Variability in mammography use among older women.
To determine rates of and explore factors associated with mammography use among older women. Retrospective review of part B (physician) bills submitted to Medicare during 1990. Health Care Financing Administration (HCFA) data, including sociodemographic information and part B physician bills for all services delivered to Medicare-eligible women in 1990. Women age 65 or older as of January 1, 1990, residing in one of 10 states with part B coverage through December 31, 1990. The outcome was receipt of a mammogram (yes/no). We explored factors associated with mammography use within three age groups: 65 to 74, 75 to 84, and 85+. The factors considered were race, state, median income of ZIP Code of residence (from the 1990 US Census, and used to divide the population into quintiles within each state), and number of primary care visits (0, 1, 2, and 3+). Overall, 15% of women had a mammogram: 20% of women age 65 to 74, 12% of women age 75 to 84, and 4% of women age 85 and older. Mammography use was lowest in Oklahoma and highest in Washington. However, in each state the older the age category, the less the mammography use (e.g., 9% vs 5% vs 2% in Oklahoma and 25% vs 16% vs 5% in Washington for women 65-74, 75-84, and 85+, respectively). Mammography use was lower for black than for white women age 65 to 74 (14% vs 21%, P < .001) and 75 to 84 (9% vs 12%, P < .001). Women in each of these two age groups had lower mammography use if they resided in the lowest income quintile and highest if they resided in the highest income quintile (17% vs 23% 65-74, and 10% vs 13% 75-84, P values < .001). Among the oldest women (those 85+), mammography use was low (4%) and varied minimally by race and income (P = .907 and .003, respectively). In all age groups, mammography use was lowest among women who did not have a primary care visit, was greater among women who had at least one visit, and continued to rise with increasing numbers of visits (all P values < .001). For example, among women age 75 to 84, mammography use increased from 5% to 10%, 14%, and 17% for those with 0, 1, 2, and 3+ visits. We found that mammography use was less for women who were older, of black race, who did not visit a primary care provider, and who lived in areas with lower median income and certain geographic locations (states). Similar factors influenced mammography use in women age 65 to 74, where there is greater consensus as to who should receive a mammogram, and women age 75 to 84, where there is neither consensus nor data. Surprisingly, neither race nor income had much influence on mammography use among women age 85 or older.


Resolution of psoriasis by a leukocyte-targeting bacterial protein in a humanized mouse model.
Psoriasis is a very common chronic skin disease, affecting 2-3% of the world's population or more than 125 million individuals worldwide. The characteristic lesion of psoriasis is due to rapid proliferation and shortened transition of keratinocytes through the epidermis. Proinflammatory white blood cells (WBCs) migrate into the psoriatic plaques, and the pathogenic cytokine environment causes the changes in keratinocyte proliferation and differentiation. Enhanced migration of WBCs is due to the upregulation and activation of adhesion molecules such as leukocyte function antigen-1 (LFA-1), which binds intercellular adhesion molecule-1 (ICAM-1) on endothelial cells. Targeting LFA-1 and preventing interaction with ICAM-1 has proven an effective strategy for treating psoriasis. We show here that a natural leukocyte-targeting bacterial protein (leukotoxin (LtxA)) that binds LFA-1 can inhibit proliferation of activated WBCs from psoriasis patients and demonstrates significant therapeutic efficacy in a psoriasis xenograft transplantation model. In ex vivo studies, LtxA preferentially targeted proinflammatory WBC subtypes, including activated CD25(+) T cells and CD14(+)CD16(+) monocytes. LFA-1 has been shown to have a significant role in the pathogenesis of numerous autoimmune and inflammatory diseases, and we propose that LtxA may be a highly effective agent for treating these diseases.


Histone H3 is absent from organelle nucleoids in BY-2 cultured tobacco cells.
The core histone proteins (H2A, H2B, H3 and H4) are nuclear-localised proteins that play a central role in the formation of nucleosome structure. They have long been considered to be absent from extra-nuclear, DNA-containing organelles; that is plastids and mitochondria. Recently, however, the targeting of core histone H3 to mitochondria, and the presence of nucleosome-like structures in mitochondrial nucleoids, were proposed in cauliflower and tobacco respectively. Thus, we examined whether histone H3 was present in plant organelles and participated in the organisation of nucleoid structure, using highly purified organelles and organelle nucleoids isolated from BY-2 cultured tobacco cells. Immunofluorescence microscopic observations and Western blotting analyses demonstrated that histone H3 was absent from organelles and organelle nucleoids, consistent with the historical hypothesis. Thus, the organisation of organelle nucleoids, including putative nucleosome-like repetitive structures, should be constructed and maintained without participation of histone H3.


Complementary logics of target-setting: hierarchist and experimentalist governance in the Scottish National Health Service.
Where policy ends are contested and means for change are ambiguous, imposing central targets on local organisations - what we call hierarchist governance - is problematic. The concept of experimentalist governance suggests that target-setting should rather be a learning process between central regulators and local organisations. However, the relationship between experimentalist and hierarchist governance remains unclear. Existing literature suggests that the learning-oriented experimentalist logic is hard to reconcile with a hierarchist logic focussed on accountability for results. We examine whether complementary use of hierarchist and experimentalist ideas is possible. Drawing on experiences from Scotland, we find that experimentalist and hierarchist logics can co-exist in the same performance management system. Each logic served distinct roles with respect to target-setting, implementation and accountability. The emphasis on experimentalism was stronger where ends and means were contested (the case of shifting the balance of care for older people) than where both ends and means seemed obvious initially (the case of health care-associated infections, where target-setting followed a more hierarchist logic). However, governance drifted towards experimentalism when rising rates of community-acquired infections decreased clarity about effective interventions. The nature of policy issues and changes therein over time appear to be important conditions for synergies between governance logics.


Overexpression of placental leptin in diabetic pregnancy: a critical role for insulin.
Leptin, a small peptide produced by adipocytes, is implicated in an increasing number of endocrine regulations, including adiposity, satiety, puberty, and fertility. Although the factors involved in controlling maternal and fetal weight gain during pregnancy have not been fully elucidated, leptin has recently emerged as such a potential factor. In our study, we report the presence of high amounts of leptin mRNA and immunoreactive protein in the human placenta, establishing the placental synthesis of this hormone. A large (three- to fivefold) augmentation in leptin mRNA and protein was found in placentas from insulin-treated diabetic women. This finding was associated with increased concentrations of leptin and insulin in venous cord blood without modification of maternal circulating leptin levels. These data provide evidence that the placenta is a site for regulated leptin production in utero. Insulin is likely to play a critical role in this regulation, thus emphasizing the importance of placental leptin signaling in diabetic pregnancy.


Myotonic dystrophy: the burden for patients and their partners.
Dystrophia myotonica is characterized by progressive muscular weakness, myotonia, mental slowness and lack of initiative, which causes problems in daily life both for patients and for their spouses. Some couples seem to deal with these problems satisfactorily, while for others they are quite burdensome. The aim of this study was to describe the relationship of severity of dystrophia myotonica and psychological wellbeing in patients and partners. Sixty-nine couples, in whom one partner had dystrophia myotonica, completed questionnaires on severity of dystrophia myotonica, marital satisfaction, anxiety and depression (Hospital Anxiety and Depression Scale), hopelessness (Beck Hopelessness Scale) and general psychological health (General Health Questionnaire-12). For patients, a worse view of the future, worse general wellbeing, more anxiety and more depression was associated with a greater need for help. For partners, worse general wellbeing and more anxiety was associated with a lack of initiative of the patient and less marital satisfaction. It is noteworthy that 40% of patients and particularly female partners had Beck Hopelessness Scale scores suggestive of clinically relevant depression. Dystrophia myotonica places a heavy burden on patients, and especially on female partners. The need for help and dependency has more influence on the wellbeing of patients than the symptoms of dystrophia myotonica themselves. Marital satisfaction is a strong predictor of better wellbeing, both for patients and, even more so, for partners.


Development of an osmotic pump system for controlled delivery of diclofenac sodium.
Based on an elementary osmotic pump, controlled release systems of diclofenac sodium (DS) were designed to deliver the drug in a zero-order release pattern. Osmotic pump tablets containing 100 mg DS were prepared and coated with either semipermeable (SPM) or microporous (PM) membranes. The tablet coats were composed of hydrophobic triacetin (TA) or hydrophilic polyethylene glycol 400 (PEG 400) incorporated in cellulose acetate (CA) solution, for SPM and PM, respectively. Variable tablet core compositions such as swelling polymers (PEO and HPMC) and osmotic agents (lactose, NaCl, and KCl) were studied. An optimized, sensitive and well controlled in vitro release design, based on the flow-through cell (FTC), was utilized to discriminate between preparations. The results revealed that the presence of PEG 400 in the coating membrane accelerated the drug release rate, while TA suppressed the release rate of DS. In the case of SPM, the amount of DS released was inversely proportional to the membrane thickness, where 5% (w/w) weight gain gave a higher DS release rate than 10% (w/w). Results of different tablet core compositions revealed that the release rate of DS decreased as PEO molecular weight increased. HPMC K15M showed the lowest DS release rate. The presence of lactose, KCl, or NaCl pronouncedly affected DS release rate depending on polymer type in the core. Scanning electron microscopy (SEM) confirmed formation of pores in the membrane that accounts for faster DS release rate. These results revealed that DS could be formulated as an osmotic pump system with a prolonged, zero-order release pattern.


Theoretical model of the laser imaging of small aerosols: applications to aerosol sizing.
A theoretical model is presented for the formation of small-particle shadow images in a single-lens laser-imaging system. The model uses a modification of classical Lorenz-Mie theory, presented by the authors in an earlier paper, to calculate the external electromagnetic fields resulting from the interaction of a Gaussian laser beam with a finite absorbing spherical particle. Propagation of the electric field through the imaging system components is developed from a scalar viewpoint using the thin-lens transformation and the Fresnel approximation to the Huygens-Fresnel propagation equation. The theoretical model is valid for either transparent or absorbing spheres and has no restrictions on the allowable degree or direction of aerosol defocus. Direct comparisons between theoretical calculations and experimental observations are reported for 53-microm-diameter transparent water droplets and 66-microm-diameter absorbing nickel spheres for defocus ranging from -2 mm (toward the lens) to +2 mm (away from the lens). Theory and experiment showed good agreement in the boundary edge gradient and the location of the external peaks, while observable differences existed in the magnitude of the central spots. Theoretical results, comparing water and nickel aerosols, showed observable differences in the calculated average internal intensity (AII). In contrast, the boundary edge gradient showed less dependence on changes in the optical properties of the particle. These results indicate that criteria, such as the AII, used in focus determination must be reevaluated when applying in-focus sizing algorithms to aerosols with significantly different optical properties.


Neuro-ophthalmological presentation of non-invasive Aspergillus sinus disease in the non-immunocompromised host.
Two cases of non-invasive aspergillosis of the nose and paranasal sinuses are described. The first presented with left proptosis and ophthalmoplegia. Imaging and histology showed a maxillary sinus aspergilloma. The second case presented as a compressive optic neuropathy and histology showed allergic aspergillus sinusitis. The pathological distinction between invasive and non-invasive forms of aspergillus sinusitis is important as in invasive aspergillosis surgical treatment is most effectively combined with systemic antifungal treatment, whereas in aspergilloma of the paranasal sinuses surgical drainage of the sinuses alone is usually sufficient, and in allergic aspergillus sinusitis surgery is best combined with systemic or topical steroids. The distinction between invasive and non-invasive forms is particularly important as both may present with cranial neuropathies.


Lateral line layout correlates with the differential hydrodynamic pressure on swimming fish.
The lateral line of fish includes the canal subsystem that detects hydrodynamic pressure gradients and is thought to be important in swimming behaviors such as rheotaxis and prey tracking. Here, we explore the hypothesis that this sensory system is concentrated at locations where changes in pressure are greatest during motion through water. Using high-fidelity models of rainbow trout, we mimic the flows encountered during swimming while measuring pressure with fine spatial and temporal resolution. The variations in pressure for perturbations in body orientation and for disturbances to the incoming stream are seen to correlate with the sensory network. These findings support a view of the lateral line as a "hydrodynamic antenna" that is configured to retrieve flow signals and also suggest a physical explanation for the nearly universal sensory layout across diverse species.


Cell fate determination factor DACH1 inhibits c-Jun-induced contact-independent growth.
The cell fate determination factor DACH1 plays a key role in cellular differentiation in metazoans. DACH1 is engaged in multiple context-dependent complexes that activate or repress transcription. DACH1 can be recruited to DNA via the Six1/Eya bipartite transcription (DNA binding/coactivator) complex. c-Jun is a critical component of the activator protein (AP)-1 transcription factor complex and can promote contact-independent growth. Herein, DACH1 inhibited c-Jun-induced DNA synthesis and cellular proliferation. Excision of c-Jun with Cre recombinase, in c-jun(f1/f1) 3T3 cells, abrogated DACH1-mediated inhibition of DNA synthesis. c-Jun expression rescued DACH1-mediated inhibition of cellular proliferation. DACH1 inhibited induction of c-Jun by physiological stimuli and repressed c-jun target genes (cyclin A, beta-PAK, and stathmin). DACH1 bound c-Jun and inhibited AP-1 transcriptional activity. c-jun and c-fos were transcriptionally repressed by DACH1, requiring the conserved N-terminal (dac and ski/sno [DS]) domain. c-fos transcriptional repression by DACH1 requires the SRF site of the c-fos promoter. DACH1 inhibited c-Jun transactivation through the delta domain of c-Jun. DACH1 coprecipitated the histone deacetylase proteins (HDAC1, HDAC2, and NCoR), providing a mechanism by which DACH1 represses c-Jun activity through the conserved delta domain. An oncogenic v-Jun deleted of the delta domain was resistant to DACH1 repression. Collectively, these studies demonstrate a novel mechanism by which DACH1 blocks c-Jun-mediated contact-independent growth through repressing the c-Jun delta domain.


Sex differences in the level of Bcl-2 family proteins and caspase-3 activation in the sexually dimorphic nuclei of the preoptic area in postnatal rats.
In developing rats, sex differences in the number of apoptotic cells are found in the central division of the medial preoptic nucleus (MPNc), which is a significant component of the sexually dimorphic nucleus of the preoptic area, and in the anteroventral periventricular nucleus (AVPV). Specifically, male rats have more apoptotic cells in the developing AVPV, whereas females have more apoptotic cells in the developing MPNc. To determine the mechanisms for the sex differences in apoptosis in these nuclei, we compared the expression of the Bcl-2 family members and active caspase-3 in postnatal female and male rats. Western blot analyses for the Bcl-2 family proteins were performed using preoptic tissues isolated from the brain on postnatal day (PD) 1 (day of birth) or on PD8. In the AVPV-containing tissues of PD1 rats, there were significant sex differences in the level of Bcl-2 (female > male) and Bax (female < male) proteins, but not of Bcl-xL or Bad proteins. In the MPNc-containing tissues of PD8 rats, there were significant sex differences in the protein levels for Bcl-2 (female < male), Bax (female > male), and Bad (female < male), but not for Bcl-xL. Immunohistochemical analyses showed significant sex differences in the number of active caspase-3-immunoreactive cells in the AVPV on PD1 (female < male) and in the MPNc on PD8 (female > male). We further found that active caspase-3-immunoreactive cells of the AVPV and MPNc were immunoreactive for NeuN, a neuronal marker. These results suggest that there are sex differences in the induction of apoptosis via the mitochondrial pathway during development of the AVPV and MPNc.


Sustained release methylphenidate for the treatment of ADHD in amphetamine abusers: a pilot study.
The efficacy of stimulant treatment in patients with substance use disorders and comorbid attention deficit hyperactivity disorder (ADHD) has been tested for cocaine and alcohol dependence but so far no studies have been conducted in amphetamine dependent individuals. The present trial was a pilot study aiming to test the feasibility of treating amphetamine dependent patients with comorbid ADHD with central stimulant medication. The study was a double-blind, placebo controlled trial with parallel groups design comparing the efficacy of a fixed dose (72mg) of OROS methylphenidate (MPH) with placebo (PL) in reducing ADHD symptoms in currently abstinent adults with amphetamine dependence and ADHD. Twenty-four treatment seeking patients who met the DSM IV criteria for amphetamine dependence and ADHD were randomized to MPH/PL. The trial was conducted at an outpatient facility with twice weekly visits, measuring ADHD symptoms and drug use. Patients rated their ADHD symptoms on a weekly basis and provided supervised urine specimens for drug toxicology twice weekly. All patients participated in weekly sessions of a skills training programme. Both the groups significantly reduced their self-rated ADHD symptoms during the 12-week treatment but there was no difference between the two treatment arms. Drug use, both measured by urine toxicology and self-report did not differ between the groups. No difference was found between the two groups with regards to craving for amphetamine or in retention in treatment. Larger studies with higher doses combined with individual dosage and longer follow-up periods are warranted.


Induced increase in virulence of low virulence highly [corrected] pathogenic avian influenza by serial intracerebral passage in chickens.
Two highly pathogenic avian influenza (HPAI) virus clones that met the criteria for high-pathogenicity avian influenza viruses, by possessing a multibasic hemagglutinin (HA) cleavage site, were isolated from an H5N1 outbreak in Norfolk, England, in 1991-92. These two isolates, A/turkey/England/50-92/91 (50-92) and A/turkey/England/87-92/91 (87-92), displayed differences in virulence as determined by intravenous pathogenicity index-3 and -0, respectively. DNA sequencing of these two isolates identified 10 amino acid differences throughout the genome: three in HA and polymerase B2 (PB2) and two in polymerase B1 (PB1) and single mutations in nucleoprotein (NP) and polymerase A (PA). Serial intracerebral passages were performed in 1- or 2-day-old specific pathogen free (SPF) chicks with 87-92. Viruses reisolated from each bird passage displayed increases in intracerebral pathogenicity index values (from 0 to 1.9) and therefore virulence. Reverse transcriptase polymerase chain reaction and DNA sequencing on viruses isolated at each passage displayed nine out of the 10 mutations associated with the higher pathogenic genotype of 50-92, except for the mutation found in NP, which retained the amino acid residue associated with 87-92. Serial passage through 9-day-old SPF embryonated chicken eggs and serial intravenous passage in 6-wk-old birds could not reproduce these results. These results further highlight that nucleotide changes in the genome other than at the HA cleavage site can attenuate the virulence of HPAI viruses.


Swedish social insurance officers' experience of their working conditions when dealing with applications for disability pension.
The aim of this study was to describe how Swedish social insurance officers experienced their working conditions, when dealing with applications for disability pensions (DPs). A qualitative research design was selected to describe their experiences. Open-ended interviews with ten social insurance officers were analyzed with inductive content analysis. This analysis showed that the working conditions were influenced by rules and regulations and the social insurance officers' competence. The social insurance officers' powerful positions and how their discretion was implemented made them feel responsible for performing their work well. They felt that the large number of clients hampered them from being able to offer the clients the activities they were entitled to, and from paying each client sufficient attention. There was a need for time to reflect and to improve management, in order to better develop the way in which DPs were handled. There was a difference in culture between the older social insurance officers, who had experience-based training, and the younger social insurance officers, who had academic qualifications. The results from this study could be used to better develop the organisation of work in the social insurance agency, and in further educational activities.


Biomedical applications of radiation force of ultrasound: historical roots and physical basis.
Radiation force is a universal phenomenon in any wave motion, electromagnetic or acoustic. Although acoustic and electromagnetic waves are both characterized by time variation of basic quantities, they are also both capable of exerting a steady force called radiation force. In 1902, Lord Rayleigh published his classic work on the radiation force of sound, introducing the concept of acoustic radiation pressure, and some years later, further fundamental contributions to the radiation force phenomenon were made by L. Brillouin and P. Langevin. Many of the studies discussing radiation force published before 1990 were related to techniques for measuring acoustic power of therapeutic devices; also, radiation force was one of the factors considered in the search for noncavitational, nonthermal mechanisms of ultrasonic bioeffects. A major surge in various biomedical applications of acoustic radiation force started in the 1990s and continues today. Numerous new applications emerged including manipulation of cells in suspension, increasing the sensitivity of biosensors and immunochemical tests, assessing viscoelastic properties of fluids and biological tissues, elasticity imaging, monitoring ablation of lesions during ablation therapy, targeted drug and gene delivery, molecular imaging and acoustical tweezers. We briefly present in this review the major milestones in the history of radiation force and its biomedical applications. In discussing the physical basis of radiation force and its applications, we present basic equations describing the relationship of radiation stress with parameters of acoustical fields and with the induced motion in the biological media. Momentum and force associated with a plane-traveling wave, equations for nonlinear and nonsteady-state acoustic streams, radiation stress tensor for solids and biological tissues and radiation force acting on particles and microbubbles are considered.


Non-steroidal anti-inflammatory drug use in the elderly.
The efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of inflammation and pain of various origins is well established. Prescribing these drugs, however, remains a challenge because a great variety of gastrointestinal and cardiovascular safety issues need to be considered, particularly in older patients. Recent recommendations suggest that the prescription of non-selective NSAIDs and/or selective cyclo-oxygenase-2 inhibitors (coxibs) may be appropriate in patients with low gastrointestinal risk (no prior gastrointestinal events, no concomitant treatments with other damaging drugs). Gastroprotection is appropriate in patients with gastrointestinal risk factors and in older patients. In patients at high risk for gastrointestinal and cardiovascular events, however, NSAID or coxib prescriptions are contraindicated. Multidimensional impairment is a crucial point in evaluating the clinical outcome of older patients; thus, a comprehensive geriatric assessment is useful in predicting adverse outcomes, including morbidity and mortality.


Atmospheric escape from the TRAPPIST-1 planets and implications for habitability.
The presence of an atmosphere over sufficiently long timescales is widely perceived as one of the most prominent criteria associated with planetary surface habitability. We address the crucial question of whether the seven Earth-sized planets transiting the recently discovered ultracool dwarf star TRAPPIST-1 are capable of retaining their atmospheres. To this effect, we carry out numerical simulations to characterize the stellar wind of TRAPPIST-1 and the atmospheric ion escape rates for all of the seven planets. We also estimate the escape rates analytically and demonstrate that they are in good agreement with the numerical results. We conclude that the outer planets of the TRAPPIST-1 system are capable of retaining their atmospheres over billion-year timescales. The consequences arising from our results are also explored in the context of abiogenesis, biodiversity, and searches for future exoplanets. In light of the many unknowns and assumptions involved, we recommend that these conclusions must be interpreted with due caution.


Brow suspension, a minimally invasive technique in facial rejuvenation.
People tend to prefer noninvasive or minimally invasive methods of facial rejuvenation, especially when it involves their face, which is the hallmark of a person's identity and impossible to hide. It is widely known that brow ptosis gives the face a "tired look" and also accentuates deformities of the upper eyelid. Most people who are interested in facial rejuvenation may not accept even a minor surgery, such as an endoscopic surgery. The senior author has developed a minimally invasive method of suspending the brow at a higher position. In this technique, there is neither surgical dissection nor a surgical incision except for four stab incisions and suture insertion, which is why we refer to it as a nonsurgical brow suspension. It is done under local anesthesia, and the brows are fixed in the position that they assume when the patient is supine. In the past 6 years, we performed 387 brow suspensions on 324 female and 63 male patients. The youngest patient was 19 years old, and the oldest was 74 years old. A retrospective chart review was done. These 387 cases were reviewed by comparison of preoperative and postoperative photographs. This approach was not only used for patients who were not interested in surgical rejuvenation but was also combined with lipofilling, laser resurfacing, and/or upper blepharoplasty. This technique is useful for correcting postsurgical brow asymmetry. We present this technique as an adjunct to the established techniques of facial rejuvenation. Despite the high patient acceptance and technical ease, it is not a replacement for the established techniques of facial rejuvenation.


Home-based, early intervention with mechatronic toys for preterm infants at risk of neurodevelopmental disorders (CARETOY): a RCT protocol.
Preterm infants are at risk for neurodevelopmental disorders, including motor, cognitive or behavioural problems, which may potentially be modified by early intervention. The EU CareToy Project Consortium (http://www.caretoy.eu) has developed a new modular system for intensive, individualized, home-based and family-centred early intervention, managed remotely by rehabilitation staff. A randomised controlled trial (RCT) has been designed to evaluate the efficacy of CareToy training in a first sample of low-risk preterm infants. The trial, randomised, multi-center, evaluator-blinded, parallel group controlled, is designed according to CONSORT Statement. Eligible subjects are infants born preterm without major complications, aged 3-9 months of corrected age with specific gross-motor abilities defined by Ages & Stages Questionnaire scores. Recruited infants, whose parents will sign a written informed consent for participation, will be randomized in CareToy training and control groups at baseline (T0). CareToy group will perform four weeks of personalized activities with the CareToy system, customized by the rehabilitation staff. The control group will continue standard care. Infant Motor Profile Scale is the primary outcome measure and a total sample size of 40 infants has been established. Bayley-Cognitive subscale, Alberta Infants Motor Scale and Teller Acuity Cards are secondary outcome measures. All measurements will be performed at T0 and at the end of training/control period (T1). For ethical reasons, after this first phase infants enrolled in the control group will perform the CareToy training, while the training group will continue standard care. At the end of open phase (T2) all infants will be assessed as at T1. Further assessment will be performed at 18 months corrected age (T3) to evaluate the long-term effects on neurodevelopmental outcome. Caregivers and rehabilitation staff will not be blinded whereas all the clinical assessments will be performed, videotaped and scored by blind assessors. The trial is ongoing and it is expected to be completed by April 2015. This paper describes RCT methodology to evaluate CareToy as a new tool for early intervention in preterm infants, first contribution to test this new type of system. It presents background, hypotheses, outcome measures and trial methodology. ClinicalTrials.gov: NCT01990183. EU grant ICT-2011.5.1-287932.


Is there a Consensus in the Management of Distal Radial Fractures?
This unique postal survey was setup to assess the agreement on treatment options in displaced distal radius fractures and whether or not there existed a consensus amongst the surgeons contacted. With this in view we contacted 244 surgeons and 166 completed answers were received.We chose two common examples of displaced distal radius fractures. Case one was a 38 year old teacher with a closed, displaced extra-articular fracture (Frykman type II) of her left non-dominant hand and case two was a 42 year old carer, with a closed, displaced intra-articular fracture (Frykman type VII) of her right dominant wrist. There was a questionnaire included with these radiographs.In the first case, 82 (49%) surgeons favoured MUA + K-wiring, 47 (28%) favoured volar plating and 14 (8%) an external fixator. In the second case, 28 (17%) surgeons favoured MUA + K-wiring, 53 (32%) advocated volar plating and 33 (20%) an external fixator. Furthermore surgeons with specialist Upper limb interest were more likely to apply a volar plate (63% in either case) whilst the surgeons with general or other areas of expertise (18% in first case and 23% for second case).In conclusion there is no consensus among the Orthopaedic surgeons in treating displaced distal radial fractures. A multicentered randomized clinical trial would help elucidate the best treatment options.


Perspectives of health care providers on the provision of intermittent preventive treatment in pregnancy in health facilities in Malawi.
Nearly 20 years after the adoption by the government of Malawi of the provision of intermittent preventive treatment in pregnancy (IPTp) for malaria, only 55% of pregnant women received at least two doses of sulfadoxine-pyrimethamine (SP) in 2010. Although several reasons for the low coverage have been suggested, few studies have examined the views of health care providers. This study examined the experiences of the nurses and midwives in providing antenatal care (ANC) services. This study was conducted in health facilities in Malawi that provide routine ANC services. Providers of ANC in Malawi were selected from in eight health care facilities of Malawi. Selected providers were interviewed using a semi-structured interview guide designed to address a series of themes related to their working conditions and their delivery of IPTp. Nurses displayed detailed knowledge of ANC services and the rationale behind them. Nurses understood that they should provide two doses of IPTp during a pregnancy, but they did not agree on the timing of the doses. Nurses gave SP as directly observed therapy (DOT) at the clinic. Nurses did not give SP pills to women to take home with them because they did not trust that women would take the pills. Women who resisted taking SP explained they do not take drugs if they had not eaten, or they feared side effects, or they were not sick. Reasons for not giving the first or second dose of SP included a delay in the first ANC visit, testing positive for HIV, and presenting with malaria. None of the nurses were able to show any specific written guidelines on when to give SP. The challenges faced by the nurses include being overworked and persuading women to take SP under observation. The findings show that the nurses had gained the knowledge and technical skills to provide appropriate ANC services. With regard to IPTp, nurses need guidelines that would be available at the health facility about how and when to give SP. The adoption of the WHO guidelines and their diffusion to health care facilities could help increase the coverage of IPTp2 (at least two doses of sulfadoxine-pyrimethamine) in Malawi.


Mutations in the zinc finger protein gene, ZNF469, contribute to the pathogenesis of keratoconus.
Mutations in the zinc finger protein gene ZNF469 cause recessive brittle cornea syndrome, characterized by spontaneous corneal perforations. Genome-wide association studies (GWAS) have implicated common variants in this gene as a determinant for central corneal thickness (CCT). We investigated the contribution of ZNF469 in a sample set of keratoconus patients. Forty-three patients with keratoconus (49% Māori or Pacific [Polynesian]) were recruited. If a family history was present, family members were recruited. Participants underwent comprehensive examination, and a DNA sample was collected. Mutational analysis of ZNF469 was undertaken using Sanger sequencing, including an ancestrally matched Polynesian control population. Bioinformatic databases of exome variation and protein prediction software were used to determine presence and frequency and the pathogenicity for each observed change. Fourteen nonsynonymous missense single nucleotide polymorphisms (SNPs) were observed in ZNF469. Of the 43 probands, at least one probable disease-causing variant was detected in 20 (46%) (16/32 sporadic, 4/11 familial) and two variants in 5 (11.6%) (3/32 sporadic, 2/11 familial). Only heterozygous changes segregated with disease. Three "deleterious" changes observed in the Polynesian controls were removed from analysis; therefore pathogenic variants occurred in 10/43 (23.3%). Rare missense mutations in ZNF469, predicted to be pathogenic, occurred heterozygously, at a frequency of 23% in a keratoconus population. ZNF469 is associated with CCT in GWAS and is therefore likely to play a role in the synthesis and/or organization of corneal collagen fibers. The pathogenic changes observed either genetically predispose toward a "thin" cornea, which then becomes keratoconic, or are directly pathogenic.


Utility of CD127 combined with FOXP3 for identification of operational tolerance after liver transplantation.
Loss of cell surface expression of CD127 on CD4(+)CD25(++) regulatory T-cells (Tregs) may be a useful marker to efficiently isolate Tregs. As FOXP3 was specifically used to identify Tregs, combining these two markers could give better identification for patient with operational tolerance (OT) after liver transplantation. To testify this mixed lymphocyte reaction (MLR), the function of circulating CD4(+)CD25(++)CD127(dim) cells (CD127(dim) cells) was examined in immunosuppression (IS)-free pediatric recipients after liver transplantation (LTx) (group operational tolerance: OT) (Gr-tol n=25) compared to recipients who could not stop IS due to clinically overt rejection (group intolerance) (Gr-intol n=18), recipients who were weaning IS (Gr-weaning n=11) and age-matched healthy volunteers (Gr-vol n=11). In addition, the frequencies of CD127(dim) cells vs CD4(+)CD25(++)CD127(dim)FOXP3(+) (CD127(dim)FOXP3(+)) cells were compared in these four groups by FACS analyses. Our results showed that The proliferation of CD4 cells to donor antigens was reduced compared to third-party antigens only in Gr-tol (P=0.022) but not in other groups (P=NS). Depletion of CD127(dim) cells resulted in a donor antigen-specific abrogation of this MLR hyporesponsiveness in Gr-tol (P<0.001) but not other groups (P=NS). This implied that CD127 efficiently isolated donor antigen-specific Tregs. The frequencies of CD127(dim) cells were significantly lower in Gr-intol (5.2%±1.9%) compared to those in Gr-tol (7.8%±1.8%) (P<0.001) as were the frequencies of CD127(dim) FOXP3(+) cells (Gr-tol: 5.4%±1.7% vs Gr-intol: 2.9%±1.0%, P<0.001). Of interest, there were fewer CD127(dim)FOXP3(+) cells in Gr-intol (2.9%±1%) than in Gr-weaning (5.1%±1.8%) (P=0.002), but no difference in CD127(dim) cells (Gr-intol: 5.2%±1.9% vs Gr-weaning: 6.7%±2.0%) (NS). Thus, combining FOXP3 with CD127 for phenotype analysis demonstrated an unequivocal difference between Gr-intol and Gr-weaning that was not detected by CD127 alone. In conclusion CD127 was a useful surface marker to isolate donor-antigen-specific-Tregs in OT after LTx. The additive effect of its combination with FOXP3 is important in phenotypical Treg analyses of OT patients.


Protein markers of cancer-associated fibroblasts and tumor-initiating cells reveal subpopulations in freshly isolated ovarian cancer ascites.
In ovarian cancer, massive intraperitoneal dissemination is due to exfoliated tumor cells in ascites. Tumor-initiating cells (TICs or cancer stem cells) and cells showing epithelial-mesenchymal-transition (EMT) are particularly implicated. Spontaneous spherical cell aggregates are sometimes observed, but although similar to those formed by TICs in vitro, their significance is unclear. Cells freshly isolated from malignant ascites were separated into sphere samples (S-type samples, n=9) and monolayer-forming single-cell suspensions (M-type, n=18). Using western blot, these were then compared for expression of protein markers of EMT, TIC, and of cancer-associated fibroblasts (CAFs). S-type cells differed significantly from M-type by expressing high levels of E-cadherin and no or little vimentin, integrin-β3 or stem cell transcription factor Oct-4A. By contrast, M-type samples were enriched for CD44, Oct-4A and for CAF markers. Independently of M- and S-type, there was a strong correlation between TIC markers Nanog and EpCAM. The CAF marker α-SMA correlated with clinical stage IV. This is the first report on CAF markers in malignant ascites and on SUMOylation of Oct-4A in ovarian cancer. In addition to demonstrating potentially high levels of TICs in ascites, the results suggest that the S-type population is the less tumorigenic one. Nanog(high)/EpCAM(high) samples represent a TIC subset which may be either M- or S-type, and which is separate from the CD44(high)/Oct-4A(high) subset observed only in M-type samples. This demonstrates a heterogeneity in TIC populations in vivo which has practical implications for TIC isolation based on cell sorting. The biological heterogeneity will need to be addressed in future therapeutical strategies.


Abnormal uterine bleeding.
It is not uncommon for a woman to suffer from abnormal uterine bleeding (AUB) or heavy menstrual bleeding (HMB) at some point during her lifetime. Once pathology is excluded, in practice, management needs to be individualised, taking into account the improvement of the woman's symptoms and quality of life. Peer-reviewed journals, governmental and professional society publications. There is now agreement on a structured, universal approach to the diagnosis of AUB, with the aide memoirs PALM (polyps, adenomyosis, leiomyoma, malignancy) and COEIN (coagulopathies, ovulatory dysfunction, endometrial, iatrogenic, not otherwise classified). Once malignancy and significant pelvic pathology have been ruled out, medical treatment is an effective first-line therapeutic option, with surgery, including endometrial ablation and hysterectomy, offered when medical management has failed to resolve symptoms and fertility is no longer desired. There remains controversy around the management of the types and subtypes of adenomyosis and leiomyoma, and understanding their impact on clinical reproductive outcomes. Standardised assessment tools for measuring outcomes of AUB are being developed. Novel diagnostic and monitoring tools should be developed to help stratify treatment for women with AUB, particularly relating to 'unclassified' and 'endometrial' causes.


Molecular structure of the lipoamide dehydrogenase domain of a surface antigen from Neisseria meningitidis.
The protein p64k from the surface of the Neisseria meningitidis bacteria has been characterized as a two-domain protein. It contains a dihydrolipoamide dehydrogenase domain of 482 residues, involving a FAD prosthetic group as a cofactor, and a smaller lipoic acid binding domain of 86 residues. The two domains are joined by a flexible segment rich in alanine and proline residues. The structure of the dihydrolipoamide dehydrogenase domain was determined by X-ray diffraction. It was solved by a combination of molecular replacement and multiple isomorphous replacement techniques and refined to 2.7 A resolution. In the crystal, the recombinant p64k mimics the functional homo-dimer by using one of the crystallographic 2-fold axes. The reactive disulphide bridge Cys161-Cys166 is in the oxidised state and the FAD is bound in an extended conformation. This main domain contains the major antigenic determinant of the protein, an extended loop of 32 residues at the surface of the protein. A mis-attribution at residue 553 in the sequence has been detected by inspection of electron density maps and the geometry. However, when compared to the other dihydrolipoamide dehydrogenases, there are some significant differences: (1) an unusual number of cis-proline residues and (2) a new motif built around a 2-fold axis by the sulphur atoms of residues Met558, Cys560 and their symmetry related equivalents.


Biomechanics Simulations Using Cubic Hermite Meshes with Extraordinary Nodes for Isogeometric Cardiac Modeling.
Cubic Hermite hexahedral finite element meshes have some well-known advantages over linear tetrahedral finite element meshes in biomechanical and anatomic modeling using isogeometric analysis. These include faster convergence rates as well as the ability to easily model rule-based anatomic features such as cardiac fiber directions. However, it is not possible to create closed complex objects with only regular nodes; these objects require the presence of extraordinary nodes (nodes with 3 or >= 5 adjacent elements in 2D) in the mesh. The presence of extraordinary nodes requires new constraints on the derivatives of adjacent elements to maintain continuity. We have developed a new method that uses an ensemble coordinate frame at the nodes and a local-to-global mapping to maintain continuity. In this paper, we make use of this mapping to create cubic Hermite models of the human ventricles and a four-chamber heart. We also extend the methods to the finite element equations to perform biomechanics simulations using these meshes. The new methods are validated using simple test models and applied to anatomically accurate ventricular meshes with valve annuli to simulate complete cardiac cycle simulations.


Selective control of amino acid metabolism by the GCN2 eIF2 kinase pathway in Saccharomyces cerevisiae.
When eukaryotic cells are deprived of amino acids, uncharged tRNAs accumulate and activate the conserved GCN2 protein kinase. Activated Gcn2p up-regulates the general amino acid control pathway through phosphorylation of the translational initiation factor eIF2. In Saccharomyces cerevisiae, Gcn2p is the only kinase that phosphorylates eIF2 to regulate translation through this mechanism. We addressed changes in yeast growth and tRNA aminoacylation, or charging, during amino acid depletion in the presence and absence of GCN2. tRNA charging was measured using a microarray technique which simultaneously measures all cytosolic tRNAs. A fully prototrophic strain, and its isogenic gcn2 Delta counterpart, were used to study depletion for each of the 20 amino acids, with a focus on Trp, Arg, His and Leu, which are metabolically distinct and together provide a good overview on amino acid metabolism. While the wild-type strain had no observable phenotype upon depletion for any amino acid, the gcn2 Delta strain showed slow growth in media devoid of only Trp or Arg. Consistent with the growth phenotypes, profiles of genome-wide tRNA charging revealed significant decrease in cognate tRNA charging only in the gcn2 Delta strain upon depletion for Trp or Arg. In contrast, there was no change in tRNA charging during His and Leu depletion in either the wild-type or gcn2 Delta strains, consistent with the null effect on growth during loss of these amino acids. We determined that the growth phenotype of Trp depletion is derived from feedback inhibition of aromatic amino acid biosynthesis. By removing Phe and Tyr from the media in addition to Trp, regular growth was restored and tRNATrp charging no longer decreased. The growth phenotype of Arg depletion is derived from unbalanced nitrogen metabolism. By supplementing ornithine upon Arg depletion, both growth and tRNAArg charging were partially restored. Under mild stress conditions the basal activity of Gcn2p is sufficient to allow for proper adaptation to amino acid depletion. This study highlights the importance of the GCN2 eIF2 kinase pathway for maintaining metabolic homeostasis, contributing to appropriate tRNA charging and growth adaptation in response to culture conditions deficient for the central amino acids, tryptophan and arginine.


An actin-nucleating activity in polymorphonuclear leukocytes is modulated by chemotactic peptides.
We examined the actin-nucleating activity in polymorphonuclear leukocyte lysates prepared at various times after chemotactic peptide addition. The actin nucleation increases two- to threefold within 15 s after peptide addition, decays to basal levels within 90 s, and is largely independent of cytoplasmic calcium fluxes. The peptide-induced nucleation sites behave as free barbed ends and therefore may increase the level of polymerized actin in vivo. The new nucleation sites may also determine the cellular sites of actin polymerization. This localization of actin polymerization could be important for the directional extension of lamellipodia during chemotaxis.


Pfiesteria: review of the science and identification of research gaps. Report for the National Center for Environmental Health, Centers for Disease Control and Prevention.
In connection with the CDC National Conference on Pfiesteria, a multidisciplinary panel evaluated Pfiesteria-related research. The panel set out what was known and what was not known about adverse effects of the organism on estuarine ecology, fish, and human health; assessed the methods used in Pfiesteria research; and offered suggestions to address data gaps. The panel's expertise covered dinoflagellate ecology; fish pathology and toxicology; laboratory measurement of toxins, epidemiology, and neurology. The panel evaluated peer-reviewed and non-peer-reviewed literature available through June 2000 in a systematic conceptual framework that moved from the source of exposure, through exposure research and dose, to human health effects. Substantial uncertainties remain throughout the conceptual framework the panel used to guide its evaluation. Firm evidence demonstrates that Pfiesteria is toxic to fish, but the specific toxin has not been isolated or characterized. Laboratory and field evidence indicate that the organism has a complex life cycle. The consequences of human exposure to Pfiesteria toxin and the magnitude of the human health problem remain obscure. The patchwork of approaches used in clinical evaluation and surrogate measures of exposure to the toxin are major limitations of this work. To protect public health, the panel suggests that priority be given research that will provide better insight into the effects of Pfiesteria on human health. Key gaps include the identity and mechanism of action of the toxin(s), the incomplete description of effects of exposure in invertebrates, fish, and humans, and the nature and extent of exposures that place people at risk.


Lithium storage mechanisms in purpurin based organic lithium ion battery electrodes.
Current lithium batteries operate on inorganic insertion compounds to power a diverse range of applications, but recently there is a surging demand to develop environmentally friendly green electrode materials. To develop sustainable and eco-friendly lithium ion batteries, we report reversible lithium ion storage properties of a naturally occurring and abundant organic compound purpurin, which is non-toxic and derived from the plant madder. The carbonyl/hydroxyl groups present in purpurin molecules act as redox centers and reacts electrochemically with Li-ions during the charge/discharge process. The mechanism of lithiation of purpurin is fully elucidated using NMR, UV and FTIR spectral studies. The formation of the most favored six membered binding core of lithium ion with carbonyl groups of purpurin and hydroxyl groups at C-1 and C-4 positions respectively facilitated lithiation process, whereas hydroxyl group at C-2 position remains unaltered.


Acetyl-11-keto-β-boswellic acid extracted from Boswellia serrata promotes Schwann cell proliferation and sciatic nerve function recovery.
Frankincense can promote blood circulation. Acetyl-11-keto-β-boswellic acid (AKBA) is a small molecule with anti-inflammatory properties that is derived from Boswellia serrata. Here, we hypothesized that it may promote regeneration of injured sciatic nerve. To address this hypothesis, we established a rat model of sciatic nerve injury using a nerve clamping method. Rats were administered AKBA once every 2 days at doses of 1.5, 3, and 6 mg/kg by intraperitoneal injection for 30 days from the 1st day after injury. Sciatic nerve function was evaluated using the sciatic functional index. Degree of muscle atrophy was measured using the triceps surae muscle Cuadros index. Neuropathological changes were observed by hematoxylin-eosin staining. Western blot analysis was used to detect expression of phospho-extracellular signal-regulated kinase 1 and 2 (p-ERK1/2) in injured nerve. S100 immunoreactivity in injured nerve was detected by immunohistochemistry. In vivo experiments showed that 3 and 6 mg/kg AKBA significantly increased sciatic nerve index, Cuadros index of triceps muscle, p-ERK1/2 expression, and S100 immunoreactivity in injured sciatic nerve of sciatic nerve injury model rats. Furthermore, for in vitro experiments, Schwann cells were treated with AKBA at 0-20 μg/mL. Proliferation of Schwann cells was detected by Cell Counting Kit-8 colorimetry assay. The results showed that 2 μg/mL AKBA is the optimal therapeutic concentration. In addition, ERK phosphorylation levels increased following 2 μg/mL AKBA treatment. In the presence of the ERK1/2 inhibitor, PD98059 (2.5 μL/mL), the AKBA-induced increase in p-ERK1/2 protein expression was partially abrogated. In conclusion, our study shows that AKBA promotes peripheral nerve regeneration with ERK protein phosphorylation playing a key role in this process.


[Epidemiology of Tuberculosis in Mexico, 1981-1998. Inconsistencies between reports of the WHO and the Ministry of health].
To describe the tuberculosis morbidity and mortality trends in Mexico, by comparing the data reported by the Ministry of Health (MH) and the World Health Organization (WHO) between 1981 and 1998. The number of cases notified in the past few years, their rates, and the trends of the disease in Mexico were analyzed. The incidence of smear-positive pulmonary tuberculosis was estimated for 1997 and 1998 with the annual tuberculosis infection risk (ATIR), to estimate the percentage of bacilliferous cases in 1997-1998. WHO reported more tuberculosis cases for Mexico than the MH. However, this difference has decreased throughout the years. The notification of smear-positive cases remained stable during 1993-1998. The estimated percentages of detection were 66% for 1997 and 26% for 1998 (based on ATIR of 0.5%). Tuberculosis mortality decreased gradually (6.7% per year) between 1990 and 1998, whereas the number of new cases increased, suggesting the persistence of disease transmission in the population. Inconsistencies between case notifications from national data and WHO were considerable, but decreased progressively during the study period. According to ATIR estimations, a considerable number of infectious tuberculosis cases are not detected. The English version of this paper is available at: http://www.insp.mx/salud/index.html.


Kids Out; evaluation of a brief multimodal cluster randomized intervention integrated in health education lessons to increase physical activity and reduce sedentary behavior among eighth graders.
Most Finnish adolescents are not sufficiently physically active. Health education (HE) provides beneficial starting point for physical activity (PA) promotion in schools. This study evaluates an intervention integrated into three HE lessons to increase PA and reduce sedentary behavior (SB) among eighth graders. All public secondary schools in Tampere, Finland participated and were randomized to intervention (INT, n = 7) and comparison group (COM, n = 7). In INT (690 students, 36 classes) the teachers (n = 14) implemented behavioral theory-driven content during three HE lessons. In COM (860 students, 41 classes) the teachers (n = 14) carried out standard lessons. The evaluation was based on RE-AIM: Effectiveness was assessed from baseline to 4 weeks (Follow-up 1) and Maintenance from 4 weeks to 7 months (Follow-up 2) with change in students' PA and SB and related psychosocial and parental factors. Methods included questionnaire, accelerometer and activity diary. Linear mixed models with baseline adjustments and random effect correction were used to compare the difference in change between INT and COM. Data on Reach, Adoption and Implementation were collected during the process. Intervention effects were only seen in the self-reported data favoring INT in the weekly number of days with at least 1 h of brisk leisure PA (0.3 [95%CI 0.1 to 0.6]), proportion of students meeting PA recommendations (4.1 [95%CI 2.5 to 5.7]), proportion of students reporting that their family sets limitations for screen time (5.4 [95%CI 3.3 to 7.4]) and in the number of days on which the students intended to do leisure PA in the following week (0.3 [95%CI 0.1 to 0.6]). The effects on PA were still beneficial for INT at Follow-up 2. The intervention reached 96% of the students, was adopted in all 7 schools and was implemented by 13/14 teachers in 35/36 classes. The intervention was feasible and had small favorable effects on students' self-reported PA, intention to do PA and family norm in screen time. The effects on PA persisted until Follow-up 2. It is likely that for greater impacts the HE lessons should have been supported with other actions without compromising feasibility. NCT01633918 (June 27th, 2012).


Collective adaptability in a replication network of minimal nucleobase sequences.
A major challenge for understanding the origins of life is to explore how replication networks can engage in an evolutionary process. Herein, we shed light on this problem by implementing a network constituted by two different types of extremely simple biological components: the amino acid cysteine and the canonical nucleobases adenine and thymine, connected through amide bonds to the cysteine amino group and oxidation of its thiol into three possible disulfides. Supramolecular and kinetic analyses revealed that both self- and mutual interactions between such dinucleobase compounds drive their assembly and replication pathways. Those pathways involving sequence complementarity led to enhanced replication rates, suggesting a potential bias for selection. The interplay of synergistic dynamics and competition between replicators was then simulated, under conditions that are not easily accessible with experiments, in an open reactor parametrized and constrained with the unprecedentedly complete experimental kinetic data obtained for our replicative network. Interestingly, the simulations show bistability, as a selective amplification of different species depending on the initial mixture composition. Overall, this network configuration can favor a collective adaptability to changes in the availability of feedstock molecules, with disulfide exchange reactions serving as 'wires' that connect the different individual auto- and cross-catalytic pathways.


A comparison of the performance and impact of breast cancer screening programmes in East Anglia, U.K. and Bouches du Rhône, France.
The purpose of this study was to compare results from the first screening round of two breast cancer screening programmes of similar design implemented in different health care settings. The East Anglian programme is part of the U.K. National Health Service Breast Screening Programme, which is a centralised programme with a limited number of dedicated screening units. The Bouches du Rhône programme is one of 13 French programmes based on a decentralised model using existing radiology clinics. Compliance and cancer detection rates were lower in the Bouches du Rhône programme. Detection rates for small invasive cancers (< or = 10 mm) were similar in the two programmes, although larger cancers (> or = 20 mm) were detected in the Bouches du Rhône programme. Significantly, the shift towards more favourable distribution of prognostic characteristics associated with screen-detected breast cancers compared with those arising outside the programme is less marked in the Bouches du Rhône programme. This is probably due to the more favourable underlying disease status in the district resulting from a long history of breast awareness and spontaneous mammography.


Tumor necrosis factor-alpha stimulates aromatase gene expression in human adipose stromal cells through use of an activating protein-1 binding site upstream of promoter 1.4.
Expression of aromatase P450 (P450arom; the product of the CYP19 gene) in human adipose stromal cells in primary culture is markedly stimulated by serum in the presence of dexamethasone (DEX). Under these conditions, the majority of P450arom transcripts contain untranslated exon 1.4 at their 5'-ends. Previously, we observed that the region of the CYP19 gene upstream of exon 1.4 contains a TATA-less promoter, a glucocorticoid response element, and an interferon-gamma-activating sequence. These act to mediate the action of interleukin-6 and related cytokines to stimulate aromatase expression in the presence of DEX. In the present study, we found that tumor necrosis factor-alpha (TNF alpha) also acts synergistically with DEX to stimulate aromatase expression in adipose stromal cells in serum-free medium. We observed that the action of TNF alpha can be mimicked by ceramide. Maximal aromatase activity was obtained when cells were incubated with 5 ng/ml TNF alpha or 100 nM ceramide in the presence of 250 nM DEX. Levels of c-fos and c-jun proteins also were increased by TNF alpha or ceramide in the presence of DEX. Upstream of the interferon-gamma-activating sequence site there is an imperfect activating protein-1 (AP-1) binding site (2-bp mismatch). Gel retardation analysis using nucleotide probes containing the putative AP-1-binding sequence and nuclear extracts of human adipose stromal cells cultured in the presence of TNF alpha or ceramide plus DEX revealed that adipose stromal cells nuclear proteins bind to this site and that binding was competed by a 100-fold excess of a consensus AP-1 sequence. In addition, binding activity was competed by both anti-c-fos and anti-c-jun sera. Mutation or deletion of the putative AP-1 element resulted in the loss of TNF alpha- plus DEX-induced activity of reporter constructs comprised of 515 bp of the exon 1.4 flanking sequence linked to the luciferase gene. These results suggest that TNF alpha, probably acting through ceramide formation, stimulates the binding of both c-fos and c-jun to the AP-1 element upstream of exon 1.4. These act cooperatively with the ligand-activated glucocorticoid receptor to induce aromatase expression in adipose stromal cells in primary culture. We conclude that this TNF alpha signal transduction pathway may play an important role in the regulation of estrogen biosynthesis in adipose tissue.


Microwaves induce peripheral vasodilation squirrel monkeys.
Vasomotor activity in cutaneous tail veins was indexed by changes in local skin temperature during exposure of the whole body to 12.3-centimeter continuous microwaves. At an ambient temperature (26 degrees C) just below that at which tail vessels normally vasodilate, criterion dilation was initiated by 5-minute exposures to a microwave power density of 8 milliwatts per square centimeter. This intensity deposits energy equivalent to approximately 20 percent of the monkey's resting metabolic rate but produces no observable change in deep body temperature. Intensity increments of 3 to 4 milliwatts per square centimeter for 1 degree C reductions in ambient temperature below 26 degrees C produced identical responses. That no vasodilation occurred during infrared exposures of equivalent power density suggests that noncutaneous thermosensitive structures may mediate microwave activation of thermoregulatory responses in the peripheral vasomotor system.


Biophysical isolation and identification of circulating tumor cells.
Isolation and enumeration of circulating tumor cells (CTCs) from blood is important for determining patient prognosis and monitoring treatment. Methods based on affinity to cell surface markers have been applied to both purify (via immunoseparation) and identify (via immunofluorescence) CTCs. However, variability of cell biomarker expression associated with tumor heterogeneity and evolution and cross-reactivity of antibody probes have long complicated CTC enrichment and immunostaining. Here, we report a truly label-free high-throughput microfluidic approach to isolate, enumerate, and characterize the biophysical properties of CTCs using an integrated microfluidic device. Vortex-mediated deformability cytometry (VDC) consists of an initial vortex region which enriches large CTCs, followed by release into a downstream hydrodynamic stretching region which deforms the cells. Visualization and quantification of cell deformation with a high-speed camera revealed populations of large (>15 μm diameter) and deformable (aspect ratio >1.2) CTCs from 16 stage IV lung cancer samples, that are clearly distinguished by increased deformability compared to contaminating blood cells and rare large cells isolated from healthy patients. The VDC technology demonstrated a comparable positive detection rate of putative CTCs above healthy baseline (93.8%) with respect to standard immunofluorescence (71.4%). Automation allows full enumeration of CTCs from a 10 mL vial of blood within <1 h after sample acquisition, compared with 4+ hours with standard approaches. Moreover, cells are released into any collection vessel for further downstream analysis. VDC shows potential for accurate CTC enumeration without labels and confirms the unique highly deformable biophysical properties of large CTCs circulating in blood.


Digital gene expression approach over multiple RNA-Seq data sets to detect neoblast transcriptional changes in Schmidtea mediterranea.
The freshwater planarian Schmidtea mediterranea is recognised as a valuable model for research into adult stem cells and regeneration. With the advent of the high-throughput sequencing technologies, it has become feasible to undertake detailed transcriptional analysis of its unique stem cell population, the neoblasts. Nonetheless, a reliable reference for this type of studies is still lacking. Taking advantage of digital gene expression (DGE) sequencing technology we compare all the available transcriptomes for S. mediterranea and improve their annotation. These results are accessible via web for the community of researchers. Using the quantitative nature of DGE, we describe the transcriptional profile of neoblasts and present 42 new neoblast genes, including several cancer-related genes and transcription factors. Furthermore, we describe in detail the Smed-meis-like gene and the three Nuclear Factor Y subunits Smed-nf-YA, Smed-nf-YB-2 and Smed-nf-YC. DGE is a valuable tool for gene discovery, quantification and annotation. The application of DGE in S. mediterranea confirms the planarian stem cells or neoblasts as a complex population of pluripotent and multipotent cells regulated by a mixture of transcription factors and cancer-related genes.


Early metoprolol administration before coronary reperfusion results in increased myocardial salvage: analysis of ischemic myocardium at risk using cardiac magnetic resonance.
Beta-blockers improve clinical outcome when administered early after acute myocardial infarction. However, whether beta-blockers actually reduce the myocardial infarction size is still in dispute. Cardiac magnetic resonance imaging can accurately depict the left ventricular (LV) ischemic myocardium at risk (T2-weighted hyperintense region) early after myocardial infarction, as well as the extent of necrosis (delayed gadolinium enhancement). The aim of this study was to determine whether early administration of metoprolol could increase myocardial salvage, measured as the difference between the extent of myocardium at risk and myocardial necrosis. Twelve Yorkshire pigs underwent a 90-minute left anterior descending coronary occlusion, followed by reperfusion. They were randomized to metoprolol (7.5 mg during myocardial infarction) or placebo. Global and regional LV function, extent of myocardium at risk, and myocardial necrosis were quantified by cardiac magnetic resonance imaging studies performed 4 and 22 days after reperfusion in 10 survivors. Despite similar extent of myocardium at risk in metoprolol- and placebo-treated pigs (30.9% of LV versus 30.6%; P=NS), metoprolol resulted in 5-fold-larger salvaged myocardium (32.4% versus 6.2% of myocardium at risk; P=0.015). The LV ejection fraction significantly improved in metoprolol-treated pigs between days 4 and 22 (37.2% versus 43.0%; P=0.037), whereas it remained unchanged in pigs treated with placebo (35.1% versus 35.0%; P=NS). The extent of myocardial salvage was related directly to LV ejection fraction improvement (P=0.031) and regional LV wall motion recovery (P=0.039) at day 22. Early metoprolol administration during acute coronary occlusion increases myocardial salvage. The extent of myocardial salvage, measured as the difference between myocardium at risk and myocardial necrosis, was associated with regional and global LV motion improvement.


Flavonoid and lignan intake in relation to bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.
There is growing evidence of the protective role of dietary intake of flavonoids and lignans on cancer, but the association with bladder cancer has not been thoroughly investigated in epidemiological studies. We evaluated the association between dietary intakes of total and subclasses of flavonoids and lignans and risk of bladder cancer and its main morphological type, urothelial cell carcinoma (UCC), within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. A cohort of 477 312 men and women mostly aged 35-70 years, were recruited in 10 European countries. At baseline, dietary flavonoid and lignan intakes were estimated using centre-specific validated questionnaires and a food composition database based on the Phenol-Explorer, the UK Food Standards Agency and the US Department of Agriculture databases. During an average of 11 years of follow-up, 1575 new cases of primary bladder cancer were identified, of which 1425 were UCC (classified into aggressive (n=430) and non-aggressive (n=413) UCC). No association was found between total flavonoid intake and bladder cancer risk. Among flavonoid subclasses, significant inverse associations with bladder cancer risk were found for intakes of flavonol (hazard ratio comparing fifth with first quintile (HRQ5-Q1) 0.74, 95% confidence interval (CI): 0.61-0.91; P-trend=0.009) and lignans (HRQ5-Q1 0.78, 95% CI: 0.62-0.96; P-trend=0.046). Similar results were observed for overall UCC and aggressive UCC, but not for non-aggressive UCC. Our study suggests an inverse association between the dietary intakes of flavonols and lignans and risk of bladder cancer, particularly aggressive UCC.


Intraobserver and interobserver variability in distinguishing between endocervical and endometrial adenocarcinoma on problematic cases of cervical curettings.
We conducted a prospective study where 4 pathologists examined patients' problematic cases of cervical curetting for adenocarcinoma to determine whether it is of endocervical or endometrial origin based on 3 parameters: age, morphology, and immunohistochemistry (IHC) panel. Our aims were to evaluate the intraobserver and interobserver variability and to compare the results using those parameters to the final hysterectomy specimens. The value of morphology, morphology+age, and the combined parameters (morphology+age+IHC) in predicting the correct origin of the tumor was evaluated. The intraobserver agreements ranged from fair to almost perfect for each of morphology, morphology+age, and the combined parameters. The interobserver agreements were fair in the first review and ranged from slight to fair in the second review. The agreements between the diagnosis based on morphology, morphology+age, and the combined parameters compared with the final diagnosis on the hysterectomy specimen were slight (kappa=0.137), fair (kappa=0.290), and moderate (kappa=0.497), respectively. We concluded that (i) discriminating between endocervical and endometrial carcinoma is highly subject to intraobserver and interobserver variability. (ii) Surprisingly, this variability is not affected by pathologists' experience. (iii) An IHC panel adds a useful piece of information to predict the tumor origin. Lastly, even though the combination of morphology, age, and IHC is far from perfect in predicting the correct origin of the tumor, it is still the best available method.


White matter protection with insulin-like growth factor 1 and hypothermia is not additive after severe reversible cerebral ischemia in term fetal sheep.
Moderate cerebral hypothermia significantly improves survival without disability from perinatal hypoxia-ischemia. However, protection is partial. Insulin-like growth factor 1 (IGF-1) plays a key role in oligodendrocyte survival and myelination. The purpose of this study was to test the hypothesis that the combination of IGF-1 plus hypothermia could reduce postischemic white matter damage compared with hypothermia alone. Unanesthetized near-term fetal sheep received 30 min of cerebral ischemia, followed by either an infusion of 3 μg of IGF-1 intracerebroventricularly from 4.5 to 5.5 h plus cooling from 5.5 to 72 h (IGF-1 + hypothermia; n = 8), vehicle infusion plus cooling from 5.5 to 72 h (vehicle + hypothermia; n = 12), sham cooling plus sham infusion (ischemia control; n = 12) or sham ischemia (n = 5). The fetal extradural temperature was reduced from 39.4 ± 0.1°C to between 30 and 33°C. White matter was assessed after 5 days. Ischemia was associated with severe loss of CNPase-positive oligodendrocytes in white matter compared with sham ischemia (380 ± 138 vs. 1,180 ± 152 cells/field; mean ± SD; p < 0.001). Delayed hypothermia reduced cell loss (847 ± 297 cells/field, p < 0.01, vs. ischemia control), but there was no significant difference between vehicle + hypothermia and IGF-1 + hypothermia (1,015 ± 211 cells/field; NS). Ischemia was associated with increased caspase 3 expression in white matter (216 ± 41 vs. 19 ± 18 cells/field; p < 0.001). Hypothermia reduced numbers of activated caspase 3-positive cells (116 ± 81 cells/field; p < 0.05), with no significant difference between vehicle + hypothermia and IGF-1 + hypothermia (91 ± 27 cells/field; NS). In conclusion, delayed cotreatment with IGF-1 plus hypothermia after ischemia was associated with an improvement in white matter damage similar to that achieved by hypothermia alone.


Intrarater and interrater variability of point of care coagulation testing using the ROTEM delta.
This study aimed to assess intrarater and interrater variability of coagulation point-of-care testing (POCT) using ROTEM delta operated by trained staff. Arterial blood samples were taken from 43 anesthetized piglets aged up to 6 weeks and weighing 4-6 kg. The following clotting measurements were recorded: clotting time, clot formation time (CFT), maximum clot firmness (MCF) and alpha angle using ROTEM delta assays ExTEM, InTEM, FibTEM and ApTEM. Intrarater variability was assessed when a single operator performed the same assay simultaneously in all four channels of the ROTEM device. Interrater variability was assessed by two different operators simultaneously performing the same assay. Variance components of the data were analyzed using linear mixed modeling. Three hundred and forty-three tests from 86 samples were loaded and analyzed. The intraclass correlation coefficient (ICC) was more than 0.7 for clotting measurements except for CFT and alpha in InTEM. For intrarater and interrater assessment, different relative variability for the ROTEM measurements were found with consistently higher variability for clotting time and CFT and lower variability of MCF and alpha angle. Interrater variability was not statistically significant as supported using Akaike's information criterion. Piglet coagulation testing using ROTEM delta showed a high ICC. Variability was significantly lower in MCF and angle alpha compared with clotting time and CFT. No further variability was added by a second user. Based on these data, ROTEM delta appears to be suitable as POCT.


Characterization of trapped lignin-degrading microbes in tropical forest soil.
Lignin is often the most difficult portion of plant biomass to degrade, with fungi generally thought to dominate during late stage decomposition. Lignin in feedstock plant material represents a barrier to more efficient plant biomass conversion and can also hinder enzymatic access to cellulose, which is critical for biofuels production. Tropical rain forest soils in Puerto Rico are characterized by frequent anoxic conditions and fluctuating redox, suggesting the presence of lignin-degrading organisms and mechanisms that are different from known fungal decomposers and oxygen-dependent enzyme activities. We explored microbial lignin-degraders by burying bio-traps containing lignin-amended and unamended biosep beads in the soil for 1, 4, 13 and 30 weeks. At each time point, phenol oxidase and peroxidase enzyme activity was found to be elevated in the lignin-amended versus the unamended beads, while cellulolytic enzyme activities were significantly depressed in lignin-amended beads. Quantitative PCR of bacterial communities showed more bacterial colonization in the lignin-amended compared to the unamended beads after one and four weeks, suggesting that the lignin supported increased bacterial abundance. The microbial community was analyzed by small subunit 16S ribosomal RNA genes using microarray (PhyloChip) and by high-throughput amplicon pyrosequencing based on universal primers targeting bacterial, archaeal, and eukaryotic communities. Community trends were significantly affected by time and the presence of lignin on the beads. Lignin-amended beads have higher relative abundances of representatives from the phyla Actinobacteria, Firmicutes, Acidobacteria and Proteobacteria compared to unamended beads. This study suggests that in low and fluctuating redox soils, bacteria could play a role in anaerobic lignin decomposition.


Linking the Medical and Educational Home to Support Children With Autism Spectrum Disorder: Practice Recommendations.
Children with autism spectrum disorder (ASD) present with complex medical problems that are often exacerbated by a range of other intellectual and psychiatric comorbidities. These children receive care for their physical and mental health from a range of providers within numerous child-serving systems, including their primary care clinic, school, and the home and community. Given the longitudinal nature in which care is provided for this chronic disorder, it is particularly necessary for services and providers to coordinate their care to ensure optimal efficiency and effectiveness. There are 2 primary venues that serve as a "home" for coordination of service provision for children with ASD and their families-the "medical home" and the "educational home." Unfortunately, these venues often function independently from the other. Furthermore, there are limited guidelines demonstrating methods through which pediatricians and other primary care providers (PCPs) can coordinate care with schools and school-based providers. The purpose of this article is 2-fold: (1) we highlight the provision of evidence-based care within the medical home and educational home and (2) we offer practice recommendations for PCPs in integrating these systems to optimally address the complex medical, intellectual, and psychiatric symptomology affected by autism.


Endpoints in trials for clinical liver transplantation.
The past decade has seen significant improvements in patient and graft survival following liver transplantation. Likewise, acute rejection rates have been dramatically reduced with newer immunologic agents. To this end, past and present conventional endpoints, such as short-term graft survival and acute rejection rates, are no longer adequate themselves. Alternative endpoints, such as long-term patient or graft survival are ideal endpoints as these would capture a number of secondary endpoints over this time. This approach requires, however, a large cohort of patients with longer follow-up. Using other endpoints such as renal function or histologic parameters, which may predict long-term outcomes, may be beneficial. The use of multiple endpoints in composite fashion may also be beneficial in predicting outcomes. Renal function following liver transplantation, or histological indices may be used potentially as a composite endpoint, in combination with conventional endpoints, such as graft loss, death and acute rejection. The evolution of immunosuppressive therapeutics has resulted in a change in the standard agents used and thus the need for contemporary control groups. One balanced approach for assessing newer immunosuppressive therapies might be to use composite endpoints, combining conventional endpoints (graft loss, death, acute rejection) with contemporary endpoints (renal function, histological indices). A re-assessment of contemporary control groups is warranted.


Socioeconomic differences in health-care use and outcomes for stroke and ischaemic heart disease in China during 2009-16: a prospective cohort study of 0·5 million adults.
China initiated major health-care reforms in 2009 aiming to provide universal health care for all by 2020. However, little is known about trends in health-care use and health outcomes across different socioeconomic groups in the past decade. We used data from the China Kadoorie Biobank (CKB), a nationwide prospective cohort study of adults aged 30-79 years in 2004-08, in ten regions (five urban, five rural) in China. Individuals who were alive in 2009 were included in the present study. Data for all admissions were obtained by linkage to electronic hospital records from the health insurance system, and to region-specific disease and death registers. Generalised linear models were used to estimate trends in annual hospital admission rates, 28-day case fatality rates, and mean length of stay for stroke, ischaemic heart disease, and any cause in all relevant individuals. 512 715 participants were recruited to the CKB between June 25, 2004, and July 15, 2008, 505 995 of whom were still alive on Jan 1, 2009, and contributed to the present study. Among them, we recorded 794 824 hospital admissions (74 313 for stroke, 69 446 for ischaemic heart disease) between 2009 and 2016. After adjustment for demographic, socioeconomic, lifestyle, and morbidity factors, hospitalisation rates increased annually by 3·6% for stroke, 5·4% for ischaemic heart disease, and 4·2% for any cause, between 2009 and 2016. Higher socioeconomic groups had higher hospitalisation rates, but the annual proportional increases were higher in those with lower education or income levels, those enrolled in the urban or rural resident health insurance scheme, and for those in rural areas. Lower socioeconomic groups had higher case fatality rates for stroke and ischaemic heart disease, but greater reductions in case fatality rates than higher socioeconomic groups. By contrast, mean length of stay decreased by around 2% annually for stroke, ischaemic heart disease, and any cause, but decreased to a greater extent in higher than lower socioeconomic groups for stroke and ischaemic heart disease. Between 2009 and 2016, lower socioeconomic groups in China had greater increases in hospital admission rates and greater reductions in case fatality rates for stroke and ischaemic heart disease. Additional strategies are needed to further reduce socioeconomic differences in health-care use and disease outcomes. Wellcome Trust, Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, China Ministry of Science and Technology, and Chinese National Natural Science Foundation.


Kinetic limitations of intracranial joints in Brachylophosaurus canadensis and Edmontosaurus regalis (Dinosauria: Hadrosauridae), and their implications for the chewing mechanics of hadrosaurids.
The highly specialized tooth morphology and arrangement of the dental battery of hadrosaurids has led to much speculation surrounding the chewing mechanics of this successful group of herbivorous dinosaurs. Pleurokinesis, a long established hypothesis explaining the ornithopod chewing mechanism, proposes a transverse power stroke in hadrosaurids that was accommodated by vertical adduction of the mandible, lateral rotation of the maxilla at the maxilla-premaxilla joint, lateral rotation of the jugal-maxilla complex at its contact with the lacrimal, and posterolateral rotation of the quadrate at its contact with the squamosal. A secondary series of movements were also thought to have occurred as a consequence of these primary movements. In this article, the intracranial joint morphology is described for both Brachylophosaurus canadensis and Edmontosaurus regalis and their permissive kinematics are established. Based on this evidence, the movements associated with pleurokinesis are not accommodated in these hadrosaurine dinosaurs. Rather, the movements that seem most likely to have produced the observed dental wear patterns are those associated with the mandible about the jaw joint. The structure of this joint appears well-suited to have accommodated some translation as well as rotation of the mandible about the quadrate condyle. Three-dimensional modeling of the alternate mandibular movements reveals that not all the combined labiolingual width of the lingual and buccal facets of the tooth row was involved in the power stroke. Rather, limits on the degree of mandibular long axis rotation suggest that only the lingual facet and the more medial portion of the buccal facet were utilized.


Deficient MWF mapping in multiple sclerosis using 3D whole-brain multi-component relaxation MRI.
Recent multiple sclerosis (MS) MRI research has highlighted the need to move beyond the lesion-centric view and to develop and validate new MR imaging strategies that quantify the invisible burden of disease in the brain and establish much more sensitive and specific surrogate markers of clinical disability. One of the most promising of such measures is myelin-selective MRI that allows the acquisition of myelin water fraction (MWF) maps, a parameter that is correlated to brain white matter (WM) myelination. The aim of our study was to apply the newest myelin-selective MRI method, multi-component Driven Equilibrium Single Pulse Observation of T1 and T2 (mcDESPOT) in a controlled clinical MS pilot trial. This study was designed to assess the capabilities of this new method to explain differences in disease course and degree of disability in subjects spanning a broad spectrum of MS disease severity. The whole-brain isotropically-resolved 3D acquisition capability of mcDESPOT allowed for the first time the registration of 3D MWF maps to standard space, and consequently a formalized voxel-based analysis of the data. This approach combined with image segmentation further allowed the derivation of new measures of MWF deficiency: total deficient MWF volume (DV) in WM, in WM lesions, in diffusely abnormal white matter and in normal appearing white matter (NAWM). Deficient MWF volume fraction (DVF) was derived from each of these by dividing by the corresponding region volume. Our results confirm that lesion burden does not correlate well with clinical disease activity measured with the extended disability status scale (EDSS) in MS patients. In contrast, our measurements of DVF in NAWM correlated significantly with the EDSS score (R2=0.37; p<0.001). The same quantity discriminated clinically isolated syndrome patients from a normal control population (p<0.001) and discriminated relapsing-remitting from secondary-progressive patients (p<0.05); hence this new technique may sense early disease-related myelin loss and transitions to progressive disease. Multivariate analysis revealed that global atrophy, mean whole-brain myelin water fraction and white matter atrophy were the three most important image-derived parameters for predicting clinical disability (EDSS). Overall, our results demonstrate that mcDESPOT-defined measurements in NAWM show great promise as imaging markers of global clinical disease activity in MS. Further investigation will determine if this measure can serve as a risk factor for the conversion into definite MS and for the secondary transition into irreversible disease progression.


Randomized controlled trial on effectiveness of mHealth (mobile/smartphone) based Preterm Home Care Program on developmental outcomes of preterms: Study protocol.
To describe a randomized controlled trial protocol designed to evaluate the effectiveness of mobile health based Preterm Home Care Program (mHealthPHCP) known as "NeoRaksha" mobile health application in improving parent-infant-interaction, growth and development of preterms. A prospective, randomized controlled clinical trial. The protocol is approved and funded by Department of Biotechnology, Government of India on 2 August 2016. A total of 300 preterm-mother dyads admitted to neonatal intensive care unit of a tertiary care hospital will be recruited and randomized to intervention and control group. The intervention group would receive mobile health based Preterm Home Care Program and the control group would receive standard preterm care. Intervention group will be followed up at home by community health workers known as Accredited Social Health Activist who will be trained in using the NeoRaksha mobile health application. Preterms outcomes will be assessed during follow-up at hospital. Supporting continuity of preterm care is vital as parents and preterms experience transition from Neonatal Intensive Care unit to their home. Empowering mothers and community health workers by integrating mobile technology into health care can help promote healthy preterms, enhance development outcomes and follow-up, which in turn can reduce the mortalities, morbidities, and disabilities associated with prematurity. The results of this study could open up new horizons in integrating hospital and home based preterm care through technology, which paves way to scale up the model across the countries.


Low-bandwidth and non-compute intensive remote identification of microbes from raw sequencing reads.
Cheap DNA sequencing may soon become routine not only for human genomes but also for practically anything requiring the identification of living organisms from their DNA: tracking of infectious agents, control of food products, bioreactors, or environmental samples. We propose a novel general approach to the analysis of sequencing data where a reference genome does not have to be specified. Using a distributed architecture we are able to query a remote server for hints about what the reference might be, transferring a relatively small amount of data. Our system consists of a server with known reference DNA indexed, and a client with raw sequencing reads. The client sends a sample of unidentified reads, and in return receives a list of matching references. Sequences for the references can be retrieved and used for exhaustive computation on the reads, such as alignment. To demonstrate this approach we have implemented a web server, indexing tens of thousands of publicly available genomes and genomic regions from various organisms and returning lists of matching hits from query sequencing reads. We have also implemented two clients: one running in a web browser, and one as a python script. Both are able to handle a large number of sequencing reads and from portable devices (the browser-based running on a tablet), perform its task within seconds, and consume an amount of bandwidth compatible with mobile broadband networks. Such client-server approaches could develop in the future, allowing a fully automated processing of sequencing data and routine instant quality check of sequencing runs from desktop sequencers. A web access is available at http://tapir.cbs.dtu.dk. The source code for a python command-line client, a server, and supplementary data are available at http://bit.ly/1aURxkc.


Diurnal and circadian rhythms in the tomato transcriptome and their modulation by cryptochrome photoreceptors.
Circadian clocks are internal molecular time-keeping mechanisms that provide living organisms with the ability to adjust their growth and physiology and to anticipate diurnal environmental changes. Circadian clocks, without exception, respond to light and, in plants, light is the most potent and best characterized entraining stimulus. The capacity of plants to respond to light is achieved through a number of photo-perceptive proteins including cryptochromes and phytochromes. There is considerable experimental evidence demonstrating the roles of photoreceptors in providing light input to the clock. In order to identify genes regulated by diurnal and circadian rhythms, and to establish possible functional relations between photoreceptors and the circadian clock in tomato, we monitored the temporal transcription pattern in plants entrained to long-day conditions, either by large scale comparative profiling, or using a focused approach over a number of photosensory and clock-related genes by QRT-PCR. In parallel, focused transcription analyses were performed in cry1a- and in CRY2-OX tomato genotypes. We report a large series of transcript oscillations that shed light on the complex network of interactions among tomato photoreceptors and clock-related genes. Alteration of cryptochrome gene expression induced major changes in the rhythmic oscillations of several other gene transcripts. In particular, over-expression of CRY2 had an impact not only on day/night fluctuations but also on rhythmicity under constant light conditions. Evidence was found for widespread diurnal oscillations of transcripts encoding specific enzyme classes (e.g. carotenoid biosynthesis enzymes) as well as for post-transcriptional diurnal and circadian regulation of the CRY2 transcript.


Immunohistochemical staining of papillary breast lesions.
The separation of ductal papilloma from intraductal papillary carcinoma of the breast on hematoxylin and eosin stained sections often presents diagnostic difficulty. Immunohistochemical staining is often employed in diagnosis, historically with smooth muscle actin (SMA). In this study, the staining characteristics of a panel of myoepithelial markers (calponin, p63, P-cadherin), were compared with SMA, and the epithelial expression of CD44s was assessed in 99 papillary lesions. SMA, calponin, and p63 demonstrated myoepithelial cells in 61%, 63%, and 65% of papillary lesions, respectively. However, specificity was quite variable. Calponin-stained stromal myofibroblasts (35% of cases), vessel pericytes (92%), and endothelial cells (69%), though each to a lesser degree than SMA. Calponin also showed cross reactivity with epithelium in 18% of cases. p63 was almost completely restricted to myoepithelial cell nuclei, and did not stain vascular smooth muscle or myofibroblasts. However, p63 stained the epithelial component in one papillary carcinoma, a basal layer of cells in 1 biphasic invasive carcinoma, and the cytoplasm in 1 case. P-cadherin stained both epithelial and myoepithelial cells. The epithelial expression of CD44s and did not distinguish papillomas from papillary carcinomas. Thus, P-cadherin and CD44s are not useful in the characterization of papillary lesions. Given increased specificity as compared with SMA, the combination of p63 and calponin is recommended for analysis of breast papillary lesions.


Disease transmission and introgression can explain the long-lasting contact zone of modern humans and Neanderthals.
Neanderthals and modern humans both occupied the Levant for tens of thousands of years prior to the spread of modern humans into the rest of Eurasia and their replacement of the Neanderthals. That the inter-species boundary remained geographically localized for so long is a puzzle, particularly in light of the rapidity of its subsequent movement. Here, we propose that infectious-disease dynamics can explain the localization and persistence of the inter-species boundary. We further propose, and support with dynamical-systems models, that introgression-based transmission of alleles related to the immune system would have gradually diminished this barrier to pervasive inter-species interaction, leading to the eventual release of the inter-species boundary from its geographic localization. Asymmetries between the species in the characteristics of their associated 'pathogen packages' could have generated feedback that allowed modern humans to overcome disease burden earlier than Neanderthals, giving them an advantage in their subsequent spread into Eurasia.


Phenotypic variations of TRAIL sensitivity in cloned populations of prostate cancer cells.
Factors that regulate the induction of apoptosis of tumour cells are potential candidates for therapeutic intervention for the majority of cancers. Studying modifiers of apoptotic responses, such as members of the tumour necrosis factor receptor superfamily, may give clues as to how induction of apoptosis in tumours could be maximized to enhance the benefit of treatment regimes. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-tumour molecule since its activity is specific for tumour cell populations. TRAIL binds to death receptors, inducing apoptosis in susceptible cells. The mechanisms which determine whether tumour cells are susceptible to TRAIL are unclear, and several mechanisms have been proposed, including expression of osteoprotegerin (OPG), decoy receptors, and factors that affect intracellular signalling of pro-apoptotic molecules, such as c-FLIP. Here we show that experiments to modulate the activity of one of these factors, OPG, by over-expression and also by stable knockdown of OPG expression, alters the TRAIL sensitivity of PC3 prostate cancer cells. However we show that some observed effects, which appear to support the hypothesis that OPG prevents TRAIL-induced apoptosis of tumour cells, may be due to variation of the TRAIL response of sub-clones of tumour cells, even within a cloned population. These results highlight potential limitations of experiments designed to test contribution of factors affecting intrinsic apoptosis susceptibility using cloned tumour cell populations.