Does happiness itself directly affect mortality? The prospective UK Million Women Study.
Poor health can cause unhappiness and poor health increases mortality. Previous reports of reduced mortality associated with happiness could be due to the increased mortality of people who are unhappy because of their poor health. Also, unhappiness might be associated with lifestyle factors that can affect mortality. We aimed to establish whether, after allowing for the poor health and lifestyle of people who are unhappy, any robust evidence remains that happiness or related subjective measures of wellbeing directly reduce mortality. The Million Women Study is a prospective study of UK women recruited between 1996 and 2001 and followed electronically for cause-specific mortality. 3 years after recruitment, the baseline questionnaire for the present report asked women to self-rate their health, happiness, stress, feelings of control, and whether they felt relaxed. The main analyses were of mortality before Jan 1, 2012, from all causes, from ischaemic heart disease, and from cancer in women who did not have heart disease, stroke, chronic obstructive lung disease, or cancer at the time they answered this baseline questionnaire. We used Cox regression, adjusted for baseline self-rated health and lifestyle factors, to calculate mortality rate ratios (RRs) comparing mortality in women who reported being unhappy (ie, happy sometimes, rarely, or never) with those who reported being happy most of the time. Of 719,671 women in the main analyses (median age 59 years [IQR 55-63]), 39% (282,619) reported being happy most of the time, 44% (315,874) usually happy, and 17% (121,178) unhappy. During 10 years (SD 2) follow-up, 4% (31,531) of participants died. Self-rated poor health at baseline was strongly associated with unhappiness. But after adjustment for self-rated health, treatment for hypertension, diabetes, asthma, arthritis, depression, or anxiety, and several sociodemographic and lifestyle factors (including smoking, deprivation, and body-mass index), unhappiness was not associated with mortality from all causes (adjusted RR for unhappy vs happy most of the time 0·98, 95% CI 0·94-1·01), from ischaemic heart disease (0·97, 0·87-1·10), or from cancer (0·98, 0·93-1·02). Findings were similarly null for related measures such as stress or lack of control. In middle-aged women, poor health can cause unhappiness. After allowing for this association and adjusting for potential confounders, happiness and related measures of wellbeing do not appear to have any direct effect on mortality. UK Medical Research Council, Cancer Research UK.


Association of Combined Tobacco Smoking and Oral Contraceptive Use With Cervical Intraepithelial Neoplasia 2 or 3 in Korean Women.
Cigarette smoking and oral contraceptive (OC) use have been associated with cervical neoplasia, and the combination of smoking and OC use could influence cervical carcinogenesis. We aimed to assess the joint effect of smoking and OC use on the risk of cervical intraepithelial neoplasia (CIN). From a cohort of human papillomavirus-positive subjects recruited from 6 hospitals in Korea from March 2006 to November 2012, a total of 678 subjects (411 control, 133 CIN 1, and 134 CIN 2 or 3 cases) were selected for this study (mean age, 43 years). The risk of CIN associated with smoking and OC use on additive and multiplicative scales was estimated via multinomial logistic regression after adjustment for potential confounding factors. The relative excess risk due to interaction (RERI) and the synergy index (S) were used to evaluate the additive interaction. OC users (odds ratio [OR] 1.98; 95% confidence interval [CI], 1.07-3.69) and long-term OC use (≥20 months; OR 2.71; 95% CI, 1.11-6.59) had a higher risk of CIN 2/3, but had no association with CIN 1, compared to non-OC users. Smokers and heavy smoking (≥8 cigarettes/day) were not associated with any CIN grade. Combined smoking and OC use (OR 4.91; 95% CI, 1.68-14.4; RERI/S, 3.77/27.4; P for multiplicative interaction = 0.003) and combined heavy smoking and long-term OC use (OR 11.5; 95% CI, 1.88-70.4; RERI/S, 9.93/18.8; P for multiplicative interaction = 0.009) had a higher risk of CIN 2/3 but had no association with CIN 1 compared to combined non-smoking and non-OC use. OC use and smoking acted synergistically to increase the risk of CIN 2 or 3 in Korean women.


Demonstration of scrapie strain diversity in infected PC12 cells.
Scrapie strain replication in the nerve growth factor-induced, differentiated PC12 cell culture system was examined. Differences in replication between mouse-derived agents were demonstrated, with the 139A scrapie strain yielding 100- to 1000-fold higher levels of infectivity than the ME7 scrapie strain. Replication was not detected in PC12 cells infected with either the hamster-derived 263K or rat-derived 139R scrapie strains. Studies on the neurotransmitters in infected PC12 cells demonstrated that the adrenergic pathway was unchanged but the cholinergic pathway was altered. Furthermore, the degree of alteration correlated with the level of scrapie strain replication. Comparison of infectivity titres and enzymatic changes in ME7-infected PC12 cells with those in Chandler agent-infected mouse neuroblastoma cells suggests that the significant changes in neurotransmitter levels in cultures exhibiting low titres of infectivity involve factors in addition to strain replication. The variation in the range of scrapie strain replication in PC12 cells is discussed in relationship to species barrier, cell targeting, genetic susceptibility and species strain specificity. These studies further emphasize the value of the PC12 cell model system in examining the scrapie strain-host cell interaction and in addition support the concept of variation among scrapie strains.


Long-term full-thickness embryonic rabbit retinal transplants.
To establish the light and electron microscopic morphology of long-term full-thickness embryonic rabbit retinal transplants, with special attention paid to graft- host integration. Eighteen rabbits received a complete embryonic neuroretina 19 days after conception. The transplants were positioned under the host retina, flat against the host retinal pigment epithelium with proper polarity, using a vitrectomy technique. After surviving 3 to 10 months, the transplants were examined by light and electron microscopy. The outer retina of the host had degenerated in all specimens. In 16 of the 18 eyes, well-laminated transplants with correct polarity, measuring up to 3.2 mm in length, were found. The transplants displayed long outer segments facing the host retinal pigment epithelium, and they were laminated to the level of the inner plexiform layer in which fusion with the host was often evident. Fusion was more prominent in the oldest transplants. Electron microscopy revealed bundles of neurites at different levels of maturation in close contact with Müller cell fimbriae at regular intervals along the graft-host border. Full-thickness embryonic rabbit retinal transplants positioned with correct polarity develop into large laminated retinas and survive without immunosuppression for at least 10 months. Host and graft adapt and almost reconstruct the normal retinal appearance. Ultrastructurally, well-developed photoreceptors and many normal synapse types are seen, and neuron sprouting is evident at the graft-host border.


Structural analysis of O-polysaccharide chains extracted from different Salmonella Typhimurium strains.
Salmonella Typhimurium is the major cause of invasive nontyphoidal Salmonella disease in Africa, with high mortality among children and HIV-infected individuals. Currently, no vaccine is available for use in humans. Antibodies directed against the O-polysaccharide of the lipopolysaccharide molecule of Salmonella mediate bacterial killing and are protective, and conjugation of the O-polysaccharide to a carrier protein represents a possible strategy for vaccine development. Here we have purified the O-polysaccharide from six different strains of S. Typhimurium and fully characterized them using analytical methods including HPLC-SEC, HPAEC-PAD, GC, GC-MS, 1D and 2D NMR spectroscopy. All the O-polysaccharide samples showed a similar bimodal molecular mass distribution, but differed with respect to the amount and position of O-acetylation and glucosylation. For some strains, O-acetyl groups were found not only on C-2 of abequose (factor 5 specificity), but also on C-2 and C-3 of rhamnose; glucose was found to be linked 1→4 or 1→6 to galactose in different amounts according to the strain of origin. This structural variability could have an impact on the immunogenicity of corresponding glycoconjugate vaccines and different strains need to be evaluated in order to identify the appropriate source of O-polysaccharide to use for the development of a candidate conjugate vaccine with broad coverage against S. Typhimurium.


Restoration of the nail apparatus following fingertip amputation by perionychial grafts supported by local flaps, in children and adults.
Fingertip amputations are a common injury in both adults and children. Replantation with revascularisation provides the gold standard result but is not always possible due to lack of expertise, degree of injury or patient factors. Perionychial grafts harvested from the amputated digit tip, anatomically restored and supported by a local flap are already known to be an effective option in the treatment of adult fingertip amputations. Such procedures can be performed by surgeons familiar with local flap techniques, can result in nail apparatus survival even with greater degrees of tissue injury and do not require prolonged protection or immobilisation. We present a consecutive series of four adults and four children who underwent perionychial grafts with flap support, to report the range of nail apparatus outcomes and to demonstrate this technique's relative utility in children.


Plasmonic Hot-Carrier-Mediated Tunable Photochemical Reactions.
Hot-carrier generation from surface plasmon decay has found applications in many branches of physics, chemistry, materials science, and energy science. Recent reports demonstrated that the hot carriers generated from plasmon decay in nanoparticles can transfer to attached molecules and drive photochemistry which was thought impossible previously. In this work, we have computationally explored the atomic-scale mechanism of a plasmonic hot-carrier-mediated chemical process, H2 dissociation. Numerical simulations demonstrate that, after photoexcitation, hot carriers transfer to the antibonding state of the H2 molecule from the nanoparticle, resulting in a repulsive-potential-energy surface and H2 dissociation. This process occurs when the molecule is close to a single nanoparticle. However, if the molecule is located at the center of the gap in a plasmonic dimer, dissociation is suppressed due to sequential charge transfer, which efficiently reduces occupation in the antibonding state and, in turn, reduces dissociation. An asymmetric displacement of the molecule in the gap breaks the symmetry and restores dissociation when the additional charge transfer is significantly suppressed. Thus, these models demonstrate the possibility of structurally tunable photochemistry via plasmonic hot carriers.


Inadvertent intrathecal use of ionic contrast media for myelography.
To describe instances of inadvertent intrathecal injection of ionic contrast media and to consider treatment approaches, and diagnostic and medicolegal issues. Ten cases of inadvertent injection, of which nine were reported to the manufacturers/authors and one appeared in the literature, are related with emphasis on similarity of reactions. Six criteria are enumerated and used to coin the term "ascending tonic-clonic seizure syndrome." Therapeutic possibilities seem limited, but several methods for controlling seizures are suggested. The importance of identifying the contrast material is underscored. Awareness of the grave possibility of administering the wrong contrast material is the first step in avoiding this problem; awareness of the symptoms is the first step toward therapy.


Circumvention of outer surface protein A immunity by host-adapted Borrelia burgdorferi.
Outer surface protein A (OspA), which is abundantly expressed in cultured Borrelia burgdorferi, appears to be down-regulated or masked following low-dose infection, and OspA immunization did not prevent infection, dissemination, or disease development with host-adapted spirochetes. Seroconversion of mice to B. burgdorferi OspA depended on dose and viability of inoculated spirochetes. Mice inoculated with > 10(4) live spirochetes and > 10(7) heat-killed spirochetes seroconverted to OspA, but mice inoculated with fewer spirochetes did not seroconvert to OspA at 2 weeks after inoculation. Growth temperature of spirochetes was not a factor for infectious dose or seroconversion to OspA. Spirochetes grown at 30, 34, or 38 degrees C had the same median infectious dose. Growth temperature did not influence infectious dose when mice were inoculated intraperitoneally or intradermally and did not influence dose-related immunologic recognition of OspA. Mice hyperimmunized with recombinant OspA-glutathione S-transferase (GT) fusion protein or GT (controls) were challenged by syringe inoculation with 10(3) spirochetes or by transplantation of infected skin from syngenic mice infected for 2 or 8 weeks. OspA-GT-immunized mice resisted syringe challenge but developed disseminated infections following transplantation of infected skin. Identical results were obtained in mice passively immunized with hyperimmune serum to OspA-GT or GT and then challenged by syringe or infected skin transplant. The number of spirochetes in infected skin, determined by quantitative PCR directed toward both plasmid and genomic targets, was less than the syringe challenge dose.


Familial primary biliary cirrhosis and autoimmune cholangitis.
Autoimmune cholangitis has been proposed as a separate disease entity from primary biliary cirrhosis without serum antimitochondrial antibodies. The ultimate answer to the question of whether autoimmune cholangitis and primary biliary cirrhosis are distinct will require detailed comparison of aetiologic factors and pathogenic mechanisms. Two families are described each of which has one member with classical antimitochondrial antibody positive biopsy-proven primary biliary cirrhosis and a first degree relative with antimitochondrial antibody negative but antinuclear antibody positive autoimmune cholangitis (biopsy proven in one case). Study of such families should allow analysis of the contribution of shared genetic risk factors versus varying environmental triggering mechanisms to disease pathogenesis. We suggest a European registry of families, such as the two described, which are rare within one centre, to facilitate elucidation of pathogenetic factors.


The fitness landscape of the codon space across environments.
Fitness landscapes map the relationship between genotypes and fitness. However, most fitness landscape studies ignore the genetic architecture imposed by the codon table and thereby neglect the potential role of synonymous mutations. To quantify the fitness effects of synonymous mutations and their potential impact on adaptation on a fitness landscape, we use a new software based on Bayesian Monte Carlo Markov Chain methods and re-estimate selection coefficients of all possible codon mutations across 9 amino acid positions in Saccharomyces cerevisiae Hsp90 across 6 environments. We quantify the distribution of fitness effects of synonymous mutations and show that it is dominated by many mutations of small or no effect and few mutations of larger effect. We then compare the shape of the codon fitness landscape across amino acid positions and environments, and quantify how the consideration of synonymous fitness effects changes the evolutionary dynamics on these fitness landscapes. Together these results highlight a possible role of synonymous mutations in adaptation and indicate the potential mis-inference when they are neglected in fitness landscape studies.


Efficacy of ReBound Diathermy as a Thermal Heating Agent: A Critically Appraised Topic.
Clinical Scenario: ReBound is a portable shortwave diathermy unit used to heat tissues using the same principle as induction drum shortwave diathermy. It is unclear if ReBound can vigorously (4°C) heat intramuscular tissue as efficiently as other thermal agents. Clinical Question: In adults (P), is ReBound diathermy (I) compared with other thermal agents (C) effective at increasing intramuscular tissue temperature by 4°C (O)? Summary of Key Findings: (1) Three studies were included for review, all randomized crossover studies. (2) All studies agreed ReBound does not achieve vigorous (4°C) heating effects during a 30-minute treatment to the triceps surae muscle (depth = 1 and 3 cm). (3) Studies agreed that the heat generated by ReBound dissipates slower than (P < .001) or similar to pulsed shortwave diathermy at 3 cm and faster than moist hot packs (P < .001) at 1 cm. (4) One study found that intramuscular tissue temperatures increased more with ReBound (3.69°C [1.50°C]) than moist hot packs (2.82°C [0.90°C]) at superficial depths (1 cm, d = 0.70). (5) Two studies compared ReBound with MegaPulse II pulsed shortwave diathermy at a 3 cm depth. One found that the MegaPulse II increased intramuscular tissue temperature by 4.32°C (1.79°C) compared with the ReBound's 2.31°C (0.87°C) increase (d = 1.43). The final study reported that the MegaPulse II increased triceps surae muscle temperature by 3.47°C (0.92°C) versus ReBound at 3.08°C (1.19°C) (d = 0.37). (6) The combined results are an increase of 3.81 (1.38°C) for the MegaPulse II and 2.77 (1.12°C) for ReBound (d = 0.83). Clinical Bottom Line: Results strongly indicate that the ReBound should not be used for vigorous (4°C) heating effects in the triceps surae muscle at 1 and 3 cm. Clinicians can use ReBound when traveling or instead of moist hot packs for moderate (2°C-3°C) heating effects at deep and superficial levels (1 and 3 cm) for large treatment areas with subcutaneous fat thickness <15 mm. Strength of Recommendation: Consistent level B findings indicate that ReBound does not achieve vigorous heating effects (4°C).


Effect of vinpocetine (cognitol™) on cognitive performances of a nigerian population.
Chronic medical disorders are often complicated by cognitive impairments, making medical intervention that can alleviate cognitive disturbances desirable. Vinpocetine enhances cerebral utilization of oxygen and glucose and consequently improves cerebral functions including memory. This study assessed the efficacy of vinpocetine (Cognitol™) in improving memory and concentration in cognitively impaired patients. A prospective analytical study of 56 cognitively impaired patients compared with age, sex and level of education matched 56 controls. Cognitive performance was assessed with the Short Blessed Test, which was pilot-tested. Baseline cognitive performances of the patients and controls were obtained and thereafter cognitive performances of the patients were assessed at 6 and 12 weeks after administration of vinpocetine at a dose of 5 mg twice-a-day. Comparative analysis of their performances at baseline was done using the Student t-test, while the improvement in patients' performances and effect of disease variables on cognitive performances were analyzed with one-way analysis of variance and likelihood ratio analysis respectively. The mean (standard deviation) [SD] ages of the cognitively impaired patients (56/112) and controls (56/112) were 49.5 (18.9) and 53.8 (15.8) years respectively (P = 0.19; 95% confidence interval [CI]: 2.2-10.8). The pilot study yielded an optimal cut-off error score of 6 with a sensitivity of 71.4%, specificity of 96.4% and accuracy of 83.9%. Patients performed significantly worse than the controls (P < 0.001; 95% CI 6.7-11.4). There were significant improvements in memory and concentration with vinpocetine therapy (P < 0.05). The clinical variables of the patients had no effect on the trend of cognitive performances. Vinpocetine was effective in improving memory and concentration of patients with epilepsy and dementia although the efficacy was minimal in demented patients.


Establishment and validation of a standard protocol for the detection of minimal residual disease in B lineage childhood acute lymphoblastic leukemia by flow cytometry in a multi-center setting.
Minimal residual disease detection, used for clinical management of children with acute lymphoblastic leukemia, can be performed by molecular analysis of antigen-receptor gene rearrangements or by flow cytometric analysis of aberrant immunophenotypes. For flow minimal residual disease to be incorporated into larger national and international trials, a quality assured, standardized method is needed which can be performed in a multi-center setting. We report a four color, flow cytometric protocol established and validated by the UK acute lymphoblastic leukemia Flow minimal residual disease group. Quality assurance testing gave high inter-laboratory agreement with no values differing from a median consensus value by more than one point on a logarithmic scale. Prospective screening of B-ALL patients (n=206) showed the method was applicable to 88.3% of patients. The minimal residual disease in bone marrow aspirates was quantified and compared to molecular data. The combined risk category concordance (minimal residual disease levels above or below 0.01%) was 86% (n=134). Thus, this standardized protocol is highly reproducible between laboratories, sensitive, applicable, and shows good concordance with molecular-based analysis.


A Multilevel Investigation of Resiliency Scales for Children and Adolescents: The Relationships Between Self-Perceived Emotion Regulation, Vagally Mediated Heart Rate Variability, and Personal Factors Associated With Resilience.
Personal resiliency refers to individual attributes that are related to the process of successfully adapting to the environment in the face of adverse conditions, also known as resilience. Emotion regulation is increasingly found as a core component in mental health and found to modulate individual differences in the management of emotional responses. The Resiliency Scales for Children and Adolescents (RSCA; Prince-Embury, 2006, 2007) were designed to systematically identify and quantify core personal qualities of resiliency in youth, and includes Sense of Mastery scale (MAS), Sense of Relatedness scale (REL), and Emotional Reactivity (REA) scale. The following study was first conducted to confirm the Three-Factor model of Personal Resiliency in a Norwegian student sample using factor analytic procedures. Secondly and the main purpose of the study, was to investigate if personal resiliency is associated with self-reported measures related to emotion regulation, and with resting vagally mediated heart rate variability (vmHRV) as a psychophysiological index of emotion regulation capacity. A revised scale adapted to the Norwegian sample was developed. Results indicate that protective indices related to personal resiliency are associated with both self-reported adaptive emotion regulation and outcome, and partly related to high capacity for emotion regulation indicated by vmHRV. Risk related to personal vulnerability was associated with maladaptive emotion regulation and outcome, but was not associated with emotion regulation capacity. Together the findings provide supporting evidence of both self-reported and psychophysiological correlates between emotion regulatory processes and personal resiliency indicated by RSCA.


[Covid-19 serology in nursing home and long-term care: prevalence of seroconversion in the Amiens-Picardie University Hospital].
Since December 2019, an emerging infectious viral disease implicating a coronavirus SARS-CoV-2 has caused a global pandemic. Elderly people, being more fragile, are the most affected by the severity and lethality of this disease. The NH and LTCU of the Amiens University Hospital registered their first Covid-19 cases in February 2020, which lead to the opening of a Covid-19 dedicated unit and of specific protocol for confinement. This descriptive study was analyzing the prevalence of Covid-19 seroconversion within the NH and the LTCU of the Amiens University Hospital. Both this screening test and the nasopharyngeal swab PCRs were in order to assess the impact of the Covid-19 epidemic in NH and LTCU. On June 15th and 16th, the serological tests for Covid-19 were positive for 146 (66.1%) of the residents tested. The seroconversion rate was significantly different (p < 0.001) between the NH (88.7%) and the LTCU (45.6%). During the epidemic, there was no excess mortality index within the NH and LTCU services of the Amiens University Hospital. Among frail patients, the role of immunosenescence can be discussed to account for the absence of this inflammatory reaction. This study showed that isolating the infected patient in a dedicated unit significantly reduces the risk of seroconversion and contamination compared to isolating them within their own unit.


Glycosylation of Trypanosoma cruzi TcI antigen reveals recognition by chagasic sera.
Chagas disease is considered the most important parasitic disease in Latin America. The protozoan agent, Trypanosoma cruzi, comprises six genetic lineages, TcI-TcVI. Genotyping to link lineage(s) to severity of cardiomyopathy and gastrointestinal pathology is impeded by the sequestration and replication of T. cruzi in host tissues. We describe serology specific for TcI, the predominant lineage north of the Amazon, based on expression of recombinant trypomastigote small surface antigen (gTSSA-I) in the eukaryote Leishmania tarentolae, to allow realistic glycosylation and structure of the antigen. Sera from TcI-endemic regions recognised gTSSA-I (74/146; 50.7%), with no cross reaction with common components of gTSSA-II/V/VI recombinant antigen. Antigenicity was abolished by chemical (periodate) oxidation of gTSSA-I glycosylation but retained after heat-denaturation of conformation. Conversely, non-specific recognition of gTSSA-I by non-endemic malaria sera was abolished by heat-denaturation. TcI-specific serology facilitates investigation between lineage and diverse clinical presentations. Glycosylation cannot be ignored in the search for immunogenic antigens.


Assessing the impact of triazine herbicides on organophosphate insecticide toxicity to the earthworm Eisenia fetida.
A standard Organization for Economic Cooperation and Development (OECD) filter paper test was used to assess the acute toxicity of chlorpyrifos, atrazine, cyanazine, and simazine to the earthworm Eisenia fetida. Acute toxicity of chlorpyrifos was also determined in combination with the three-triazine herbicides. Surprisingly, atrazine and cyanazine caused mortality at concentrations lower than chlorpyrifos. Atrazine and cyanazine also increased the toxicity of chlorpyrifos 7.9- and 2.2-fold, respectively. However, simazine caused no toxicity to the worms and did not affect chlorpyrifos toxicity in binary mixture experiments. Possible mechanisms for the greater-than-additive toxicity for the binary combinations of atrazine and cyanazine with chlorpyrifos were investigated, including changes in uptake and biotransformation rates of chlorpyrifos in the presence of atrazine. Uptake of chlorpyrifos into the worms decreased slightly when atrazine was present in the system, therefore eliminating increased uptake as a possible explanation for the increased toxicity. Body residue analysis of worms indicated increased metabolite formation, suggesting the greater-than-additive response may be due to increased biotransformation to more toxic oxon metabolites.


Delay in consulting a medical practitioner about rectal bleeding.
The aims were to estimate the incidence of rectal bleeding in the community, and to determine the proportion of individuals who delay or fail to seek medical advice after a first episode of rectal bleeding. The data were collected as part of a large scale general population survey of the health practices and attitudes of individuals in a randomly selected sample of 2121 households. The survey was conducted in the Newcastle and Lake Macquarie areas of New South Wales, Australia, during 1987-88. Information about rectal bleeding was collected from 1213 individuals aged 40 years and over. Of the 1213 people aged 40 years and over, 239 (20%) reported noticing rectal bleeding at some time in their life. However, since an estimated 4.5% had noticed rectal bleeding for the first time in the past year the true lifetime incidence of rectal bleeding is likely to be much higher. Of the 77 individuals who had noticed a first occurrence of rectal bleeding more than three months but less than five years prior to the interview, 23 (30%) had either not sought medical advice or had only done so after a period of delay. The most commonly reported reason for delay or failure to consult was thinking that the bleeding was not serious and would clear up by itself. The data suggest that prompt investigation of rectal bleeding is not occurring in a relatively large proportion of cases. However, in the absence of firm evidence that early detection improves prognosis, and considering the costs of screening, it would be premature to initiate programmes which encourage people to seek care promptly for this symptom.


Effect on oxidative stress, hepatic chemical metabolizing parameters, and genotoxic damage of mad honey intake in rats.
A total of 66 male Wistar rats were used and six groups (control: 10 animals and experimental: 12 animals) were formed. While a separate control group was established for each study period, mad honey application to the animals in the experimental group was carried out with a single dose (12.5 g kg-1 body weight (b.w.); acute stage), at a dose of 7.5 g kg-1 b.w. for 21 days (subacute stage), and at a dose of 5 g kg-1 b.w. for 60 days (chronic stage). Tissue and blood oxidative stress markers (malondialdehyde (MDA), nitric oxide (NO), 4-hydroxynonenal (HNE), superoxide dismutase, catalase, glutathione (GSH) peroxidase, and glucose-6-phosphate dehydrogenase), hepatic chemical metabolizing parameters in the liver (cytochrome P450 2E1, nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase, nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome c reductase (CYTC), GSH S-transferase (GST), and GSH), and micronucleus and comet test in some samples were examined. Findings from the study showed that single and repeated doses given over the period increased MDA, NO, and HNE levels while decreasing/increasing tissue and blood antioxidant enzyme activities. From hepatic chemical metabolizing parameters, GST activity increased in the subacute and chronic stages and CYTC activity increased in the acute period, whereas GSH level decreased in the subacute stage. Changes in tail and head intensities were found in most of the comet results. Mad honey caused oxidative stresses for each exposure period and made some significant changes on the comet test in certain periods for some samples obtained. In other words, according to the available research results obtained, careless consumption of mad honey for different medical purposes is not appropriate.


Hooked on a memory: How rumination about past positive events might contribute to grandiose ideas?
Dwelling about positive experiences has been found to be positively related to mania and grandiose ideas. Nevertheless, besides some important limitations, past research has also neglected the nature (or characteristics) of memories individuals dwell on, and that might be specifically associated with grandiose ideas. Thus, the present study aimed to replicate previous studies while considering the role of specificity and the importance of memory used to increase grandiose feelings. In total, 219 participants were included and, after completing the memory induction, were randomized to either the rumination condition or the distraction condition. They also completed different questionnaires assessing positive rumination and grandiose ideas. Overall, rumination, compared to the distraction condition, led to the maintenance of grandiose ideas and positive affect from T2 to T3. Regression analysis showed that the specificity of memory was associated with grandiose ideas at T2, which predicted grandiose ideas at T3. Our results confirm rumination's causal role in forming grandiose ideas. We also found that autobiographical memory and, more specifically, the capacity to recall past positive experiences coupled with repeatedly thinking about them might constitute a fundamental pathway leading to the persistence of such beliefs. The use of a non-clinical sample limits the results and needs replication in clinical samples.


Molecular determinants of mouse neurovirulence and mosquito infection for Western equine encephalitis virus.
Western equine encephalitis virus (WEEV) is a naturally occurring recombinant virus derived from ancestral Sindbis and Eastern equine encephalitis viruses. We previously showed that infection by WEEV isolates McMillan (McM) and IMP-181 (IMP) results in high (∼90-100%) and low (0%) mortality, respectively, in outbred CD-1 mice when virus is delivered by either subcutaneous or aerosol routes. However, relatively little is known about specific virulence determinants of WEEV. We previously observed that IMP infected Culex tarsalis mosquitoes at a high rate (app. 80%) following ingestion of an infected bloodmeal but these mosquitoes were infected by McM at a much lower rate (10%). To understand the viral role in these phenotypic differences, we characterized the pathogenic phenotypes of McM/IMP chimeras. Chimeras encoding the E2 of McM on an IMP backbone (or the reciprocal) had the most significant effect on infection phenotypes in mice or mosquitoes. Furthermore, exchanging the arginine, present on IMP E2 glycoprotein at position 214, for the glutamine present at the same position on McM, ablated mouse mortality. Curiously, the reciprocal exchange did not confer mouse virulence to the IMP virus. Mosquito infectivity was also determined and significantly, one of the important loci was the same as the mouse virulence determinant identified above. Replacing either IMP E2 amino acid 181 or 214 with the corresponding McM amino acid lowered mosquito infection rates to McM-like levels. As with the mouse neurovirulence, reciprocal exchange of amino acids did not confer mosquito infectivity. The identification of WEEV E2 amino acid 214 as necessary for both IMP mosquito infectivity and McM mouse virulence indicates that they are mutually exclusive phenotypes and suggests an explanation for the lack of human or equine WEE cases even in the presence of active transmission.


Do glycoalbumin levels preferentially reflect changes in postprandial glucose excursions?
To evaluate whether plasma glycated albumin, which provides an integrated measure of plasma glucose levels over the preceding 2-4 weeks, better reflects changes in postprandial glucose excursions than HbA1c . People with suboptimum glycaemic control on dual oral therapy were enrolled in the Treating-to-Target-in-Type 2 diabetes (4-T) trial, in which participants were randomized to the addition of once-daily basal insulin, twice-daily biphasic insulin or thrice-daily prandial insulin. Glycated albumin levels were assayed enzymatically from baseline and 1-year fasting plasma samples. We evaluated robust correlations of glycated albumin and HbA1c both with fasting and postprandial glucose levels at these two time points, and with insulin-induced changes in the postprandial excursion. Requisite data were available for 625 of the participants in the 4-T trial. Their mean (±sd) age was 62 ± 10 years and body weight was 85.8 ± 15.9 kg, and their median (interquartile range) diabetes duration was 9 (6, 13) years. Partial correlations at baseline and 1 year between postprandial glucose excursions and glycated albumin/HbA1c , after adjusting for fasting glucose, were 0.27/0.15 and 0.22/0.18, respectively. Glycated albumin, compared with HbA1c , explained 66% more of the variation in postprandial glucose excursions at baseline. At 1 year, postprandial glucose excursions on basal, biphasic and prandial and insulin therapy were reduced by 0.43, 0.78 and 1.88 mmol/l, respectively. These reductions were associated with changes in both glycated albumin and HbA1c (P < 0.01), with a stronger association for glycated albumin. Changes in glycated albumin and HbA1c reflect changes in postprandial glucose excursions to a similar extent.


Individual Patient-reported Activity Levels Before and After Joint Arthroplasty Are Neither Accurate nor Reproducible.
Patients often are asked to report walking distances before joint arthroplasty and when discussing their results after surgery, but little evidence demonstrates whether patient responses accurately represent their activity. Are patients accurate in reporting distance walked, when compared with distance measured by an accelerometer, within a 50% margin of error? Patients undergoing THA or TKA were recruited over a 16-month period. One hundred twenty-one patients were screened and 66 patients (55%) were enrolled. There were no differences in mean age (p = 0.68), proportion of hips versus knees (p = 0.95), or sex (p = 0.16) between screened and enrolled patients. Each patient wore a FitBit Zip accelerometer for 1 week and was blinded to its measurements. The patients reported their perceived walking distance in miles daily. Data were collected preoperatively and 6 to 8 weeks postoperatively. Responses were normalized against the accelerometer distances and Wilcoxon one-tailed signed-rank testing was performed to compare the mean patient error with a 50% margin of error, our primary endpoint. We found that patients' self-reported walking distances were not accurate. The mean error of reporting was > 50% both preoperatively (p = 0.002) and postoperatively (p < 0.001). The mean magnitude of error was 69% (SD 58%) preoperatively and 93% (SD 86%) postoperatively and increased with time (p = 0.001). Patients' estimates of daily walking distances differed substantially from those patients' walking distances as recorded by an accelerometer, the accuracy of which has been validated in treadmill tests. Providers should exercise caution when interpreting patient-reported activity levels. Level III, diagnostic study.


Rhizobium etli CE3 bacteroid lipopolysaccharides are structurally similar but not identical to those produced by cultured CE3 bacteria.
Rhizobium etli CE3 bacteroids were isolated from Phaseolus vulgaris root nodules. The lipopolysaccharide (LPS) from the bacteroids was purified and compared with the LPS from laboratory-cultured R. etli CE3 and from cultures grown in the presence of anthocyanin. Comparisons were made of the O-chain polysaccharide, the core oligosaccharide, and the lipid A. Although LPS from CE3 bacteria and bacteroids are structurally similar, it was found that bacteroid LPS had specific modifications to both the O-chain polysaccharide and lipid A portions of their LPS. Cultures grown with anthocyanin contained modifications only to the O-chain polysaccharide. The changes to the O-chain polysaccharide consisted of the addition of a single methyl group to the 2-position of a fucosyl residue in one of the five O-chain trisaccharide repeat units. This same change occurred for bacteria grown in the presence of anthocyanin. This methylation change correlated with the inability of bacteroid LPS and LPS from anthocyanin-containing cultures to bind the monoclonal antibody JIM28. The core oligosaccharide region of bacteroid LPS and from anthocyanin-grown cultures was identical to that of LPS from normal laboratory-cultured CE3. The lipid A from bacteroids consisted exclusively of a tetraacylated species compared with the presence of both tetra- and pentaacylated lipid A from laboratory cultures. Growth in the presence of anthocyanin did not affect the lipid A structure. Purified bacteroids that could resume growth were also found to be more sensitive to the cationic peptides, poly-l-lysine, polymyxin-B, and melittin.


Cytochrome bc1-cy fusion complexes reveal the distance constraints for functional electron transfer between photosynthesis components.
Photosynthetic (Ps) growth of purple non-sulfur bacteria such as Rhodobacter capsulatus depends on the cyclic electron transfer (ET) between the ubihydroquinone (QH2): cytochrome (cyt) c oxidoreductases (cyt bc1 complex), and the photochemical reaction centers (RC), mediated by either a membrane-bound (cyt c(y)) or a freely diffusible (cyt c2) electron carrier. Previously, we constructed a functional cyt bc1-c(y) fusion complex that supported Ps growth solely relying on membrane-confined ET ( Lee, D.-W., Ozturk, Y., Mamedova, A., Osyczka, A., Cooley, J. W., and Daldal, F. (2006) Biochim. Biophys. Acta 1757, 346-352 ). In this work, we further characterized this cyt bc1-c(y) fusion complex, and used its derivatives with shorter cyt c(y) linkers as "molecular rulers" to probe the distances separating the Ps components. Comparison of the physicochemical properties of both membrane-embedded and purified cyt bc1-c(y) fusion complexes established that these enzymes were matured and assembled properly. Light-activated, time-resolved kinetic spectroscopy analyses revealed that their variants with shorter cyt c(y) linkers exhibited fast, native-like ET rates to the RC via the cyt bc1. However, shortening the length of the cyt c(y) linker decreased drastically this electronic coupling between the cyt bc1-c(y) fusion complexes and the RC, thereby limiting Ps growth. The shortest and still functional cyt c(y) linker was about 45 amino acids long, showing that the minimal distance allowed between the cyt bc1-c(y) fusion complexes and the RC and their surrounding light harvesting proteins was very short. These findings support the notion that membrane-bound Ps components form large, active structural complexes that are "hardwired" for cyclic ET.


Microevolution in lower Central America: genetic characterization of the Chibcha-speaking groups of Costa Rica and Panama, and a consensus taxonomy based on genetic and linguistic affinity.
There is evidence that Amerindians have continuously occupied the lower Central American Isthmus for as long as 10,000 years. There remains some doubt about the relationships of these original colonizers to the resident peoples of this zone at the time of European contact (approximately A.D. 1500). We present new genetic data for up to 48 genetic loci for 570 members of six Chibcha-speaking tribes of lower Central America--the Boruca, Bribri, Cabecar, and Guatuso of Costa Rica and the Kuna and Teribe of Panama--and delineate the genetic affinities among the various groups (these six tribes and the Guaymi and Bokota) of lower Central America. We convert standard genetic distance metrics into a form that is linear with the effective time since divergence, and we compare the genetic distances with linguistic distances for the same groups (r = .74, P less than .001). Geographic affinity accounts for some of the genetic divergence among groups (r = .49, P less than .084) and for some of the linguistic divergence (r = .53, P less than .037), but the correspondence between geographic position and taxonomic affinity is not high. We combine all of the genetic and linguistic data to construct a synthetic overview taxonomy of the lower Central American Chibcha. Both the genetic and linguistic data exhibit hierarchical organization of tribal groups, showing a general east-to-west pattern of grouping, with greater affinities between close neighbors. The presence of private genetic variants of some antiquity within the region and their absence outside the zone, coupled with the essential absence of the DI*A polymorphism of mongoloid origin that is widespread outside the zone, argue for a relatively isolated development of the Central American Chibcha. Our results do not support the old view of lower Central America as a frontier between more advanced cultures to the north and south. Any such explanation would require recent waves of migration from outside the region, migration that is not compatible with either the genetic or linguistic data or with the archaeological history of the region.


Comparison of Transradial and Transfemoral Approaches for Percutaneous Coronary Intervention in Patients With Acute Coronary Syndrome and Anemia.
Anemia is an independent predictor of bleeding complications and poor clinical outcomes after percutaneous coronary intervention. Percutaneous coronary transradial intervention (TRI) is better than percutaneous coronary transfemoral intervention (TFI) in terms of reducing bleeding complications that can affect the prognosis. This study aims to investigate the clinical outcomes between TRI and TFI for patients with anemia. We analyzed periprocedure complications, in-hospital mortality, and major adverse cardiac events for one year in the Korean TRI registry from January 2013 to April 2014. Patients with chronic kidney disease for whom TFI is preferred were excluded. Anemia was defined as hemoglobin <13 g/dl for men and <12 g/dl for women. A total of 1,279 patients were finally enrolled. Of these, 348 patients had anemia. Among them, 253 patients (72.7%) underwent TRI and 95 patients (27.3%) underwent TFI. There were no significant differences of baseline demographic characteristics between the TRI and TFI groups, except for the incidence of dyslipidemia (TRI 23.7% vs TFI 12.6%, p = 0.023). Multivariate logistic regression analysis revealed lower incidence of composite severe bleeding complications (hazard ratio 0.34, 95% CI 0.12 to 0.99, p = 0.049) and lower incidence of in-hospital mortality than TFI group (hazard ratio 0.74, 95% CI 0.62 to 0.88, p = 0.042). In conclusion, this study suggests that the TRI for patients with anemia may be translated into better prognosis in terms of lower rates of bleeding complications and in-hospital mortality.


High urban population density of birds reflects their timing of urbanization.
Living organisms generally occur at the highest population density in the most suitable habitat. Therefore, invasion of and adaptation to novel habitats imply a gradual increase in population density, from that at or below what was found in the ancestral habitat to a density that may reach higher levels in the novel habitat following adaptation to that habitat. We tested this prediction of invasion biology by analyzing data on population density of breeding birds in their ancestral rural habitats and in matched nearby urban habitats that have been colonized recently across a continental latitudinal gradient. We estimated population density in the two types of habitats using extensive point census bird counts, and we obtained information on the year of urbanization when population density in urban habitats reached levels higher than that of the ancestral rural habitat from published records and estimates by experienced ornithologists. Both the difference in population density between urban and rural habitats and the year of urbanization were significantly repeatable when analyzing multiple populations of the same species across Europe. Population density was on average 30 % higher in urban than in rural habitats, although density reached as much as 100-fold higher in urban habitats in some species. Invasive urban bird species that colonized urban environments over a long period achieved the largest increases in population density compared to their ancestral rural habitats. This was independent of whether species were anciently or recently urbanized, providing a unique cross-validation of timing of urban invasions. These results suggest that successful invasion of urban habitats was associated with gradual adaptation to these habitats as shown by a significant increase in population density in urban habitats over time.


Transcriptome Profiling of Pediatric Core Binding Factor AML.
The t(8;21) and Inv(16) translocations disrupt the normal function of core binding factors alpha (CBFA) and beta (CBFB), respectively. These translocations represent two of the most common genomic abnormalities in acute myeloid leukemia (AML) patients, occurring in approximately 25% pediatric and 15% of adult with this malignancy. Both translocations are associated with favorable clinical outcomes after intensive chemotherapy, and given the perceived mechanistic similarities, patients with these translocations are frequently referred to as having CBF-AML. It remains uncertain as to whether, collectively, these translocations are mechanistically the same or impact different pathways in subtle ways that have both biological and clinical significance. Therefore, we used transcriptome sequencing (RNA-seq) to investigate the similarities and differences in genes and pathways between these subtypes of pediatric AMLs. Diagnostic RNA from patients with t(8;21) (N = 17), Inv(16) (N = 14), and normal karyotype (NK, N = 33) were subjected to RNA-seq. Analyses compared the transcriptomes across these three cytogenetic subtypes, using the NK cohort as the control. A total of 1291 genes in t(8;21) and 474 genes in Inv(16) were differentially expressed relative to the NK controls, with 198 genes differentially expressed in both subtypes. The majority of these genes (175/198; binomial test p-value < 10(-30)) are consistent in expression changes among the two subtypes suggesting the expression profiles are more similar between the CBF cohorts than in the NK cohort. Our analysis also revealed alternative splicing events (ASEs) differentially expressed across subtypes, with 337 t(8;21)-specific and 407 Inv(16)-specific ASEs detected, the majority of which were acetylated proteins (p = 1.5 x 10(-51) and p = 1.8 x 10(-54) for the two subsets). In addition to known fusions, we identified and verified 16 de novo fusions in 43 patients, including three fusions involving NUP98 in six patients. Clustering of differentially expressed genes indicated that the homeobox (HOX) gene family, including two transcription factors (MEIS1 and NKX2-3) were down-regulated in CBF compared to NK samples. This finding supports existing data that the dysregulation of HOX genes play a central role in biology CBF-AML hematopoiesis. These data provide comprehensive transcriptome profiling of CBF-AML and delineate genes and pathways that are differentially expressed, providing insights into the shared biology as well as differences in the two CBF subsets.


Next-Generation Sequencing of Cerebrospinal Fluid for the Diagnosis of Neurocysticercosis.
Background: Neurocysticercosis (NCC) is the most common helminthic infection of the central nervous system (CNS). The diagnosis of NCC is sometimes challenging due to its heterogenous clinical manifestations and the variable sensitivity and specificity of neuroimaging and serological tests. Methods: Next-generation sequencing (NGS) of cerebrospinal fluid (CSF) was used to detect pathogens in patients with clinically suspected CNS infections. A series of patients diagnosed with NCC is reviewed here. Results: Using NGS of CSF, four patients were diagnosed with NCC. The reads corresponding to Taenia solium ranged from 478 to 117,362, with genomic coverage of 0.0564-11.15%. Reads corresponding to T. solium were not found in non-template controls and far exceeded those of the background microorganisms in patients with NCC, facilitating the interpretation of the NGS results. Conclusions: This case series demonstrates that NGS of CSF is promising in the diagnosis of NCC in difficult to diagnose cases. Larger studies are needed in the future.


Motion perception in central field loss.
Motion information is essential in daily life because it provides cues to depth, timing, object identification, and self-motion, as well as input to the oculomotor system. As the peripheral visual field is exquisitely sensitive to motion, we investigated the periphery of individuals with central visual field loss (CFL) to determine whether speed and direction discrimination are intact in this population. We compared CFL participants' (N = 8), older (N = 6), and young controls' (N = 6) ability to discriminate motion speed and direction in a two-spatial-alternative forced-choice design. Participants viewed moving dots on the left and right of a fixation marker and judged which side had the faster speed or more clockwise direction. For the young control group, we repeated the experiment with the stimulus limited to thin strips of fixed width at eccentricities of 5°, 10°, and 15°. There was no significant difference in mean speed or direction discrimination thresholds of CFL participants and older controls for either velocity. Young controls had significantly lower thresholds than the CFL group for both tasks. We did not find an effect of visual acuity, viewing eccentricity, or scotoma location on individuals' ability to discriminate speed or direction. Our results indicate that for high-visibility stimuli moving at 5°-10°/s, speed and direction discrimination are intact in the periphery of individuals with CFL.


Multi-wavelength fiber optical parametric oscillator with ultra-narrow wavelength spacing.
We propose a novel multi-wavelength fiber optical parametric oscillator (MW-FOPO) based on a ring cavity. A highly nonlinear fiber and a Mach-Zehnder interferometer formed by two 3-dB optical couplers are used as the gain medium and the comb filter, respectively. Multi-wavelength lasing of the MW-FOPO with an ultra-narrow wavelength spacing of about 0.08 nm is achieved. The output spectrum of the MW-FOPO covers a wavelength regime from 1510 nm to 1615 nm (for lasing wavelengths with the power that exceeds -60 dBm). The stability of the MW-FOPO is discussed and experimentally demonstrated. A comparison of the output spectra between the MW-FOPO and the multi-wavelength Erbium-doped fiber laser is also presented.


The dynamics and associations of airway neutrophilia post lung transplantation.
Bronchoalveolar lavage (BAL) neutrophilia has been repeatedly observed in lung transplant recipients with established bronchiolitis obliterans syndrome (BOS). Little is known of the fluctuations in BAL and airway neutrophilic inflammation post-transplant. This prospective longitudinal study aimed to evaluate the dynamic changes of lung allograft neutrophils with time, immunosuppression, infection and BOS. A total of 28, initially healthy, BOS 0, lung transplant recipients underwent 134 bronchoscopic assessments, including BAL and endobronchial biopsies (EBB) (with immunohistochemistry) over 3-year follow up. Subsequently, 21 developed BOS 0p and 16 ultimately BOS. Compared to controls, there was early and persistent BAL neutrophilia (p < 0.05), contrasting with an initially normal EBB that shows a progressive increased airway wall neutrophil infiltrate. BAL neutrophilia (but not airway wall neutrophilia) was most striking when there was concomitant bronchopulmonary infection, particularly in the patients with BOS. Univariate and multivariate analyses suggested that BAL neutrophilia was linked to markers of infection while EBB neutrophilia was linked with coexistent inflammation with macrophages and lymphocytes. (i) BAL neutrophilia is predominantly associated with infection; (ii) Airway wall neutrophilia (as monitored by EBB) increases with time post-transplant and is not associated with infection; (iii) By itself, BOS is not the major contributor to BAL and EBB neutrophilia.


Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial.
This analysis provides long-term follow-up in patients with BRAF wild-type advanced melanoma receiving first-line therapy based on anti-programmed cell death 1 receptor inhibitors. To compare the 3-year survival with nivolumab vs that with dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma. This follow-up of a randomized phase 3 trial analyzed 3-year overall survival data from the randomized, controlled, double-blind CheckMate 066 phase 3 clinical trial. For this ongoing, multicenter academic institution trial, patients were enrolled from January 2013 through February 2014. Eligible patients were 18 years or older with confirmed unresectable previously untreated stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 but without a BRAF mutation. Patients were treated until progression or unacceptable toxic events with nivolumab (3 mg/kg every 2 weeks plus dacarbazine-matched placebo every 3 weeks) or dacarbazine (1000 mg/m2 every 3 weeks plus nivolumab-matched placebo every 2 weeks). Overall survival. At minimum follow-ups of 38.4 months among 210 participants in the nivolumab group (median age, 64 years [range, 18-86 years]; 57.6% male) and 38.5 months among 208 participants in the dacarbazine group (median age, 66 years [range, 25-87 years]; 60.1% male), 3-year overall survival rates were 51.2% (95% CI, 44.1%-57.9%) and 21.6% (95% CI, 16.1%-27.6%), respectively. The median overall survival was 37.5 months (95% CI, 25.5 months-not reached) in the nivolumab group and 11.2 months (95% CI, 9.6-13.0 months) in the dacarbazine group (hazard ratio, 0.46; 95% CI, 0.36-0.59; P < .001). Complete and partial responses, respectively, were reported for 19.0% (40 of 210) and 23.8% (50 of 210) of patients in the nivolumab group compared with 1.4% (3 of 208) and 13.0% (27 of 208) of patients in the dacarbazine group. Additional analyses were performed on outcomes with subsequent therapies. Treatment-related grade 3/4 adverse events occurred in 15.0% (31 of 206) of nivolumab-treated patients and in 17.6% (36 of 205) of dacarbazine-treated patients. There were no deaths due to study drug toxic effects. Nivolumab led to improved 3-year overall survival vs dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma. ClinicalTrials.gov identifier: NCT01721772.


Non-melanoma skin cancer of the head and neck: the aid of reflectance confocal microscopy for the accurate diagnosis and management.
Non-melanoma skin cancer (NMSC) represents the most common cutaneous neoplasms of the head and neck. In recent years, novel non-invasive diagnostic tool have been developed, and among these we have the reflectance confocal microscopy (RCM), that offers the evaluation of the skin at real time with cellular resolution. Numerous studies have identified the main confocal features of skin tumours, demonstrating the good correlation of these features with certain dermatoscopic patterns and histologic findings. The aim of this analysis was to provide new insight into the role of RCM in the diagnosis and management of NMSC of the head and neck. Data comes from the most recent literature, taking into account previous essential reported information in this field. The study eligibility criteria were: studies providing update information, focusing on RCM findings in NMSC, without restrictions for age, sex, ethnicity. A search concerning the role of dermoscopy and RCM in the diagnosis of NMSC was performed on Medline. Duplicated studies, single case report and papers with language other than English were excluded from this study. RCM clues were analysed for NMSC in association with clinical, dermoscopic and histopathologic findings. Moreover, some new findings have been described and possible applications for NMSC of the head and neck have been discussed. RCM allows tissue imaging in vivo contributing to a more accurate diagnosis of NMSC of the head and neck, sparing time for the patient and costs for the public health system. RCM can also be used for selection of the biopsy site and it is helpful in defining the surgical safety margins to keep during the excision of skin cancers.


Presentation of childhood cancers to a paediatric shared care unit.
To describe the pathways by which children with cancer present to a shared care oncology unit. A population-based retrospective cohort study of children diagnosed with cancer between the years 2004 and 2014. District General Hospital with a level 2 Paediatric Oncology Shared Care Unit. 93 children aged 0-15 years . Time to presentation (TTP) was defined as time from initial symptoms to time seen by secondary paediatrics. Time to diagnosis (TTD) was defined as time from initial symptoms to diagnosis at a Principal Treatment Centre. Patient pathways to diagnosis were mapped and routes for different cancers were compared. Only 2/93 cases (2.1%) in 10 years were referred via the 2-week pathway. Most presentations were acute via immediate general practitioner (GP) referral or self-referral to the emergency department 62/93 (67%). Leukaemia presented acutely and via the GP more often than via self-presentation to the emergency department 21/28 (75% vs 25%), while solid tumours were self-referred to the emergency department 21/34 (62% vs 38%) more often than via the GP. TTP and TTD were calculated for 87 patients. Wilms' tumour demonstrated the shortest median TTP of 7 days and TTD of 16 days. Lymphoma had the longest TTD, with TTP 107 days and TTD 120 days. Pathways to diagnosis via other specialties were longer. The majority of children diagnosed with cancer present via acute services, with the route varying between tumour types. Only two cases in 10 years were referred via the 2-week pathway, thus challenging its relevance in the paediatric population.


Working memory load and distraction: dissociable effects of visual maintenance and cognitive control.
We establish a new dissociation between the roles of working memory (WM) cognitive control and visual maintenance in selective attention as measured by the efficiency of distractor rejection. The extent to which focused selective attention can prevent distraction has been shown to critically depend on the level and type of load involved in the task. High perceptual load that consumes perceptual capacity leads to reduced distractor processing, whereas high WM load that reduces WM ability to exert priority-based executive cognitive control over the task results in increased distractor processing (e.g., Lavie, Trends in Cognitive Sciences, 9(2), 75-82, 2005). WM also serves to maintain task-relevant visual representations, and such visual maintenance is known to recruit the same sensory cortices as those involved in perception (e.g., Pasternak & Greenlee, Nature Reviews Neuroscience, 6(2), 97-107, 2005). These findings led us to hypothesize that loading WM with visual maintenance would reduce visual capacity involved in perception, thus resulting in reduced distractor processing-similar to perceptual load and opposite to WM cognitive control load. Distractor processing was assessed in a response competition task, presented during the memory interval (or during encoding; Experiment 1a) of a WM task. Loading visual maintenance or encoding by increased set size for a memory sample of shapes, colors, and locations led to reduced distractor response competition effects. In contrast, loading WM cognitive control with verbal rehearsal of a random letter set led to increased distractor effects. These findings confirm load theory predictions and provide a novel functional distinction between the roles of WM maintenance and cognitive control in selective attention.


Towards improved precision in the quantification of surface-enhanced Raman scattering (SERS) enhancement factors: a renewed approach.
This paper demonstrates a renewed procedure for the quantification of surface-enhanced Raman scattering (SERS) enhancement factors with improved precision. The principle of this method relies on deducting the resonance Raman scattering (RRS) contribution from surface-enhanced resonance Raman scattering (SERRS) to end up with the surface enhancement (SERS) effect alone. We employed 1,8,15,22-tetraaminophthalocyanato-cobalt(II) (4α-Co(II)TAPc), a resonance Raman- and electrochemically redox-active chromophore, as a probe molecule for RRS and SERRS experiments. The number of 4α-Co(II)TAPc molecules contributing to RRS and SERRS phenomena on plasmon inactive glassy carbon (GC) and plasmon active GC/Au surfaces, respectively, has been precisely estimated by cyclic voltammetry experiments. Furthermore, the SERS substrate enhancement factor (SSEF) quantified by our approach is compared with the traditionally employed methods. We also demonstrate that the present approach of SSEF quantification can be applied for any kind of different SERS substrates by choosing an appropriate laser line and probe molecule.


Novel nomograms to predict recurrence and progression in primary non-muscle-invasive bladder cancer: validation of predictive efficacy in comparison with European Organization of Research and Treatment of Cancer scoring system.
To develop and validate novel nomograms to predict recurrence and progression after transurethral resection of bladder tumor (TURBT) in Korean patients with non-muscle-invasive bladder cancer (NMIBC). We retrospectively analyzed the clinical data on 970 newly diagnosed NMIBC patients after TURBT between 2000 and 2013 in a single institution. We used multivariate Cox proportional hazard models to identify the significant predictors of recurrence and progression, which resulted in the construction of the nomograms predicting the 5-year probability of recurrence and progression. We internally validated the nomograms using the area under the receiver-operating characteristics' curves and calibration plots. In addition, the clinical usefulness of each nomogram was assessed and compared with that of the European Organization of Research and Treatment of Cancer (EORTC)-scoring system using decision curve analysis (DCA). The significant factors related to recurrence were gross hematuria at diagnosis, previous or concomitant upper urinary tract urothelial carcinoma (UTUC), pT1 tumor, high tumor grade, multiple tumors, and intravesical therapy. The significant predictors of progression were previous or concomitant UTUC, pT1 tumor, high tumor grade, carcinoma in situ, and lymphovascular invasion. The 5-year predictive accuracy of each nomogram was 65% for recurrence and 70% for progression, respectively. Compared with the EORTC-scoring system, the nomograms were generally well calibrated. On DCA, each nomogram presented better net benefit gains than did the EORTC-scoring system across a wide range of threshold probabilities. Our novel nomograms are not completely accurate, but they show a reasonable level of discriminative ability, adequate calibration, and meaningful net benefit gain for the prediction of recurrence and progression after TURBT in Korean NMIBC patients. Additional external validation will be required to generalize the nomograms which we developed.


Prevention of the recurrence of symptom and lesions after conservative surgery for endometriosis.
Although surgical excision of endometriosis both improves pain and enhances fertility, recurrence can further exacerbate pain and reduce fertility, which in turn impacts the quality of life and increases personal as well as social costs. Therefore, it is crucial to prevent the recurrence of symptoms and lesions after conservative surgery. This article reviews evidence regarding the prevention of postoperative recurrence of endometriosis reported since the 1990s. Over the past 5 years, many new studies have been conducted and have demonstrated that long-term postoperative medication markedly reduces the recurrence. Most of these studies used oral contraceptives (OC), with either the cyclic or continuous regimen, while some used oral or intrauterine progestin. Continuous OC is more efficacious than cyclic OC, especially for dysmenorrhea. The levonorgestrel-releasing intrauterine system is also shown to prevent recurrence of dysmenorrhea and possibly endometriosis lesions. Dienogest, a new progestin, is shown to reduce the recurrence of endometrioma. Similar to the case of ovarian endometriosis, long-term postoperative medication after conservative surgery for deep infiltrating or extragenital endometriosis seems important, although data are limited. Regardless of the lesion and the medication type, patients who discontinued medication experienced a higher incidence of recurrence, indicating that the protective effect of these medications seems to vanish rapidly after the discontinuation. On the basis of these facts, together with the pathogenesis of recurrence (retrograde menstruation and ovulation), regular and prolonged medication until the patient wishes to conceive is highly recommended to prevent the postoperative recurrence of endometriosis.


International Atomic Energy Agency study with referring physicians on patient radiation exposure and its tracking: a prospective survey using a web-based questionnaire.
To assess the following themes among referring physicians: (A) importance of acquiring information about previous diagnostic exposures; (B) knowledge about radiation doses involved, familiarity with radiation units and, age-related radiosensitivity; (C) opinion on whether patients should be provided information about radiation dose and (D) self-assessment of appropriateness of referrals. A prospective survey using a web-based questionnaire. International survey among referring physicians. Referring physicians from 28 countries. Knowledge, opinion and practice of the four themes of the survey. All 728 responses from 28 countries (52.3% from developed and 47.7% from developing countries) indicated that while the vast majority (71.7%) of physicians feel that being aware of history of CT scans would always or mostly lead them to a better decision on referring patients for CT scans, only 43.4% often enquire about it. The majority of referring physicians (60.5%) stated that having a system that provides quick information about patient exposure history would be useful. The knowledge about radiation doses involved is poor, as only one-third (34.7%) of respondents chose the correct option of the number of chest x-rays with equivalence of a CT scan. In total, 70.9% of physicians stated that they do not feel uncomfortable when patients ask about radiation risk from CT scans they prescribe. Most physicians (85.6%) assessed that they have rarely prescribed CT scans of no clinical use in patient management. This first ever multinational survey among referring physicians from 28 countries indicates support for a system that provides radiation exposure history of the patient, demonstrates poor knowledge about radiation doses, supports radiation risk communication with patients and mandatory provisions for justification of a CT examination.


Superficial and Fundamental Correspondences in the Terahertz/IR (6-15 THz) Absorption Spectra of Aspirin and Benzoic Acid.
The terahertz absorption spectra of aspirin and benzoic acid have been measured in the range 200-500 cm-1 (6-15 THz). Density-functional theory (DFT) modeling has assigned fundamental vibrational modes to the observed absorption bands. Hydrogen bonds between the crystalline planes of aspirin resulted in better agreement between the experimental and modeled spectra than for benzoic acid. The similar structure of these two molecules suggests a similar absorption spectrum, which indeed was obtained experimentally. However, the detailed crystal structure and molecular differences result in some of the apparently common absorption bands being assigned to different vibrational modes through the DFT modeling. Thus, our study importantly reveals that even though crystalline forms of two similar molecules may have similar experimental terahertz spectra, the resemblance may be superficial rather than fundamental.


Factors predictive of postoperative morbidity and cost in patients with endometrial cancer.
To identify patient characteristics and perioperative factors predictive of 30-day morbidity and cost in patients with endometrial carcinoma. Data of consecutive patients treated with hysterectomy for endometrial carcinoma between 1999 and 2008 were collected prospectively. Thirty predictors were chosen from more than 130 collected based on anticipated clinical relevance and prevalence (more than 3%). Complications were graded per the Accordion Classification. Multivariable models were developed using stepwise and backward variable selection methods. Thirty-day cost analyses were expressed in 2010 Medicare dollars. Of 1,369 patients, significant predictors (P<.01) of grade 2 and higher morbidity included American Society of Anesthesiologists physical status classification system class higher than 2 (odds ratio [OR] 2.1), preoperative white blood count (OR 2.1 per doubling), history of deep vein thrombosis (OR 2.1), pelvic and para-aortic lymphadenectomy (OR 2.3 compared with no lymphadenectomy), laparotomy (OR 2.8 compared with minimally invasive surgery), myometrial invasion more than 50% (OR 2.4), operating time (OR 1.9 per doubling), and grade 4 surgical complexity (OR 2.7 compared with grade 1). After controlling for patient factors in a multivariable model, laparotomy, pelvic, and para-aortic lymphadenectomy were associated with significant increases in cost compared with the use of minimally invasive surgery or hysterectomy alone. This analysis identifies patient and perioperative care factors predictive of 30-day morbidity and cost. These data are useful for preoperative counseling, for defining equitable reimbursement and factors critical for risk-adjustment when comparing outcomes, and for identifying areas for quality improvement in patients with endometrial carcinoma. Given the marked increases in morbidity and cost associated with laparotomy and lymphadenectomy, minimally invasive surgery and selective lymphadenectomy should be standard treatment for patients with endometrial carcinoma.


Function of the p55 tumor necrosis factor receptor "death domain" mediated by phosphatidylcholine-specific phospholipase C.
Tumor necrosis factor (TNF) is a pleiotropic mediator of inflammation that has been implicated in the pathogenesis of devastating clinical syndromes including septic shock. We have investigated the role of a TNF-responsive phosphatidylcholine-specific phospholipase C (PC-PLC) for the cytotoxic and proinflammatory activity of TNF. We show here that the cytotoxicity signaled for by the so-called "death domain" of the p55 TNF receptor is associated with the activation of PC-PLC. The xanthogenate tricyclodecan-9-yl (D609), a specific and selective inhibitor of PC-PLC, blocked the cytotoxic action of TNF on L929 and Wehi164 cells. In vivo, D609 prevented both adhesion molecule expression in the pulmonary vasculature and the accompanying leukocyte infiltration in TNF-treated mice. More strikingly, D609 protects BALB/c mice from lethal shock induced either by TNF, lipopolysaccharide, or staphylococcal enterotoxin B. Together these findings imply PC-PLC as an important mediator of the pathogenic action of TNF, suggesting that PC-PLC may serve as a novel target for anti-inflammatory TNF antagonists.


Evaluation of the Standard Diagnostics Leptospira IgM ELISA for diagnosis of acute leptospirosis in Lao PDR.
The diagnostic utility of the Standard Diagnostics Leptospira IgM ELISA for detection of acute leptospirosis was assessed in febrile adults admitted in Vientiane, Laos. Using the cut-off suggested by the manufacturer [optical density (OD) ≥0.75], the assay demonstrated limited diagnostic capacity with a sensitivity of 95% and a specificity of 41% compared with the Leptospira microscopic agglutination test, which is the serological gold standard. However, re-evaluation of the diagnostic cut-off to an OD of 1.7 demonstrated improved diagnostic accuracy overall (sensitivity 70%; specificity 78%).


Color to gray: visual cue preservation.
Both commercial and scientific applications often need to transform color images into gray-scale images, e.g., to reduce the publication cost in printing color images or to help color blind people see visual cues of color images. However, conventional color to gray algorithms are not ready for practical applications because they encounter the following problems: 1) Visual cues are not well defined so it is unclear how to preserve important cues in the transformed gray-scale images; 2) some algorithms have extremely high time cost for computation; and 3) some require human-computer interactions to have a reasonable transformation. To solve or at least reduce these problems, we propose a new algorithm based on a probabilistic graphical model with the assumption that the image is defined over a Markov random field. Thus, color to gray procedure can be regarded as a labeling process to preserve the newly well--defined visual cues of a color image in the transformed gray-scale image. Visual cues are measurements that can be extracted from a color image by a perceiver. They indicate the state of some properties of the image that the perceiver is interested in perceiving. Different people may perceive different cues from the same color image and three cues are defined in this paper, namely, color spatial consistency, image structure information, and color channel perception priority. We cast color to gray as a visual cue preservation procedure based on a probabilistic graphical model and optimize the model based on an integral minimization problem. We apply the new algorithm to both natural color images and artificial pictures, and demonstrate that the proposed approach outperforms representative conventional algorithms in terms of effectiveness and efficiency. In addition, it requires no human-computer interactions.


Generating the Evidence for Typhoid Vaccine Introduction: Considerations for Global Disease Burden Estimates and Vaccine Testing Through Human Challenge.
Typhoid fever has had a major impact on human populations, with the causative pathogen Salmonella enterica serovar Typhi implicated in many outbreaks through history. The current burden of disease is estimated at 11-18 million infections annually, with the majority of infections located in Africa and South Asia. Data that have been used to estimate burden are limited to a small number of blood-culture surveillance studies, largely from densely populated urban centers. Extrapolating these data to estimate disease burden within and across countries highlights the lack of precision in global figures. A number of approaches have been developed, characterizing different geographical areas by water-based risk factors for typhoid infection or broader measures of health and development to more accurately extrapolate incidence. Recognition of the substantial disease burden is essential for policy-makers considering vaccine introduction. Typhoid vaccines have been in development for >100 years. The Vi polysaccharide (ViPS) and Ty21a vaccines have had a World Health Organization (WHO) recommendation for programmatic use in countries with high burden for 10 years, with 1 ViPS vaccine also having WHO prequalification. Despite this, uptake and introduction of these vaccines has been minimal. The development of a controlled human infection model (CHIM) enabled the accelerated testing of the newly WHO-prequalified ViPS-tetanus toxoid protein conjugate vaccine, providing efficacy estimates for the vaccine, prior to larger field trials. There is an urgency to the global control of enteric fever due to the escalating problem of antimicrobial resistance. With more accurate burden of disease estimates and a vaccine showing efficacy in CHIM, that control is now a possibility.


A Paleocene penguin from New Zealand substantiates multiple origins of gigantism in fossil Sphenisciformes.
One of the notable features of penguin evolution is the occurrence of very large species in the early Cenozoic, whose body size greatly exceeded that of the largest extant penguins. Here we describe a new giant species from the late Paleocene of New Zealand that documents the very early evolution of large body size in penguins. Kumimanu biceae, n. gen. et sp. is larger than all other fossil penguins that have substantial skeletal portions preserved. Several plesiomorphic features place the new species outside a clade including all post-Paleocene giant penguins. It is phylogenetically separated from giant Eocene and Oligocene penguin species by various smaller taxa, which indicates multiple origins of giant size in penguin evolution. That a penguin rivaling the largest previously known species existed in the Paleocene suggests that gigantism in penguins arose shortly after these birds became flightless divers. Our study therefore strengthens previous suggestions that the absence of very large penguins today is likely due to the Oligo-Miocene radiation of marine mammals.


High-Dimensional Bayesian Geostatistics.
With the growing capabilities of Geographic Information Systems (GIS) and user-friendly software, statisticians today routinely encounter geographically referenced data containing observations from a large number of spatial locations and time points. Over the last decade, hierarchical spatiotemporal process models have become widely deployed statistical tools for researchers to better understand the complex nature of spatial and temporal variability. However, fitting hierarchical spatiotemporal models often involves expensive matrix computations with complexity increasing in cubic order for the number of spatial locations and temporal points. This renders such models unfeasible for large data sets. This article offers a focused review of two methods for constructing well-defined highly scalable spatiotemporal stochastic processes. Both these processes can be used as "priors" for spatiotemporal random fields. The first approach constructs a low-rank process operating on a lower-dimensional subspace. The second approach constructs a Nearest-Neighbor Gaussian Process (NNGP) that ensures sparse precision matrices for its finite realizations. Both processes can be exploited as a scalable prior embedded within a rich hierarchical modeling framework to deliver full Bayesian inference. These approaches can be described as model-based solutions for big spatiotemporal datasets. The models ensure that the algorithmic complexity has ~ n floating point operations (flops), where n the number of spatial locations (per iteration). We compare these methods and provide some insight into their methodological underpinnings.


Susceptibility of bacterial isolates from Turkey--a report from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program.
The study monitored the susceptibility of nosocomial pathogens to meropenem and comparator antimicrobial agents isolated as part of the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program from Turkish university hospitals. In terms of minimum inhibitory concentration 90% (MIC(90)) values, meropenem was two- and eight-fold more active than imipenem against Escherichia coli and Klebsiella pneumoniae, respectively. 40.5% of K. pneumoniae, 23.1% of Klebsiella oxytoca and 15.3% of E. coli isolates were extended-spectrum beta-lactamase (ESBL) producers. Piperacillin/tazobactam was the most active agent against isolates of Pseudomonas aeruginosa, followed by meropenem and imipenem. Against Acinetobacter baumannii isolates, meropenem and imipenem were the most active agents. Continued surveillance by the MYSTIC Program appears to be prudent to help focus on effective empiric treatment regimens.


The HALT polycystic kidney disease trials: design and implementation.
Two HALT PKD trials will investigate interventions that potentially slow kidney disease progression in hypertensive autosomal dominant polycystic kidney disease (ADPKD) patients. Studies were designed in early and later stages of ADPKD to assess the impact of intensive blockade of the renin-angiotensin-aldosterone system and level of BP control on progressive renal disease. Design, settings, participants, and measurements: PKD-HALT trials are multicenter, randomized, double-blind, placebo-controlled trials studying 1018 hypertensive ADPKD patients enrolled over 3 yr with 4 to 8 yr of follow-up. In study A, 548 participants, estimated GFR (eGFR) of >60 ml/min per 1.73 m(2) were randomized to one of four arms in a 2-by-2 design: combination angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) therapy versus ACEi monotherapy at two levels of BP control. In study B, 470 participants, eGFR of 25 to 60 ml/min per 1.73 m2 compared ACEi/ARB therapy versus ACEi monotherapy, with BP control of 120 to 130/70 to 80 mmHg. Primary outcomes of studies A and B are MR-based percent change kidney volume and a composite endpoint of time to 50% reduction of baseline estimated eGFR, ESRD, or death, respectively. This report describes design issues related to (1) novel endpoints such as kidney volume, (2) home versus office BP measures, and (3) the impact of RAAS inhibition on kidney and patient outcomes, safety, and quality of life. HALT PKD will evaluate potential benefits of rigorous BP control and inhibition of the renin-angiotensin-aldosterone system on kidney disease progression in ADPKD.


Non-invasive Diagnosis of Fibrosis in Non-alcoholic Fatty Liver Disease.
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed as well as in developing countries. Its prevalence continues to rise currently affecting approximately 20-30% of adults and 10% of children in the United States. Non-alcoholic fatty liver disease represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign non-progressive clinical course, to non-alcoholic steatohepatitis (NASH), a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Liver biopsy remains the gold standard for evaluating the degree of hepatic necroinflammation and fibrosis; however, several non-invasive investigations, such as serum biomarkers, have been developed to establish the diagnosis and also to evaluate treatment response. There has been a substantial development of non-invasive risk scores, biomarker panels, and radiological modalities to identify at risk patients with NAFLD without recourse to liver biopsy on a routine basis. Examples include combination of serum markers like NAFLD fibrosis score (NFS), BARD score, fibrometer, FIB4, and non-invasive tools like fibroscan which assess fibrosis in patients with NAFLD. Other markers of fibrosis that have been evaluated include high-sensitivity C-reactive protein, plasma pentraxin 3, interleukin-6, and cytokeratin-18. This review focuses on the methods currently available in daily clinical practice in hepatology and touches briefly on the potential future markers under investigation.


Enhancement of absolute fracture risk prognosis with genetic marker: the collagen I alpha 1 gene.
An important objective of genetic research in osteoporosis is to translate genotype data into the prognosis of fracture. The present study sought to develop a prognostic model for predicting osteoporotic fracture by using information from a genetic marker and clinical risk factors. It was designed as a prospective epidemiological study which involved 894 women of Caucasian background aged 60+ years who had been followed for a median of 9 years (from 1989 and 2008, range 0.2-18 years). During the follow-up period, fragility fracture was ascertained by X-ray reports for all women. Bone mineral density (BMD) at the femoral neck was measured by dual-energy X-ray absorptiometry. Genotypes of the Sp1 binding site in the first intron of the collagen I alpha 1 (COLIA1) gene polymorphism were determined by polymerase chain reaction, digestion with BalI restriction enzyme, and agarose gel electrophoresis. The relationship between COL1A1 genotype and fracture was assessed by the Cox proportional hazards model, from which nomograms were developed for individualizing the risk of fracture. The distribution of COL1A1 genotypes was consistent with the Hardy-Weinberg equilibrium law: GG (63.8%), GT (32.6%), and TT (3.6%). During the follow-up period, there were 322 fractures, including 77 hip and 127 vertebral fractures. There was an overrepresentation of the TT genotype in the fracture group (6.2%) compared with the nonfracture group (2.3%). Compared with carriers of GT and GG, women carrying the TT genotype had increased risk of any fracture (relative risk [RR] = 1.91, 95% CI 1.21-3.00), hip fracture (RR = 3.67, 95% CI 1.69-8.00), and vertebral fracture (RR = 3.36, 95% CI 1.81-6.24). The incorporation of COL1A1 genotypes improved the risk reclassification by 2% for any fragility fracture, 4% for hip fracture, and 5% for vertebral fracture, beyond age, BMD, prior fracture, and fall. Three nomograms were constructed for predicting fracture risk in an individual woman based on age, BMD, and COLIA1 genotypes. These data suggest that the COLIA1 Sp1 polymorphism is associated with the risk of fragility fracture in Caucasian women and that the polymorphism could enhance the predictive accuracy of fracture prognosis. The nonograms presented here can be useful for individualizing the short- and intermediate-term prognosis of fracture risk and help identify high-risk individuals for intervention for appropriate management of osteoporosis.


Comparison of fast electron transfer kinetics at platinum, gold, glassy carbon and diamond electrodes using Fourier-transformed AC voltammetry and scanning electrochemical microscopy.
Heterogeneous electron transfer (ET) processes at electrode/electrolyte interfaces are of fundamental and applied importance and are extensively studied by a range of electrochemical techniques, all of which have various attributes but also limitations. The present study focuses on the one-electron oxidation of tetrathiafulvalene (TTF) and reduction of tetracyanoquinodimethane (TCNQ) in acetonitrile solution by two powerful electrochemical techniques: Fourier-transformed large amplitude alternating current voltammetry (FTACV); and scanning electrochemical microscopy (SECM), both of which are supported by detailed theoretical models. At conventional Pt, Au and glassy carbon (GC) electrode materials, the apparent (overall) charge transfer kinetic values determined by FTACV give standard ET rate constants, k, that are fast and close to the reversible limit. They are in good agreement with highly localised k measurements determined by SECM under conditions of high mass transport rates. In contrast, the impact of both the complex heterogeneous surface of polycrystalline boron doped diamond (pBDD) and degenerate p-type doping results in a range of k values across the electrode surface compared to the overall k measured for both processes studied. Moreover, the reduced availability of charge carriers at the electrode surface, at each energy state, compared to a metal, which decreases as the potential becomes more negative, results in lower k0 values at pBDD than Pt, Au and GC. The measurement technique also has an influence: SECM measurements are made at much higher local current density than FTACV, and for TCNQ/TCNQ˙-, which has the more negative formal potential, limited charge carrier availability results in k > k, with unusual apparent charge transfer coefficients and voltammetric waveshapes from SECM. These data thus highlight the importance of understanding the influence of the measurement technique and further demonstrate how ET kinetics at pBDD differ from conventional electrodes, in this case for processes in an organic solvent, which has received much less attention compared to aqueous systems for studies with pBDD.


Acute Disseminated Encephalomyelitis after Oral Therapy with Herbal Extracts: A Case Report.
Acute disseminated encephalomyelitis (ADEM) is a rare demyelinating disease of the central nervous system, commonly attributed to infections or vaccinations. Toxic or allergenic compounds can also trigger a response in the immune system and may cause demyelination. We present a case with ADEM after using oral herbal medications. A 25 year-old male developed bilateral central facial palsy and severe quadriparesis after taking herbal drugs (containing echinacea and many other herbal ingredients) for two weeks. He had used the extract to increase his potency and reproductivity. He had no past history of recent immunization or viral infection. The clinical findings, cerebrospinal fluid (CSF) analysis and brain magnetic resonance imaging (MRI) were compatible with ADEM. The neurological findings were improved after seven doses of pulse methylprednisolone treatment. To our knowledge, this is the third report in the literature that links herbal therapy and demyelinating disease. Most of the ADEM cases related to herbal therapy in the literature similarly used echinacea. It is our opinion that other ingredients of the herbal extract used by our case, besides echinacea, could have the potential to cause a trigger in the immune system. Further studies are needed to clarify the immunological effects of different kinds of herbal compounds, as well as the effects of different parts of the plants and the results of various dosages. Moreover, ingredients should also be tested for toxicity, adverse effects and drug interactions.


Airway Care Interventions for Invasively Ventilated Critically Ill Adults-A Dutch National Survey.
Airway care interventions may prevent accumulation of airway secretions and promote their evacuation, but evidence is scarce. Interventions include heated humidification, nebulization of mucolytics and/or bronchodilators, manual hyperinflation and use of mechanical insufflation-exsufflation (MI-E). Our aim is to identify current airway care practices for invasively ventilated patients in intensive care units (ICU) in the Netherlands. A self-administered web-based survey was sent to a single pre-appointed representative of all ICUs in the Netherlands. Response rate was 85% (72 ICUs). We found substantial heterogeneity in the intensity and combinations of airway care interventions used. Most (81%) ICUs reported using heated humidification as a routine prophylactic intervention. All (100%) responding ICUs used nebulized mucolytics and/or bronchodilators; however, only 43% ICUs reported nebulization as a routine prophylactic intervention. Most (81%) ICUs used manual hyperinflation, although only initiated with a clinical indication like difficult oxygenation. Few (22%) ICUs used MI-E for invasively ventilated patients. Use was always based on the indication of insufficient cough strength or as a continuation of home use. In the Netherlands, use of routine prophylactic airway care interventions is common despite evidence of no benefit. There is an urgent need for evidence of the benefit of these interventions to inform evidence-based guidelines.


Endangered species: review of law triggered by tellico impasse.
To condense the evolution of life on Earth . . . suppose the whole history of the planet is contained within a single year. The conditions suitable for life do not develop until late June. The oldest known fossils are living creatures around mid-October, and life is abundant . . . by the end of that month. In mid-December, dinosaurs and other reptiles dominate the scene. Mammals . . . appear in large numbers only a little before Christmas. On New Year's Eve, at about five minutes to midnight, man emerges. . . . The period since 1600 A.D., when man-induced extinction began to increase rapidly, amounts to three seconds, and the quarter century just begun, when the disappearance of species may be on the scale of all the mass extinctions of the past put together, will take another sixth of a second-a twinkling of an eye in evolutionary time.


Comparison of deep wound infection rates using a synthetic dural substitute (neuro-patch) or pericranium graft for dural closure: a clinical review of 1 year.
The need to repair dural defects has prompted the use of dura mater substitutes. Many synthetic materials have been used for dural closure. Neuro-Patch (B. Braun Médical S.A., Boulogne, France) is a nonabsorbable microporous fleece composed of polyester urethane that has been approved for human use by the European Union since 1995. To the best of our knowledge, no clinical series with Neuro-Patch have been published thus far, particularly with regard to septic complications. The aim of our study was to compare the safety of Neuro-Patch with that of pericranium graft with regard to postoperative wound infections. This is a retrospective study of 1 year's experience including all patients who underwent dural plasty with a Neuro-Patch (n = 61) or pericranium graft (n = 63). The follow-up period was at least 12 months after surgery. Before wound infection rates in the two groups were compared, factors suspected of being risks for neurosurgical site infection were evaluated. Patient characteristics (mean age, neurological diagnosis), surgical procedures, prophylactic antibiotics, and risk factors for surgical infections (including duration of surgery, emergency, contaminated operations, and external cerebrospinal fluid drainage) were similar in the Neuro-Patch and pericranium groups. Deep wound infection rates in the Neuro-Patch and pericranium groups were 15 and 5%, respectively (P = 0.06), and cerebrospinal fluid leaks were significantly more frequent in the Neuro-Patch group (13 versus 1.6%, P < 0.05). The results of our investigations show that Neuro-Patch raised the risk of wound infection, as do foreign materials implanted in the body. Synthetic dural grafts should be reserved for when autologous grafts are not sufficient or possible. An extensive prospective multicenter randomized trial is needed to confirm our results.