An unusual case of recurrent hyperparathyroidism and papillary thyroid cancer.
To report an unusual occurrence of recurrent hyperparathyroidism due to papillary thyroid carcinoma. We describe the clinical history, physical examination findings, laboratory values, imaging findings, and pathologic findings of a woman who developed recurrent hyperparathyroidism 13 years after successful parathyroidectomy. A 59-year-old woman presented to our clinic with recurrent primary hyperparathyroidism. In 1994, she presented with nephrolithiasis and underwent resection of a right superior parathyroid adenoma that resulted in clinical and biochemical cure. Her clinical course had been followed at periodic intervals, and she had been symptom-free and normocalcemic. In 2007, she again developed nephrolithiasis and was documented to have recurrent hyperparathyroidism. Imaging studies suggested a parathyroid adenoma near the right inferior pole of the thyroid. The patient had reoperative neck exploration. No obvious parathyroid adenoma was found and a right thyroid lobectomy was performed, which resulted in normalization of intraoperative intact parathyroid hormone levels, and the incision was closed. Final pathology demonstrated no parathyroid adenoma, but instead, a 1-cm papillary thyroid carcinoma that stained positive for parathyroid hormone. More than 6 months after surgery, she remains clinically and biochemically cured. Recurrent hyperparathyroidism occurs secondary to multiple causes. This case demonstrates the challenge a surgeon faces in managing recurrent disease and highlights a rare phenomenon of papillary thyroid cancer causing recurrent hyperparathyroidism.


Hepatic Inflammation Confers Protective Immunity Against Liver Stages of Malaria Parasite.
Deciphering the mechanisms by which Plasmodium parasites develop inside hepatocytes is an important step toward the understanding of malaria pathogenesis. We propose that the nature and the magnitude of the inflammatory response in the liver are key for the establishment of the infection. Here, we used mice deficient in the multidrug resistance-2 gene (Mdr2-/-)-encoded phospholipid flippase leading to the development of liver inflammation. Infection of Mdr2-/- mice with Plasmodium berghei ANKA (PbANKA) sporozoites (SPZ) resulted in the blockade of hepatic exo-erythrocytic forms (EEFs) with no further development into blood stage parasites. Interestingly, cultured primary hepatocytes from mutant and wild-type mice are equally effective in supporting EEF development. The abortive infection resulted in a long-lasting immunity in Mdr2-/- mice against infectious SPZ where neutrophils and IL-6 appear as key effector components along with CD8+ and CD4+ effector and central memory T cells. Inflammation-induced breakdown of liver tolerance promotes anti-parasite immunity and provides new approaches for the design of effective vaccines against malaria disease.


The study of CD20 and CD45.Ro antibodies in the inflammatory infiltrate involved in acne and seborrheic dermatitis.
The aim of our study was to evaluate the role of CD20 and CD45.Ro antibodies in acne and seborrheic dermatitis. A number of 20 patients with papular, pustular or nodular acne and another 20 patients with seborrheic dermatitis were available for our study. We removed bioptic material from all of them and we perform histochemical and immunohistochemical processing within the Laboratory of Histology, Histopathology and Immunohistochemistry of the University of Medicine and Pharmacy of Craiova. In acne, we could reveal a positive CD45.Ro immunomarking in rare lymphoid cells situated in the middle derma at a distance from the affected pilosebaceous follicle and in the inflammatory infiltrate subepidermically, and also a negative immunomarking in the inflammatory cells from the proximity of the affected pilosebaceous follicle. In patients with seborrheic dermatitis we noticed a positive immunomarking infiltrate of the papillary derma and a positive immunomarking of membrane for CD45.Ro in many lymphoid cells of the inflammatory infiltrate situated in the papillary derma predominantly disposed perivasculary. Conclusions. The absence of the cells marked with CD45.Ro in the proximity of the pilosebaceous follicle interested in acne excludes the direct participation of B- and T-lymphocytes in the perifollicular inflammatory process, though the T-lymphocytes can be revealed in a small number at a distance from the affected follicle. The inflammatory infiltrate from the seborrheic dermatitis proved to be rich in positive CD45.Ro cells and poorer in positive CD20 cells.


Management of Failed Surgery for Anterior Glenohumeral Instability: Synopsis of Clinical Evidence.
Failed surgical treatment of anterior shoulder instability should be treated according to clinical principles similar to primary stabilization by addressing risk factors related to the damaged static glenohumeral stabilizers (labrum, capsule and its components, and bony damage to the humeral head and scapular glenoid). In relatively rare conditions when failed primary surgery involves patients with functionally low demands, conservative treatment by strengthening dynamic muscular stabilizers might be considered; otherwise, surgical revision should be strongly considered aimed at improving quality of life. Although the overall failure rate following primary and revision surgery is expected to be below 4%, it is clear that revision surgery is technically demanding. Therefore, the initial recognition and correction of the exact pathology causing glenohumeral instability is crucial to avoid failure of primary surgery and to facilitate the success of the revision procedure, if necessary.


Molecular subtype-specific clinical diagnosis of prion diseases.
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare transmissible disease caused by accumulation of pathological prion protein (PrP(sc)) in the CNS. According to the codon 129 polymorphism (methionine or valine) and the prion protein type 1 or 2, a classification into distinct subtypes was established. Further analysis of these subtypes detected atypical clinical forms with longer disease duration or younger age at onset. The CJD subtype influences sensitivity of the technical investigations such as 14-3-3 in CSF, periodic sharp wave complexes in the EEG or hyperintense basal ganglia in MRI. A further characterization of these subtypes is important for reliable diagnosis and identification of rare disease variants. The aim is to establish specific patterns of test results and clinical findings. These improvements in diagnostics may be the reason for the apparent increase in sCJD incidence in Germany from 0.9 in 1994 to 1.6 in a million in 2005. Despite careful surveillance, no patient with variant CJD has been detected to date in Germany. Here we present the data of the CJD surveillance of the last 13 years. Additionally, the improvements in diagnostics and differential diagnosis are discussed.


The risk of elevated prolactin levels in pediatric patients exposed to antipsychotics for the treatment of schizophrenia and schizophrenia spectrum disorders: protocol for a systematic review and meta-analysis.
Antipsychotic medications, particularly second-generation antipsychotics, are increasingly being used to alleviate the symptoms of schizophrenia and other severe mental disorders in the pediatric population. While evidence-based approaches examining efficacy and safety outcomes have been reported, no review has evaluated prolactin-based adverse events for antipsychotic treatments in schizophrenia and schizophrenia spectrum disorders. Searches involving MEDLINE, EMBASE, CENTRAL, PsycINFO, and clinical trial registries (ClinicalTrials.gov, Drug Industry Document Archive [DIDA], International Clinical Trials Registry Platform [ICTRP]) will be used to identify relevant studies. Two reviewers will independently screen abstracts and relevant full-text articles of the papers identified by the initial search according to the prospectively defined eligibility criteria. Data extraction will be conducted in duplicate independently. Pairwise random effects meta-analyses and network meta-analyses will be conducted on individual drug and class effects where appropriate. This systematic review will evaluate prolactin-based adverse events of first- and second-generation antipsychotics in the pediatric population with schizophrenia and schizophrenia spectrum disorders. It will also seek to strengthen the evidence base of the safety of antipsychotics by incorporating both randomized controlled trials and observational studies. PROSPERO CRD42014009506.


Embracing diversity and inclusivity in an academic setting: Insights from the Organization for Human Brain Mapping.
Scientific research aims to bring forward innovative ideas and constantly challenges existing knowledge structures and stereotypes. However, women, ethnic and cultural minorities, as well as individuals with disabilities, are systematically discriminated against or even excluded from promotions, publications, and general visibility. A more diverse workforce is more productive, and thus discrimination has a negative impact on science and the wider society, as well as on the education, careers, and well-being of individuals who are discriminated against. Moreover, the lack of diversity at scientific gatherings can lead to micro-aggressions or harassment, making such meetings unpleasant, or even unsafe environments for early career and underrepresented scientists. At the Organization for Human Brain Mapping (OHBM), we recognized the need for promoting underrepresented scientists and creating diverse role models in the field of neuroimaging. To foster this, the OHBM has created a Diversity and Inclusivity Committee (DIC). In this article, we review the composition and activities of the DIC that have promoted diversity within OHBM, in order to inspire other organizations to implement similar initiatives. Activities of the committee over the past four years have included (a) creating a code of conduct, (b) providing diversity and inclusivity education for OHBM members, (c) organizing interviews and symposia on diversity issues, and (d) organizing family-friendly activities and providing childcare grants during the OHBM annual meetings. We strongly believe that these activities have brought positive change within the wider OHBM community, improving inclusivity and fostering diversity while promoting rigorous, ground-breaking science. These positive changes could not have been so rapidly implemented without the enthusiastic support from the leadership, including OHBM Council and Program Committee, and the OHBM Special Interest Groups (SIGs), namely the Open Science, Student and Postdoc, and Brain-Art SIGs. Nevertheless, there remains ample room for improvement, in all areas, and even more so in the area of targeted attempts to increase inclusivity for women, individuals with disabilities, members of the LGBTQ+ community, racial/ethnic minorities, and individuals of lower socioeconomic status or from low and middle-income countries. Here, we present an overview of the DIC's composition, its activities, future directions and challenges. Our goal is to share our experiences with a wider audience to provide information to other organizations and institutions wishing to implement similar comprehensive diversity initiatives. We propose that scientific organizations can push the boundaries of scientific progress only by moving beyond existing power structures and by integrating principles of equity and inclusivity in their core values.


MRI findings of rapidly progressive hepatocellular carcinoma.
The purpose of this study is to determine the magnetic resonance imaging (MRI) and patient characteristics in subjects with hepatocellular carcinoma (HCC) that exhibit rapid progression. In this unblinded retrospective study, initial and follow up MR images were reviewed, before and after rapid progression of HCC, respectively. Rapid progression was defined as a lesion <3 cm which exhibited >3 cm increase in one year or 2 cm increase in 6 months. Patient characteristics and MRI findings were determined using clinical information from the institution clinical information system and records from the Radiology and Pathology Departments, Hepatology Division and Liver Transplant Service of the Department of Medicine. Seven individuals were identified with HCC that showed rapid progression. Five of the patients had underlying hepatitis C, one had alcoholic hepatitis, and one had immunosuppression due to liver transplantation. On initial MRI, six patients had early intense ring enhancing lesions, which rapidly progressed in size. Five patients died within 6 months, one within 1 year after progression despite treatment. Six of the seven patients also had multiple other liver nodules on initial MRI; those that showed ring enhancement rapidly progressed but those without, did not show rapid progression. Patients with rapidly progressive HCC had underlying hepatitis C and intense ring enhancement on initial MRI. This group of patients should be evaluated further to determine if they might benefit from early intervention.


Is health-related quality of life between 90 and 180 days following stroke associated with long-term unmet needs?
Understanding the relationship between health-related quality of life (HRQoL) and long-term unmet needs is important for guiding services to optimise life following stroke. We investigated whether HRQoL between 90 and 180 days following stroke was associated with long-term unmet needs. Data from Australian Stroke Clinical Registry (AuSCR) registrants who participated in the Australian Stroke Survivor Needs Survey were used. Outcome data, including the EQ-5D, are routinely collected in AuSCR between 90 and 180 days post-stroke. Unmet needs were assessed at a median of 2 years and categorised into: health; everyday living; work/leisure; and support domains. Multivariable regression was used to determine associations between the EQ-5D dimensions and the likelihood of experiencing unmet needs and the visual analogue scale (VAS) (rating 0-100) and number of reported unmet needs. In total, 173 AuSCR registrants completed the Needs Survey (median age 69 years, 67 % male; 77 % ischaemic stroke). VAS scores were negatively associated with the number of reported long-term unmet needs [irr 0.98, (95 % CI 0.97, 0 99) p < 0.001]. Having EQ-5D activity limitations was associated with unmet living needs (aOR 4.5, 95 % CI 1.1, 18.8). Requiring living supports at 90-180 days was associated with unmet health needs (aOR 4.9, 95 % CI 1.5, 16.1). Those with pain at 90-180 days were less likely to report unmet health (aOR 0.09, 95 % CI 0.02, 0.4) and support needs (aOR 0.2, 95 % CI 0.06, 0.6). Routinely collected HRQoL data can identify survivors at risk of experiencing long-term unmet needs. This information is important for targeting service delivery to optimise outcomes following stroke.


Prescribing for pain--how do nurses contribute? A national questionnaire survey.
To provide information on the profile and practice of nurses in the UK who prescribe medication for pain. Pain is widely under-reported and under-treated and can have negative consequences for health and psychosocial well-being. Indications are that nurses can improve treatment and access to pain medications when they prescribe. Whilst nurses working in many practice areas treat patients with pain, little is known about the profile, prescribing practice or training needs of these nurses. A descriptive questionnaire survey. An online questionnaire was used to survey 214 nurses who prescribed for pain in the UK between May and July 2010. Data were analysed using descriptive statistics and non-parametric tests. Half the participants (50%) worked in primary care, 32% in secondary care and 14% worked across care settings. A range of services were provided, including general practice, palliative care, pain management, emergency care, walk-in-centres and out-of-hours. The majority (86%) independently prescribed 1-20 items per week. Non-opioid and weak opioids analgesics were prescribed by most (95%) nurses, whereas fewer (35%) prescribed strong opioids. Training in pain had been undertaken by 97% and 82% felt adequately trained, although 28% had problems accessing training. Those with specialist training prescribed a wider range of pain medications, were more likely to prescribe strong opioids and were more often in pain management roles. Nurses prescribe for pain in a range of settings with an emphasis on the treatment of minor ailments and acute pain. A range of medications are prescribed, and most nurses have access to training. The nursing contribution to pain treatment must be acknowledged within initiatives to improve pain management. Access to ongoing training is required to support nurse development in this area of practice to maximise benefits.


The evidence-base for complementary medicine in children: a critical overview of systematic reviews.
The use of complementary and alternative medicine (CAM) in paediatric populations is common yet, to date, there has been no synthesis of the evidence of its effectiveness in that population. This overview of systematic review evaluates the evidence for or against the effectiveness of CAM for any childhood condition. Medline, AMED and Cochrane were searched from inception until September 2009. Reference lists of retrieved articles were hand-searched. Experts in the field of CAM were contacted. No language restrictions were applied. 17 systematic reviews were included in this overview, covering acupuncture, chiropractic, herbal medicine, homeopathy, hypnotherapy, massage and yoga. Results were unconvincing for most conditions although there is some evidence to suggest that acupuncture may be effective for postoperative nausea and vomiting, and that hypnotherapy may be effective in reducing procedure-related pain. Most of the reviews failed to mention the incidence of adverse effects of CAMs. Although there is some encouraging evidence for hypnosis, herbal medicine and acupuncture, there is insufficient evidence to suggest that other CAMs are effective for the treatment of childhood conditions. Many of the systematic reviews included in this overview were of low quality, as were the randomised clinical trials within those reviews, further reducing the weight of that evidence. Future research in CAM for children should conform to the reporting standards outlined in the CONSORT and PRISMA guidelines.


Do online social media cut through the constraints that limit the size of offline social networks?
The social brain hypothesis has suggested that natural social network sizes may have a characteristic size in humans. This is determined in part by cognitive constraints and in part by the time costs of servicing relationships. Online social networking offers the potential to break through the glass ceiling imposed by at least the second of these, potentially enabling us to maintain much larger social networks. This is tested using two separate UK surveys, each randomly stratified by age, gender and regional population size. The data show that the size and range of online egocentric social networks, indexed as the number of Facebook friends, is similar to that of offline face-to-face networks. For one sample, respondents also specified the number of individuals in the inner layers of their network (formally identified as support clique and sympathy group), and these were also similar in size to those observed in offline networks. This suggests that, as originally proposed by the social brain hypothesis, there is a cognitive constraint on the size of social networks that even the communication advantages of online media are unable to overcome. In practical terms, it may reflect the fact that real (as opposed to casual) relationships require at least occasional face-to-face interaction to maintain them.


Transcriptional consequences of aneuploidy.
Aneuploidy, or an aberrant karyotype, results in developmental disabilities and has been implicated in tumorigenesis. However, the causes of aneuploidy-induced phenotypes and the consequences of aneuploidy on cell physiology remain poorly understood. We have performed a metaanalysis on gene expression data from aneuploid cells in diverse organisms, including yeast, plants, mice, and humans. We found highly related gene expression patterns that are conserved between species: genes that were involved in the response to stress were consistently upregulated, and genes associated with the cell cycle and cell proliferation were downregulated in aneuploid cells. Within species, different aneuploidies induced similar changes in gene expression, independent of the specific chromosomal aberrations. Taken together, our results demonstrate that aneuploidies of different chromosomes and in different organisms impact similar cellular pathways and cause a stereotypical antiproliferative response that must be overcome before transformation.


The Case: Chronic Kidney Disease Unmasked by Single-Subject Research.
We present a 42-year-old man with a BMI of 32, who was referred because of proteinuria and decreased renal function. We were impressed by his markedly muscular physique. A renal biopsy was performed, which showed focal segmental glomerular sclerosis (FSGS). Is this patient merely an obese person with FSGS or is something else going on here? We performed extensive clinical and laboratory examinations, genetic testing, and anthropometric data monitoring over time. We transferred our methodology for routine FSGS mutation screening (Sanger sequencing) to the Ion Torrent PGM platform with a new custom-targeted NGS gene panel (Ion Ampliseq FSGS panel) and tested the performance of the system in two cohorts of patients with FSGS. We discuss FSGS in bodybuilders, including possible mechanisms, and review the literature.


Behavior of Four Olive Cultivars During Salt Stress.
Olive is considered as a moderately salt tolerant plant, however, tolerance to salt appears to be cultivar-dependent and genotypic responses have not been extensively investigated. In this work, saline stress was induced in four olive cultivars: Arbequina, Koroneiki, Royal de Cazorla and Fadak 86. The plants were grown in 2.5 l pots containing 60% peat and 40% of pumice mixture for 240 days and were irrigated three times a week with half-strength Hoagland solution containing 0, 100 and 200 mM NaCl. The effects of salt stress on growth, physiological and biochemical parameters were determined after 180, 210, and 240 days of treatment. Saline stress response was evaluated in leaves by measuring the activity of GSH and CAT enzymatic activity, as well as proline levels, gas exchanges, leaves relative water content and chlorophyll content, and proline content. All the studied cultivars showed a decrease in Net Photosynthesis, leaves chlorophyll content and plant growth (mainly leaves dry weight) and an increase in the activity of GSH and CAT. In addition, the reduction of proline content in leaf tissues, induced an alteration of osmotic regulation. Among the studied cultivars Royal and Koroneiki better counteracting the effects of saline stress thanks to a higher activity of two antioxidant enzymes.


The phonation critical condition in rectangular glottis with wide prephonatory gaps.
The effect of the pressure recovery at glottal exit is introduced to modify the one-mass model. Using the modified one-mass model, the phonation critical condition, including phonation threshold pressure and phonation threshold flow, is analyzed by using the small-amplitude oscillation theory. It is found that the phonation threshold pressure is not sensitive to the change of the prephonatory glottal width at a wide glottal gap. This result agrees with previous experimental observations and suggests that the low slope of dependence of phonation threshold pressure on prephonatory gap found by Chan and Titze [J. Acoust. Soc. Am. 119, 2351-2362 (2006)] could be a consequence of the pressure recovery effect at the glottal exit. In addition, it is predicted that the phonation threshold flow is always significantly increased with the prephonatory gap even at a wide prephonatory glottal gap. Therefore, the phonation threshold flow has an advantage in assessing the phonatory system at a wide prephonatory gap in comparison with the phonation threshold pressure. The phonation threshold flow can be a useful aerodynamic parameter for pathological conditions in which the incomplete glottal gap is often seen.


Plasma observations during the Mars atmospheric "plume" event of March-April 2012.
We present initial analysis and conclusions from plasma observations made during the reported "Mars plume event" of March - April 2012. During this period, multiple independent amateur observers detected a localized, high-altitude "plume" over the Martian dawn terminator [Sanchez-Lavega et al., Nature, 2015, doi:10.1038/nature14162], the cause of which remains to be explained. The estimated brightness of the plume exceeds that expected for auroral emissions, and its projected altitude greatly exceeds that at which clouds are expected to form. We report on in-situ measurements of ionospheric plasma density and solar wind parameters throughout this interval made by Mars Express, obtained over the same surface region, but at the opposing terminator. Measurements in the ionosphere at the corresponding location frequently show a disturbed structure, though this is not atypical for such regions with intense crustal magnetic fields. We tentatively conclude that the formation and/or transport of this plume to the altitudes where it was observed could be due in part to the result of a large interplanetary coronal mass ejection (ICME) encountering the Martian system. Interestingly, we note that the only similar plume detection in May 1997 may also have been associated with a large ICME impact at Mars.


Anthroposophic medicine: an integrative medical system originating in europe.
Anthroposophic medicine is an integrative multimodal treatment system based on a holistic understanding of man and nature and of disease and treatment. It builds on a concept of four levels of formative forces and on the model of a three-fold human constitution. Anthroposophic medicine is integrated with conventional medicine in large hospitals and medical practices. It applies medicines derived from plants, minerals, and animals; art therapy, eurythmy therapy, and rhythmical massage; counseling; psychotherapy; and specific nursing techniques such as external embrocation. Anthroposophic healthcare is provided by medical doctors, therapists, and nurses. A Health-Technology Assessment Report and its recent update identified 265 clinical studies on the efficacy and effectiveness of anthroposophic medicine. The outcomes were described as predominantly positive. These studies as well as a variety of specific safety studies found no major risk but good tolerability. Economic analyses found a favorable cost structure. Patients report high satisfaction with anthroposophic healthcare.


Mephedrone use and associated adverse effects in school and college/university students before the UK legislation change.
Mephedrone is a synthetic cathinone that is commonly used as a recreational drug among those who attend nightclubs. There have been increasing reports of toxicity associated with its use and it was controlled as a Class B drug under the Misuse of Drugs Act (1971) in the UK on 16 April 2010. There has been a suggestion from media reports that mephedrone use is common in children/students but there is no data on the prevalence of its use among the general population. The aim of this study was to determine the prevalence and frequency of use of mephedrone among school and college/university aged individuals and to collect data on the sources of mephedrone and acute harm related to its use. Data was collected using a questionnaire survey in schools, colleges and universities in the Tayside area of Scotland, UK in February 2010. A total of 1006 individuals completed the survey [501 (49.8%) males and 505 (50.2%) females], of whom 349 classified their educational institute as a school and 657 as a college/university. Among them 205 (20.3%) reported previous use of mephedrone; 23.4% reported using only using mephedrone on one occasion previously, although 4.4% reported daily use. A total of 56% of those who had used mephedrone, reported at least one unwanted effect associated with its use. A total of 17.6% of users reported 'addiction or dependence' symptoms associated with their mephedrone use. A total of 48.8% of users sourced mephedrone from street level dealers, 10.7% from the Internet. We have shown in this study that the use of mephedrone among school and college/university students is common and that users found it easy to obtain. There was a high prevalence of unwanted effects associated with its use. Further work is needed to determine the impact of the recent changes in the UK legislation relating to mephedrone and other related cathinones and whether this has been effective in reducing the prevalence of mephedrone use.


Investigation of genomic methylation status using methylation-specific and bisulfite sequencing polymerase chain reaction.
Epigenetic modification plays a central role in the regulation of gene expression and therefore in the development of disease states. In particular, genomic methylation of cytosines within CpG dinucleotides is crucial to development, gene silencing, and chromosome inactivation. Importantly, aberrant methylation profiles of various genes are associated with cancer as well as autoimmune disease, psychiatric and neurodegenerative disorders, diabetes, and heart disease. Various methods are available for the detection and quantification of methylation in a given sample. Most of these methods rely upon bisulfite conversion of DNA, which converts unmethylated cytosines to uracil, while methylated cytosines remain as cytosines. Methylation-specific amplification of DNA can be used to detect methylation at one or more (typically up to about 4) CpG sites by using primers specific to either methylated or unmethylated DNA. Alternatively, amplification of both methylated and unmethylated DNA followed by sequencing can be used to detect methylation status at multiple CpG sites. The following chapter provides protocols for bisulfite conversion of DNA, methylation-specific PCR and bisulfite sequencing PCR.


Methodological challenges in evaluating health care financing equity in data-poor contexts: lessons from Ghana, South Africa and Tanzania.
Measurement of the incidence of health financing contributions across socio-economic groups has proven valuable in informing health care financing reforms. However, there is little evidence as to how to carry out financing incidence analysis (FIA) in lower income settings. We outline some of the challenges faced when carrying out a FIA in Ghana, Tanzania and South Africa and illustrate how innovative techniques were used to overcome data weaknesses in these settings. FIA was carried out for tax, insurance and out-of-pocket (OOP) payments. The primary data sources were Living Standards Measurement Surveys (LSMS) and household surveys conducted in each of the countries; tax authorities and insurance funds also provided information. Consumption expenditure and a composite index of socioeconomic status (SES) were used to assess financing equity. Where possible conventional methods of FIA were applied. Numerous challenges were documented and solution strategies devised. LSMS are likely to underestimate financial contributions to health care by individuals. For tax incidence analysis, reported income tax payments from secondary sources were severely under-reported. Income tax payers and shareholders could not be reliably identified. The use of income or consumption expenditure to estimate income tax contributions was found to be a more reliable method of estimating income tax incidence. Assumptions regarding corporate tax incidence had a huge effect on the progressivity of corporate tax and on overall tax progressivity. LSMS consumption categories did not always coincide with tax categories for goods subject to excise tax (e.g., wine and spirits were combined, despite differing tax rates). Tobacco companies, alcohol distributors and advertising agencies were used to provide more detailed information on consumption patterns for goods subject to excise tax by income category. There was little guidance on how to allocate fuel levies associated with 'public transport' use. Hence, calculations of fuel tax on public transport were based on individual expenditure on public transport, the average cost per kilometre and average rates of fuel consumption for each form of transport. For insurance contributions, employees will not report on employer contributions unless specifically requested to and are frequently unsure of their contributions. Therefore, we collected information on total health insurance contributions from individual schemes and regulatory authorities. OOP payments are likely to be under-reported due to long recall periods; linking OOP expenditure and illness incidence questions--omitting preventive care; and focusing on the last service used when people may have used multiple services during an illness episode. To derive more robust estimates of financing incidence, we collected additional primary data on OOP expenditures together with insurance enrolment rates and associated payments. To link primary data to the LSMS, a composite index of SES was used in Ghana and Tanzania and non-durable expenditure was used in South Africa. We show how data constraints can be overcome for FIA in lower income countries and provide recommendations for future studies.


Liposomes in topical ophthalmic drug delivery: an update.
Topical route of administration is the most commonly used method for the treatment of ophthalmic diseases. However, presence of several layers of permeation barriers starting from the tear film till the inner layers of cornea make it difficult to achieve the therapeutic concentrations in the target tissue within the eye. In order to circumvent these barriers and to provide sustained and targeted drug delivery, tremendous advances have been made in developing efficient and safe drug delivery systems. Liposomes due to their unique structure prove to be extremely beneficial drug carriers as they can entrap both the hydrophilic and hydrophobic drugs. The conventional liposomes had several drawbacks particularly their tendency to aggregate, the instability and leakage of entrapped drug and susceptibility to phagocytosis. Due to this reason, for a long time, liposomes as drug delivery systems did not attract much attention of researchers and clinicians. However, over recent years development of new generation liposomes has opened up new approaches for targeted and sustained drug delivery using liposomes and has rejuvenated the interest of researchers in this field. In this review we present a summary of current literature to understand the anatomical and physiological limitation in achieving adequate ocular bioavailability of topically applied drugs and utility of liposomes in overcoming these limitations. The recent developments related to new generation liposomes are discussed.


Value propositions of mHealth projects.
While mHealth holds great potential for addressing global health disparities, a majority of the initiatives never proceed beyond the pilot stage. One fundamental concern is that mHealth projects are seldom designed from the customer's perspective to address their specific problems and/or create appreciable value. A customer-centric view, where direct tangible benefits of interventions are identified and communicated effectively, can drive customer engagement and advance projects toward self-sustaining business models. This article reviews the business models of 234 mHealth projects to identify nine distinct value propositions that solve specific problems for customers. Each of these value propositions is discussed with real-world examples, analyses of their design approaches and business strategies, and common enablers as well as hurdles to surviving past the pilot stage. Furthermore, a deeper analysis of 42 mHealth ventures that have achieved self-sustainability through project revenue provides a host of practical and poignant insights into the design of systems that can fulfil mHealth's promise to address healthcare challenges in the long term.


Sensemaking and the co-production of safety: a qualitative study of primary medical care patients.
This study explores the ways in which patients make sense of 'safety' in the context of primary medical care. Drawing on qualitative interviews with primary care patients, we reveal patients' conceptualisation of safety as fluid, contingent, multi-dimensional, and negotiated. Participant accounts drew attention to a largely invisible and inaccessible (but taken for granted) architecture of safety, the importance of psycho-social as well as physical dimensions and the interactions between them, informal strategies for negotiating safety, and the moral dimension of safety. Participants reported being proactive in taking action to protect themselves from potential harm. The somewhat routinised and predictable nature of the primary medical care consultation, which is very different from 'one off' inpatient spells, meant that patients were not passive recipients of care. Instead they had a stock of accumulated knowledge and experience to inform their actions. In addition to highlighting the differences and similarities between hospital and primary care settings, the study suggests that a broad conceptualisation of patient safety is required, which encompasses the safety concerns of patients in primary care settings.


Chromatin accessibility landscape and regulatory network of high-altitude hypoxia adaptation.
High-altitude adaptation of Tibetans represents a remarkable case of natural selection during recent human evolution. Previous genome-wide scans found many non-coding variants under selection, suggesting a pressing need to understand the functional role of non-coding regulatory elements (REs). Here, we generate time courses of paired ATAC-seq and RNA-seq data on cultured HUVECs under hypoxic and normoxic conditions. We further develop a variant interpretation methodology (vPECA) to identify active selected REs (ASREs) and associated regulatory network. We discover three causal SNPs of EPAS1, the key adaptive gene for Tibetans. These SNPs decrease the accessibility of ASREs with weakened binding strength of relevant TFs, and cooperatively down-regulate EPAS1 expression. We further construct the downstream network of EPAS1, elucidating its roles in hypoxic response and angiogenesis. Collectively, we provide a systematic approach to interpret phenotype-associated noncoding variants in proper cell types and relevant dynamic conditions, to model their impact on gene regulation.


Small RNA-mediated responses to low- and high-temperature stresses in cotton.
MicroRNAs (miRNAs) are one class of endogenous non-coding RNAs modulating the expression of target genes involved in plant development and stress tolerance, by degrading mRNA or repressing translation. In this study, small RNA and mRNA degradome sequencing were used to identify low- and high-temperature stress-responsive miRNAs and their targets in cotton (Gossypium hirsutum). Cotton seedlings were treated under different temperature conditions (4, 12, 25, 35, and 42 °C) and then the effects were investigated. In total, 319 known miRNAs and 800 novel miRNAs were identified, and 168 miRNAs were differentially expressed between different treatments. The targets of these miRNAs were further analysed by degradome sequencing. Based on studies from Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, the majority of the miRNAs are from genes that are likely involved in response to hormone stimulus, oxidation-reduction reaction, photosynthesis, plant-pathogen interaction and plant hormone signal transduction pathways. This study provides new insight into the molecular mechanisms of plant response to extreme temperature stresses, and especially the roles of miRNAs under extreme temperatures.


Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting.
Cancer immunoediting, the process by which the immune system controls tumour outgrowth and shapes tumour immunogenicity, is comprised of three phases: elimination, equilibrium and escape. Although many immune components that participate in this process are known, its underlying mechanisms remain poorly defined. A central tenet of cancer immunoediting is that T-cell recognition of tumour antigens drives the immunological destruction or sculpting of a developing cancer. However, our current understanding of tumour antigens comes largely from analyses of cancers that develop in immunocompetent hosts and thus may have already been edited. Little is known about the antigens expressed in nascent tumour cells, whether they are sufficient to induce protective antitumour immune responses or whether their expression is modulated by the immune system. Here, using massively parallel sequencing, we characterize expressed mutations in highly immunogenic methylcholanthrene-induced sarcomas derived from immunodeficient Rag2(-/-) mice that phenotypically resemble nascent primary tumour cells. Using class I prediction algorithms, we identify mutant spectrin-β2 as a potential rejection antigen of the d42m1 sarcoma and validate this prediction by conventional antigen expression cloning and detection. We also demonstrate that cancer immunoediting of d42m1 occurs via a T-cell-dependent immunoselection process that promotes outgrowth of pre-existing tumour cell clones lacking highly antigenic mutant spectrin-β2 and other potential strong antigens. These results demonstrate that the strong immunogenicity of an unedited tumour can be ascribed to expression of highly antigenic mutant proteins and show that outgrowth of tumour cells that lack these strong antigens via a T-cell-dependent immunoselection process represents one mechanism of cancer immunoediting.


Remembering Collective Violence: Broadening the Notion of Traumatic Memory in Post-Conflict Rehabilitation.
In the aftermath of war and armed conflict, individuals and communities face the challenge of dealing with recollections of violence and atrocity. This article aims to contribute to a better understanding of processes of remembering and forgetting histories of violence in post-conflict communities and to reflect on related implications for trauma rehabilitation in post-conflict settings. Starting from the observation that memory operates at the core of PTSD symptomatology, we more closely explore how this notion of traumatic memory is conceptualized within PTSD-centered research and interventions. Subsequently, we aim to broaden this understanding of traumatic memory and post-trauma care by connecting to findings from social memory studies and transcultural trauma research. Drawing on an analysis of scholarly literature, this analysis develops into a perspective on memory that moves beyond a symptomatic framing toward an understanding of memory that emphasizes its relational, political, moral, and cultural nature. Post-conflict memory is presented as inextricably embedded in communal relations, involving ongoing trade-offs between individual and collective responses to trauma and a complex negotiation of speech and silence. In a concluding discussion, we develop implications of this broadened understanding for post-conflict trauma-focused rehabilitation.


Depressed mood is a factor in glycemic control in type 1 diabetes.
The diabetes literature contains conflicting evidence on the relationship between depression and glycemic control. This may be due, in part, to the fact that past studies failed to distinguish between patients with type 1 and type 2 diabetes. Because these are actually completely different diseases that are often treated differently and consequently make different demands on patients, the relationship between glycemic control and depressed mood in type 1 and type 2 diabetes was examined separately. The relationship between Beck Depression Inventory (BDI) scores and HbA1c, as an index of long-term glycemic control, was measured in samples of 30 patients with type 1 and 34 patients with type 2 diabetes. Groups of patients with type 1 and type 2 diabetes did not differ in mean BDI score or HbA1c level. Correlation analysis revealed a significant positive relationship between BDI scores and HbA1c in the type 1 group (r = .44, p < .02) but not in the type 2 group (r = -0.06, p > .05). This relationship was evident throughout the entire range of BDI scores and was not restricted to scores indicative of clinical depression. Patients with type 1 diabetes who had higher HbA1c and BDI scores reported a lower frequency of home blood glucose monitoring. Variations in depressive mood, below the level of clinical depression, are associated with meaningful differences in glycemic control in type 1 but not type 2 diabetes. Preliminary data analysis suggests that this effect may be mediated, at least in part, by decreased self-care behaviors in patients with more depressed mood.


Expression of renal cell carcinoma antigen (RCC) in renal epithelial and nonrenal tumors: diagnostic Implications.
Antibody to renal cell carcinoma (RCC) antigen, a normal human proximal brush border antigen, has recently become commercially available and reported to be highly specific and a relatively sensitive marker for RCC. Of the nonrenal tumors occasional carcinomas have been reported to express RCC, notably breast carcinoma. Using tissue microarrays, we investigated the use of RCC on a large number of renal epithelial neoplasms (RENs) and nonrenal tumors, especially those potentially confused with REN. Three tissue microarrays containing 241 REN samples, 192 samples of a wide variety of neoplasms and 170 adrenal tumor samples, respectively, were stained with RCC monoclonal antibody. RCC expression was scored for staining intensity and percentage expression. Out of 241 REN, 173 were positive for RCC (sensitivity 72%): clear cell 72%, papillary 95%, chromophobe 91%, unclassified 85%, oncocytoma 75%, sarcomatoid 20%, and metastatic RCC 40%. The overall immunostaining intensity was consistently much higher in papillary and clear cell RCC than in other tumors. Seventy-six out of 362 nonrenal tumor samples demonstrated either focal or diffuse expression for RCC (specificity 79%). These included: adrenocortical neoplasms 37/170 (22%), colonic 11/29 (37.5%), breast 9/27 (33%), prostate 5/18 (27.7%), ovary 2/17 (11.7%), melanoma 3/18 (16.6%), lung 3/21 (14.2%), and parathyroid 3/3 (100%). RCC expression was seen equally among adrenal adenoma and carcinoma group. Eight out of 28 (28.5%) normal adrenal cores also stained for RCC. RCC is a relatively useful marker in the differential diagnosis of REN only if used in a panel with other positive and negative markers. RCC does not reliably differentiate REN, especially classic clear cell type, from adrenocortical neoplasms, which are frequently confused due to close anatomic proximity and similar morphology. RCC also does not reliably differentiate subtypes of renal epithelial neoplasms.


Ecological approaches to human nutrition.
Malnutrition affects a large number of people throughout the developing world. Approaches to reducing malnutrition rarely focus on ecology and agriculture to simultaneously improve human nutrition and environmental sustainability. However, evidence suggests that interdisciplinary approaches that combine the knowledge bases of these disciplines can serve as a central strategy in alleviating hidden hunger for the world's poorest. To describe the role that ecological knowledge plays in alleviating hidden hunger, considering human nutrition as an overlooked ecosystem service. We review existing literature and propose a framework that expands on earlier work on econutrition. We provide novel evidence from case studies conducted by the authors in western Kenya and propose a framework for interdisciplinary collaboration to alleviate hidden hunger, increase agricultural productivity, and improve environmental sustainability. Our review supports the concept that an integrated approach will impact human nutrition. We provide evidence that increased functional agrobiodiversity can alleviate anemia, and interventions that contribute to environmental sustainability can have both direct and indirect effects on human health and nutritional well-being. Integrated and interdisciplinary approaches are critical to reaching development goals. Ecologists must begin to consider not only how their field can contribute to biodiversity conservation, but also, the relationship between biodiversity and provisioning of nontraditional ecosystem services such as human health. Likewise, nutritionists and agronomists must recognize that many of the solutions to increasing human wellbeing and health can best be achieved by focusing on a healthy environment and the conservation of ecosystem services.


Omega-3 fatty acids.
Omega-3 fatty acids have been shown to significantly reduce the risk for sudden death caused by cardiac arrhythmias and all-cause mortality in patients with known coronary heart disease. Fatty fish, such as salmon and tuna, and fish oil are rich sources of the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid. Flaxseed, canola oil, and walnuts also are good dietary sources of omega-3 fatty acids. In addition to being antiarrhythmic, the omega-3 fatty acids are antithrombotic and anti-inflammatory. In contrast, omega-6 fatty acids, which are present in most seeds, vegetable oils, and meat, are prothrombotic and proinflammatory. Omega-3 fatty acids also are used to treat hyperlipidemia, hypertension, and rheumatoid arthritis. There are no significant drug interactions with omega-3 fatty acids. The American Heart Association recommends consumption of two servings of fish per week for persons with no history of coronary heart disease and at least one serving of fish daily for those with known coronary heart disease. Approximately 1 g per day of eicosapentaenoic acid plus docosahexaenoic acid is recommended for cardioprotection. Higher dosages of omega-3 fatty acids are required to reduce elevated triglyceride levels (2 to 4 g per day) and to reduce morning stiffness and the number of tender joints in patients with rheumatoid arthritis (at least 3 g per day). Modest decreases in blood pressure occur with significantly higher dosages of omega-3 fatty acids.


Stroke as a late treatment effect of Hodgkin's Disease: a report from the Childhood Cancer Survivor Study.
The objectives of this report are to examine the incidence of and risk factors for stroke among childhood Hodgkin's disease (HD) survivors. The Childhood Cancer Survivor Study is a multi-institutional cohort study of more than 5-year cancer survivors diagnosed between 1970 and 1986 and a sibling comparison group. Incidence rates of stroke among HD survivors (n = 1,926) and siblings (n = 3,846) were calculated and compared. Cox proportional hazards models were used to estimate the hazard ratios, reported as relative risks (RR), of developing stroke between HD survivors and siblings. Nine siblings reported a stroke, for an incidence of 8.00 per 100,000 person-years (95% CI, 3.85 to 14.43 per 100,000 person-years). Twenty-four HD survivors reported a stroke. The incidence of late-occurring stroke among HD survivors was 83.6 per 100,000 person-years (95% CI, 54.5 to 121.7 per 100,000 person-years). The RR of stroke among HD survivors was 4.32 (95% CI, 2.01 to 9.29; P = .0002). All 24 survivors received mantle radiation exposure (median dose, 40 Gy). The incidence of late-occurring stroke among HD survivors treated with mantle radiation was 109.8 per 100,000 person-years (95% CI, 70.8 to 161.1 per 100,000 person-years). The RR of late-occurring stroke among HD survivors treated with mantle radiation was 5.62 (95% CI, 2.59 to 12.25; P < .0001). Survivors of childhood HD are at increased risk of stroke. Mantle radiation exposure is strongly associated with subsequent stroke. Potential mechanisms may include carotid artery disease or cardiac valvular disease.


Important areas of the central binocular visual field for daily functioning in the visually impaired.
To determine the areas of the central binocular visual field which correspond best with self-reported vision related activity limitations (VRAL) in individuals with visual impairment using a clinically relevant and accessible technique. One hundred participants with mixed visual impairment undertook binocular threshold visual field testing using a Humphrey 30-2 SITA Fast program. The Activity Inventory (AI) was administered to assess overall, mobility related and reading related self-reported VRAL as part of a face-to-face clinical interview. Different eccentricities of the binocular field (central 5, 5-10, and 10-30°) were compared to self-reported VRAL in bivariate analyses and further explored using multivariate analyses. All areas of the binocular visual field were significantly associated with self-reported VRAL in bivariate analyses, with greater field loss associated with increased VRAL (p < 0.001). Multivariate analyses identified that function of the central 5-10° best predicted overall self-reported VRAL, and function of the central 5° (especially the right-hand-side) and the central 10-30° (especially 10-20°) best predicted self-reported VRAL in reading and mobility tasks, respectively. The results highlight the association between central binocular visual fields and self-reported VRAL in people with visual impairment. Central binocular fields can be measured using a widely available threshold test in order to understand the likely functional limitations of those with vision loss, particularly in mobility tasks. Self-reported VRAL can be estimated using the regression equations and graphs provided and difficulty levels in specific tasks can be determined.


Macromolecular organization and in vitro growth characteristics of scaffold-free neocartilage grafts.
Recent advances in tissue engineering offer considerable promise for the repair of focal lesions in articular cartilage. Here we describe (1) the macromolecular organization of tissue-engineered neocartilage grafts at light and electron microscopic levels, (2) their in vitro development, and (3) the effect of chondrocyte dedifferentiation, induced by monolayer expansion, on their resultant structure. We show that grafts produced from primary cultures of chondrocytes are hyaline in appearance with identifiable zonal strata as evidenced by cell morphology, matrix organization, and immunohistochemical composition. Like native articular cartilage, their surface zone contains type I collagen, surface zone proteoglycan, biglycan and decorin with type II collagen, aggrecan, chondroitin sulfate, chondroitin-4-sulfate, and keratan sulfate, becoming more prominent with depth. Assessment of cell viability by Live/Dead staining and cell-cycle analysis with BrDU suggest that the in vitro tissue has a high cellular turnover and develops through both appositional and interstitial growth mechanisms. Meanwhile, cell-tracker studies with CMFDA (5-chloromethyl-fluorescein diacetate) demonstrate that cell sorting in vitro is not involved in their zonal organization. Finally, passage expansion of chondrocytes in monolayer culture causes progressive reductions in graft thickness, loss of zonal architecture, and a more fibrocartilaginous tissue histology, consistent with a dedifferentiating chondrocyte phenotype.


Unfriendly Fire: How the Tobacco Industry is Destroying the Future of Our Children.
Tobacco has long been known to be one of the greatest causes of morbidity and mortality in the adults, but the effects on the foetus and young children, which are lifelong, have been less well appreciated. Developing from this are electronic nicotine delivery systems or vapes, promulgated as being less harmful than tobacco. Nicotine itself is toxic to the foetus, with permanent effects on lung structure and function. Most vapes contain nicotine, but they also contain many other compounds which are inhaled and for which there are no toxicity studies. They also contain known toxic substances, whose use is banned by European Union legislation. Accelerating numbers of young people are vaping, and this does not reflect an exchange of vapes for cigarettes. The acute toxicity of e-cigarettes is greater than that of tobacco, and includes acute lung injury, pulmonary haemorrhage and eosinophilic and lipoid pneumonia. Given the worse acute toxicity, it should be impossible to be complacent about medium and long term effects of vaping. Laboratory studies have demonstrated changes in lung proteomics and the innate immune system with vaping, some but not all of which overlap with tobacco. It would be wrong to consider vapes as a weaker form of tobacco, they have their own toxicity. Children and young people are being targeted by the vaping industry (which is largely the same as the tobacco industry), including on-line, and unless an efficient legislative program is put in place, a whole new generation of nicotine addicts will result.


Can Temporal Repetitive Transcranial Magnetic Stimulation be Enhanced by Targeting Affective Components of Tinnitus with Frontal rTMS? A Randomized Controlled Pilot Trial.
Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has been investigated as a new treatment tool for chronic tinnitus during the last years and has shown moderate efficacy. However, there is growing evidence that tinnitus is not a pathology of a specific brain region, but rather the result of network dysfunction involving both auditory and non-auditory brain regions. In functional imaging studies the right dorsolateral prefrontal cortex has been identified as an important hub in tinnitus related networks and has been shown to particularly reflect the affective components of tinnitus. Based on these findings we aimed to investigate whether the effects of left low-frequency rTMS can be enhanced by antecedent right prefrontal low-frequency rTMS. Fifty-six patients were randomized to receive either low-frequency left temporal rTMS or a combination of low-frequency right prefrontal followed by low-frequency left temporal rTMS. The change of the tinnitus questionnaire (TQ) score was the primary outcome, secondary outcome parameters included the Tinnitus Handicap Inventory, numeric rating scales, and the Beck Depression Inventory. The study is registered in clinicaltrials.gov (NCT01261949). Directly after therapy there was a significant improvement of the TQ-score in both groups. Comparison of both groups revealed a trend toward more pronounced effects for the combined group (effect size: Cohen's d = 0.176), but this effect did not reach significance. A persistent trend toward better efficacy was also observed in all other outcome criteria. Additional stimulation of the right prefrontal cortex seems to be a promising strategy for enhancing TMS effects over the temporal cortex. These results further support the involvement of the right DLPFC in the pathophysiology of tinnitus. The small effect size might be due to the study design comparing the protocol to an active control condition.


Dispersion-to-spectrum mapping in nonlinear fibers based on optical wave-breaking.
In this work we recognize new strategies involving optical wave-breaking for controlling the output pulse spectrum in nonlinear fibers. To this end, first we obtain a constant of motion for nonlinear pulse propagation in waveguides derived from the generalized nonlinear Schrödinger equation. In a second phase, using the above conservation law we theoretically analyze how to transfer in a simple manner the group-velocity-dispersion curve of the waveguide to the output spectral profile of pulsed light. Finally, the computation of several output spectra corroborates our proposition.


Malaria: looking for selection signatures in the human PKLR gene region.
The genetic component of susceptibility to malaria is both complex and multigenic and the better-known protective polymorphisms are those involving erythrocyte-specific structural proteins and enzymes. In vivo and in vitro data have suggested that pyruvate kinase deficiency, which causes a nonspherocytic haemolytic anaemia, could be protective against malaria severity in humans, but this hypothesis remains to be tested. In the present study, we conducted a combined analysis of Short Tandem Repeats (STRs) and Single Nucleotide Polymorphisms (SNPs) in the pyruvate kinase-encoding gene (PKLR) and adjacent regions (chromosome 1q21) to look for malaria selective signatures in two sub-Saharan African populations from Angola and Mozambique, in several groups with different malaria infection outcome. A European population from Portugal, including a control and a pyruvate kinase-deficient group, was used for comparison. Data from STR and SNP loci spread along the PKLR gene region showed a considerably higher differentiation between African and Portuguese populations than that usually found for neutral markers. In addition, a wider region showing strong linkage disequilibrium was found in an uncomplicated malaria group, and a haplotype was found to be associated with this clinical group. Altogether, this data suggests that malaria selective pressure is acting in this genomic region.


Differential diagnosis of parkinsonism: a metabolic imaging study using pattern analysis.
Idiopathic Parkinson's disease can present with symptoms similar to those of multiple system atrophy or progressive supranuclear palsy. We aimed to assess whether metabolic brain imaging combined with spatial covariance analysis could accurately discriminate patients with parkinsonism who had different underlying disorders. Between January, 1998, and December, 2006, patients from the New York area who had parkinsonian features but uncertain clinical diagnosis had fluorine-18-labelled-fluorodeoxyglucose-PET at The Feinstein Institute for Medical Research. We developed an automated image-based classification procedure to differentiate individual patients with idiopathic Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. For each patient, the likelihood of having each of the three diseases was calculated by use of multiple disease-related patterns with logistic regression and leave-one-out cross-validation. Each patient was classified according to criteria defined by receiver-operating-characteristic analysis. After imaging, patients were assessed by blinded movement disorders specialists for a mean of 2.6 years before a final clinical diagnosis was made. The accuracy of the initial image-based classification was assessed by comparison with the final clinical diagnosis. 167 patients were assessed. Image-based classification for idiopathic Parkinson's disease had 84% sensitivity, 97% specificity, 98% positive predictive value (PPV), and 82% negative predictive value (NPV). Imaging classifications were also accurate for multiple system atrophy (85% sensitivity, 96% specificity, 97% PPV, and 83% NPV) and progressive supranuclear palsy (88% sensitivity, 94% specificity, 91% PPV, and 92% NPV). Automated image-based classification has high specificity in distinguishing between parkinsonian disorders and could help in selecting treatment for early-stage patients and identifying participants for clinical trials. National Institutes of Health and General Clinical Research Center at The Feinstein Institute for Medical Research.


Radioactive labelling of borme mosaic virus.
Brome mosaic virus (BMV) can be radioactively labelled by allowing virus synthesis to take place in barley leaves whose cut ends are placed in solutions of radio active precursors of BMV. When barley plants are infected by inoculation of the first emerging leaf, the rate of incorporation of both [14C]-leucine and [32P]-ortho-phosphate into virus particles was found to be maximal in the second leaf, cut and labelled 4 to 5 days after inoculation. The rate of incorporation declined when the labelling or the cutting and labelling were delayed, even though assembly of particles still took place from pre-formed components. An exposure of 72 h to an appropriate amount of 32P yielded highly radioactive BMV RNA for possible sequencing studies. A specific radioactivity (32P) of the order of 1 mCi/mg RNA can be obtained readily.


Effect of stable glutamine compounds on porcine islet culture.
Pig islets are characterized by significant fragility, preventing successful islet culture prior to xenotransplantation. To improve outcome after culture, we compared the effects of glutamine supplementation on survival and viability of isolated pig islets during culture. Pig islets were suspended in CMRL 1066 supplemented either with 2.5 mmol/L N-acetyl-L-alanyl-L-glutamine (NALG), a stable compound of L-glutamine, or with 2.5 or 5.0 mmol/L of free L-glutamine (L-Glu). After 24 hours of preincubation, islets were stressed for additional 48 hours with H2O2, DETA, or a cytokine mix. Twenty-four-hour survival of unstressed controls precultured with 2.5 mmol/L NALG was significantly decreased compared with islets pretreated with 2.5 or 5.0 mmol/L L-Glu (P < .01). Fresh islets, viability decreased significantly after NALG preincubation, but was maintained after preincubation in 2.5 or 5.0 mmol/L L-Glu (not significant vs fresh; P < .05 vs NALG). Compared with NALG pretreatment L-Glu did not significantly ameliorate the relative survival (related to cultured controls) of islets during proinflammatory treatment. Nevertheless, the beneficial effect of L-Glu preculture on absolute survival (related to freshly isolated islets) of stressed islets was still present in contrast to NALG pretreatment (P < .01). Viability of stressed islets was significantly protected by L-Glu but not by NALG. Pig islet culture is significantly improved if L-glutamine is administered in an unbound form compared with the stable compound NALG. Stress resistance of pig islets seems to be increased by free L-glutamine as well.


A signal capture and proofreading mechanism for the KDEL-receptor explains selectivity and dynamic range in ER retrieval.
ER proteins of widely differing abundance are retrieved from the Golgi by the KDEL-receptor. Abundant ER proteins tend to have KDEL rather than HDEL signals, whereas ADEL and DDEL are not used in most organisms. Here, we explore the mechanism of selective retrieval signal capture by the KDEL-receptor and how HDEL binds with 10-fold higher affinity than KDEL. Our results show the carboxyl-terminus of the retrieval signal moves along a ladder of arginine residues as it enters the binding pocket of the receptor. Gatekeeper residues D50 and E117 at the entrance of this pocket exclude ADEL and DDEL sequences. D50N/E117Q mutation of human KDEL-receptors changes the selectivity to ADEL and DDEL. However, further analysis of HDEL, KDEL, and RDEL-bound receptor structures shows that affinity differences are explained by interactions between the variable -4 H/K/R position of the signal and W120, rather than D50 or E117. Together, these findings explain KDEL-receptor selectivity, and how signal variants increase dynamic range to support efficient ER retrieval of low and high abundance proteins.


Self-management interventions for young people with chronic conditions: A systematic overview.
To provide a systematic overview of self-management interventions (SMI) for young people with chronic conditions with respect to content, formats, theories, and evaluated outcomes. Embase, Medline, PsycINFO, Web-of-Science, CINAHL, and Cochrane were searched. Reviews' reference lists were scrutinized. Selected studies were: Original research articles in English published between 2003 and March 2014; about the evaluation of SMI for 7 to 25-year-olds with somatic chronic conditions/physical disabilities; with clear outcomes and intervention descriptions. The classification of medical, role and emotion management served to review content. Formats, theories, and evaluated outcomes were summarized. 86 studies were reviewed. Most aimed at medical management and were unclear about theoretical bases. Although a variety of outcomes was evaluated and the distribution over self-management domains was quite unpredictable, outcomes conceptually related to specific content. A content-based framework for the evaluation of self-management interventions is presented. SMI relate to self-management tasks and skill-building. Yet, conceptualizations of self-management support often remained unclear and content focuses predominantly on the medical domain, neglecting psycho-social challenges for chronically ill young people. Future evaluations should match outcomes/themes to content and characteristics. Our framework and overview of SMI characteristics and outcomes may assist clinicians in providing self-management support.


Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial.
Daclizumab, a humanised monoclonal antibody, modulates interleukin-2 signalling by blocking the α subunit (CD25) of the interleukin-2 receptor. We assessed whether daclizumab high-yield process (HYP) would be effective when given as monotherapy for a 1 year treatment period in patients with relapsing-remitting multiple sclerosis. We did a randomised, double-blind, placebo-controlled trial at 76 centres in the Czech Republic, Germany, Hungary, India, Poland, Russia, Ukraine, Turkey, and the UK between Feb 15, 2008, and May 14, 2010. Patients aged 18-55 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1:1), via a central interactive voice response system, to subcutaneous injections of daclizumab HYP 150 mg or 300 mg, or placebo, every 4 weeks for 52 weeks. Patients and study personnel were masked to treatment assignment, except for the site pharmacist who prepared the study drug for injection, but had no interaction with the patient. The primary endpoint was annualised relapse rate. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00390221. 204 patients were assigned to receive placebo, 208 to daclizumab HYP 150 mg, and 209 to daclizumab HYP 300 mg, of whom 188 (92%), 192 (92%), and 197 (94%), respectively, completed follow-up to week 52. The annualised relapse rate was lower for patients given daclizumab HYP 150 mg (0·21, 95% CI 0·16-0·29; 54% reduction, 95% CI 33-68%; p<0·0001) or 300 mg (0·23, 0·17-0·31, 50% reduction, 28-65%; p=0·00015) than for those given placebo (0·46, 0·37-0·57). More patients were relapse free in the daclizumab HYP 150 mg (81%) and 300 mg (80%) groups than in the placebo group (64%; p<0·0001 in the 150 mg group and p=0·0003 in the 300 mg group). 12 (6%) patients in the placebo group, 15 (7%) of those in the daclizumab 150 mg group, and 19 (9%) in the 300 mg group had serious adverse events excluding multiple sclerosis relapse. One patient given daclizumab HYP 150 mg who was recovering from a serious rash died because of local complication of a psoas abscess. Subcutaneous daclizumab HYP administered every 4 weeks led to clinically important effects on multiple sclerosis disease activity during 1 year of treatment. Our findings support the potential for daclizumab HYP to offer an additional treatment option for relapsing-remitting disease. Biogen Idec and AbbVie Biotherapeutics Inc.


Improving quality of life using compound mind-body therapies: evaluation of a course intervention with body movement and breath therapy, guided imagery, chakra experiencing and mindfulness meditation.
Assess changes in quality of life and in sense of coherence (SOC), after an intervention involving a self-development course using mind-body medicine (MBM) activities. A questionnaire study using a health-related quality of life (HRQOL) instrument, the SWEDQUAL, with 13 subscales and scores ranging from 0 to 100, combined with the SOC-13 scale, healthcare utilisation, medication and sick listing data. A training centre for MBM. Eligible course attendants (study group, SG, n = 83) assessed their HRQOL before and 6 months after a 1-week course. A control group (CG) of individuals who had previously attended the course (n = 69), matched for age, sex and length of course time to the SG, also made assessments. Changes in HRQOL and SOC in SG and CG. Of the 13 HRQOL subscales, eight showed clinically significant improvement in the SG (>9%, p < 0.01), namely, General health perceptions (9%), Emotional well-being [negative (45%) and positive (26%)], Cognitive functioning (24%), Sleep (15%), Pain (10%), Role limitation due to emotional health (22%) and Family functioning (16%). Sexual, marital and physical function and role in the SG as well as all CG scores were similar to average population values. The assessed SOC also improved in the SG after intervention (p < 0.01), challenging previous statements of 'the stableness of SOC'. Use of psychotropic medication was slightly reduced in the younger aged SG participants after intervention. This group of men and women (SG), starting from a clinically significant low health assessment, had improved their HRQOL and SOC after the course intervention.


Assessing heat-related health risk in Europe via the Universal Thermal Climate Index (UTCI).
In this work, the potential of the Universal Thermal Climate Index (UTCI) as a heat-related health risk indicator in Europe is demonstrated. The UTCI is a bioclimate index that uses a multi-node human heat balance model to represent the heat stress induced by meteorological conditions to the human body. Using 38 years of meteorological reanalysis data, UTCI maps were computed to assess the thermal bioclimate of Europe for the summer season. Patterns of heat stress conditions and non-thermal stress regions are identified across Europe. An increase in heat stress up to 1 °C is observed during recent decades. Correlation with mortality data from 17 European countries revealed that the relationship between the UTCI and death counts depends on the bioclimate of the country, and death counts increase in conditions of moderate and strong stress, i.e., when UTCI is above 26 and 32 °C. The UTCI's ability to represent mortality patterns is demonstrated for the 2003 European heatwave. These findings confirm the importance of UTCI as a bioclimatic index that is able to both capture the thermal bioclimatic variability of Europe, and relate such variability with the effects it has on human health.


Brain pH in head injury: an image-guided 31P magnetic resonance spectroscopy study.
It has been suggested that brain acidosis may follow head trauma, and therapies aimed at correcting acidosis have been proposed. Direct measurements of intracellular pH, however, have thus far not been possible in clinical situations. We have studied the intracellular brain pH in 22 patients after head injury (mean Glasgow Coma Score 6.1). Patients were investigated by a combined approach of phosphorus 31 magnetic resonance spectroscopy and magnetic resonance imaging (overall examination time 50-75 min) at a mean time of 11 days after injury (36 hours to 24 days). 31P spectra were obtained in 11 patients on assisted ventilation and in 11 patients on spontaneous ventilation. These spectra were analyzed to yield the pH in the regions studied in all the patients. All pH values were in the normal or alkalotic range when compared with 6 age-matched normal controls. No differences were found between patients on assisted ventilation and patients on spontaneous ventilation. When analyzed as a group, the brain pH in the focal lesions appeared to increase in the first days, to reach a peak in the alkalotic range in the second week, and to return toward normal within 3 weeks from acute injury. Our results suggest that there is no evidence of posttraumatic intracellular brain acidosis in recent human head injury, and therefore, therapies aimed at alkalinizing brain cells need to be reconsidered.


A relationship between attractiveness and performance in professional cyclists.
Females often prefer to mate with high quality males, and one aspect of quality is physical performance. Although a preference for physically fitter males is therefore predicted, the relationship between attractiveness and performance has rarely been quantified. Here, I test for such a relationship in humans and ask whether variation in (endurance) performance is associated with variation in facial attractiveness within elite professional cyclists that finished the 2012 Tour de France. I show that riders that performed better were more attractive, and that this preference was strongest in women not using a hormonal contraceptive. Thereby, I show that, within this preselected but relatively homogeneous sample of the male population, facial attractiveness signals endurance performance. Provided that there is a relationship between performance-mediated attractiveness and reproductive success, this suggests that human endurance capacity has been subject to sexual selection in our evolutionary past.


Tracking retrograde flow in keratocytes: news from the front.
Actin assembly at the leading edge of the cell is believed to drive protrusion, whereas membrane resistance and contractile forces result in retrograde flow of the assembled actin network away from the edge. Thus, cell motion and shape changes are expected to depend on the balance of actin assembly and retrograde flow. This idea, however, has been undermined by the reported absence of flow in one of the most spectacular models of cell locomotion, fish epidermal keratocytes. Here, we use enhanced phase contrast and fluorescent speckle microscopy and particle tracking to analyze the motion of the actin network in keratocyte lamellipodia. We have detected retrograde flow throughout the lamellipodium at velocities of 1-3 microm/min and analyzed its organization and relation to the cell motion during both unobstructed, persistent migration and events of cell collision. Freely moving cells exhibited a graded flow velocity increasing toward the sides of the lamellipodium. In colliding cells, the velocity decreased markedly at the site of collision, with striking alteration of flow in other lamellipodium regions. Our findings support the universality of the flow phenomenon and indicate that the maintenance of keratocyte shape during locomotion depends on the regulation of both retrograde flow and actin polymerization.


Synthesis and properties of long [n]cumulenes (n ≥ 5).
Molecules composed of a contiguous sequence of double bonds, the [n]cumulenes, share structural similarities to both of their conjugated relatives, the polyenes and polyynes. The synthesis and properties of [n]cumulenes are, however, quite different from those of either polyenes or polyynes. At an infinite length, [n]cumulenes would provide one structural form of the hypothetical sp-hybridized carbon allotrope carbyne, while shorter derivatives offer model compounds to help to predict the properties of carbyne. Finally, derivatization of the π-electron framework of [n]cumulenes provides a number of different synthetic transformations, with cycloaddition reactions being the most common. In this review, both historical and recent synthetic achievements toward long [n]cumulenes (n ≥ 5) are discussed. This is followed by a description of our current understanding of the physical and electronic structure of [n]cumulenes based on UV/vis spectroscopy and X-ray crystallography. Finally, the reactivity of long [n]cumulenes is described.


First Report of Corynespora Leaf Spot Caused by C. cassiicola on Golden Vicary Privet (Ligustrum × vicaryi) in China.
Golden vicary privet (Ligustrum × vicaryi Rehd.), a hybrid between L. ovalifolium 'Aureum' Rehd. and L. vulgare L., is widely used as a landscape shrub for horticultural ornamentation. From 2009 to 2011, a leaf spot disease of L. × vicaryi was observed in the parks in Luoyang, Henan Province, China. Lesions were initially brown and punctiform, and with age the lesions turned into elliptic, subcircular to irregular and pale brown, faintly zonate, and depressed. Fully mature lesions were mostly irregular to circular, 5 to 15 mm in diameter, centers tan to dark brown, with reddish brown to reddish purple margins of varying width. The disease eventually caused substantial premature defoliation. After infected leaves were collected from parks and maintained in a humid atmosphere, a layer of black mold developed on the surface of the lesions. Conidiophores were cylindrical, straight to slightly curved, brown, unbranched (2 to 7 septa), and were 98.5 to 403.9 μm in length, 4.5 to 6.6 μm in width. Conidia were solitary or in short chains containing two to five spores, and were cylindrical or obclavate, straight or flexuose (3 to 19 pseudosepta), pale olivaceous brown or brown when mature, and were 78.8 to 315.2 μm in length by 5.3 to 12.3 μm in width. Morphological characteristics of the fungus were similar to those of Corynespora cassiicola (Berk. & Curt.) Wei (1). Lesions on leaves were excised, surface sterilized, and plated on potato dextrose agar (PDA) and incubated at 25°C for 2 to 3 days. A fungus was isolated from the lesions, and pure isolates that were obtained after from single spored isolates were cultured on PDA. Colonies on PDA formed concentric growth rings, abundant aerial mycelia, and were grey or dark brown in color. The isolate ST1 was selected as a representative for molecular identification. The ITS1-5.8S-ITS2 region of the isolate was amplified by PCR with primers ITS1/ITS4 (3) and sequenced. BLAST analysis of the 559 bp amplicon (GenBank Accession No. KC138855) indicated 100% sequence similarity with C. cassiicola (GU138988) (2). To validate Koch's postulates, pathogenicity tests were performed by spraying leaves of five healthy potted L. vicaryi with a 106 conidia per ml aqueous suspension. Control plants were inoculated with sterile water. Plants were covered with plastic bags for 24 h after inoculation and maintained at 25°C. After 3 days, all inoculated plants showed typical symptoms, whereas water sprayed controls remained healthy. C. cassiicola was consistently reisolated from these lesions. The reisolated conidia showed the same morphological characteristics as described above. To our knowledge, this is the first report of leaf spot caused by C. cassiicola on L. × vicaryi in China. Its confirmation is a significant step toward management recommendations for growers. References: (1) M. B. Ellis et al. Corynespora cassiicola. CMI Descriptions of Pathogenic Fungi and Bacteria, no. 303. Commonwealth Mycological Institute, Kew, UK, 1971. (2) X. B. Liu et al. Plant Dis. 94:916, 2010. (3) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, 1990.


Toward a highly accurate ambulatory system for clinical gait analysis via UWB radios.
In this paper, we propose and investigate a low-cost and low-complexity wireless ambulatory human locomotion tracking system that provides a high ranging accuracy (intersensor distance) suitable for the assessment of clinical gait analysis using wearable ultra wideband (UWB) transceivers. The system design and transceiver performance are presented in additive-white-gaussian noise and realistic channels, using industry accepted channel models for body area networks. The proposed system is theoretically capable of providing a ranging accuracy of 0.11 cm error at distances equivalent to interarker distances, at an 18 dB SNR in realistic on-body UWB channels. Based on real measurements, it provides the target ranging accuracy at an SNR = 20 dB. The achievable accuracy is ten times better than the accuracy reported in the literature for the intermarker-distance measurement. This makes it suitable for use in clinical gait analysis, and for the characterization and assessment of unstable mobility diseases, such as Parkinson's disease.


Patients' experience of wearing multimodal sensor devices intended to detect epileptic seizures: A qualitative analysis.
The health management of patients with epilepsy could be improved by wearing devices that reliably detect when epileptic seizures happen. For the devices to be widely adopted, they must be acceptable and easy to use for patients, and their views are very important. Previous studies have collected feedback from patients on hypothetical devices, but very few have examined experience of wearing actual devices. This study assessed the first-hand experiences of people with epilepsy using wearable devices, continuously over a period of time. The aim was to understand how acceptable and easy they were to use, and whether it is reasonable to expect that people will use them. Adults with a diagnosis of epilepsy admitted routinely to a hospital epilepsy monitoring unit were asked to wear one, or more, wearable biosensor devices, tested for seizure detection. The devices are designed to continuously monitor and record signals from the body (biosignals). Participants completed semistructured interviews about their experiences of wearing the device(s). A systematic thematic analysis extracted themes from the interviews, focusing on acceptability and usability. Feedback was organized into (1) participants' experiences of the devices, any support they required and reasons for stopping wearing them; (2) their thoughts about using this technology outside a hospital setting. Twenty-one people with epilepsy wore one, or more, wearable devices for an average of 112.81 (SD = 71.83) hours. Participants found the devices convenient, and had no problem wearing them in hospital or sharing the data collected from them with the researchers and medical professionals. However, the presence of wires, bulky size, discomfort, and need for support, moderated experience. Participants' thoughts about wearing them in everyday life were strongly influenced by how visible and perceived accuracy. Willingness to use a smartphone app to complete questionnaires depended on the frequency, number of questions, and support. Overall, this work provides evidence about the feasibility and acceptability of using wearable devices to monitor seizure activity in people with epilepsy. Key barriers and facilitators to use while in hospital and hypothetical use in everyday life were identified and will be helpful for guiding future implementation.


Deconstruction of the SS18-SSX fusion oncoprotein complex: insights into disease etiology and therapeutics.
Synovial sarcoma is a translocation-associated sarcoma where the underlying chromosomal event generates SS18-SSX fusion transcripts. In vitro and in vivo studies have shown that the SS18-SSX fusion oncoprotein is both necessary and sufficient to support tumorigenesis; however, its mechanism of action remains poorly defined. We have purified a core SS18-SSX complex and discovered that SS18-SSX serves as a bridge between activating transcription factor 2 (ATF2) and transducin-like enhancer of split 1 (TLE1), resulting in repression of ATF2 target genes. Disruption of these components by siRNA knockdown or treatment with HDAC inhibitors rescues target gene expression, leading to growth suppression and apoptosis. Together, these studies define a fundamental role for aberrant ATF2 transcriptional dysregulation in the etiology of synovial sarcoma.


Trust behavior in Parkinson's disease: results of a trust game experiment.
Parkinson's Disease (PD) is a neurodegenerative disease characterized by motor symptoms, but in which behavioral and cognitive disturbances are also common. Trust, due to its pervasiveness in society, has become a major research topic in several scientific disciplines. However, empirical evidence for trust behavior in neurological patients, and specifically for movement disorders such as PD, is missing. Evidence from healthy subjects, however, indicates that three brain regions are involved in trust perceptions and behavior, namely the limbic system, basal ganglia, and frontal cortex. PD affects all these brain regions. Therefore, we hypothesized that PD patients and healthy controls show differences in trust behavior. We conducted an experiment using the trust game, an established paradigm to investigate trust behavior in both patient and healthy populations alike, controlling for risky decision making. Twenty patients suffering from PD diagnosed according to UK PDS Brain Bank criteria and twenty healthy controls (matched for age, gender, education, and income) were recruited. We excluded those suffering from clinically relevant neuropsychiatric comorbidities. We found that PD patients exhibit significantly lower levels of trust than do healthy controls. Importantly, our results cannot be explained by lower levels of risk-taking. Moreover, our results indicate that the trust deficit is independent of medication, disease duration, and severity of motor symptoms. Application of a standard procedure for measuring trust behavior revealed that PD patients exhibit lower levels of trust in other humans than do healthy controls. Against this background we make a call for further research to determine the underlying pathophysiology of reduced trust in PD.


Glioblastomas on the move.
The mechanism by which the tumor suppressor PTEN slows tumor cell migration is not well characterized. A recent study by Raftopoulou et al. shows that a lack of PTEN protein phosphatase activity accelerates the migration of glioblastoma cells. The protein phosphatase activity of PTEN is directly or indirectly responsible for dephosphorylating a PTEN residue, threonine-383, which is necessary for slowing cell migration. These findings have implications for the design of new therapies against glioblastomas and other highly invasive cancers.


Potential for HER-2/neu molecular targeted therapy for invasive bladder carcinoma: comparative study of immunohistochemistry and fluorescent in situ hybridization.
Analysis of HER-2/neu expression in invasive bladder carcinoma was performed in order to evaluate the potential for molecular targeted therapy targeting HER-2. The subjects were 40 patients who were pathologically diagnosed with invasive transitional cell carcinoma of the bladder (pT2 to pT4). A Hercep test kit was used to detect HER-2 expression, and a Path Vysion kit was used for gene amplification. On immunohistochemical (IHC) staining, the primary tumors were HER-2 positive in 17 patients (17/40, 42.5%). According to the classification of grade, one Grade 2 patient (1/3) and 16 Grade 3 patients (16/37) were positive (P=0.99). According to the classification of stage, 12 pT2 patients (12/22, 54.5%), 2 pT3 patients (2/13, 15.3%), and 3 pT4 patients (3/5, 60%) were positive (P=0.55). Lymph node metastasis was found in 10 patients, and 3 pN2 patients were HER-2 positive (3/6, 50%) (P=0.32). A statistically significant difference was observed between HER-2-positive primary tumors and metastatic lymph nodes (P=0.02). In fluorescent in situ hybridization (FISH), HER-2/neu gene amplification was detected in the primary tumors in 5 patients (5/40, 12.5%). In all these patients, IHC staining was determined as 3+. Lymph node metastasis was found in 3 pN2 patients (3/6) (P=0.32), and in these patients with HER-2/neu gene-amplified metastatic lymph nodes, the primary tumors were also positive for gene amplification (P=0.02). In these cases, IHC staining was 3+ as well. The concordance rate of IHC-positive cases with cases positive for HER-2/neu gene amplification in FISH was 12.5% (5/40), and the concordance rate of IHC 3+ and gene amplification was 71%. This result suggests that, at present, patients who may potentially benefit from molecular targeted therapy targeting HER-2/neu for invasive bladder carcinoma should be identified by gene amplification analysis using FISH in IHC 3+ patients. In addition, it suggested that efficacy of molecular targeted therapy can be expected even for patients with metastatic lymph nodes as long as the primary tumors are positive for HER-2 expression.


A dual role for SOX10 in the maintenance of the postnatal melanocyte lineage and the differentiation of melanocyte stem cell progenitors.
During embryogenesis, the transcription factor, Sox10, drives the survival and differentiation of the melanocyte lineage. However, the role that Sox10 plays in postnatal melanocytes is not established. We show in vivo that melanocyte stem cells (McSCs) and more differentiated melanocytes express SOX10 but that McSCs remain undifferentiated. Sox10 knockout (Sox10(fl); Tg(Tyr::CreER)) results in loss of both McSCs and differentiated melanocytes, while overexpression of Sox10 (Tg(DctSox10)) causes premature differentiation and loss of McSCs, leading to hair graying. This suggests that levels of SOX10 are key to normal McSC function and Sox10 must be downregulated for McSC establishment and maintenance. We examined whether the mechanism of Tg(DctSox10) hair graying is through increased expression of Mitf, a target of SOX10, by asking if haploinsufficiency for Mitf (Mitf(vga9) ) can rescue hair graying in Tg(DctSox10) animals. Surprisingly, Mitf(vga9) does not mitigate but exacerbates Tg(DctSox10) hair graying suggesting that MITF participates in the negative regulation of Sox10 in McSCs. These observations demonstrate that while SOX10 is necessary to maintain the postnatal melanocyte lineage it is simultaneously prevented from driving differentiation in the McSCs. This data illustrates how tissue-specific stem cells can arise from lineage-specified precursors through the regulation of the very transcription factors important in defining that lineage.


Effect of CC chemokine ligand 5 and CC chemokine receptor 5 genes polymorphisms on the risk and clinicopathological development of oral cancer.
Inflammation can be induced by cytokines, chemokines, and their receptors, and it is believed to be a risk factor on tumor initiation and progression. The contribution of CC chemokine ligand 5 (CCL5) and CC chemokine receptor 5 (CCR5) on the risk and prognosis of oral cancer is still poorly investigated. The aims of this study were to investigate the impacts of single nucleotide polymorphisms (SNPs) in CCL5 and CCR5 genes and the synergistic effects of these SNPs on the risk and clinicopathological characteristics of oral cancer. In this case-control study, a total of 253 oral cancer patients and 347 controls were recruited. The genetic polymorphisms of CCL5-28, -403 and CCR5-59029 were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) genotyping analysis. The results of statistical analysis showed that the subjects with CCL5-28 CG, CCL5-28 CG or GG, and CCL5-403 TT polymorphic genotype as well as the subjects with the combinations of CCL5-28 CG/-403 CT and CCL5-28 CG/-403 TT genotypes having a significant higher risk to oral cancer than those with wild-type genotypes. Moreover, the oral cancer patients with the combination of CCL5-28 CG/-403 TT genotype presented a lower risk for developing a moderately or poorly differentiated status as compared to those with the combination of CCL5-28 CC/-403 CC genotype. These results suggest that the SNPs in CCL5-28 and -403 genes could increase the risk to have oral cancer, and the combinative effect of CCL5-28 CG and -403 TT genes might also increase the oral cancer risk but reduce the clinicopathological development of oral cancer patients.


Surveillance of Chagas disease in pregnant women in Madrid, Spain, from 2008 to 2010.
One of the most important modes of transmission of Trypanosoma cruzi infection in areas where it is not endemic is vertical transmission: from mother to child. The objective of this report is to assess the efficacy of different programmes of serological screening to monitor infection with T. cruzi in pregnant Latin American women living in Madrid (Spain). To achieve this, a retrospective study was undertaken from January 2008 to December 2010 in seven hospitals in the Autonomous Community of Madrid. Serological screening programmes were classified in two main strategies: a selective one (pregnant women from Bolivia) and a universal one (pregnant women from Latin America). A total of 3,839 pregnant women were tested and the overall prevalence was 3.96%. The rate of congenital transmission was 2.6%. The current monitoring programmes have variable coverage ranging between 26% (selective screening) and 100% (universal screening). Monitoring of pregnant women from Latin America only reaches full coverage if universal screening of pregnant women is carried out at any moment of pregnancy, including at delivery. A common national regulation is necessary in order to ensure homogenous implementation of screening.


Multi-Scale Approach for the Evaluation of Bone Mineralization in Strontium Ranelate-Treated Diabetic Rats.
Long-term diabetes mellitus can induce osteopenia and osteoporosis, an increase in the incidence of low-stress fractures, and/or delayed fracture healing. Strontium ranelate (SrR) is a dual-action anti-osteoporotic agent whose use in individuals with diabetic osteopathy has not been adequately evaluated. In this study, we studied the effects of an oral treatment with SrR and/or experimental diabetes on bone composition and biomechanics. Young male Wistar rats (half non-diabetic, half with streptozotocin/nicotinamide-induced diabetes) were either untreated or orally administered 625 mg/kg/day of SrR for 6 weeks. After sacrifice, femora from all animals were evaluated by a multi-scale approach (X-ray diffraction, Fourier transform infrared spectroscopy, inductively coupled plasma optical-emission spectrometry, static histomorphometry, pQCT, and mechanical testing) to determine chemical, crystalline, and biomechanical properties. Untreated diabetic animals (versus untreated non-diabetic) showed a decrease in femoral mineral carbonate content, in cortical thickness and BMC, in trabecular osteocyte density, in maximum load supported at rupture and at yield point, and in overall toughness at mid-shaft. Treatment of diabetic animals with SrR further affected several parameters of bone (some already impaired by diabetes): crystallinity index (indicating less mature apatite crystals); trabecular area, BMC, and vBMD; maximum load at yield point; and structural elastic rigidity. However, SrR was also able to prevent the diabetes-induced decreases in trabecular osteocyte density (completely) and in bone ultimate strength at rupture (partially). Our results indicate that SrR treatment can partially but significantly prevent some bone structural mechanical properties as previously affected by diabetes, but not others (which may even be worsened).