[Critical thoughts on current laser surgery of the cornea].
To analyze critically refractive surgery of the cornea by excimer laser and to compare laser surgery with other methods of treatment of refractive errors of the eye. This analysis has to be restricted to a comparison of the treatment of myopia by keratotomy and photoablation with the ArF excimer laser. Correction of hypermetropia and of astigmatismus has to be left out, along with all the other methods to correct myopia, such as glasses, contact lenses, keratomileusis, epikeratoplasty, alloplastic implants, implantation of intraocular lenses with negative power, and replacement of the clear lens by an posterior chamber lens. The essential literature is screened. For intrastromal ablation with the picosecond Nd:YLF laser we relay on own experiences, also with the use of the ArF excimer laser we are not without own experiences. RESULTS AND STATEMENTS: For comparison of refractive surgery of the cornea not only the PERK study and the recommendations of the American Academy of Ophthalmology have to be considered, but also the newest developments in radial keratotomy such as two-step incision and reoperation with reopening of the keratotomy wounds. With these techniques the same precision can be reached as with the excimerlaser, and also higher myopias can be corrected. The dangers of the procedure, such as infection, perforation at surgery or laceration by contusion remain much larger. Intrastromal photoablation did not reach clinical maturity. Superficial photoablation is an almost safe procedure. A reduction of 3 D of myopia can be reached with satisfying precision, although higher myopias are still a problem. Pain following the ablation is considerable. Haze and disturbed vision at night can be present; infectious keratitis is rare, but possible. The critical fact of both procedures, keratotomy and photoablation with excimer laser, remains that healthy eyes are treated; therefore, even rare complications weigh much heavier than if sick eyes are treated. Because this is cosmetic surgery, the individuum asking for this type of procedure has to pay for on his own. Olson demands: "In determining when new technology is acceptable, we must consider the financial cost and the expected benefit to society. Is it an equitable tradeoff?" If we look at refractive surgery, especially laser photoablation, in the context of the needs for ophthalmic care of the whole world, then this type of surgery is out of proportion. The balance could be restored if, with every laser application, funds were given for third-world projects. Excimer-laser surgery may be justified insofar as the research with these lasers leads to useful therapeutic methods.


The efficacy of 5% dapsone gel plus oral isotretinoin versus oral isotretinoin alone in acne vulgaris: A randomized double-blind study.
Acne vulgaris, a common human skin condition, is an inflammatory disease characterized by comedones, papules, nodules and possibly scarring. This study aimed to evaluate the efficacy of a combination of 5% dapsone gel plus oral isotretinoin in the treatment of acne vulgaris. A randomized, placebo-controlled, study was carried out on patients with moderate to severe acne. The patients were randomly divided in two groups: (dapsone gel and vehicle gel). All Patients were administered oral isotretinoin 20 mg daily and topical gel twice a day for 8 weeks. The Global Acne Assessment Score (GAAS), the number lesions and side-effects were documented at base line and weeks 4, 8 and 12. A total of 58 patients (age range: 18-25 years) were included in our study. The number of lesions was significantly lower in the dapsone-treated group at all follow-up visits (P < 0.001). The mean GAAS score in the dapsone-treated group and in the Placebo-treated group decreased, but there was no statistical difference in two groups (P < 0.001). The side-effects on the dapsone-treated group were a mild burning sensation in 7 patients (24.13%), mild erythema of the skin and mild dryness in 4 (13.79%) and 3 (10.34%) cases respectively (P < 0.001). In our study, adverse effects were common but they were minor and tolerable. No clinically significant changes in laboratory parameters were observed (P < 0.001). Dapsone gel was an effective medication for patients who received isotretinoin for acne vulgaris treatment resulting in a significant reduction of the number of lesions.


A sensitive and affordable multiplex RT-qPCR assay for SARS-CoV-2 detection.
With the ongoing COVID-19 (Coronavirus Disease 2019) pandemic, caused by the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), there is a need for sensitive, specific, and affordable diagnostic tests to identify infected individuals, not all of whom are symptomatic. The most sensitive test involves the detection of viral RNA using RT-qPCR (quantitative reverse transcription PCR), with many commercial kits now available for this purpose. However, these are expensive, and supply of such kits in sufficient numbers cannot always be guaranteed. We therefore developed a multiplex assay using well-established SARS-CoV-2 targets alongside a human cellular control (RPP30) and a viral spike-in control (Phocine Herpes Virus 1 [PhHV-1]), which monitor sample quality and nucleic acid extraction efficiency, respectively. Here, we establish that this test performs as well as widely used commercial assays, but at substantially reduced cost. Furthermore, we demonstrate >1,000-fold variability in material routinely collected by combined nose and throat swabbing and establish a statistically significant correlation between the detected level of human and SARS-CoV-2 nucleic acids. The inclusion of the human control probe in our assay therefore provides a quantitative measure of sample quality that could help reduce false-negative rates. We demonstrate the feasibility of establishing a robust RT-qPCR assay at approximately 10% of the cost of equivalent commercial assays, which could benefit low-resource environments and make high-volume testing affordable.


Thrombosis in inflammatory bowel disease: are we tailoring prophylaxis to those most at risk?
Inflammatory bowel disease (IBD) is a disease-specific risk factor for incident and recurrent venous thromboembolism (VTE). The reasons are acquired, multifactorial, and related to prothrombotic aberrations during active disease, although the mechanisms remain incompletely elucidated. VTE represents a potentially life-threatening extraintestinal manifestation of IBD, but the associated morbidity and mortality can be reduced by appropriate use of thromboprophylaxis. Nevertheless, despite international guidelines advocating thromboprophylaxis in hospitalised patients with IBD, practice is highly variable, since 65% of gastroenterologists may not use pharmacological VTE prophylaxis in hospitalised patients with acute severe colitis. Furthermore, there is no guidance on appropriate prophylaxis for ambulatory outpatients with active disease who are at an appreciable risk of VTE. Thus the question: are we tailoring thromboprophylaxis to those patients with IBD who are most at risk?


Multimodal Randomized Functional MR Imaging of the Effects of Methylene Blue in the Human Brain.
Purpose To investigate the sustained-attention and memory-enhancing neural correlates of the oral administration of methylene blue in the healthy human brain. Materials and Methods The institutional review board approved this prospective, HIPAA-compliant, randomized, double-blinded, placebo-controlled clinical trial, and all patients provided informed consent. Twenty-six subjects (age range, 22-62 years) were enrolled. Functional magnetic resonance (MR) imaging was performed with a psychomotor vigilance task (sustained attention) and delayed match-to-sample tasks (short-term memory) before and 1 hour after administration of low-dose methylene blue or a placebo. Cerebrovascular reactivity effects were also measured with the carbon dioxide challenge, in which a 2 × 2 repeated-measures analysis of variance was performed with a drug (methylene blue vs placebo) and time (before vs after administration of the drug) as factors to assess drug × time between group interactions. Multiple comparison correction was applied, with cluster-corrected P < .05 indicating a significant difference. Results Administration of methylene blue increased response in the bilateral insular cortex during a psychomotor vigilance task (Z = 2.9-3.4, P = .01-.008) and functional MR imaging response during a short-term memory task involving the prefrontal, parietal, and occipital cortex (Z = 2.9-4.2, P = .03-.0003). Methylene blue was also associated with a 7% increase in correct responses during memory retrieval (P = .01). Conclusion Low-dose methylene blue can increase functional MR imaging activity during sustained attention and short-term memory tasks and enhance memory retrieval. © RSNA, 2016 Online supplemental material is available for this article.


Performance and impact of disposable and reusable respirators for healthcare workers during pandemic respiratory disease: a rapid evidence review.
To synthesise evidence concerning the range of filtering respirators suitable for patient care and guide the selection and use of different respirator types. Comparative analysis of international standards for respirators and rapid review of their performance and impact in healthcare. Websites of international standards organisations, Medline and Embase, hand-searching of references and citations. Studies of healthcare workers (including students) using disposable or reusable respirators with a range of designs. We examined respirator performance, clinician adherence and performance, comfort and impact, and perceptions of use. We included standards from eight authorities across Europe, North and South America, Asia and Australasia and 39 research studies. There were four main findings. First, international standards for respirators apply across workplace settings and are broadly comparable across jurisdictions. Second, effective and safe respirator use depends on proper fitting and fit testing. Third, all respirator types carry a burden to the user of discomfort and interference with communication which may limit their safe use over long periods; studies suggest that they have little impact on specific clinical skills in the short term but there is limited evidence on the impact of prolonged wearing. Finally, some clinical activities, particularly chest compressions, reduce the performance of filtering facepiece respirators. A wide range of respirator types and models is available for use in patient care during respiratory pandemics. Careful consideration of performance and impact of respirators is needed to maximise protection of healthcare workers and minimise disruption to care.


Effects of 1α,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells.
There is evidence from epidemiological and in vitro studies that the biological effects of testosterone (T) on cell cycle and survival are modulated by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in prostate cancer. To investigate the cross talk between androgen- and vitamin D-mediated intracellular signaling pathways, the individual and combined effects of T and 1,25(OH)2D3 on global gene expression in LNCaP prostate cancer cells were assessed. Stringent statistical analysis identifies a cohort of genes that lack one or both androgen response elements (AREs) or vitamin D response elements (VDREs) in their promoters, which are nevertheless differentially regulated by both steroids (either additively or synergistically). This suggests that mechanisms in addition to VDR- and AR-mediated transcription are responsible for the modulation of gene expression. Microarray analysis shows that fifteen miRNAs are also differentially regulated by 1,25(OH)2D3 and T. Among these miR-22, miR-29ab, miR-134, miR-1207-5p and miR-371-5p are up regulated, while miR-17 and miR-20a, members of the miR-17/92 cluster are down regulated. A number of genes implicated in cell cycle progression, lipid synthesis and accumulation and calcium homeostasis are among the mRNA targets of these miRNAs. Thus, in addition to their well characterized effects on transcription, mediated by either or both cognate nuclear receptors, 1,25(OH)2D3 and T regulate the steady state mRNA levels by modulating miRNA-mediated mRNA degradation, generating attenuation feedback loops that result in global changes in mRNA and protein levels. Changes in genes involved in calcium homeostasis may have specific clinical importance since the second messenger Ca2+ is known to modulate various cellular processes, including cell proliferation, cell death and cell motility, which affects prostate cancer tumor progression and responsiveness to therapy. These data indicate that these two hormones combine to drive a differentiated phenotype, and reinforce the idea that the age dependent decline in both hormones results in the de-differentiation of prostate tumor cells, which results in increased proliferation, motility and invasion common to aggressive tumors. These studies also reinforce the potential importance of miRNAs in prostate cancer progression and therapeutic outcomes.


Treatment of iron deficiency anemia with intravenous iron preparations.
We aimed to determine the effects of intravenous iron therapy on blood parameters in pediatric patients who do not tolerate oral iron therapy for any reason. The patient group consisted of candidates for elective operations requiring blood transfusions in order to raise hemoglobin (Hb) concentrations rapidly and for whom oral iron administration is useless and compliance with long-term treatment is definitely impossible due to sociocultural factors. Sixty-two children were included in the study. Venous blood samples were taken at diagnosis, and after 1 week and 1, 2 and 3 months. Hb, hematocrit, erythrocyte indices (mean erythrocyte volume, mean erythrocyte Hb and mean erythrocyte Hb concentration), serum iron (SI) levels, iron binding capacity, transferrin receptor (CD71) and serum ferritin levels were measured. Iron sucrose was used as an intravenous iron preparation. All children showed improvements in iron deficiency anemia. A statistically significant elevation occurred between the time of diagnosis and week 1 (p<0.05) in nearly all parameters. SI was raised until at least 1 month of therapy. There was no significant difference between transferrin receptors measured before and after the intravenous iron therapy. Ferritin did not exceed the values achieved in the 1st month. Mild side effects were encountered in only 8 (12.9%) patients. Treatment was not discontinued because of side effects in any case. The patients in the control group were given an oral form containing ferroglycine sulfate. Intravenous iron therapy can replace oral therapy in patients whose blood parameters must be raised rapidly and in situations where oral iron administration would not be appropriate for any reason. However, reinforcement with oral iron therapy or additional intravenous doses would be appropriate.


Lost productivity among military personnel with cardiovascular disease.
Cardiovascular disease (CVD) is associated with significant productivity loss among all occupational groups. However, the increased occupational requirements of military personnel pose physical and psychological demands that could lead to greater lost productivity of CVD. The aim of this study was to determine the economic cost of lost productivity of military patients with CVD. A prospective cross-sectional study was undertaken on all military patients attending a specialist CVD clinic in Tehran, Iran. All participants were interviewed using face-to-face questioning using a Valuation of Lost Productivity questionnaire. Data captured included paid and unpaid time lost due to CVD, military job characteristics and their work environment. Ordered logistic regression was used to examine the determinants of lost productivity. The mean time of lost productivity was 118 hours over a 3-month period, of which 70 and 48 hours were paid and unpaid work, respectively. The average cost per patient of total lost productivity was estimated to be US$303 over a 3-month period. CVDs are associated with significant lost productivity among military personnel. There is a statistically significant relation between some military occupation characteristics and lost productivity from CVD. Level of income, teamwork and physical activity have the greatest effects on lost productivity. Military workers who were suffering from other chronic conditions (in addition to CVD) were four times more likely to lose productivity. A supportive work environment should be created for military personnel with emphasis on developing teamwork, improving worker's attitudes towards disease and giving priority to workers with comorbidities.


Response inhibition in pedophilia: an FMRI pilot study.
The failure to inhibit pleasurable but inappropriate urges is associated with frontal lobe pathology and has been suggested as a possible cause of pedophilic behavior. However, imaging and neuropsychological findings about frontal pathology in pedophilia are heterogeneous. In our study we therefore address inhibition behaviorally and by means of functional imaging, aiming to assess how inhibition in pedophilia is related to a differential recruitment of frontal brain areas. Eleven pedophilic subjects and 7 nonpedophilic controls underwent fMRI while performing a go/no-go task composed of neutral letters. Pedophilic subjects showed a slower reaction time and less accurate visual target discrimination. fMRI voxel-level ANOVA revealed as a main effect of the go/no-go task an activation of prefrontal and parietal brain regions in the no-go condition, while the left anterior cingulate, precuneus and gyrus angularis became more activated in the go condition. In addition, a group × task interaction was found in the left precuneus and gyrus angularis. This interaction was based on an attenuated deactivation of these brain regions in the pedophilic group during performance of the no-go condition. The positive correlation between blood oxygen level-dependent imaging signal and reaction time in these brain areas indicates that attenuated deactivation is related to the behavioral findings. Slower reaction time and less accurate visual target discrimination in pedophilia was accompanied by attenuated deactivation of brain areas belonging to the default mode network. Our findings thus support the notion that behavioral differences might also derive from self-related processes and not necessarily from frontal lobe pathology.


First Report of Powdery Mildew Caused by Golovinomyces asterum var. solidaginis on Invasive Weed Solidago gigantea in Korea.
Solidago gigantea Aiton (syn. S. serotina Aiton), known as giant goldenrod, is native to North America and has been invasive in Europe and Asia. In Korea, this plant was accidentally introduced around the 1960s and has become widely naturalized by replacing indigenous plants and disrupting the native ecosystem (3). In October 2012, hundreds of giant goldenrod plants growing wild in riverine areas and roadsides were found affected by a powdery mildew in Busan, Korea. Voucher specimens were deposited in the Korea University Herbarium (KUS). Symptoms first appeared as circular to irregular white patches, which subsequently showed abundant hyphal growth on both sides of the leaves. Appressoria on the mycelium were nipple-shaped to moderately lobed. Conidiophores measured 120 to 240 × 10 to 12.5 μm, were arising laterally from hyphal mother cells, and produced 2 to 6 immature conidia in chains with a sinuate outline, followed by 2 to 3 cells. Foot-cells in conidiophores were 42 to 70 μm long and characterized by a distinctly curved base. Conidia were hyaline, ellipsoid to ovate, measured 28 to 42 × 17 to 24 μm (length/width ratio = 1.4 to 2.1), contained small oil drops, lacked distinct fibrosin bodies, and produced germ tubes on the subterminal position. No chasmothecia were observed. The morphological characteristics described above were typical of the Euoidium type anamorph of the genus Golovinomyces, and the fungus measurements and structures were consistent with those of G. asterum var. solidaginis U. Braun (1). To confirm the identity of the causal fungus, the complete ITS region of rDNA from isolate KUS-F27219 was amplified with primers ITS5 and P3 (4) and sequenced. The resulting 508-bp sequence was deposited in GenBank (Accession No. KC513763). A GenBank BLAST search of this sequence revealed >99% similarity with the ITS sequences of G. cichoracearum from Australia (GQ183940 ex Solidago sp.) and Japan (AB077625 ex S. altissima L. and AB077627 ex S. virgaurea subsp. asiatica Kitam. ex Hara). The G. cichoracearum isolates on Solidago spp. listed above are now placed in G. asterum var. solidaginis (1). Pathogenicity was confirmed through inoculation by gently pressing diseased leaves onto leaves of five healthy potted giant goldenrods. Five non-inoculated plants served as controls. Plants were maintained in a greenhouse at 24 to 30°C. Inoculated plants developed signs and symptoms after 7 days, whereas the control plants remained symptomless. The fungus present on inoculated plants was morphologically identical to that originally observed, fulfilling Koch's postulates. Association of S. gigantea with Golovinomyces powdery mildews has been known in North America, South America, Europe, New Zealand, Central Asia (Iran, Kazakhstan, and Kyrgyzstan), and Japan (2). To our knowledge, this is the first report of powdery mildew caused by G. asterum var. solidaginis on S. gigantea in Korea. Our field observations suggest that the powdery mildew could be a limiting factor to suppress the expansion of this invasive weed in Korea. References: (1) U. Braun and R. T. A. Cook. Taxonomic Manual of the Erysiphales (Powdery Mildews), CBS Biodiversity Series No.11. CBS, Utrecht, 2012. (2) D. F. Farr and A. Y. Rossman. Fungal Databases. Syst. Mycol. Microbiol. Lab., Online publication, ARS, USDA, retrieved January 22, 2013. (3) S. M. Oh et al. Kor. J. Weed Sci. 22:280, 2002. (4) S. Takamatsu et al. Mycol. Res. 113:117, 2009.


Self-management for adult patients with cancer: an integrative review.
Individuals with cancer are surviving long term, categorizing cancer as a chronic condition, and with it, numerous healthcare challenges. Symptoms, in particular, can be burdensome and occur from prediagnosis through many years after treatment. Symptom severity is inversely associated with functional status and quality of life. Management of these millions of survivors of cancer in a stressed healthcare system necessitates effective self-care strategies. The purpose of this integrative review is to evaluate intervention studies led by nurse principal investigators for self-care management in patients with cancer. PubMed, CINAHL (Cumulative Index to Nursing and Allied health Literature), and the Cochrane Database were searched from January 2000 through August 2012. Search terms included "symptom management and cancer," "self-management and cancer," and "self-care and cancer." All articles for consideration included intervention studies with a nurse as the primary principal investigator. Forty-six articles were included yielding 3 intervention areas of educational and/or counseling sessions, exercise, and complementary and alternative therapies. Outcomes were predominately symptom focused and often included functional status and quality of life. Few studies had objective measures. Overarching themes were mitigation, but not prevention or elimination of symptoms, and improved quality of life related to functional status. No one intervention was superior to another for any given outcome. Current interventions that direct patients in self-care management of symptoms and associated challenges with cancer/survivorship are helpful, but incomplete. No one intervention can be recommended over another. Guiding patients with cancer in self-care management is important for overall functional status and quality of life. Further investigation and tailored interventions are warranted.


Same clock, different time read-out: Spontaneous brain oscillations and their relationship to deficient coding of cognitive content.
Neuronal oscillations provide an efficient means of communication, fostering functional neural states supporting action and reaction. High in the action hierarchy, cognitive abilities are severely compromised in neuropsychiatric disease such as schizophrenia. Current thinking highlights a clocking mechanism provided by the phase of an ongoing slow oscillation that offers a temporal frame for coding of perceptual and computational elements. Yet unclear is whether and how a dysregulated clocking mechanism accounts for diminished cognitive performance. Neuromagnetic oscillatory activity was related to cognitive performance assessed by the MATRICS Consensus Cognitive Battery in 58 healthy individuals (HC) and 46 schizophrenia patients (SZ). HC showed a correlation between gamma-band oscillations (>40 Hz) and working memory performance. This relationship was disrupted in several ways in SZ. First, patients evidenced lower gamma power, poorer working memory performance, and no relationship between these measures. Second, the power spectra were dominated by ~10 Hz alpha oscillations with no group differences in amplitude. However, analysis of phase-to-amplitude coupling (PAC) revealed exaggerated clocking of gamma activity by alpha phase in SZ, associated with poor working memory performance. Third, despite entrainment by the same 10 Hz clock, gamma amplitude was abnormally distributed across the duty cycle in SZ, a potential consequence of compromised interneuron inhibition. Fourth, SZ showed over-engagement of a fronto-parietal network measured by gamma phase coherence, suggesting a brain state hindering cognitive output. Such an endogenous temporal organization may be a core dysfunction in SZ: a segregation/integration input imbalance fostering reduced cognitive performance and compromised behavioral output.


Not All Flavor Expertise Is Equal: The Language of Wine and Coffee Experts.
People in Western cultures are poor at naming smells and flavors. However, for wine and coffee experts, describing smells and flavors is part of their daily routine. So are experts better than lay people at conveying smells and flavors in language? If smells and flavors are more easily linguistically expressed by experts, or more "codable", then experts should be better than novices at describing smells and flavors. If experts are indeed better, we can also ask how general this advantage is: do experts show higher codability only for smells and flavors they are expert in (i.e., wine experts for wine and coffee experts for coffee) or is their linguistic dexterity more general? To address these questions, wine experts, coffee experts, and novices were asked to describe the smell and flavor of wines, coffees, everyday odors, and basic tastes. The resulting descriptions were compared on a number of measures. We found expertise endows a modest advantage in smell and flavor naming. Wine experts showed more consistency in how they described wine smells and flavors than coffee experts, and novices; but coffee experts were not more consistent for coffee descriptions. Neither expert group was any more accurate at identifying everyday smells or tastes. Interestingly, both wine and coffee experts tended to use more source-based terms (e.g., vanilla) in descriptions of their own area of expertise whereas novices tended to use more evaluative terms (e.g., nice). However, the overall linguistic strategies for both groups were en par. To conclude, experts only have a limited, domain-specific advantage when communicating about smells and flavors. The ability to communicate about smells and flavors is a matter not only of perceptual training, but specific linguistic training too.


Smoking and the Five-Factor Model of personality.
Investigating the association between personality traits and smoking status using a comprehensive model of personality, the Five-Factor Model (FFM). Cross-sectional survey. Setting Baltimore, MD, USA. Participants Adult elderly Americans (n = 1638). A self-administered survey on cigarette smoking and the Revised NEO Personality Inventory (NEO-PI-R). Current smokers scored higher than never smokers on neuroticism and lower on agreeableness and conscientiousness; former smokers scored intermediate on these higher-order dimensions. Neuroticism was related to smoking particularly among individuals with low conscientiousness, as indicated by an interaction effect between the two factors. There were no differences on extraversion and openness to experience. At the lower-order facet level, smokers were characterized by inability to resist cravings (high impulsiveness), search for stimulation (high excitement-seeking), lack of perseverance (low self-discipline) and lack of careful consideration of the consequences of their actions (low deliberation). At the higher-order factor level, this study replicates and extends previous studies using a comprehensive model of personality (FFM). The greater specificity provided by the facet-level analysis appears to explain some of the conflicting results in the literature, and the use of an older sample provides insight especially into the former smokers group. Personality research may lead to a deeper understanding of cigarette smoking and can potentially contribute to policies and programs of smoking prevention and cessation.


SpZ12-1, a negative regulator required for spatial control of the territory-specific CyIIIa gene in the sea urchin embryo.
The CyIIIa cytoskeletal actin gene of the sea urchin Strongylocentrotus purpuratus is activated in late cleavage and expressed exclusively in the aboral ectoderm territory of the embryo. Previous gene transfer studies defined a 2.3 kb cis-regulatory region that is necessary and sufficient for correct temporal and spatial expression of a CyIIIa.CAT fusion gene. In this paper, a negative regulatory element within this region was identified that is required for repression of the CyIIIa gene in skeletogenic mesenchyme cells. The repression mediated by this regulatory element takes place after initial territorial specification. A cDNA clone encoding a DNA-binding protein with twelve Zn fingers (SpZ12-1) was isolated by probing an expression library with this cis-element. Deletion analysis of the SpZ12-1 protein confirmed that a DNA-binding domain is located within the Zn finger region. SpZ12-1 is the only DNA-binding protein in embryo nuclear extract that interacts with the specific cis-target sites required for repression of CyIIIa.CAT in skeletogenic mesenchyme and is likely to be the trans factor that mediates this repression.


[Primary congenital glaucoma].
Primary congenital glaucoma (PCG) is a rare genetic disease usually diagnosed during the first year of life. It occurs because of developmental anomalies of the chamber angle that prevents drainage of aqueous humor, thereby elevating intraocular pressure. Its incidence is 1 in 10,000 live newborns in Western societies and 1 in 1,200 live newborns in the Arab-Bedouin population of the Negev region in Israel. Most cases of PCG appear to be sporadic. The cytochrome P4501B1 gene located within the GLC3A locus on chromosome 2p21 is mutated in individuals with PCG. The triad of epiphora, photophobia, and blepharospasm is classical for PCG. General anesthesia is usually required for an adequate examination of intraocular pressure, corneal diameter, optic disc, and axial length in young children. Congenital glaucoma is almost always managed surgically, with medical therapy being used only as a temporizing measure before surgery or when surgical intervention has repeatedly failed. At least 50% of eyes with PCG presenting at birth will become legally blind (visual acuity < 6/60). Patients with PCG require follow-up examinations throughout their lives.


Beyond antidoping and harm minimisation: a stakeholder-corporate social responsibility approach to drug control for sport.
Debate about the ethics of drug control in sport has largely focused on arguing the relative merits of the existing antidoping policy or the adoption of a health-based harm minimisation approach. A number of ethical challenges arising from antidoping have been identified, and a number of, as yet, unanswered questions remain for the maturing ethics of applying harm minimisation principles to drug control for sport. This paper introduces a 'third approach' to the debate, examining some implications of applying a stakeholder theory of corporate social responsibility (CSR) to the issue of doping in sport. The introduction of the stakeholder-CSR model creates an opportunity to challenge the two dominant schools by enabling a different perspective to contribute to the development of an ethically robust drug control for sport.


A class III histidine kinase acts as a novel virulence factor in Botrytis cinerea.
Filamentous ascomycetes contain large numbers of histidine kinases (HK) that belong to eleven classes. Members of class III from different species were previously shown to be involved in osmoregulation and resistance to dicarboximide and phenylpyrrole fungicides. We have inactivated the gene encoding the single group III HK, BOS1, in the economically important plant pathogen Botrytis cinerea. BOS1 inactivation had pleiotropic effects on the fungus. Besides the expected osmosensitivity and resistance to fungicides, null mutants presented additional characteristics indicating that BOS1 is necessary for normal macroconidiation and full virulence. On standard culture media, null mutants very rarely formed conidiophores and those few conidiophores failed to produce conidia. This defect could be partially restored with 1 M sorbitol, suggesting that another BOS1-independent signal cascade may be involved in macroconidiation. The mutants were not found to be hypersensitive to various oxidative stresses but were more resistant to menadione. Finally, pathogenicity tests showed that bos1-null mutants were significantly reduced in the ability to infect host plants. Appressorium morphogenesis was not altered; however, in planta growth was severely reduced. To our knowledge, this is the first class III HK characterized as a pathogenicity factor in a plant-pathogenic ascomycete.


Chronic treatment with tetrahydrobiopterin reverses endothelial dysfunction and oxidative stress in hypercholesterolaemia.
Reduced availability of tetrahydrobiopterin (BH(4)), an essential cofactor of nitric oxide (NO) synthase (NOS), decreases NO production and increases reactive oxygen species. Both mechanisms contribute to atherosclerotic vascular disease. Although acute supplementation of BH(4) improves endothelial dysfunction, the effect of chronic BH(4) in humans is unknown. To investigate the effect of chronic BH(4) supplementation on endothelial function and oxidative stress in hypercholesterolaemia. Randomised double-blind, placebo-controlled trial. University Hospital. 22 hypercholesterolaemic patients (low-density lipoprotein (LDL) >4.5 mmol/l) were randomised to 4 weeks of oral BH(4) (400 mg twice daily) or placebo. Age-matched healthy volunteers served as controls. Endothelium-dependent and -independent vasodilatation was assessed by venous occlusion plethysmography. To elucidate the mechanisms of BH(4) effect, NO release and superoxide anion (O(2)(-)) production were measured in human aortic endothelial cells exposed to native LDL (2.6 mmol cholesterol/l). BH(4) plasma levels were significantly increased by oral supplementation. NO-mediated vasodilatation to acetylcholine was reduced in patients compared with controls and restored by BH(4). No effect of BH(4) on endothelium-independent vasodilatation was seen. Furthermore, 8-F(2 )isoprostane plasma levels, a marker of vascular oxidative stress, were reduced by BH(4). In LDL-treated endothelial cells, BH(4) levels and NO release were reduced and O(2)(-) production increased compared with control cells. Exogenous BH(4) normalised NO and O(2)(-) production. In hypercholesterolaemia, endothelial dysfunction and oxidative stress can be reversed by chronic oral treatment with BH(4). Thus, BH(4) availability is essential for maintaining NO synthesis and low O(2)(-) production by endothelial NOS in vivo, and may provide a rational therapeutic approach to prevent cardiovascular disease.


Biomolecular imaging of 13C-butyrate with dissolution-DNP: Polarization enhancement and formulation for in vivo studies.
Magnetic Resonance Spectroscopy of hyperpolarized isotopically enriched molecules facilitates the non-invasive real-time investigation of in vivo tissue metabolism in the time-frame of a few minutes; this opens up a new avenue in the development of biomolecular probes. Dissolution Dynamic Nuclear Polarization is a hyperpolarization technique yielding a more than four orders of magnitude increase in the 13C polarization for in vivo Magnetic Resonance Spectroscopy studies. As reported in several studies, the dissolution Dynamic Nuclear Polarization polarization performance relies on the chemico-physical properties of the sample. In this study, we describe and quantify the effects of the different sample components on the dissolution Dynamic Nuclear Polarization performance of [1-13C]butyrate. In particular, we focus on the polarization enhancement provided by the incremental addition of the glassy agent dimethyl sulfoxide and gadolinium chelate to the formulation. Finally, preliminary results obtained after injection in healthy rats are also reported, showing the feasibility of an in vivo Magnetic Resonance Spectroscopy study with hyperpolarized [1-13C]butyrate using a 3T clinical set-up.


Assessment of shear stress related parameters in the carotid bifurcation using mouse-specific FSI simulations.
The ApoE(-)(/)(-) mouse is a common small animal model to study atherosclerosis, an inflammatory disease of the large and medium sized arteries such as the carotid artery. It is generally accepted that the wall shear stress, induced by the blood flow, plays a key role in the onset of this disease. Wall shear stress, however, is difficult to derive from direct in vivo measurements, particularly in mice. In this study, we integrated in vivo imaging (micro-Computed Tomography-µCT and ultrasound) and fluid-structure interaction (FSI) modeling for the mouse-specific assessment of carotid hemodynamics and wall shear stress. Results were provided for 8 carotid bifurcations of 4 ApoE(-)(/)(-) mice. We demonstrated that accounting for the carotid elasticity leads to more realistic flow waveforms over the complete domain of the model due to volume buffering capacity in systole. The 8 simulated cases showed fairly consistent spatial distribution maps of time-averaged wall shear stress (TAWSS) and relative residence time (RRT). Zones with reduced TAWSS and elevated RRT, potential indicators of atherosclerosis-prone regions, were located mainly at the outer sinus of the external carotid artery. In contrast to human carotid hemodynamics, no flow recirculation could be observed in the carotid bifurcation region.


Clinical Benefits of Indocyanine Green Fluorescence in Robot-Assisted Partial Nephrectomy.
Background: To compare the intraoperative and postoperative outcomes of indocyanine green (ICG) administration in robot-assisted partial nephrectomy (RAPN) and report the differences in the results between patients with benign and malignant renal tumors. Methods: From 2017 to 2020, 132 patients underwent RAPN at our institution, including 21 patients with ICG administration. Clinical data obtained from our institution's RAPN database were retrospectively reviewed. Intraoperative, postoperative, pathological, and functional outcomes of RAPN were assessed. Results: The pathological results indicated that among the 127 patients, 38 and 89 had received diagnoses of benign and malignant tumors, respectively. A longer operative time (311 vs. 271 min; p = 0.006) but superior preservation of estimated glomerular filtration rate (eGFR) at 3-month follow-up (90% vs. 85%; p = 0.031) were observed in the ICG-RAPN group. Less estimated blood loss, shorter warm ischemia time, and superior preservation of eGFR at postoperative day 1 and 6-month follow-up were also noted, despite no significant differences. Among the patients with malignant tumors, less estimated blood loss (30 vs. 100 mL; p < 0.001) was reported in the ICG-RAPN subgroup. Conclusions: Patients with ICG-RAPN exhibited superior short-term renal function outcomes compared with the standard RAPN group. Of the patients with malignant tumors, ICG-RAPN was associated with less blood loss than standard RAPN without a more positive margin rate. Further studies with larger cohorts and prospective designs are necessary to verify the intraoperative and functional advantages of the green dye.


Hierarchical Nearest-Neighbor Gaussian Process Models for Large Geostatistical Datasets.
Spatial process models for analyzing geostatistical data entail computations that become prohibitive as the number of spatial locations become large. This article develops a class of highly scalable nearest-neighbor Gaussian process (NNGP) models to provide fully model-based inference for large geostatistical datasets. We establish that the NNGP is a well-defined spatial process providing legitimate finite-dimensional Gaussian densities with sparse precision matrices. We embed the NNGP as a sparsity-inducing prior within a rich hierarchical modeling framework and outline how computationally efficient Markov chain Monte Carlo (MCMC) algorithms can be executed without storing or decomposing large matrices. The floating point operations (flops) per iteration of this algorithm is linear in the number of spatial locations, thereby rendering substantial scalability. We illustrate the computational and inferential benefits of the NNGP over competing methods using simulation studies and also analyze forest biomass from a massive U.S. Forest Inventory dataset at a scale that precludes alternative dimension-reducing methods. Supplementary materials for this article are available online.


Dissociation of sympathetic nervous system and adrenal medullary responses.
The relative importance of sympathetic nerve (SNS) activity and adrenal medullary secretion in various physiological situations has generally been inferred from measurements of norepinephrine (NE) and epinephrine (E), respectively, in urine or plasma. Increasing evidence, however, indicates that under certain conditions the adrenal medulla may release substantial amounts of NE as well as E. In several of these circumstances, estimates of SNS activity based on the measurement of NE turnover in peripheral tissues of experimental animals indicate diminished SNS function, a reduction that is independent of adrenal medullary secretion. These reciprocal alterations in SNS and adrenal medullary activity fall into two patterns. First, when SNS activity is suppressed by fasting, adrenal medullary responses to various stimuli are enhanced. Second, for certain stimuli the SNS response is biphasic, with an initial suppression followed by subsequent stimulation; during the first phase adrenal medullary secretion is markedly increased. The physiological contribution of the adrenal medulla, therefore, would be particularly important under conditions of SNS suppression.


The pediatric resuscitative thoracotomy during combat operations in Iraq and Afghanistan - A retrospective cohort study.
Combat zone trauma poses a unique set of challenges and injury patterns not seen in the civilian setting. The role of the pediatric resuscitative thoracotomy in combat zones remains unclear given a paucity of data regarding procedure outcomes in this setting. We compare outcomes among children in traumatic arrest undergoing resuscitative thoracotomy versus cardiopulmonary (CPR) resuscitation only. We queried the Department of Defense Trauma Registry (DODTR) from 2007 to 2016 for all pediatric subjects that underwent a resuscitative thoracotomy or CPR in the prehospital or emergency department setting during operations in Iraq or Afghanistan. We removed CPR subjects with mechanisms of injury not matched in the thoracotomy cohort. During the study period, there were 3439 pediatric encounters. We identified 13 subjects who underwent a resuscitative thoracotomy and 66 subjects who underwent CPR without thoracotomy with matching mechanisms of injury. When comparing the two cohorts those in the thoracotomy group had higher median thorax body region scores (median 3 versus 0, p = .001), but a trend towards higher rates of survival to discharge (31% versus 9%, p = .108). The youngest survivor in the thoracotomy cohort was less than 1 year old. We observed a trend towards higher survival among subjects that underwent a resuscitative thoracotomy survived to hospital discharge compared to subjects undergoing CPR without thoracotomy. The literature will benefit from further data to confirm an association between this procedure and a survival benefit among pediatric subjects in the resource limited setting. Furthermore, improvements in documentation will guide equipping and training providers expected to care for pediatric trauma patients.


Valine-based biphenylsulphonamide matrix metalloproteinase inhibitors as tumor imaging agents.
Among matrix metalloproteinases (MMPs), the subfamily of gelatinases (MMP-2, MMP-9) is of particular interest due to their ability to degrade type IV collagen and other non-fibrillar collagen domains and proteins such as fibronectin and laminin. Whilst malignant cells often over-express various MMPs, the gelatinases have been most consistently detected in malignant tissues and associated with tumor growth, metastatic potential and angiogenesis. Radiosynthesis of carboxylic (1') and hydroxamic (2') MMPIs resulted in radiochemical yields of 70 +/- 5% (n = 6) and 60 +/- 5% (n = 4), respectively. Evaluation in A549-inoculated athymic mice showed a tumor uptake of 2. 0+/- 0.7%ID/g (3 h p.i.), a tumor/blood ratio of 0.5 and a tumor/muscle ratio of 4.6 at 48 h p.i. for 1'. For compound 2' a tumor uptake of 0.7 +/- 0.2%ID/g (3 h p.i.), a tumor/blood ratio of 1.2 and a tumor/muscle ratio of 1.8 at 24 h p.i. were observed. HPLC analysis of the blood (plasma) showed no dehalogenation or other metabolites of 1' 2 h p.i. For compound 2', 65.4% of intact compound was found in the blood (plasma) and one polar metabolite (31%) was detected whereas in the tumor 91.8% of the accumulated activity was caused by intact compound and only 8.1% by the metabolite. Planar imaging, using a Toshiba GCA-9300A/hg SPECT camera, showed that tumor tissue could be visualized and that image quality improved by decreasing specific activity resulting in lower liver uptake, indicating some degree of saturable binding in the liver. In vivo evaluation of these radioiodinated carboxylic and hydroxamic MMP inhibitor tracers revealed that MMP inhibitors could have potential as tumor imaging agents, but that further research is necessary.


When You Can't Walk a Mile: Walking Limitation Prevalence and Associations Among Middle-Aged and Older US Adults with Arthritis: A Cross-Sectional, Population-Based Study.
We examined walking limitations and associated characteristics among middle-aged and older US adults with arthritis, overall, and by sex. Using 2005-2006 Arthritis Conditions and Health Effects Survey (ACHES) data (n = 1793), we estimated "a lot" and "any" ("a lot" or "a little" combined) walking limitation for more than 1 mile (1.6 km) among US adults 45 years or older with arthritis and examined associations (sociodemographics, arthritis symptoms and effects, psychosocial measures, and physical health) with walking limitations in unadjusted and multivariable (MV) adjusted logistic regression models using prevalence ratios (PRs) and 95% confidence intervals, accounting for the complex survey design. Respondents frequently reported "a lot" (48%) and "any" (72%) limitation for more than 1 mile. Women reported higher prevalence of all levels of walking limitation versus men (eg, 51% vs 42% for "a lot" overall); additionally, the gap for walking limitations between women and men widened with age. Limitation was high for both sexes at all ages, affecting 1-in-3 to 4-in-5, depending on level of walking limitation. The strongest MV associations for "a lot" of walking limitation among all respondents included substantial and modest arthritis-attributable life interference (PR = 2.5 and 1.6, respectively), age 75 years or older (PR = 1.5), and physical inactivity and fair/poor self-rated health (PR = 1.4 for both). Walking limitations among middle-aged and older adults are substantial. Existing proven interventions that improve walking ability and physical function may help this population to reduce and delay disability.


On-line monitoring of oxygen as a method to qualify the oxygen consumption rate of wines.
Measuring the oxygen content during winemaking and bottle storage has become increasingly popular due to its impact on the sensory quality and longevity of wines. Nevertheless, only a few attempts to describe the kinetics of oxygen consumption based on the chemical composition of wines have been published. Therefore, this study proposes firstly a new fitting approach describing oxygen consuming kinetics and secondly the use of an Artificial Neural Network approach to describe and compare the oxygen avidity of wines according to their basic chemical composition (i.e. the content of ethanol, titratable acidity, total sulfur dioxide, total phenolics, iron and copper). The results showed no significant differences in the oxygen consumption rate between white and red wines, and allowed the sorting of the wines studied according to their oxygen consumption rate.


Ice-Prevention and De-Icing Capacity of Epoxy Resin Filled with Hybrid Carbon-Nanostructured Forms: Self-Heating by Joule Effect.
In this study, CNTs and graphite have been incorporated to provide electrical conductivity and self-heating capacity by Joule effect to an epoxy matrix. Additionally, both types of fillers, with different morphology, surface area and aspect ratio, were simultaneously incorporated (hybrid CNTs and graphite addition) into the same epoxy matrix to evaluate the effect of the self-heating capacity of carbon materials-based resins on de-icing and ice-prevention capacity. The self-heating capacity by Joule effect and the thermal conductivity of the differently filled epoxy resin were evaluated for heating applications at room temperature and at low temperatures for de-icing and ice-prevention applications. The results show that the higher aspect ratio of the CNTs determined the higher electrical conductivity of the epoxy resin compared to that of the epoxy resin filled with graphite, but the 2D morphology of graphite produced the higher thermal conductivity of the filled epoxy resin. The presence of graphite enhanced the thermal stability of the filled epoxy resin, helping avoid its deformation produced by the softening of the epoxy resin (the higher the thermal conductivity, the higher the heat dissipation), but did not contribute to the self-heating by Joule effect. On the other hand, the feasibility of electrically conductive epoxy resins for de-icing and ice-prevention applications by Joule effect was demonstrated.


An activatable prodrug for the treatment of metastatic tumors.
Metastatic cancers have historically been difficult to treat. However, metastatic tumors have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H2O2), supporting the hypothesis that a prodrug could be activated by intracellular H2O2 and lead to a potential antimetastatic therapy. In this study, prodrug 7 was designed to be activated by H2O2-mediated boronate oxidation, resulting in activation of the fluorophore for detection and release of the therapeutic agent, SN-38. Drug release from prodrug 7 was investigated by monitoring fluorescence after addition of H2O2 to the cancer cells. Prodrug 7 activated by H2O2, selectively inhibited tumor cell growth. Furthermore, intratracheally administered prodrug 7 showed effective antitumor activity in a mouse model of metastatic lung disease. Thus, this H2O2-responsive prodrug has therapeutic potential as a novel treatment for metastatic cancer via cellular imaging with fluorescence as well as selective release of the anticancer drug, SN-38.


Intracapsular cataract extraction: experience of a general surgeon in Niger, West Africa.
Cataract is the major cause of blindness in the world and affects an estimated 20 million persons globally. In Africa, there is an incidence of half a million new cases of cataract blindness annually, with a backlog of 3 million persons requiring sight-restoring surgery. The burden of this form of curable blindness resides mainly in less developed nations, which typically have limited numbers of ophthalmologists and medical resources. The experience and results of a general surgeon working in rural West Africa, without prior ophthalmic skills but with limited training in the field, are reported. Data on all consecutive planned intracapsular cataract extractions performed between January 1994 and July 1995 inclusive were collected prospectively and the visual outcome as well as surgical complications were analysed. A total of 243 planned intracapsular cataract extractions were performed. Data were incomplete or missing in five cases leaving 238 for analysis. All the patients were blind pre-operatively, with visual acuities of 3/60 or less. Functional vision (6/60 or better) was restored in 95% of all cases. General surgeons can be satisfactorily trained in the art of intracapsular cataract extractions, with good visual outcomes. This is very useful in the setting of undeveloped countries where there are severe limitations of resources, and the recruitment of trained general surgeons will help reduce the burden of curable blindness in these regions.


Glucagon regulates gluconeogenesis through KAT2B- and WDR5-mediated epigenetic effects.
Circulating pancreatic glucagon is increased during fasting and maintains glucose balance by stimulating hepatic gluconeogenesis. Glucagon triggering of the cAMP pathway upregulates the gluconeogenic program through the phosphorylation of cAMP response element-binding protein (CREB) and the dephosphorylation of the CREB coactivator CRTC2. Hormonal and nutrient signals are also thought to modulate gluconeogenic gene expression by promoting epigenetic changes that facilitate assembly of the transcriptional machinery. However, the nature of these modifications is unclear. Using mouse models and in vitro assays, we show that histone H3 acetylation at Lys 9 (H3K9Ac) was elevated over gluconeogenic genes and contributed to increased hepatic glucose production during fasting and in diabetes. Dephosphorylation of CRTC2 promoted increased H3K9Ac through recruitment of the lysine acetyltransferase 2B (KAT2B) and WD repeat-containing protein 5 (WDR5), a core subunit of histone methyltransferase (HMT) complexes. KAT2B and WDR5 stimulated the gluconeogenic program through a self-reinforcing cycle, whereby increases in H3K9Ac further potentiated CRTC2 occupancy at CREB binding sites. Depletion of KAT2B or WDR5 decreased gluconeogenic gene expression, consequently breaking the cycle. Administration of a small-molecule KAT2B antagonist lowered circulating blood glucose concentrations in insulin resistance, suggesting that this enzyme may be a useful target for diabetes treatment.


Understanding FOXP3: progress towards achieving transplantation tolerance.
Regulatory T cells (Treg) suppress immune responses, making them an exciting therapeutic target for achieving operational transplant tolerance. Recent observations have identified forkhead box P3 (FOXP3) as a master gene required for the development and function of Treg. Improving our understanding of FOXP3 may facilitate methods for identifying and generating Treg.


Bifurcation analysis in a vortex flow generated by an oscillatory magnetic obstacle.
A numerical simulation and a theoretical model of the two-dimensional flow produced by the harmonic oscillation of a localized magnetic field (magnetic obstacle) in a quiescent viscous, electrically conducting fluid are presented. Nonuniform Lorentz forces produced by induced currents interacting with the oscillating magnetic field create periodic laminar flow patterns that can be characterized by three parameters: the oscillation Reynolds number, Reomega, the Hartmann number, Ha, and the dimensionless amplitude of the magnetic obstacle oscillation, D. The analysis is restricted to oscillations of small amplitude and Ha=100. The resulting flow patterns are described and interpreted in terms of position and evolution of the critical points of the instantaneous streamlines. It is found that in most of the cycle, the flow is dominated by a pair of counter rotating vortices that switch their direction of rotation twice per cycle. The transformation of the flow field present in the first part of the cycle into the pattern displayed in the second half occurs via the generation of hyperbolic and elliptic critical points. The numerical solution of the flow indicates that for low frequencies (v.e. Reomega=1), two elliptic and two hyperbolic points are generated, while for high frequencies (v.e. Reomega=100), a more complex topology involving four elliptic and two hyperbolic points appear. The bifurcation map for critical points of the instantaneous streamline is obtained numerically and a theoretical model based on a local analysis that predicts most of the qualitative properties calculated numerically is proposed.


Examining the relationships between life satisfaction and alcohol, tobacco and marijuana use among school-aged children.
There are many known risk factors associated with youth substance use. Nonetheless, the impact of life satisfaction (LS) on the use of alcohol, tobacco and marijuana by adolescents still remains largely unknown. The present analysis utilized data from the Health Behavior in School-Aged Children 2009-10 US study. Multilevel logistic regression models were used to assess the relationship between LS and individual substance use. Multilevel multinomial regression models examined the relationship with total number of substances used. After controlling for numerous variables associated with substance use, individuals reporting low LS were significantly more likely to ever use tobacco (OR = 1.34, 95% CI = [1.01, 1.78]), alcohol (OR = 1.45, 95% CI = [1.10, 1.92]) and marijuana (OR = 1.98, 95% CI = [1.39, 2.82]). Additionally, students with low LS were significantly more likely to use two substances (OR = 1.90, 95% CI = [1.15, 3.14]) and three substances concurrently (OR = 2.00, 95% CI = [1.27, 3.16]). The present study identified strong associations between LS and individual, as well as concurrent, substance use among adolescents. Interventions aiming to reduce adolescent substance use may benefit from incorporating components to improve LS.


Problem behaviour and traumatic dental injuries in adolescents.
To explore the relationship between problem behaviour and traumatic dental injuries (TDI) among 15- to 16-year-old schoolchildren from East London. This cross-sectional study used data from 794 adolescents who participated in phase III of the Research with East London Adolescents Community Health Survey (RELACHS), a school-based prospective study of a representative sample of adolescents. Participants completed a questionnaire and were clinically examined for TDI, overjet and lip coverage. The Strength and Difficulties Questionnaire (SDQ) was used to assess problem behaviour, which provided a total score and five domain scores (emotional symptoms, conduct problems, hyperactivity, peer problems and pro-social behaviour). The association between problem behaviour and TDI was assessed in unadjusted and adjusted logistic regression models. Adjusted models controlled for demographic (sex, age and ethnicity), socio-economic (parental employment) and clinical factors (overjet and lip coverage). The prevalence of TDI was 17% and the prevalence of problem behaviour, according to the SDQ, was 10%. In the adjusted model, adolescents with problem behaviour were 1.87 (95% confidence interval: 1.03-3.37) times more likely to have TDI than those without problem behaviour. In subsequent analysis by SDQ domains, it was found that only peer problems were associated with TDI (OR = 1.78, 95% CI: 1.01-3.14), even after adjustment for confounders. This study found evidence for a relationship between problem behaviour and TDI among adolescents, which was mainly due to peer relationship problems.


Catabolic effects of adrenaline and angiotensin II in the perfused liver of normal and genetically obese (ob/ob) mice.
1. Rapid effects of hormones on the metabolism of glycogen and fatty acids were studied in the perfused liver of normal and genetically obese (ob/ob) mice. 2. In livers from normal and obese mice adrenaline and angiotensin II stimulated glycogenolysis. 3. These hormones inhibited the synthesis de novo of long-chain fatty acids in livers from normal mice, but not in livers from obese mice. 4. The proportion of acetyl-CoA carboxylase in the active form was decreased by adrenaline but not by angiotensin II in livers from obese mice. 5. The potency of hormone effects on liver suggests that they could occur in the intact animal. 6. The results add to the evidence that hepatic fatty acid synthesis in genetically obese (ob/ob) mice is irreversibly resistant to inhibition by a range of hormones. Such resistance could be of primary significance in the pathogenesis of the obesity.


Alpha-synuclein targets the plasma membrane via the secretory pathway and induces toxicity in yeast.
A pathological feature of Parkinson's disease is the presence of Lewy bodies within selectively vulnerable neurons. These are ubiquitinated cytoplasmic inclusions containing alpha-synuclein, an abundant protein normally associated with presynaptic terminals. Point mutations in the alpha-synuclein gene (A30P and A53T), as well as triplication of the wild-type (WT) locus, have been linked to autosomal dominant Parkinson's. How these alterations might contribute to disease progression is unclear. Using the genetically tractable yeast Saccharomyces cerevisiae as a model system, we find that both the WT and the A53T isoforms of alpha-synuclein initially localize to the plasma membrane, to which they are delivered via the classical secretory pathway. In contrast, the A30P mutant protein disperses within the cytoplasm and does not associate with the plasma membrane, and its intracellular distribution is unaffected by mutations in the secretory pathway. When their expression is elevated, WT and A53T, but not A30P, are toxic to cells. At moderate levels of expression, WT and A53T induce the cellular stress (heat-shock) response and are toxic to cells bearing mutations in the 20S proteasome. Our results reveal a link between plasma membrane targeting of alpha-synuclein and its toxicity in yeast and suggest a role for the quality control (QC) system in the cell's effort to deal with this natively unfolded protein.


ALTERED CALCIUM CURRENTS AND AXONAL GROWTH IN Nf1 HAPLOINSUFFICIENT MICE.
Mutations of the neurofibromin gene (NF1) cause neurofibromatosis type 1 (NF1), a disease in which learning disabilities are common. Learning deficits also are observed in mice with a heterozygous mutation of Nf1 (Nf1(+/-)). Dysregulation of regulated neurotransmitter release has been observed in Nf1(+/-) mice. However, the role of presynaptic voltage-gated Ca(2+) channels mediating this release has not been investigated. We investigated whether Ca(2+) currents and transmitter release were affected by reduced neurofibromin in Nf1(+/-) mice. Hippocampal Ca(2+) current density was greater in neurons from Nf1(+/-) mice and a greater fraction of Ca(2+) currents was activated at less depolarized potentials. In addition, release of the excitatory neurotransmitter, glutamate, was increased in neuronal cortical cultures from Nf1(+/-) mice. Dendritic complexity and axonal length were also increased in neurons Nf1(+/-) mice compared to wild-type neurons, linking loss of neurofibromin to developmental changes in hippocampal axonal/cytoskeletal dynamics. Collectively, these results show that altered Ca(2+) channel density and transmitter release, along with increased axonal growth may account for the abnormal nervous system functioning in NF1.


Artemisinin resistance in Plasmodium falciparum malaria.
Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance. In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance. We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups. P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.)


Preparation and Characterization of Cationic PLA-PEG Nanoparticles for Delivery of Plasmid DNA.
The purpose of the present work was to formulate and evaluate cationic poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) nanoparticles as novel non-viral gene delivery nano-device. Cationic PLA-PEG nanoparticles were prepared by nanoprecipitation method. The gene loaded nanoparticles were obtained by incubating the report gene pEGFP with cationic PLA-PEG nanoparticles. The physicochemical properties (e.g., morphology, particle size, surface charge, DNA binding efficiency) and biological properties (e.g., integrity of the released DNA, protection from nuclease degradation, plasma stability, in vitro cytotoxicity, and in vitro transfection ability in Hela cells) of the gene loaded PLA-PEG nanoparticles were evaluated, respectively. The obtained cationic PLA-PEG nanoparticles and gene loaded nanoparticles were both spherical in shape with average particle size of 89.7 and 128.9 nm, polydispersity index of 0.185 and 0.161, zeta potentials of +28.9 and +16.8 mV, respectively. The obtained cationic PLA-PEG nanoparticles with high binding efficiency (>95%) could protect the loaded DNA from the degradation by nuclease and plasma. The nanoparticles displayed sustained-release properties in vitro and the released DNA maintained its structural and functional integrity. It also showed lower cytotoxicity than Lipofectamine 2000 and could successfully transfect gene into Hela cells even in presence of serum. It could be concluded that the established gene loaded cationic PLA-PEG nanoparticles with excellent properties were promising non-viral nano-device, which had potential to make cancer gene therapy achievable.


Cell-replacement therapy with stem cells in neurodegenerative diseases.
In the past few years, research on stem cells has expanded greatly as a tool to develop potential therapies to treat incurable neurodegenerative diseases. Stem cell transplantation has been effective in several animal models, but the underlying restorative mechanisms are still unknown. Several mechanisms such as cell fusion, neurotrophic factor release, endogenous stem cell proliferation, and transdifferentiation may explain positive therapeutic results, in addition to replacement of lost cells. The biological issue needs to be clarified in order to maximize the potential for effective therapies. The absence of any effective pharmacological treatment and preliminary data both in experimental and clinical settings has recently identified Amyotrophic Lateral Sclerosis (ALS) as an ideal candidate disease for the development of stem cell therapy in humans. Preliminary stem transplantation trials have already been performed in patients. The review discusses relevant topics regarding the application of stem cell research to ALS but in general to other neurodegenerative diseases debating in particular the issue of transdifferentiation, endogenous neural stem cell, and factors influencing the stem cell fate.


Test ordering for preventive health care among family medicine residents.
To determine which screening tests family medicine residents order as part of preventive health care. A cross-sectional survey. Alberta and Ontario. First- and second-year family medicine residents at the University of Alberta in Edmonton, the University of Calgary in Alberta, and McMaster University in Hamilton, Ont, during the 2011 to 2012 academic year. Demographic information, Likert scale ratings assessing ordering attitudes, and selections from a list of 38 possible tests that could be ordered for preventive health care for sample 38-year-old and 55-year-old female and male patients. Descriptive and comparative statistics were calculated. A total of 318 of 482 residents (66%) completed the survey. Recommended or appropriate tests were ordered by 82% (for cervical cytology) to 95% (for fasting glucose measurement) of residents. Across the different sample patients, residents ordered an average of 3.3 to 5.7 inappropriate tests per patient, with 58% to 92% ordering at least 1 inappropriate test per patient. The estimated average excess costs varied from $38.39 for the 38-year-old man to $106.46 for the 55-year-old woman. More regular use of a periodic health examination screening template did not improve ordering (P = .88). In general, residents ordered appropriate preventive health tests reasonably well but also ordered an average of 3.3 to 5.7 inappropriate tests for each patient. Training programs need to provide better education for trainees around inappropriate screening and work hard to establish good ordering behaviour in preparation for entering practice.


Envelope-constrained neutralization-sensitive HIV-1 after heterosexual transmission.
Heterosexual transmission accounts for the majority of human immunodeficiency virus-1 (HIV-1) infections worldwide, yet the viral properties that determine transmission fitness or outgrowth have not been elucidated. Here we show, for eight heterosexual transmission pairs, that recipient viruses were monophyletic, encoding compact, glycan-restricted envelope glycoproteins. These viruses were also uniquely sensitive to neutralization by antibody from the transmitting partner. Thus, the exposure of neutralizing epitopes, which are lost in chronic infection because of immune escape, appears to be favored in the newly infected host. This reveals characteristics of the envelope glycoprotein that influence HIV-1 transmission and may have implications for vaccine design.


A randomized phase II study of lapatinib + pazopanib versus lapatinib in patients with HER2+ inflammatory breast cancer.
This multi-center Phase II study evaluated lapatinib, pazopanib, and the combination in patients with relapsed HER2+ inflammatory breast cancer. In Cohort 1, 76 patients were randomized 1:1 to receive lapatinib 1,500 mg + placebo or lapatinib 1,500 mg + pazopanib 800 mg (double-blind) once daily until disease progression, unacceptable toxicity, or death. Due to high-grade diarrhea observed with this dose combination in another study (VEG20007), Cohort 1 was closed. The protocol was amended such that an additional 88 patients (Cohort 2) were randomized in a 5:5:2 ratio to receive daily monotherapy lapatinib 1,500 mg, lapatinib 1,000 mg + pazopanib 400 mg, or monotherapy pazopanib 800 mg, respectively. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival, and safety. In Cohort 1, ORR for the lapatinib (n = 38) and combination (n = 38) arms was 29 and 45 %, respectively; median PFS was 16.1 and 14.3 weeks, respectively. Grade ≥3 adverse events (AEs) were more frequent in the combination arm (71 %) than in the lapatinib arm (24 %). Dose reductions and interruptions due to AEs were also more frequent in the combination arm (45 and 53 %, respectively) than in the lapatinib monotherapy arm (0 and 11 %, respectively). In Cohort 2, ORR for patients treated with lapatinib (n = 36), lapatinib + pazopanib (n = 38), and pazopanib (n = 13) was 47, 58, and 31 %, respectively; median PFS was 16.0, 16.0, and 11.4 weeks, respectively. In the lapatinib, combination, and pazopanib therapy arms, grade ≥3 AEs were reported for 17, 50, and 46 % of patients, respectively, and the incidence of discontinuations due to AEs was 0, 24, and 23 %, respectively. The lapatinib-pazopanib combination was associated with a numerically higher ORR but no increase in PFS compared to lapatinib alone. The combination also had increased toxicity resulting in more dose reductions, modifications, and treatment delays. Activity with single-agent lapatinib was confirmed in this population.


A Bayesian Approach to the Overlap Analysis of Epidemiologically Linked Traits.
Diseases often cooccur in individuals more often than expected by chance, and may be explained by shared underlying genetic etiology. A common approach to genetic overlap analyses is to use summary genome-wide association study data to identify single-nucleotide polymorphisms (SNPs) that are associated with multiple traits at a selected P-value threshold. However, P-values do not account for differences in power, whereas Bayes' factors (BFs) do, and may be approximated using summary statistics. We use simulation studies to compare the power of frequentist and Bayesian approaches with overlap analyses, and to decide on appropriate thresholds for comparison between the two methods. It is empirically illustrated that BFs have the advantage over P-values of a decreasing type I error rate as study size increases for single-disease associations. Consequently, the overlap analysis of traits from different-sized studies encounters issues in fair P-value threshold selection, whereas BFs are adjusted automatically. Extensive simulations show that Bayesian overlap analyses tend to have higher power than those that assess association strength with P-values, particularly in low-power scenarios. Calibration tables between BFs and P-values are provided for a range of sample sizes, as well as an approximation approach for sample sizes that are not in the calibration table. Although P-values are sometimes thought more intuitive, these tables assist in removing the opaqueness of Bayesian thresholds and may also be used in the selection of a BF threshold to meet a certain type I error rate. An application of our methods is used to identify variants associated with both obesity and osteoarthritis.


Optimizing biopsy strategy for prostate cancer: Bayesian framework of network meta-analysis and hierarchical summary receiver operating characteristic model for diagnostic accuracy.
Overdiagnosis and overtreatment are well known problems in prostate cancer (PCa). The transrectal ultrasound (TRUS) Guided biopsy (GB) as a current gold standard investigation has a low positive detection rate resulting in unnecessary biopsies. The choice of optimal biopsy strategy needs to be defined. Therefore, we undertook a Bayesian network meta analysis (NMA) and Bayesian prediction in the hierarchical summary receiver operating characteristic (HSROC) model to present a method for optimizing biopsy strategy in PCa. Twenty eight relevant studies were retrieved through online databases of EMBASE, MEDLINE, and CENTRAL up to February 2020. Markov chain Monte Carlo simulation and Surface Under the Cumulative RAnking curve were used to calculate the rank probability using odds ratio with 95% credible interval. HSROC model was used to formulate the predicted true sensitivity and specificity of each biopsy strategy. Six different PCa biopsy strategies including transrectal ultrasound GB (TRUS GB), fusion GB (FUS GB), fusion + transrectal ultrasound GB (FUS + TRUS GB), magnetic resonance imaging GB (MRI GB), transperineal ultrasound GB (TPUS GB), and contrast enhanced ultrasound GB were analyzed in this study with a total of 7584 patients. These strategies were analyzed on five outcomes including detection rate of overall PCa, clinically significant PCa, insignificant PCa, complication rate, and HSROC. The rank probability showed that the overall PCa detection rate was higher in FUS + TRUS GB, MRI GB, and FUS GB. In terms of clinically significant PCa detection, FUS + TRUS GB and FUS GB had a relatively higher clinically significant PCa detection rate, whereas TRUS GB had a relatively lower rate for clinically significant PCa detection rate. MRI GB (91% and 81%) and FUS GB (82% and 83%) had the highest predicted true sensitivity and specificity, respectively, whereas TRUS GB (62% and 83%) had a lower predicted true sensitivity and specificity. MRI GB, FUS GB, and FUS + TRUS GB were associated with lower complication rate, whereas TPUS GB and TRUS GB were more associated with higher complication rate. This NMA and HSROC model highlight the important finding that FUS + TRUS GB, FUS GB, and MRI GB were superior compared with other strategies to avoid the overdiagnosis and overtreatment of PCa. FUS GB, MRI GB, and FUS + TRUS GB had lower complication rates. These results may assist in shared decision making between patients, carers, and their surgeons.


Biomarker profile in stable Fontan patients.
As the population of adults with congenital heart disease (CHD) grows, cardiologists continue to encounter patients with complex anatomies that challenge the standard treatment of care. Single ventricle Fontan palliated patients are the most complex within CHD, with a high morbidity and mortality burden. Factors driving this early demise are largely unknown. We analyzed biomarker expression in 44 stable Fontan outpatients (29.2 ± 10.7 years, 68.2% female) seen in the outpatient Emory Adult Congenital Heart Center and compared them to 32 age, gender and race matched controls. In comparison to controls, Fontan patients had elevated levels of multiple cytokines within the inflammatory pathway including Tumor Necrosis Factor-α (TNF-α) (p < 0.001), Interleukin-6 (IL-6) (p < 0.011), Growth Derived Factor-15 (GDF-15) (p < 0.0001), β2-macroglobulin, (p = 0.0006), stem cell mobilization: Stromal Derived Factor-1∝ (SDF-1α) (p = 0.006), extracellular matrix turnover: Collagen IV (p < 0.0001), neurohormonal activation: Renin (p < 0.0001), renal dysfunction: Cystatin C (p < 0.0001) and Urokinase Receptor (uPAR) (p = 0.022), cardiac injury: Troponin-I (p < 0.0004) and metabolism: Adiponectin (p = 0.0037). Within 1 year of enrollment 50% of Fontan patients had hospitalizations, arrhythmias or worsening hepatic function. GDF-15 was significantly increased in Fontan patients with clinical events (p < 0.0001). In addition, GDF-15 moderately correlated with longer duration of Fontan (r = 0.55, p = 0.01) and was elevated in atriopulmonary (AP) Fontan circulation. Finally, in a multivariate model, VEGF-D and Collagen IV levels were found to be associated with a change in MELDXI, a marker of liver dysfunction. Multiple clinical and molecular biomarkers are upregulated in Fontan patients, suggesting a state of chronic systemic dysregulation.


Transplantation tolerance: a look at the nonhuman primate literature in the light of modern tolerance theories.
Ever since the beginning of clinical transplantation, investigators have searched for a way to transplant tissues from one person to another without chronic immunosuppression. That goal, known as allograft tolerance, has remained clinically elusive. In the past decade, however, many of the fundamental principles of tolerance have been redefined, and biological agents capable of exploiting them in vivo have been developed. Accordingly, experimental methods for tolerance induction have rapidly evolved in concert with a growing understanding of physiological tolerance to self and the development of novel immunoreactive reagents. In general, old world monkeys have become the pre-clinical testing ground for methods that have shown reasonable promise for clinical application, particularly antibodies or other biological agents with limited cross-species reactivity. As such, a survey of the nonhuman primate experience in transplantation is representative of all reasonably successful experimental attempts to develop clinically applicable tolerance regimens. This article summarizes many of the concepts currently unfolding in the tolerance literature. It also reviews the techniques for tolerance induction that have been and are currently being investigated in nonhuman primates. The validity of these models is summarized, and the older literature is reinterpreted in light of recent changes in our understanding of tolerance.


Environment-wide association study (EWAS) for type 2 diabetes in the Marshfield Personalized Medicine Research Project Biobank.
Environment-wide association studies (EWAS) provide a way to uncover the environmental mechanisms involved in complex traits in a high-throughput manner. Genome-wide association studies have led to the discovery of genetic variants associated with many common diseases but do not take into account the environmental component of complex phenotypes. This EWAS assesses the comprehensive association between environmental variables and the outcome of type 2 diabetes (T2D) in the Marshfield Personalized Medicine Research Project Biobank (Marshfield PMRP). We sought replication in two National Health and Nutrition Examination Surveys (NHANES). The Marshfield PMRP currently uses four tools for measuring environmental exposures and outcome traits: 1) the PhenX Toolkit includes standardized exposure and phenotypic measures across several domains, 2) the Diet History Questionnaire (DHQ) is a food frequency questionnaire, 3) the Measurement of a Person's Habitual Physical Activity scores the level of an individual's physical activity, and 4) electronic health records (EHR) employs validated algorithms to establish T2D case-control status. Using PLATO software, 314 environmental variables were tested for association with T2D using logistic regression, adjusting for sex, age, and BMI in over 2,200 European Americans. When available, similar variables were tested with the same methods and adjustment in samples from NHANES III and NHANES 1999-2002. Twelve and 31 associations were identified in the Marshfield samples at p<0.01 and p<0.05, respectively. Seven and 13 measures replicated in at least one of the NHANES at p<0.01 and p<0.05, respectively, with the same direction of effect. The most significant environmental exposures associated with T2D status included decreased alcohol use as well as increased smoking exposure in childhood and adulthood. The results demonstrate the utility of the EWAS method and survey tools for identifying environmental components of complex diseases like type 2 diabetes. These high-throughput and comprehensive investigation methods can easily be applied to investigate the relation between environmental exposures and multiple phenotypes in future analyses.


Effects of extracellular pH, PCO2 and HCO3- on intracellular pH in isolated type-I cells of the neonatal rat carotid body.
1. The effects of changing PCO2 extracellular pH (pHo) and HCO3- on intracellular pH (pHi) were studied in isolated neonatal rat type-I carotid body cells using the pH-sensitive fluoroprobe, carboxy-SNARF-1. 2. Simulated respiratory acidosis and alkalosis (i.e. changes in PCO2 at constant HCO3-) led to rapid (half-time t0.5 = 3 s) monotonic changes in pHi. The relationship between pHi and pHo under these conditions was linear, steep (0.63 pHi/pHo) and remarkably similar to the response predicted from a passive cell model (i.e. a cell lacking pHi regulation). 3. In order to model the above pHi changes (point 2), it was necessary to determine beta i (intrinsic intracellular buffering power). By using small incremental acid loads in the cell (progressive [NH4+]o removal), beta i was determined as a function of pHi to be: beta i = 127.6-16.04 pHi. 4. Changes in PCO2 at constant pHo (i.e. simultaneously changing HCO3-) caused rapid transient changes in pHi but did not significantly affect steady-state pHi over the range 1-10% CO2. 5. When PCO2 was held constant (5%), changing HCO3- and thus pHo (i.e. a simulated metabolic acidosis/alkalosis) led to much slower changes in pHi (t0.5 approximately 1 min). Steady-state pHi showed an almost identical dependence on pHo (slope 0.68) to that found for simulated respiratory acidosis/alkalosis. Therefore, over the range of pHo, PCO2 and [HCO3-]o tested, steady-state pHi appeared to be a unique function of pHo and independent of PCO2 and [HCO3-]o. 6. The effects on pHi of respiratory acidosis, metabolic acidosis and increases of PCO2 at constant pHo (present work) were compared with previously published work on the ability of similar manoeuvres to increase the carotid sinus nerve (CSN) discharge rate. The two sets of data showed several striking similarities: (i) in both cases, the response to a respiratory acidosis was rapid in onset, maintained and reversible; (ii) in both cases, the speed of response to a metabolic acidosis was significantly slower than in (i) but, again, it was maintained and reversible; (iii) in both cases, increases in PCO2 at constant pHo elicited a rapid response but one which was only transient with no change in the steady-state value. 7. The close correlation between the effects of changing pHo, PCO2 and [HCO3-]o on pHi and on CSN discharge suggests that a change in type-I cell pHi is the first step in the chemoreception of blood pH by the carotid body.(ABSTRACT TRUNCATED AT 400 WORDS)


The Characteristics of Child Sexual Abuse in the School Environment in Turkey.
School may represent a protective factor, boosting the mental health of the student body, while also representing a risk factor that heightens the potential for mental health problems. The present study aims to identify the individual and familial characteristics associated with the incidents of child sexual abuse (CSA) in Turkey's school environment. The incidents involving school-related CSA constituted 5.6% (N = 125) of 2,238 cases. The following was discovered: an adult committed the majority (64%) of CSA in the school environment; most adult perpetrators were teachers (62.5%). This study determined that the perpetrators manipulated the victims via methods that included physical abuse (11.2%), threats (19.2%), tricks/deception (15.2%), and taking photographs/videos with sexual content (3.2%); and CSA incidents involved intercourse (15.2%); and almost three-quarter of the victims of CSA in the school environment reported the incident late. This study indicates that peer perpetrators abuse younger victims and a greater proportion of male victims relative to adult perpetrators. In light of these findings, school security must be improved, especially in public schools, and trainings aimed at preventing bullying and sexual abuse (SA) should be given to all school staff, students, and parents.


Age- and sex-specific genomic profiles in non-small cell lung cancer.
Gene expression profiling may be useful in examining differences underlying age- and sex-specific outcomes in non-small cell lung cancer (NSCLC). To describe clinically relevant differences in the underlying biology of NSCLC based on patient age and sex. Retrospective analysis of 787 patients with predominantly early stage NSCLC performed at Duke University, Durham, North Carolina, from July 2008 to June 2009. Lung tumor samples with corresponding microarray and clinical data were used. All patients were divided into subgroups based on age (< 70 vs > or = 70 years old) or sex. Gene expression signatures representing oncogenic pathway activation and tumor biology/microenvironment status were applied to these samples to obtain patterns of activation/deregulation. Patterns of oncogenic and molecular signaling pathway activation that are reproducible and correlate with 5-year recurrence-free patient survival. Low- and high-risk patient clusters/cohorts were identified with the longest and shortest 5-year recurrence-free survival, respectively, within the age and sex NSCLC subgroups. These cohorts of NSCLC demonstrate similar patterns of pathway activation. In patients younger than 70 years, high-risk patients, with the shortest recurrence-free survival, demonstrated increased activation of the Src (25% vs 6%; P<.001) and tumor necrosis factor (76% vs 42%; P<.001) pathways compared with low-risk patients. High-risk patients aged 70 years or older demonstrated increased activation of the wound healing (40% vs 24%; P = .02) and invasiveness (64% vs 20%; P<.001) pathways compared with low-risk patients. In women, high-risk patients demonstrated increased activation of the invasiveness (99% vs 2%; P<.001) and STAT3 (72% vs 35%; P<.001) pathways while high-risk men demonstrated increased activation of the STAT3 (87% vs 18%; P<.001), tumor necrosis factor (90% vs 46%; P<.001), EGFR (13% vs 2%; P = .003), and wound healing (50% vs 22%; P<.001) pathways. Multivariate analyses confirmed the independent clinical relevance of the pathway-based subphenotypes in women (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.34-3.03; P<.001) and patients younger than 70 years (HR, 1.83; 95% CI, 1.24-2.71; P = .003). All observations were reproducible in split sample analyses. Among a cohort of patients with NSCLC, subgroups defined by oncogenic pathway activation profiles were associated with recurrence-free survival. These findings require validation in independent patient data sets.


Establishment of three-dimensional culture of neural stem/progenitor cells in collagen Type-1 Gel.
Recent studies demonstrated that transplanting neural stem/precursor cells (NSPCs) into an injured spinal cord of adult rat promotes functional recovery. The functional recovery from spinal cord injury might be enhanced by transplanting NSPCs with a scaffold that fills the cavity, entraps the NSPCs in the cavity, and acts as an attachment for neurite extension. We recently focused on collagen type-1 as a scaffold for NSPC transplantation into the injured spinal cord. In the present study, we determined the optimal conditions for culturing NSPCs in 3D collagen type-1 gel with respect to cell survival and cell migration. We, then, evaluated the ability of NSPCs to differentiate under the optimal condition. NSPCs were derived from the striatum of rat embryos. To determine the optimal cell density and collagen concentration for 3D collagen gel culture for NSPC, we performed viability assay and migration assay. Then, we examined the proportion of phenotypes differentiated from NSPC in that optimal condition. In viability assay, the viability rate increased as the NSPC density increased, and peaked at 1 x 10(7) to 5 x 10(7) cell/ml. For collagen concentration, the viability rate increased as the collagen concentration decreased. In migration assay, cell migration was most extensive at collagen concentrations between 0.3 and 0.75 mg/ml. Migration distances gradually declined as collagen concentrations increased. In the optimal condition, NSPCs differentiated into neurons (40.1%), astrocytes (53.1%), and oligodendrocytes (5.3%) in 3D collagen gel culture. The optimal conditions for NSPC culture in 3D collagen gel was a cell density between 1 x 10(7) and 5 x 10(7) cells/ml and a collagen concentration between 0.5 and 0.75 mg/ml. Under the condition, NSPCs could differentiate into neurons, astrocytes, and oligodendrocytes.


Rapid carbohydrate loading after a short bout of near maximal-intensity exercise.
One limitation shared by all published carbohydrate-loading regimens is that 2-6 d are required for the attainment of supranormal muscle glycogen levels. Because high rates of glycogen resynthesis are reported during recovery from exercise of near-maximal intensity and that these rates could in theory allow muscle to attain supranormal glycogen levels in less than 24 h, the purpose of this study was to examine whether a combination of a short bout of high-intensity exercise with 1 d of a high-carbohydrate intake offers the basis for an improved carbohydrate-loading regimen. Seven endurance-trained athletes cycled for 150 s at 130% VO2peak followed by 30 s of all-out cycling. During the following 24 h, each subject was asked to ingest 12 g.kg-1 of lean body mass (the equivalent of 10.3 g.kg-1 body mass) of high-carbohydrate foods with a high glycemic index. Muscle glycogen increased from preloading levels (+/- SE) of 109.1 +/- 8.2 to 198.2 +/- 13.1 mmol.kg-1 wet weight within only 24 h, these levels being comparable to or higher than those reported by others over a 2- to 6-d regimen. Densitometric analysis of muscle sections stained with periodic acid-Schiff not only corroborated these findings but also indicated that after 24 h of high-carbohydrate intake, glycogen stores reached similar levels in Type I, IIa, and IIb muscle fibers. This study shows that a combination of a short-term bout of high-intensity exercise followed by a high-carbohydrate intake enables athletes to attain supranormal muscle glycogen levels within only 24 h.


Peripheral electrical stimulation increases corticomotor excitability and enhances the rate of visuomotor adaptation.
Peripheral electrical stimulation (PES) modulates corticomotor excitability but its effect on motor performance has not been thoroughly investigated. The purpose of this study was to assess whether increases and/or decreases in corticomotor excitability, induced by PES, influenced motor performance using a visuomotor adaptation task. Three PES interventions (motor stimulation, sensory stimulation or sham) were delivered to the first dorsal interosseous (FDI) in 30 healthy participants matched for age, gender and handedness. Motor stimulation was applied to increase corticomotor excitability, sensory stimulation to decrease corticomotor excitability, while sham stimulation acted as a control. Corticomotor excitability was assessed using the amplitude of motor evoked potentials to transcranial magnetic stimulation recorded from FDI before and after each intervention. Following PES, participants completed a visuomotor adaptation task. This required participants to move a cursor accurately towards virtual targets with index finger movements when the cursor trajectory was rotated 30° counter clockwise. Performance was assessed as angular error (a measure of movement accuracy) and reaction time. The rate of visuomotor adaptation was greater following motor PES compared to sham, but not sensory, with no difference observed between sensory and sham. However, visuomotor adaptation performance overall (the total change in performance from beginning to end) was similar across intervention groups. These findings suggest that motor PES applied prior to task acquisition can facilitate the speed of adaptation.


Memantine is associated with longer survival than donepezil in a Veterans Affairs prescription database, 1997 to 2008.
Alzheimer's disease (AD) shortens life-expectancy, but the effects of pharmacological treatments for this disorder on mortality have not been studied. We compared two commonly prescribed medications, donepezil and memantine, with respect to the length of survival of veterans presumed to have AD. The Computerized Medical Records System at the Veterans Affairs Palo Alto Health Care System (VAPAHCS) was used to identify all patients prescribed these medications between 1997 and 2008. The VAPAHCS approved donepezil in 1997 and memantine in 2004. Kaplan-Meier and Cox regression analyses were used to test for chronological and drug-related associations with survival in 2,083 male veterans aged 55 years and older receiving prescriptions for donepezil, memantine, or both. Overall patient mortality decreased in the 2004 to 2008 era, compared with the 1997 to 2003 era, pre-memantine (HR: 0.75; 95% CI: 0.63, 0.89; p = 0.001). In analyses confined to the 2004 to 2008 era, patients prescribed memantine alone survived significantly longer than those prescribed donepezil alone (HR: 2.24; 95% CI: 1.53, 3.28; p < 0.001) or both donepezil and memantine (HR: 1.83; 95% CI: 1.14, 2.94; p = 0.012). While this study has several limitations, these findings suggest that memantine treatment is associated with an increased life-expectancy relative to donepezil treatment. Additional research is needed to replicate these unexpected findings and identify potential mechanisms to explain this apparent association, to establish if the relationship applies to other cholinesterase inhibitors, and to discover whether the findings generalize to women and patient populations with characteristics different from those of the veterans in this study.