking of vitamin B6 synthesis which in its turn impaired the reactions of transaminations participating in formation of monomycin.


Alkaloids of Amaryllidaceae as Inhibitors of Cholinesterases (AChEs and BChEs): An Integrated Bioguided Study.
Enzymatic inhibition of acetylcholinesterase (AChE) is an essential therapeutic target for the treatment of Alzheimer's disease (AD) and AChE inhibitors are the first-line drugs for it treatment. However, butyrylcholinesterase (BChE), contributes critically to cholinergic dysfunction associated with AD. Thus, the development of novel therapeutics may involve the inhibition of both cholinesterase enzymes. To evaluate, in an integrated bioguided study, cholinesterases alkaloidal inhibitors of Amaryllidaceae species. The proposed method combines high-performance thin-layer chromatography (HPTLC) with data analysis by densitometry, enzymatic bioautography with different AChEs and BChEs, the detection of bioactive molecules through gas chromatography mass spectrometry (GC-MS) analysis of spots of interest, and theoretical in silico studies. To evaluate the bioguided method, the AChE and BChE inhibitory activities of seven Amaryllidaceae plant extracts were evaluated. The alkaloid extracts of Eucharis bonplandii exhibited a high level of inhibitory activity (IC50 = 0.72 ± 0.05 μg/mL) against human recombinant AChE (hAChE). Regarding human serum BChE (hBChE), the bulb and leaf extracts of Crinum jagus had the highest activity (IC50 = 8.51 ± 0.56 μg/mL and 11.04 ± 1.21 μg/mL, respectively). In the HPTLC spots with high inhibitory activity, several alkaloids were detected using GC-MS, and some of these alkaloids were identified. Galanthamine, galanthamine N-oxide and powelline should be the most prominent inhibitors of substrate accommodation in the active site of the Torpedo californica AChE (TcAChE), hAChE and hBChE enzymes. These results are evidence of the chemical relevance of the Colombian's Amaryllidaceae species for the inhibition of cholinesterases and as potent sources for the palliative treatment of AD. Copyright © 2017 John Wiley & Sons, Ltd.


Viscoelastically tunable substrates elucidate the interface-relaxation-dependent adhesion and assembly behaviors of epithelial cells.
Recent progress in mechanobiology sheds light on the regulation of cellular phenotypes by dissipative property of matrices, i.e., viscosity, fluidity, and stress relaxation, in addition to extensively studied elasticity. However, most researches have focused on bulk mechanics, despite cells in 2D culture can only interact with matrix interface directly. Here, we studied the impact of interfacial viscosity as well as elasticity of substrates on the early stage of adhesion behaviors of epithelial cells through new material design and mechanical characterization. The materials are copolymers of ε-caprolactone and d,l-lactide photocrosslinked by benzophenone. The substrate viscoelasticity changes depending on the polymer molecular weight and irradiation time. The interfacial elasticity and relaxation were determined by atomic force microscopy with modes of nanoindentation and tip-dwelling, respectively. MDCK cells changed morphologically, ranging from loose beaded assembly to more compact spheroids and eventual spread monolayer clusters, in response to the interfacial viscoelasticity change. Such morphological changes were mainly determined by substrate interfacial relaxation, rather than interfacial elasticity. Single-cell tracking identified biphasic motility with the minimum speed at intermediate relaxation time (~350 ms), where cells showed transitional morphologies between epithelial and mesenchymal traits. In that relaxation level, partially deformed cells moved around to coalesce with surrounding cells, eventually assembling into compact cellular aggregates. These results highlight, unlike the conventional hanging-drop technique, an appropriate level of interfacial relaxation is critical for efficient cell aggregate maturation on adhesive viscoelastic matrices. This work not only elucidates that the interfacial relaxation as the essential mechanical parameter for epithelial cell adhesion and migration, but also gives useful tips for creating physiologically relevant drug screening platform.


An evaluation of the quality of Turkish community pharmacy web sites concerning HON principles.
The objective of this study was to find all the existing Web sites of Turkish community pharmacies and evaluate their "quality" in terms of Health on the Net (HON) Code of conduct principles. Multiple Internet search engines were used (google.com, yahoo.com, altavista.com, msn.com). While searching on the Internet, "eczane (pharmacy)" and "eczanesi (pharmacy of)" key words were used. The Internet search lasted for 2 months starting from March 1, 2007 until May 1, 2007. SPSS ver. 11.5 statistical program (SPSS, Inc., Chicago, IL) was used for data entry and analysis. At the end of the Internet search via all the indicated search engines, a total of 203 (all different from each other) community pharmacy Web sites were determined; of these, 14 were under construction and 6 were not accessible. As a result, 183 community pharmacy Web sites were included in the study. All of the Web sites could be accessed (100%). However, the availability of some characteristics of the pharmacies were quite poor. None of the pharmacies met all of the HON principles. Only 11 Web sites were appropriate in terms of complementarity (6.0%). Confidentiality criteria was met by only 14 pharmacies (7.7%). Nine pharmacies (4.9%) completed the "attribution" criteria. Among 183 pharmacy Web sites, the most met HON principle was the "transparency of authorship" (69 pharmacy Web sites; 37.7%). Because of the results of our study, the Turkish Pharmacists Association can take a pioneer role to apply some principles such as HON code of conduct in order to increase the quality of Turkish community pharmacists' Web sites.


Dynamic influences on a high-affinity, high-specificity interaction involving the C-terminal SH3 domain of p67phox.
An analysis of the backbone dynamics of the C-terminal Src homology 3 (SH3) domain of p67(phox), p67(phox)SH3(C), in complex with a 32-residue high-affinity (K(d) = 24 nM) peptide, Pf, from the C-terminal region of p47(phox) is presented. This paper represents the first detailed analysis of the backbone dynamics and the ligand-induced changes therein of a high-affinity, high-specificity interaction involving an SH3 domain. The dynamic features are compared with those in the high-affinity, highly specific interaction between the SH3 domain of C-terminal Src kinase (Csk-SH3) and a proline-rich peptide from proline-enriched phosphatase (PEP). Both systems share common dynamic features especially in the canonical PxxP motif recognition surface where slow micro- to millisecond time scale dynamics persist on complex formation especially in several residues that are implicated in ligand recognition and in stabilizing the SH3 fold. These residues are highly conserved in SH3 domains. Ile505, which lies outside the PxxP recognition motif on p67(phox)SH3(C) and is key in conferring high specificity to the p67(phox)SH3(C)/Pf interaction, becomes more disordered upon complex formation. This behavior is similar to that seen in the residues that constitute the specificity surface in Csk-SH3.


Bioengineering a highly vascularized matrix for the ectopic transplantation of islets.
Islet transplantation is a promising treatment for Type 1 diabetes; however limitations of the intra-portal site and poor revascularization of islets must be overcome. We hypothesize that engineering a highly vascularized collagen-based construct will allow islet graft survival and function in alternative sites. In this study, we developed such a collagen-based biomaterial. Neonatal porcine islets (NPIs) were embedded in collagen matrices crosslinked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide containing combinations of chondroitin-6-sulfate, chitosan, and laminin, and compared with controls cultured in standard media. Islets were examined for insulin secretory activity after 24 h and 4 d and for apoptotic cell death and matrix integrity after 7 d in vitro. These same NPI/collagen constructs were transplanted subcutaneously in immunoincompetent B6.Rag-/- mice and then assessed for islet survival and vascularization. At all time points assessed during in vitro culture there were no significant differences in insulin secretory activity between control islets and those embedded in the collagen constructs, indicating that the collagen matrix had no adverse effect on islet function. Less cell death was observed in the matrix with all co-polymers compared with the other matrices tested. Immunohistochemical analysis of the grafts post-transplant confirmed the presence of intact insulin-positive islets; grafts were also shown to be vascularized by von Willebrand factor staining. This study demonstrates that a collagen, chondroitin-6-sulfate, chitosan, and laminin matrix supports islet function in vitro and moreover allows islet survival and vascularization post-transplantation; therefore, this bio-engineered vascularized construct is capable of supporting islet survival.


Transtentorial diaschisis: reduction of cerebellar blood flow caused by supratentorial local cerebral ischemia in the gerbil.
To assess the effect of supratentorial cerebral ischemia on infratentorial brain function, changes in regional cerebellar blood flow (rCeBF), after right carotid occlusion for 4 hours, were studied in 30 mongolian gerbils. The regional cerebral blood flow (rCBF) in the occluded cerebral hemisphere and rCeBF in both cerebellar hemispheres were measured simultaneously by hydrogen clearance methods. Before carotid occlusion, rCBF was 0.44 +/- 0.07 ml/g brain/min, and rCeBF in the left and right cerebellar hemispheres was 0.37 +/- 0.09 and 0.40 +/- 0.09 ml/g brain/min, respectively. After carotid occlusion, rCBF decreased in all animals showing levels of above 0.20 ml/g brain/min in 14 (group A), between 0.10 and 0.19 ml/g brain/min in 7 (group B) and below 0.10 ml/g brain/min in 9 (group C). rCeBF exhibited no changes in group A and a mild reduction in group B after carotid occlusion. In group C, rCeBF was significantly reduced 30 min after carotid occlusion in the left cerebellar hemisphere followed subsequently by bilateral reduction. In groups B and C, supratentorial brain edema was observed 4 hours after occlusion, but the degree of edema was moderate. The results of the present study suggest that depression of infratentorial brain function may occur after supratentorial local cerebral ischemia, presumably due to diaschisis.


Epitope-Specific Evolution of Human B Cell Responses to Borrelia burgdorferi VlsE Protein from Early to Late Stages of Lyme Disease.
Most immunogenic proteins of Borrelia burgdorferi, the causative agent of Lyme disease, are known or expected to contain multiple B cell epitopes. However, the kinetics of the development of human B cell responses toward the various epitopes of individual proteins during the course of Lyme disease has not been examined. Using the highly immunogenic VlsE as a model Ag, we investigated the evolution of humoral immune responses toward its immunodominant sequences in 90 patients with a range of early to late manifestations of Lyme disease. The results demonstrate the existence of asynchronous, independently developing, Ab responses against the two major immunogenic regions of the VlsE molecule in the human host. Despite their strong immunogenicity, the target epitopes were inaccessible to Abs on intact spirochetes, suggesting a lack of direct immunoprotective effect. These observations document the association of immune reactivity toward specific VlsE sequences with different phases of Lyme disease, demonstrating the potential use of detailed epitope mapping of Ags for staging of the infection, and offer insights regarding the pathogen's possible immune evasion mechanisms.


Eye movement and pupil size constriction under discomfort glare.
Involuntary physiological responses offer an alternative means to psychophysical procedures for objectively evaluating discomfort glare. This study examined eye movement and pupil size responses to glare discomfort using new approaches to analysis: relative pupil size and speed of eye movement. Participants evaluated glare discomfort using the standard de Boer rating scale under various conditions manipulated to influence glare discomfort. Eye movement was recorded using an electro-oculogram (EOG), and pupil size was recorded using Tobii glasses. Ten young (mean age: 24.5 years old) and 10 senior (mean age: 61 years old) participants were recruited for this experiment. Subjective evaluation of glare discomfort was highly correlated with eye movement (multiple correlation coefficient [R(2)] of >0.94, P < 0.001) and pupil constriction (R(2) = 0.38, P < 0.001). Severe glare discomfort increased the speed of eye movement and caused larger pupil constriction. Larger variations of eye movement were found among seniors. The two physiological responses studied here to characterize discomfort glare under various lighting conditions had significant correlation with the subjective evaluation. The correlation between discomfort glare and physiological responses suggests an objective way to characterize and evaluate discomfort glare that may overcome the problems of conventional subjective evaluation. It also offers an explanation as to why long-term exposure to discomfort glare leads to visual fatigue and eyestrain.


Physical exercise and oxidative stress in muscular dystrophies: is there a good balance?
The effect of oxidative stress on muscle damage inducted by physical exercise is widely debated. It is generally agreed that endurance and intense exercise can increase oxidative stress and generate changes in antioxidant power inducing muscle damage; however, regular and moderate exercise can be beneficial for the health improving the antioxidant defense mechanisms in the majority of cases. Growing evidences suggest that an increased oxidative/nitrosative stress is involved in the pathogenesis of several muscular dystrophies (MDs). Notably, physical training has been considered useful for patients with these disorders. This review will focus on the involvement of oxidative stress in MDs and on the possible effects of physical activities to decrease oxidative damage and improve motor functions in MDs patients.


In vivo gene transfer into the testis by electroporation and viral infection--a novel way to study testis and sperm function.
The study of gene function in testis and sperm has been greatly assisted by creation of transgenic mice by injection of a transgene into the fertilised egg. However this approach is costly and laborious and is not applicable to other species of importance for the study of sperm function, such as the hamster. We have investigated alternative ways of expressing transgenes in mouse and hamster testis and sperm by in vivo gene transfer. DNA expression constructs were introduced into the testis by injection of DNA followed by electroporation, or by injection of a lentiviral vector. Expression of fluorescent proteins was assessed by fluorescence microscopy. In vivo gene transfer by electroporation led to expression of a fluorescent reporter protein and a fluorescently tagged version of sperm protein phospholipase C zeta in hamster and mouse testis and epididymal sperm. In vivo gene transfer by lentiviral infection led to high level expression of a fluorescent reporter protein in male germ cells. In conclusion, in vivo gene transfer offers a novel way to study gene function in testis and sperm and may also have potential as a way of creating transgenic versions of important model organisms such as the hamster.


TP53 mutations induced by BPDE in Xpa-WT and Xpa-Null human TP53 knock-in (Hupki) mouse embryo fibroblasts.
Somatic mutations in the tumour suppressor gene TP53 occur in more than 50% of human tumours; in some instances exposure to environmental carcinogens can be linked to characteristic mutational signatures. The Hupki (human TP53 knock-in) mouse embryo fibroblast (HUF) immortalization assay (HIMA) is a useful model for studying the impact of environmental carcinogens on TP53 mutagenesis. In an effort to increase the frequency of TP53-mutated clones achievable in the HIMA, we generated nucleotide excision repair (NER)-deficient HUFs by crossing the Hupki mouse with an Xpa-knockout (Xpa-Null) mouse. We hypothesized that carcinogen-induced DNA adducts would persist in the TP53 sequence of Xpa-Null HUFs leading to an increased propensity for mismatched base pairing and mutation during replication of adducted DNA. We found that Xpa-Null Hupki mice, and HUFs derived from them, were more sensitive to the environmental carcinogen benzo[a]pyrene (BaP) than their wild-type (Xpa-WT) counterparts. Following treatment with the reactive metabolite of BaP, benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), Xpa-WT and Xpa-Null HUF cultures were subjected to the HIMA. A significant increase in TP53 mutations on the transcribed strand was detected in Xpa-Null HUFs compared to Xpa-WT HUFs, but the TP53-mutant frequency overall was not significantly different between the two genotypes. BPDE induced mutations primarily at G:C base pairs, with approximately half occurring at CpG sites, and the predominant mutation type was G:C>T:A in both Xpa-WT and Xpa-Null cells. Further, several of the TP53 mutation hotspots identified in smokers' lung cancer were mutated by BPDE in HUFs (codons 157, 158, 245, 248, 249, 273). Therefore, the pattern and spectrum of BPDE-induced TP53 mutations in the HIMA are consistent with TP53 mutations detected in lung tumours of smokers. While Xpa-Null HUFs exhibited increased sensitivity to BPDE-induced damage on the transcribed strand, NER-deficiency did not enhance TP53 mutagenesis resulting from damage on the non-transcribed strand in this model.


Surgical data science: The new knowledge domain.
Healthcare in general, and surgery/interventional care in particular, is evolving through rapid advances in technology and increasing complexity of care with the goal of maximizing quality and value of care. While innovations in diagnostic and therapeutic technologies have driven past improvements in quality of surgical care, future transformation in care will be enabled by data. Conventional methodologies, such as registry studies, are limited in their scope for discovery and research, extent and complexity of data, breadth of analytic techniques, and translation or integration of research findings into patient care. We foresee the emergence of Surgical/Interventional Data Science (SDS) as a key element to addressing these limitations and creating a sustainable path toward evidence-based improvement of interventional healthcare pathways. SDS will create tools to measure, model and quantify the pathways or processes within the context of patient health states or outcomes, and use information gained to inform healthcare decisions, guidelines, best practices, policy, and training, thereby improving the safety and quality of healthcare and its value. Data is pervasive throughout the surgical care pathway; thus, SDS can impact various aspects of care including prevention, diagnosis, intervention, or post-operative recovery. Existing literature already provides preliminary results suggesting how a data science approach to surgical decision-making could more accurately predict severe complications using complex data from pre-, intra-, and post-operative contexts, how it could support intra-operative decision-making using both existing knowledge and continuous data streams throughout the surgical care pathway, and how it could enable effective collaboration between human care providers and intelligent technologies. In addition, SDS is poised to play a central role in surgical education, for example, through objective assessments, automated virtual coaching, and robot-assisted active learning of surgical skill. However, the potential for transforming surgical care and training through SDS may only be realized through a cultural shift that not only institutionalizes technology to seamlessly capture data but also assimilates individuals with expertise in data science into clinical research teams. Furthermore, collaboration with industry partners from the inception of the discovery process promotes optimal design of data products as well as their efficient translation and commercialization. As surgery continues to evolve through advances in technology that enhance delivery of care, SDS represents a new knowledge domain to engineer surgical care of the future.


Culture-independent bacterial community analysis of the salty-fermented fish paste products of Thailand and Laos.
A bacterial community analysis, using a culture-independent method (polymerase chain reaction-denaturing gradient gel electrophoresis), detected 17 species of bacteria including species of the genera Tetragenococcus, Lactobacillus, Pediococcus, Weissella Halanaerobium, Clostridium, and Sphingomonas in a traditional salty-fermented fish paste known as pla-ra or pa-daek in Thailand and Laos, which is used as a storage-stable multi-purpose seasoning. The representative genus of lactic acid bacteria seemed to vary in the 10 products collected from Thailand and Laos. Tetragenococci were common in products from central Thailand and Vientiane in Laos which had salinities of not less than 11% and pH values ranging from 5.6 to 6.1. However, lactobacilli were common in products from northern Thailand which had the lowest salinities (8.3-8.6%) and pH values (4.5-4.8) of all the samples examined. Two Lactobacillus and one Tetragenococcus species were detected in one product from northeastern Thailand containing 10% salt. These results suggest that salinity in pla-ra/pa-daek is an important determinant of the representative genus of lactic acid bacteria such as, Tetragenococcus or Lactobacillus. Additionally, differences in the acidity between these two groups seemed to be related to the production of d-/l-lactic acid in the lactic acid bacteria in each product. This is the first study to report a correlation between bacterial community structure and taste components in pla-ra/pa-daek products from various regions. This scientific work on a traditional fermented food will be useful in helping local producers meet differing consumer preferences in various regions.


Resource utilization and costs associated with chemotherapy-induced nausea and vomiting (CINV) following highly or moderately emetogenic chemotherapy administered in the US outpatient hospital setting.
Chemotherapy-induced nausea and vomiting (CINV), common adverse events of chemotherapy, may be associated with considerable healthcare resource utilization. This study was conducted to describe CINV-associated healthcare visits and costs following a first cycle of highly or moderately emetogenic chemotherapy (HEC or MEC). This retrospective cohort study used the Premier Perspective™ Database to identify adult patients who received their first HEC or MEC and at least one antiemetic agent from 2003 to 2007 at US hospital-based outpatient facilities. Hospital visits with a CINV-related ICD-9 diagnosis were included from the chemotherapy administration date to 30 days later or 1 day before the second chemotherapy, whichever was first. CINV costs were hospital-reported costs. Of 19,139 patients (HEC, 16%; MEC, 84%), mean (SD) age was 59 (14) years; 59% were female; 66% were white. CINV prophylaxis included 5-HT₃ antagonists (85%), dexamethasone (76%), and NK-1 antagonists (2%). Overall, 13.8% of patients had a CINV-associated visit (HEC, 18%; MEC, 13%): 0.2% for acute CINV (day of chemotherapy, excluding chemotherapy administration visit) and 13.7% for delayed CINV. CINV-associated visits included inpatient (IP, 64%), outpatient (OP, 26%), and emergency room (ER, 10%) visits. Mean (SD) costs of CINV visits were $5,299 ($6,639); for IP, $7,448 ($7,271); OP, $1,494 ($2,172); and ER, $918 ($1,071). Mean per-patient CINV-associated costs across all patients were $731 ($3,069). Sensitivity analysis excluding visits where CINV was a secondary diagnosis code resulted in a CINV incidence of 4.4%, a mean CINV visit cost of $4,043, and a mean per-patient CINV-associated cost across all patients of $176. CINV visits in the first HEC or MEC cycle were common and costly, especially inpatient hospitalizations in the delayed phase. Strategies to reduce CINV in the delayed phase could reduce healthcare utilization and costs.


On the measurement of tobacco use by adolescents. Validity of self-reports of smokeless tobacco use and validity of cotinine as an indicator of cigarette smoking.
This study assessed the validity of self-reports of smokeless tobacco use by adolescents and the validity of cotinine as a measure of adolescent cigarette smoking. For a sample of 1,854 persons aged 12-14 years living in the southeastern United States in 1985, a combination of three biochemical measures (salivary cotinine, salivary thiocyanate, and alveolar carbon monoxide) and self-reports of cigarette smoking were used to identify subjects who used only smokeless tobacco and subjects who did not use smokeless tobacco. The sensitivity and specificity of self-reports of smokeless tobacco use were 40.8% and 97.9%, respectively. It was determined that of the 175 subjects who ordinarily would be considered smokers because they had salivary cotinine levels greater than or equal to 10 ng/ml, 43.4% used only smokeless tobacco.


Cluster analysis of protein array results via similarity of Gene Ontology annotation.
With the advent of high-throughput proteomic experiments such as arrays of purified proteins comes the need to analyse sets of proteins as an ensemble, as opposed to the traditional one-protein-at-a-time approach. Although there are several publicly available tools that facilitate the analysis of protein sets, they do not display integrated results in an easily-interpreted image or do not allow the user to specify the proteins to be analysed. We developed a novel computational approach to analyse the annotation of sets of molecules. As proof of principle, we analysed two sets of proteins identified in published protein array screens. The distance between any two proteins was measured as the graph similarity between their Gene Ontology (GO) annotations. These distances were then clustered to highlight subsets of proteins sharing related GO annotation. In the first set of proteins found to bind small molecule inhibitors of rapamycin, we identified three subsets containing four or five proteins each that may help to elucidate how rapamycin affects cell growth whereas the original authors chose only one novel protein from the array results for further study. In a set of phosphoinositide-binding proteins, we identified subsets of proteins associated with different intracellular structures that were not highlighted by the analysis performed in the original publication. By determining the distances between annotations, our methodology reveals trends and enrichment of proteins of particular functions within high-throughput datasets at a higher sensitivity than perusal of end-point annotations. In an era of increasingly complex datasets, such tools will help in the formulation of new, testable hypotheses from high-throughput experimental data.


Spatiotemporal prediction of infectious diseases using structured Gaussian processes with application to Crimean-Congo hemorrhagic fever.
Infectious diseases are one of the primary healthcare problems worldwide, leading to millions of deaths annually. To develop effective control and prevention strategies, we need reliable computational tools to understand disease dynamics and to predict future cases. These computational tools can be used by policy makers to make more informed decisions. In this study, we developed a computational framework based on Gaussian processes to perform spatiotemporal prediction of infectious diseases and exploited the special structure of similarity matrices in our formulation to obtain a very efficient implementation. We then tested our framework on the problem of modeling Crimean-Congo hemorrhagic fever cases between years 2004 and 2015 in Turkey. We showed that our Gaussian process formulation obtained better results than two frequently used standard machine learning algorithms (i.e., random forests and boosted regression trees) under temporal, spatial, and spatiotemporal prediction scenarios. These results showed that our framework has the potential to make an important contribution to public health policy makers.


Leukocytosis as an alarming sign for mortality in patients hospitalized in general wards.
There is some evidence that leukocytosis without infection is associated with increased hospital mortality, but data in this regard are very incomplete. This study was designed to investigate the relationship between leukocytosis at the time of admission and mortality among patients hospitalized in general wards. During July to Nov 2004, all deceased patients who had a white blood cell (WBC) count record for the first 24 hours of admission were selected as cases. Among survivors, twice the number of cases was selected as controls. Different levels of WBC counts were compared between cases and controls. Totally 1650 patients, including 550 deceased (cases) and 1100 survivors (controls) were analyzed. Of these, 876 (53%) were males and 774 (47%) females, and 42 (3%) were admitted to ICU, 1426 (86%) to medical and 182 (11%) to surgical wards. There was a significant difference between the mean age of deceased patients (78.0 years) and survivors (53.0 years) (P<0.0001). The median WBC for deceased and surviving patients was 9.4 and 11.4×10(9)/l, respectively. Patients with a WBC >10×10(9)/l accounted for 804, among which 335 (42%) were deceased. Leukocytosis and leukopoenia were more frequent among the deceased patients compared to the survivors. The likelihood ratio for leukocytosis and leukopenia among the cases and controls was 1.4 and 2.3, respectively. Leukocytosis was identified as an alarming sign for mortality among patients admitted to general hospital wards at early stages of admission. A quick medical intervention for amendment of the causes related to leukocytosis should consequently reduce hospital mortality.


Summary of the National Toxicology Program's report of the endocrine disruptors low-dose peer review.
At the request of the U.S. Environmental Protection Agency (U.S. EPA), the National Toxicology Program organized an independent and open peer review to evaluate the scientific evidence on low-dose effects and nonmonotonic dose-response relationships for endocrine-disrupting chemicals in mammalian species. For this peer review, "low-dose effects" referred to biologic changes that occur in the range of human exposures or at doses lower than those typically used in the standard testing paradigm of the U.S. EPA for evaluating reproductive and developmental toxicity. The demonstration that an effect is adverse was not required because in many cases the long-term health consequences of altered endocrine function during development have not been fully characterized. A unique aspect of this peer review was the willing submission of individual animal data by principal investigators of primary research groups active in this field and the independent statistical reanalyses of selected parameters prior to the peer review meeting by a subpanel of statisticians. The expert peer-review panel (the panel) also considered mechanistic data that might influence the plausibility of low-dose effects and identified study design issues or other biologic factors that might account for differences in reported outcomes among studies. The panel found that low-dose effects, as defined for this review, have been demonstrated in laboratory animals exposed to certain endocrine-active agents. In some cases where low-dose effects have been reported, the findings have not been replicated. The shape of the dose-response curves for reported effects varied with the end point and dosing regimen and were low-dose linear, threshold-appearing, or nonmonotonic. The findings of the panel indicate that the current testing paradigm used for assessments of reproductive and developmental toxicity should be revisited to see whether changes are needed regarding dose selection, animal-model selection, age when animals are evaluated, and the end points being measured following exposure to endocrine-active agents.


Carboxylate cross-linked cyclodextrin: A nanoporous scaffold for enhancement of rosuvastatin oral bioavailability.
Cyclodextrins play an important role in supramolecular chemistry acting as building blocks than can be cross-linked by various linker molecules forming nano-porous structures called nanosponges (NS). NS have the ability to enhance the stability, solubility and bioavailability of various actives. This work aimed at elaborating rosuvastatin (ROS) loaded NS to improve its oral bioavailability. Carboxylate-linked NS were synthesized by reacting β-CD with pyromellitic dianhydride (PDA) at different molar ratios under specific conditions. ROS-loaded NS were prepared by lyophilisation technique and characterized for particle size, zeta potential, entrapment efficiency and drug release. Occurrence of cross-linking and ROS incorporation within the NS were assessed by DSC, FT-IR and SEM micrographs. NS prepared at a molar ratio of 1:6 of β-CD: PDA demonstrated the highest entrapment efficiency (88.76%), an optimum particle size of 275nm, a narrow size distribution (PDI of 0.392), and zeta potential of -61.9 indicating good colloidal stability. In vivo oral pharmacokinetics study in male Sprague Dawley rats showed that ROS-NS provided an outstanding enhancement in oral bioavailability compared to drug suspension and marketed tablets besides their physicochemical stability for 3month. Accordingly, ROS-NS represent a superior alternative to the conventional marketed formulation for effective ROS delivery.


Occurrence and phylogenetic analysis of bovine respiratory syncytial virus in outbreaks of respiratory disease in Norway.
Bovine respiratory syncytial virus (BRSV) is one of the major pathogens involved in the bovine respiratory disease (BRD) complex. The seroprevalence to BRSV in Norwegian cattle herds is high, but its role in epidemics of respiratory disease is unclear. The aims of the study were to investigate the etiological role of BRSV and other respiratory viruses in epidemics of BRD and to perform phylogenetic analysis of Norwegian BRSV strains. BRSV infection was detected either serologically and/or virologically in 18 (86%) of 21 outbreaks and in most cases as a single viral agent. When serology indicated that bovine coronavirus and/or bovine parainfluenza virus 3 were present, the number of BRSV positive animals in the herd was always higher, supporting the view of BRSV as the main pathogen. Sequencing of the G gene of BRSV positive samples showed that the current circulating Norwegian BRSVs belong to genetic subgroup II, along with other North European isolates. One isolate from an outbreak in Norway in 1976 was also investigated. This strain formed a separate branch in subgroup II, clearly different from the current Scandinavian sequences. The currently circulating BRSV could be divided into two different strains that were present in the same geographical area at the same time. The sequence variations between the two strains were in an antigenic important part of the G protein. The results demonstrated that BRSV is the most important etiological agent of epidemics of BRD in Norway and that it often acts as the only viral agent. The phylogenetic analysis of the Norwegian strains of BRSV and several previously published isolates supported the theory of geographical and temporal clustering of BRSV.


Platelet functional defects in women with unexplained menorrhagia.
Menorrhagia is a common clinical problem and is unexplained in more than 50% of women. Although studies suggest that von Willebrand's Disease (VWD) is found in a substantial number of women with unexplained menorrhagia, the prevalence of platelet defects in women with menorrhagia is unknown. To determine the prevalence of platelet and other hemostatic defects, we evaluated women ages 17-55 diagnosed with unexplained menorrhagia. Seventy-four women (52 white, 16 black, six other) were studied. Bleeding time was prolonged in 23 women (31.5%). Maximal percent platelet aggregation was decreased with one or more agonists in 35 (47.3%) women. The most commonly found platelet function defects were reduced aggregation responses to ristocetin in 22 women and to epinephrine in 16 women. Sixteen of 22 women with reduced ristocetin aggregation had von Willebrand ristocetin cofactor (VWF:RCo) and von Willebrand factor antigen (VWF:Ag) > 60%. Platelet ATP release was decreased with one or more agonists in 43 (58.1%) women. Of the black women studied, 11/16 (69%) had abnormal platelet aggregation studies compared with 20/52 white women (39%) (P = 0.06). Black women with menorrhagia had a higher prevalence of decreased platelet aggregation in response to ristocetin and epinephrine than did white women (P = 0.0075, P = 0.02). Ten women (13.5%) had VWF:RCo and/or VWF:Ag < 60%. Using race and blood group specific ranges, 5 (6.8%) women had decreased VWF:RCo, VWF:Ag and/or collagen binding (VWF:CB). Mild factor XI deficiency was found in two women and one woman with mild factor V deficiency and one hemophilia A carrier were identified. We conclude that the prevalence of platelet function defects and other inherited bleeding disorders is substantial in a multiracial US population of women with unexplained menorrhagia.


Ephrin-A1 promotes the malignant progression of intestinal tumors in Apc(min/+) mice.
The ephrin-A1 and EphA receptors are frequently highly expressed in different human cancers, suggesting that they may promote tumor development and progression. We generated transgenic mice carrying Fabpl(4xat-132) ephrin-A1, which express ephrin-A1 in the intestinal epithelial cells. Those mice were then mated with Apc(min/+) mice to produce the compound mice, which overexpress ephrin-A1 in the intestinal tumors of Apc(min/+) mice. We compared the number, size and histopathological features of the intestinal tumors in the Fabpl(4xat-132) ephrin-A1/Apc(min/+) compound mice with those of the Apc(min/+) mice. The compound mice showed an increased number of intestinal tumors, significantly in the large intestine, and developed more invasive tumors. Among the 20 mice of each type examined, 5 Apc(min/+) mice developed 5 invasive tumors, 1 invasive tumor in each mouse, in the proximal or middle portions of the small intestine. On the other hand, 14 out of 20 compound mice developed 29 invasive tumors and 16 of them were in the distal small intestine and the large intestine, where transgenic ephrin-A1 was highly expressed. These results suggested that the increased expression of ephrin-A1 accelerated the malignant progression of the intestinal adenoma to invasive tumors.


Submaximal endurance performance related to the ventilation thresholds.
This study was undertaken to compare the variance in time to fatigue (TF) at intensities expressed relative to VO2max, ventilation threshold 1 (VT1) or 2 (VT2). Two 3-min, 30 Watt incremental tests on the cycle ergometer were used to determine VO2max (50.7 +/- 7.2 ml X kg-1 X min-1), VT1 (51.7 +/- 3.7% VO2max) and VT2 (79.0 +/- 3.7% VO2max) for 16 subjects. At weekly intervals, subjects worked to volitional fatigue at 3 randomly-ordered power outputs that represented 73.1 +/- 2.8, 85.4 +/- 2.8 and 95.0 +/- 3.4% VO2max. A significant quadratic interaction was observed for TF values between VO2max and intensity, suggesting a different magnitude of response related to VO2max. Subject data were then grouped according to VO2max into a low (N = 5, 40-44 ml X kg-1 X min-1), medium (N = 5, 48-52 ml X kg-1 X min-1) or high (N = 6, 56-61 ml X kg-1 X min-1) category. For all groups, a decaying exponential function best described the relationship between TF and intensity. The method of expressing intensity appeared to have only a small effect on the proportion of variance explained by this logarithmic relationship (0.85 less than or equal to r2 less than or equal to 0.93). In contrast, however, a 30% reduction in the standard error of estimate for TF was observed when intensity was expressed relative to both ventilation thresholds as compared to the traditional expression of intensity relative to VO2max.(ABSTRACT TRUNCATED AT 250 WORDS)


A common molecular motif characterizes extracellular allosteric enhancers of GPCR aminergic receptors and suggests enhancer mechanism of action.
Several classes of compounds that have no intrinsic activity on aminergic systems nonetheless enhance the potency of aminergic receptor ligands three-fold or more while significantly increasing their duration of activity, preventing tachyphylaxis and reversing fade. Enhancer compounds include ascorbic acid, ethylenediaminetetraacetic acid, corticosteroids, opioid peptides, opiates and opiate antagonists. This paper provides the first review of aminergic enhancement, demonstrating that all enhancers have a common, inobvious molecular motif and work through a common mechanism that is manifested by three common characteristics. First, aminergic enhancers bind directly to the amines they enhance, suggesting that the common structural motif is reflected in common binding targets. Second, one common target is the first extracellular loop of aminergic receptors. Third, at least some enhancers are antiphosphodiesterases. These observations suggest that aminergic enhancers act on the extracellular surface of aminergic receptors to keep the receptor in its high affinity state, trapping the ligand inside the receptor. Enhancer binding produces allosteric modifications of the receptor structure that interfere with phosphorylation of the receptor, thereby inhibiting down-regulation of the receptor. The mechanism explains how enhancers potentiate aminergic activity and increase duration of activity and makes testable predictions about additional compounds that should act as aminergic enhancers.


Identification of osteoporosis using ensemble deep learning model with panoramic radiographs and clinical covariates.
Osteoporosis is becoming a global health issue due to increased life expectancy. However, it is difficult to detect in its early stages owing to a lack of discernible symptoms. Hence, screening for osteoporosis with widely used dental panoramic radiographs would be very cost-effective and useful. In this study, we investigate the use of deep learning to classify osteoporosis from dental panoramic radiographs. In addition, the effect of adding clinical covariate data to the radiographic images on the identification performance was assessed. For objective labeling, a dataset containing 778 images was collected from patients who underwent both skeletal-bone-mineral density measurement and dental panoramic radiography at a single general hospital between 2014 and 2020. Osteoporosis was assessed from the dental panoramic radiographs using convolutional neural network (CNN) models, including EfficientNet-b0, -b3, and -b7 and ResNet-18, -50, and -152. An ensemble model was also constructed with clinical covariates added to each CNN. The ensemble model exhibited improved performance on all metrics for all CNNs, especially accuracy and AUC. The results show that deep learning using CNN can accurately classify osteoporosis from dental panoramic radiographs. Furthermore, it was shown that the accuracy can be improved using an ensemble model with patient covariates.


Impaired insulin secretion and enhanced insulin sensitivity in cholecystokinin-deficient mice.
Cholecystokinin (CCK) is released in response to lipid intake and stimulates insulin secretion. We hypothesized that CCK deficiency would alter the regulation of insulin secretion and glucose homeostasis. We used quantitative magnetic resonance imaging to determine body composition and studied plasma glucose and insulin secretion of CCK gene knockout (CCK-KO) mice and their wild-type controls using intraperitoneal glucose and arginine infusions. The area of anti-insulin staining in pancreatic islets was measured by immunohistochemistry. Insulin sensitivity was assessed with euglycemic-hyperinsulemic clamps. CCK-KO mice fed a low-fat diet had a reduced acute insulin response to glucose but a normal response to arginine and normal glucose tolerance, associated with a trend toward greater insulin sensitivity. However, when fed a high-fat diet (HFD) for 10 weeks, CCK-KO mice developed glucose intolerance despite increased insulin sensitivity that was associated with low insulin secretion in response to both glucose and arginine. The deficiency of insulin secretion in CCK-KO mice was not associated with changes in β-cell or islet size. CCK is involved in regulating insulin secretion and glucose tolerance in mice eating an HFD. The impaired insulin response to intraperitoneal stimuli that do not typically elicit CCK release suggests that this hormone has chronic effects on β-cell adaptation to diet in addition to acute incretin actions.


Characteristics of Current Smokers versus Former Smokers with COPD and Their Associations with Smoking Cessation Within 4.5 Years: Results from COSYCONET.
Many patients with chronic obstructive pulmonary disease (COPD) continue smoking. We used data from the "real-life" COSYCONET COPD cohort to evaluate whether these patients differed from patients with COPD who either had ceased smoking prior to inclusion or ceased during the follow-up time of the study. The analysis was based on data from visits 1-5 (covering 4.5 years), including all patients with the diagnosis of COPD who were either ex-smokers or smokers and categorized as GOLD 1-4 or the former GOLD 0 category. We compared the characteristics of smokers and ex-smokers at baseline (visit 1), as well as the course of lung function in the follow-up of permanent ex-smokers, permanent smokers and incident ex-smokers (smokers at visit 1 who ceased smoking before visit 5). We also identified baseline factors associated with subsequent smoking cessation. Among 2500 patients who were ever-smokers, 660 were current smokers and 1840 ex-smokers at baseline. Smokers were younger than ex-smokers (mean 61.5 vs 66.0 y), had a longer duration of smoking but fewer pack-years, a lower frequency of asthma, higher forced expiratory volume in 1 sec (FEV1, 59.4 vs 55.2% predicted) and higher functional residual capacity (FRC, 147.7 vs 144.3% predicted). Similar results were obtained for the longitudinal subpopulation, comprising 713 permanent ex-smokers, 175 permanent smokers, and 55 incident ex-smokers. When analyzing the time course of lung function, higher FRC, lower FEV1 and the presence of asthma (p < 0.05 each) were associated with incident cessation prior to visit 5, while less airway obstruction was associated with smoking continuation. These findings, which were consistent in the cross-sectional and longitudinal analyses, suggest that lung hyperinflation was associated with being or becoming ex-smoker. Possibly, it is perceived by patients as one of the factors motivating their attempts to quit smoking, independent from airway obstruction.


Vascular birthmarks in children.
Several different systems of terminology for vascular birthmarks are defined using descriptive terms (capillary hemangioma, cavernous hemangioma, mixed hemangiomas, etc.) for consistency. Capillary hemangiomas have the most complete and rapid rate of resolution whereas cavernous hemangiomas are considerably slower to respond. Vascular lesions in the V1 distribution of the trigeminal nerve and in the lumbosacral area need imaging studies for presence of internal involvement. Vascular lesions that require systemic therapy are those that obstruct vision, airway, or genitourinary tract; and produce congestive heart failure or consumption of formed blood products. The various modalities of treatment including steroids, are discussed briefly.


A Mechanical Model to Interpret Cell-Scale Indentation Experiments on Plant Tissues in Terms of Cell Wall Elasticity and Turgor Pressure.
Morphogenesis in plants is directly linked to the mechanical elements of growing tissues, namely cell wall and inner cell pressure. Studies of these structural elements are now often performed using indentation methods such as atomic force microscopy. In these methods, a probe applies a force to the tissue surface at a subcellular scale and its displacement is monitored, yielding force-displacement curves that reflect tissue mechanics. However, the interpretation of these curves is challenging as they may depend not only on the cell probed, but also on neighboring cells, or even on the whole tissue. Here, we build a realistic three-dimensional model of the indentation of a flower bud using SOFA (Simulation Open Framework Architecture), in order to provide a framework for the analysis of force-displacement curves obtained experimentally. We find that the shape of indentation curves mostly depends on the ratio between cell pressure and wall modulus. Hysteresis in force-displacement curves can be accounted for by a viscoelastic behavior of the cell wall. We consider differences in elastic modulus between cell layers and we show that, according to the location of indentation and to the size of the probe, force-displacement curves are sensitive with different weights to the mechanical components of the two most external cell layers. Our results confirm most of the interpretations of previous experiments and provide a guide to future experimental work.


A crystal structure of the catalytic core domain of an avian sarcoma and leukemia virus integrase suggests an alternate dimeric assembly.
Integrase (IN) is an important therapeutic target in the search for anti-Human Immunodeficiency Virus (HIV) inhibitors. This enzyme is composed of three domains and is hard to crystallize in its full form. First structural results on IN were obtained on the catalytic core domain (CCD) of the avian Rous and Sarcoma Virus strain Schmidt-Ruppin A (RSV-A) and on the CCD of HIV-1 IN. A ribonuclease-H like motif was revealed as well as a dimeric interface stabilized by two pairs of α-helices (α1/α5, α5/α1). These structural features have been validated in other structures of IN CCDs. We have determined the crystal structure of the Rous-associated virus type-1 (RAV-1) IN CCD to 1.8 Å resolution. RAV-1 IN shows a standard activity for integration and its CCD differs in sequence from that of RSV-A by a single accessible residue in position 182 (substitution A182T). Surprisingly, the CCD of RAV-1 IN associates itself with an unexpected dimeric interface characterized by three pairs of α-helices (α3/α5, α1/α1, α5/α3). A182 is not involved in this novel interface, which results from a rigid body rearrangement of the protein at its α1, α3, α5 surface. A new basic groove that is suitable for single-stranded nucleic acid binding is observed at the surface of the dimer. We have subsequently determined the structure of the mutant A182T of RAV-1 IN CCD and obtained a RSV-A IN CCD-like structure with two pairs of buried α-helices at the interface. Our results suggest that the CCD of avian INs can dimerize in more than one state. Such flexibility can further explain the multifunctionality of retroviral INs, which beside integration of dsDNA are implicated in different steps of the retroviral cycle in presence of viral ssRNA.


Intralesional Therapy: Consensus Statements for Best Practices in Administration From the Melanoma Nursing Initiative .
Talimogene laherparepvec (T-VEC) is the first intralesional therapy for melanoma approved by the U.S. Food and Drug Administration. This oncolytic viral immunotherapy has improved outcomes for patients with locoregional recurrent melanoma and is showing promise in combination with systemic therapies. . This article aims to provide oncology nurses with expert guidance on best practices in incorporating intralesional therapy for patients diagnosed with melanoma in practice. . Members of the Melanoma Nursing Initiative explored issues related to administration of T-VEC in melanoma. The current literature and clinical experiences were reviewed. . The author offers a care step pathway (CSP) and commentary detailing best practices in infection control, drug storage, pharmacy interface, patient flow, space/staff allocation, patient education, and adverse event management with T-VEC. The CSP will help nurses improve patient outcomes and streamline the workflow with this novel therapeutic approach.


Recognition and recall in amnesics.
Although there is considerable agreement that performance in direct memory tasks (e.g., recall, recognition) is more disrupted by amnesia than performance in indirect memory tasks (e.g., mirror reading, word completion), one may be able to further circumscribe the deficit within the domain of direct memory tasks. The present article explores whether recall is disproportionately disrupted by amnesia compared to recognition. If amnesia affects memory uniformly across different direct memory measures, recall of normal controls should not differ from the recall of amnesics when recognition scores of these two groups are equated. On the other hand, if recall is disproportionately disrupted, normal recall should be superior to amnesic recall even when recognition is equated. The present study equated amnesic recognition with that of controls by providing amnesics with 8 s of study time and normal subjects with 0.5 s. Amnesics with Korsakoff's syndrome, amnesics with other etiologies, and appropriate controls were examined. Normal recall was superior to amnesic recall even when no differences were found in recognition. The results further specify the selective nature of amnesia.


Costing of three feeding regimens for home-based management of children with uncomplicated severe acute malnutrition from a randomised trial in India.
Three feeding regimens-centrally produced ready-to-use therapeutic food, locally produced ready-to-use therapeutic food, and augmented, energy-dense, home-prepared food-were provided in a community setting for children with severe acute malnutrition (SAM) in the age group of 6-59 months in an individually randomised multicentre trial that enrolled 906 children. Foods, counselling, feeding support and treatment for mild illnesses were provided until recovery or 16 weeks. Costs were estimated for 371 children enrolled in Delhi in a semiurban location after active survey and identification, enrolment, diagnosis and treatment for mild illnesses, and finally treatment with one of the three regimens, both under the research and government setting. Direct costs were estimated for human resources using a price times quantity approach, based on their salaries and average time taken for each activity. The cost per week per child for food, medicines and other consumables was estimated based on the total expenditure over the period and children covered. Indirect costs for programme management including training, transport, non-consumables, infrastructure and equipment were estimated per week per child based on total expenditures for research study and making suitable adjustments for estimations under government setting. No significant difference in costs was found across the three regimens per covered or per treated child. The average cost per treated child in the government setting was estimated at US$56 (<3500 rupees). Home-based management of SAM with a locally produced ready-to-use therapeutic food is feasible, acceptable, affordable and very cost-effective in terms of the disability-adjusted life years saved and gross national income per capita of the country. The treatment of SAM at home needs serious attention and integration into the existing health system, along with actions to prevent SAM. NCT01705769; Pre-results.


Defining the Threshold IL-2 Signal Required for Induction of Selective Treg Cell Responses Using Engineered IL-2 Muteins.
Among all T and NK cell subsets, regulatory T (Treg) cells typically respond to the lowest concentrations of IL-2 due to elevated surface expression of the IL-2R alpha chain (IL2RA; CD25) and the high affinity IL-2 receptor (IL-2R) complex. This enhanced sensitivity forms the basis for low-dose (LD) IL-2 therapy for the treatment of inflammatory diseases, where efficacy correlates with increased Treg cell number and expression of functional markers. Despite strong preclinical support for this approach, moderate and variable clinical efficacy has raised concerns that adequate Treg selectivity still cannot be achieved with LD IL-2, and/or that doses are too low to stimulate effective Treg-mediated suppression within tissues. This has prompted development of IL-2 variants with greater Treg selectivity, achieved through attenuated affinity for the signaling chains of the IL-2R complex (IL2RB or CD122 and IL2RG or CD132) and, consequently, greater reliance on high CD25 levels for full receptor binding and signaling. While certain IL-2 variants have advanced to the clinic, it remains unknown if the full range of IL-2R signaling potency and Treg-selectivity observed with low concentrations of wildtype IL-2 can be sufficiently recapitulated with attenuated IL-2 muteins at high concentrations. Using a panel of engineered IL-2 muteins, we investigated how a range of IL-2R signaling intensity, benchmarked by the degree of STAT5 phosphorylation, relates to biologically relevant Treg cell responses such as proliferation, lineage and phenotypic marker expression, and suppressor function. Our results demonstrate that a surprisingly wide dynamic range of IL-2R signaling intensity leads to productive biological responses in Treg cells, with negligible STAT5 phosphorylation associating with nearly complete downstream effects such as Treg proliferation and suppressor activity. Furthermore, we show with both in vitro and humanized mouse in vivo systems that different biological responses in Treg cells require different minimal IL-2R signaling thresholds. Our findings suggest that more than minimal IL-2R signaling, beyond that capable of driving Treg cell proliferation, may be required to fully enhance Treg cell stability and suppressor function in vivo.


The role of tubulointerstitial inflammation in the progression of chronic renal failure.
There is compelling evidence that interstitial inflammation plays a central role in the loss of renal function in chronic renal disease. The combined effects of interstitial inflammation, oxidative stress and local angiotensin II activity result in the disruption of glomerulus-tubule continuity, the development of pathogenic hypoxia, the generation of myofibroblasts and fibrosis, and the impairment of the protective autoregulation of glomerular blood flow that leads to glomerulosclerosis. The association between proteinuria and progression of chronic kidney disease is firmly established. Proximal tubular cells (PTC) exposed to high concentration of proteins produce proinflammatory and profibrotic factors. The activation of nuclear factor κB and the signal transducer and activator of transcription results in the upregulation of a variety of cytokines and chemokines, overexpression of adhesion molecules and interstitial infiltration of inflammatory cells. Fibrosis is promoted by release of transforming growth factor β, which induces myofibroblast formation and collagen deposition. Finally, the participation of vitamin D3 deficiency in the development of tubulointerstitial fibrosis is reviewed. The molecule 1,25-(OH)(2)D(3) modulates PTC proliferation, suppresses fibroblast activation and matrix production, reduces epithelial mesenchymal transition and downregulates the genes of the renin-angiotensin system, which are critical steps in the development of a scarred kidney.


Social Norms, Agency, and Marriage Aspirations in Malawi.
We evaluate whether community norms, caregiver beliefs, and adolescents' own beliefs and perceptions, focused on early marriage, predict adolescent marriage aspirations in a low-income context. The processes that contribute to adolescent marriage aspiration formation have received little attention in low-income contexts, particularly sub-Saharan Africa. Understanding how marriage aspirations are formed is important because they are associated with critical education and health outcomes. Using data that links Malawian adolescents (N=2,089) with their caregivers (N=1,452), we analyze gender stratified ordered logistic regression models to examine key relationships. We show that community norms for youngest acceptable marriage age predict when boys want to marry, but do not find conclusive evidence that they predict when girls want to marry. We also show that adolescents who believe it is acceptable to marry at an early age are more likely to want to marry early themselves. Both community norms and adolescents' own beliefs are central to the formation of their marriage aspirations. We recommend that programs incorporate adolescent beliefs and perceptions when designing child marriage interventions and measuring their impact. We also recommend theory-driven measurement of community norms to better evaluate their impact on both marriage aspirations and marriage age.


Altered Peak Knee Valgus during Jump-Landing among Various Directions in Basketball and Volleyball Athletes.
Excessive knee valgus during landing tasks is a contributing factor to knee injuries. Most studies have examined lower extremity biomechanics during the forward direction of a jump-landing task. Athletes perform many movements in the air and land in multi-directions. Therefore, the purpose of this study was to assess the peak knee valgus angle (PKVA) during one leg jump-landing in various directions. Eighteen male basketball and volleyball athletes participated in the study. Participants performed one leg jump-landing tests from a 30 cm height platform in four directions. Knee valgus motion was measured using Vicon™ motion system. The data were analyzed with repeated measures ANOVA. Direction significantly (P<0.001) influenced the PKVA during landing. Significantly higher PKVA was observed for the lateral (8.8°±4.7°) direction as compared to forward (5.8°±4.6°) direction (P<0.05). The PKVA in 30° diagonal (7.5°±4.6°) and 60° diagonal (7.7°±5.7°) directions was higher than in the forward direction (P<0.05). One leg jump-landing in lateral and diagonal directions results in a higher PKVA compared to landing in a forward direction and could lead to a higher risk of knee injury.


Activation of cdc42, rac, PAK, and rho-kinase in response to hepatocyte growth factor differentially regulates epithelial cell colony spreading and dissociation.
Hepatocyte growth factor (HGF), the ligand for the Met receptor tyrosine kinase, is a potent modulator of epithelial-mesenchymal transition and dispersal of epithelial cells, processes that play crucial roles in tumor development, invasion, and metastasis. Little is known about the Met-dependent proximal signals that regulate these events. We show that HGF stimulation of epithelial cells leads to activation of the Rho GTPases, Cdc42 and Rac, concomitant with the formation of filopodia and lamellipodia. Notably, HGF-dependent activation of Rac but not Cdc42 is dependent on phosphatidylinositol 3-kinase. Moreover, HGF-induced lamellipodia formation and cell spreading require phosphatidylinositol 3-kinase and are inhibited by dominant negative Cdc42 or Rac. HGF induces activation of the Cdc42/Rac-regulated p21-activated kinase (PAK) and c-Jun N-terminal kinase, and translocation of Rac, PAK, and Rho-dependent Rho-kinase to membrane ruffles. Use of dominant negative and activated mutants reveals an essential role for PAK but not Rho-kinase in HGF-induced epithelial cell spreading, whereas Rho-kinase activity is required for the formation of focal adhesions and stress fibers in response to HGF. We conclude that PAK and Rho-kinase play opposing roles in epithelial-mesenchymal transition induced by HGF, and provide new insight regarding the role of Cdc42 in these events.


Hypertensive hypokalemic disorders.
Hypokalemia is a common clinical problem. The kidney is responsible for long term potassium homoeostasis, as well as the serum potassium concentration. The main nephron site where K secretion is regulated is the cortical collecting duct, mainly via the effects of aldosterone. Aldosterone interacts with the mineralocorticoid receptor to increase sodium reabsorption and potassium secretion; the removal of cationic sodium makes the lumen relatively electronegative, thereby promoting passive potassium secretion from the tubular cell into the lumen through apical potassium channels. As a result, any condition that decreases the activity of renal potassium channels results in hyperkalemia (for example, amiloride intake or aldosterone deficiency) whereas their increased activity results in hypokalemia (for example, primary aldosteronism or Liddle's syndrome). The cause of hypokalemia can usually be determined from the history. If there is no apparent cause, the initial step is to see if hypokalemia is in associated with systemic hypertension or not. In the former group hypokalaemia is associated with a high mineralocorticoid effect or hyperactive sodium channel as in Liddle's syndrome. In hypertensive hypokalemic patients, measurement of the renin, aldosterone, and cortisol concentrations would be of help in differential diagnosis.


The relation of impaired vitamin A and E tolerance to fat absorption in biliary diversion.
Eleven patients have been studied after cholecystectomy with exploration of the common bile duct (CBD) and insertion of a T tube for free biliary drainage. Prior to clamping the T tube no significant rise was seen above fasting serum vitamin A and E, or serum triglyceride levels after 6 of the patients had been given these substances in a liquid test meal. In addition no rise in fasting vitamin E levels was seen after 3 subjects had been loaded for 4 days with 0.5 g DL alpha-tocopherol acetate/day. Faecal fat collections performed on 9 subjects indicated that over 70% of the ingested fat was absorbed. All these findings returned to normal when the T tube was clamped and the intraluminal flow of bile re-established. We conclude that deficiency of bile may allow the absorption of fat in the absence of fat soluble vitamins.


[Predictors of the patients' satisfaction with the quality of hospital-based medical care].
The paper reports results of sociological analysis of satisfaction of the patients with the medical care provided in in-patient facilities of Arkhangelsk and Vologda regions and Komi Republic. The authors distinguish three groups of factors (professional, organizational, informational) that determine the patients' content with the quality of medical services. The study revealed the generally low level of patients' satisfaction estimated based on selected criteria for medical aid and services.


The Structural Relationship Between Teacher Support and Willingness to Communicate: The Mediation of L2 Anxiety and the Moderation of Growth Language Mindset.
The important role of willingness to communicate (WTC) in facilitating second language (L2) learning and use has been widely endorsed. However, few studies have examined how teacher support in an L2 class may predict students' L2 WTC. Such a relationship may also be mediated by learners' L2 anxiety, a typical predictor of L2 WTC, and moderated by learners' beliefs about the malleability of their language learning ability, a construct known as growth language mindset. Framed from the Control-Value Theory (Pekrun, in Educ Psychol Rev 18(4):315-341, 2006) and the Language-Mindset Meaning System (Lou and Noels, in: Lamb, Csizér, Henry, Ryan (eds) The Palgrave handbook of motivation for language learning, Palgrave Macmillan, 2019a, System 86:102126, 2019b), this study aimed to investigate the relationships between teacher support, L2 anxiety, growth language mindset, and L2 WTC. The data were collected from 551 English-as-a-Foreign-Language (EFL) learners in Iran and analyzed using structural equation modeling (SEM). The results showed that teacher support was directly and positively associated with L2 WTC, and this relationship was significantly mediated by L2 anxiety. The relationship between teacher support and L2 WTC, however, was only significant among learners with medium and high levels of growth language mindset. In addition, growth language mindset also moderated the negative relationship between L2 anxiety and L2 WTC, with this relationship being weaker among learners with higher levels of growth language mindset. Finally, theoretical and pedagogical implications and directions for future research are presented.