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Ventriculo-peritoneal shunt placement is the most commonly performed procedure for the treatment of hydrocephalus. The complication of migration of the distal ventriculo-peritoneal shunt is one of the many complications that occur after ventriculo-peritoneal shunt placement. The migration of the ventriculo-peritoneal shunt through the vagina is infrequently reported in children. The aim of this review is to help all the providers caring for children with ventriculo-peritoneal shunts to identify issues early when encountered with this complication and thus limit morbidity and mortality. We reviewed all cases of migration of ventriculo-peritoneal shunt through the vagina in children less than 18 years of age that were published in the literature using PubMed, Google Scholar, Web of Science, and Cochrane Library. A total of 11 articles met the eligibility criteria and were included in this review among the 93 articles obtained with title and abstract screening. Previous non-shunt-related abdominal operations and shunt revisions are consistent risk factors in all cases. We did not recognize specific approaches to catheter placement or management that could have prevented this complication. Ventriculitis necessitating shunt removal and therapies requiring additional procedures and prolonged hospitalization are the major consequences identified. Awareness of this unusual complication is very important among health care providers such as emergency care health providers who are likely to be the first to encounter these children on initial presentation.

Historical salmon catch records suggest that climatic variability, and more recently human exploitation, control patterns of abundance in Atlantic salmon populations. We present the first long-term (2000-year) reconstruction of Atlantic Salmon population variations based on a Marine Derived Nutrient (MDN) lake sediment record. Our record is constructed from nitrogen isotopes (δ15N) measured from a lake sediment core, which we compare with an escapement index (EI) derived from historic net catch data on major Scottish salmon rivers. We used an isotope mixing model to demonstrate that the N isotope values are likely enriched with MDN and demonstrate that Loch Insh sediments are enriched compared with a control site (Loch Vaa) that has never had exposure to salmon. We demonstrate that current adult spawner returns are around half that of historic values prior to major human exploitation. Before the onset of widespread human exploitation and habitat degradation, large fluctuations in salmon abundance are attributed to variations in North Atlantic sea surface temperature. While our data support published reconstructions of declining Atlantic salmon stocks in Northwest European rivers over the last 1000 years, rather than point to a solely human cause, the human impact appears to be overprinted on larger-scale changes in marine habitat occurring at the transition from the warmer Medieval Climatic Anomaly (MCA) to the cooler Little Ice Age (LIA).

Here, we investigate Mid- to Late-Holocene vegetation changes in low-lying coastal areas in Tonga and how changing sea levels and recurrent volcanic eruptions have influenced vegetation dynamics on four islands of the Tongan archipelago (South Pacific). To investigate past vegetation and environmental change at Ngofe Marsh (‘Uta Vava’u), we examined palynomorphs (pollen and spores), charcoal (fire), and sediment characteristics (volcanic activity) from a 6.7-m-long sediment core. Radiocarbon dating indicated the sediments were deposited over the last 7700 years. We integrated the Ngofe Marsh data with similar previously published data from Avai’o’vuna Swamp on Pangaimotu Island, Lotofoa Swamp on Foa Island, and Finemui Swamp on Ha’afeva Island. Plant taxa were categorized as littoral, mangrove, rainforest, successional/ disturbance, and wetland groups, and linear models were used to examine relationships between vegetation, relative sea level change, and volcanic eruptions (tephra). We found that relative sea level change has impacted vegetation on three of the four islands investigated. Volcanic eruptions were not identified as a driver of vegetation change. Rainforest decline does not appear to be driven by sea level changes or volcanic eruptions. From all sites analyzed, vegetation at Finemui Swamp was most sensitive to changes in relative sea level. While vegetation on low-lying Pacific islands is sensitive to changing sea levels, island characteristics, such as area and elevation, are also likely to be important factors that mediate specific island responses to drivers of change.

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Actinic keratosis (AK) is a chronic skin condition that may progress to cutaneous squamous cell carcinoma. We conducted a systematic review of efficacy and safety for key treatments for AK of the face and scalp, including the novel 5-day tirbanibulin 1% ointment. MEDLINE, PubMed, Embase, Cochrane Library, clinical trial registries and regulatory body websites were searched. The review included 46 studies, of which 35 studies included interventions commonly used in Europe and were sufficiently homogenous to inform a Bayesian network meta-analysis of complete clearance against topical placebo or vehicle. The network meta-analysis revealed the following odds ratios and 95% credible intervals: cryosurgery 13.4 (6.2–30.3); diclofenac 3% 2.9 (1.9–4.3); fluorouracil 0.5% + salicylic acid 7.6 (4.6–13.5); fluorouracil 4% 30.3 (9.1–144.7); fluorouracil 5% 35.0 (10.2–164.4); imiquimod 3.75% 8.5 (3.5–22.4); imiquimod 5% 17.9 (9.1–36.6); ingenol mebutate 0.015% 12.5 (8.1–19.9); photodynamic therapy with aminolevulinic acid 24.1 (10.9–52.8); photodynamic therapy with methyl aminolevulinate 11.7 (6.0–21.9); tirbanibulin 1% 11.1 (6.2–20.9). Four sensitivity analyses, from studies assessing efficacy after one treatment cycle only, for ≤25 cm2 treatment area, after 8 weeks post-treatment, and with single placebo/vehicle node confirmed the findings from the base case. Safety outcomes were assessed qualitatively. These results suggest that tirbanibulin 1% offers a novel treatment for AK, with a single short treatment period, favourable safety profile and efficacy, in line with existing topical treatments available in Europe.

Population size has increasingly been taken as the driver of past human environmental impact worldwide, and particularly in the Arctic. However, sedimentary ancient DNA (sedaDNA), pollen and archaeological data show that over the last 12,000 years, paleoeconomy and culture determined human impacts on the terrestrial ecology of Arctic Norway. The large Mortensnes site complex (Ceavccageađgi, 70°N) has yielded the most comprehensive multiproxy record in the Arctic to date. The site saw occupation from the Pioneer period (c. 10,000 cal. years BP) with more intensive use from c. 4,200 to 2,000 cal. years BP and after 1,600 cal. years BP. Here, we combine on-site environmental archaeology with a near-site lake record of plant and animal sedaDNA. The rich animal sedaDNA data (42 taxa) and on-site faunal analyses reveal switches in human dietary composition from early-Holocene fish + marine mammals, to mixed marine + reindeer, then finally to marine + reindeer + domesticates (sheep, cattle, pigs), with highest reindeer concentrations in the last millennium. Archaeological evidence suggests these changes are not directly driven by climate or variation in population densities at the site or in the region, but rather are the result of changing socio-economic activities and culture, probably reflecting settlers’ origins. This large settlement only had discernable effects on its hinterland in the last 3,600 years (grazing) and more markedly in the last 1,000 years through reindeer keeping/herding and, possibly domestic stock. Near-site sedaDNA can be linked to and validate the faunal record from archaeological excavations, demonstrating that environmental impacts can be assessed at a landscape scale.

Background: COVID-19 was identified as a pandemic by the World Health Organisation (WHO) in December 2020. Advanced Clinical Practitioners (ACPs) in England working with older people with frailty, experienced their clinical role changing in response to the emergency health needs of this complex population group. In contrast to other countries, in England Advanced Clinical Practitioners are drawn from both nursing and allied health professions. Whilst much of the literature emphasises the importance of ensuring the sustainability of the Advanced Clinical Practitioners’ role, the pandemic threw further light on its potential and challenges. However, an initial review of the literature highlighted a lack of research of Advanced Clinical Practitioners’ capabilities working with uncertainty in disaster response situations. Aim: To capture the lived experience of how English Advanced Clinical Practitioners working with older people adapted their roles in response to the COVID-19 pandemic (October 2020–January 2021). Design, setting and participants: A qualitative research design was used. Following ethical approval, 23 Advanced Clinical Practitioner volunteer participants from across England with varied health professional backgrounds were recruited from Advanced Clinical Practitioners’ professional and social media networks on Twitter using a snowballing technique. Methods: Depending on preference or availability, 23 participants (nurses (18), physiotherapists (2), paramedics (2) and a pharmacist (1)) were interviewed singularly (n = 9) or as part of 3 focus groups (n = 14) using Zoom video communication. Audio recordings were transcribed and using qualitative data analysis software, NVivo 12 pro, coded for an essentialist thematic analysis of Advanced Clinical Practitioners’ responses using an inductive approach. 27 codes were identified and collated into five themes. For the purposes of this paper, four themes are discussed: experiencing different work, developing attributes, negotiating barriers and changing future provision. Findings: Advanced Clinical Practitioners successfully transferred their advanced practice skills into areas of clinical need during the pandemic. Their autonomous and generic, high level of expertise equipped them for management and leadership positions where speed of change, and the dissolution of traditional professional boundaries, were prioritised. Barriers to progress included a lack of knowledge of the Advanced Clinical Practitioner role and friction between Advanced Clinical Practitioners and physicians. Discussion and conclusion: The study demonstrated the successful adaption of the Advanced Clinical Practitioner role to enable more creative, personalised and sustainable solutions in the care of older people living with frailty during the pandemic. The potential of Advanced Clinical Practitioner development is in a juxtaposition to the threat of pandemic services being dismantled once the emergency nature of care has passed. Healthcare organisations have a vital part to play in considering the enablers and barriers of Advanced Clinical Practitioner capability-based practice when responding to uncertainty.

Shame is widely regarded as an awful feeling. It is usually characterized as an involuntary, negative, other‐mediated emotion about oneself, and differentiated from other uncomfortable self‐conscious emotions such as embarrassment by virtue of the fact that it involves a “negative global assessment” of oneself (Manion 2003, 2). I may feel embarrassment if, for example, I discover that I have been walking around a public space with a trail of toilet‐paper attached to my shoe; I will feel silly, self‐conscious, and possibly a corresponding desire to hide from the view of others, but this experience is not shameful because it does not prompt me to reassess my overall self‐worth. Shame emerges from an appreciation of why another would perceive one as inferior or lowly, not merely ridiculous. It has a moral dimension, distinct from that associated with guilt, because it is concerned with the status of the self. The subject of guilt is conscious of how she may have harmed others, whereas the subject of shame is aware that her personal failings may be visible. Hence, the student caught cheating on an exam may undergo the shameful realization that others have now seen her bad traits (laziness, willingness to cheat, and so on).

Objectives:This study investigated which databases and which combinations of databases should be used to identify economic evaluations (EEs) to inform systematic reviews. It also investigated the characteristics of studies not identified in database searches and evaluated the success of MEDLINE search strategies used within typical reviews in retrieving EEs in MEDLINE.Methods:A quasi-gold standard (QGS) set of EEs was collected from reviews of EEs. The number of QGS records found in nine databases was calculated and the most efficient combination of databases was determined. The number and characteristics of QGS records not retrieved from the databases were collected. Reproducible MEDLINE strategies from the reviews were rerun to calculate the sensitivity and precision for each strategy in finding QGS records.Results:The QGS comprised 351 records. Across all databases, 337/351 (96 percent) QGS records were identified. Embase yielded the most records (314; 89 percent). Four databases were needed to retrieve all 337 references: Embase + Health Technology Assessment database + (MEDLINE or PubMed) + Scopus. Four percent (14/351) of records could not be found in any database. Twenty-nine of forty-one (71 percent) reviews reported a reproducible MEDLINE strategy. Ten of twenty-nine (34.5 percent) of the strategies missed at least one QGS record in MEDLINE. Across all twenty-nine MEDLINE searches, 25/143 records were missed (17.5 percent). Mean sensitivity was 89 percent and mean precision was 1.6 percent.Conclusions:Searching beyond key databases for published EEs may be inefficient, providing the search strategies in those key databases are adequately sensitive. Additional search approaches should be used to identify unpublished evidence (grey literature).

Background Access to rehabilitation to prevent disability and optimise function is recommended for patients with cancer, including following cancer diagnosis. Models to integrate rehabilitation within oncology services as cancer treatment commences are required, but must be informed by those they are intended to support. We aimed to identify views of patients, carers and clinicians to develop and refine a rehabilitation model to be tested in a feasibility trial for people newly diagnosed with lung cancer or mesothelioma. Methods We conducted a focus group study with people affected by lung cancer or mesothelioma, their carers and clinicians providing their care to identify priorities for rehabilitation in this period. We sought views on core intervention components, processes and outcomes and integration with oncology services. Data were analysed using thematic analysis. Results Fifteen clinicians (oncologists, nurse specialists, physiotherapists and occupational therapists), nine patients and five carers participated. A proposed outline rehabilitation model was perceived as highly relevant for this population. Participants recommended prompt and brief rehabilitation input, delivered whilst people attend for hospital appointments or at home to maximise accessibility and acceptability. Participants recognised variation in need and all prioritised tailored support for symptom self-management, daily activities and the involvement of carers. Clinicians also prioritised achieving fitness for oncology treatment. Patients and carers prioritised a sensitive manner of approach, positivity and giving hope for the future. Participant’s recommendations for outcome measurement related to confidence in usual daily activities, symptom control and oncology treatment completion rates over objective measures of cardiorespiratory fitness. Conclusion The importance of providing tailored rehabilitation around the time of diagnosis for people with lung cancer or mesothelioma was affirmed by all participants. The refined model of rehabilitation recommended for testing in a feasibility trial is flexible, tailored and short-term. It aims to support people to self-manage symptoms, tolerate cancer treatments and to remain active and independent in daily life. It is delivered alongside scheduled hospital appointments or at home by an expert practitioner sensitive to the psycho-social sequelae that follow a diagnosis of thoracic cancer. Electronic supplementary material The online version of this article (10.1186/s40814-018-0350-0) contains supplementary material, which is available to authorized users.

In December 2015, an outbreak of pertussis was detected among staff working in the Maternity Unit of a district general hospital in Hampshire. This occurred in the background of increased pertussis activity in the community. The outbreak occurred over the Christmas holiday period causing staff shortages at a time when the departments were already overstretched. The high prevalence of upper respiratory tract infections at the time were difficult to distinguish from pertussis. This paper describes the outbreak, infection control measures implemented and the learning points.

ObjectivesTo estimate the cost of functional gastrointestinal disorders (FGIDs) and related signs and symptoms in infants to the third party payer and to parents.Study designTo estimate the cost of illness (COI) of infant FGIDs, a two-stage process was applied: a systematic literature review and a COI calculation. As no pertinent papers were found in the systematic literature review, a ‘de novo’ analysis was performed. For the latter, the potential costs for the third party payer (the National Health Service (NHS) in England) and for parents/carers for the treatment of FGIDs in infants were calculated, by using publicly available data. In constructing the calculation, estimates and assumptions (where necessary) were chosen to provide a lower bound (minimum) of the potential overall cost. In doing so, the interpretation of the calculation is that the true COI can be no lower than that estimated.ResultsOur calculation estimated that the total costs of treating FGIDs in infants in England were at least £72.3 million per year in 2014/2015 of which £49.1 million was NHS expenditure on prescriptions, community care and hospital treatment. Parents incurred £23.2 million in costs through purchase of over the counter remedies.ConclusionsThe total cost presented here is likely to be a significant underestimate as only lower bound estimates were used where applicable, and for example, costs of alternative therapies, inpatient treatments or diagnostic tests, and time off work by parents could not be adequately estimated and were omitted from the calculation. The number and kind of prescribed products and products sold over the counter to treat FGIDs suggest that there are gaps between treatment guidelines, which emphasise parental reassurance and nutritional advice, and their implementation.

Background Development of professionalism is a critical component of a military transitional year residency. Little published research exists to guide programs in meeting this challenge. Objective and Methods After significant concerns regarding resident professionalism were raised by Tripler Army Medical Center faculty, a novel transitional residency professionalism curriculum was conceived and implemented. Universal expectations of physician professionalism, as perceived by various stakeholders (patients, parents, faculty, and nurses), were explored using a small group, discussion-based curriculum. This was combined with a small group, discussion-based, lessons-learned project and a military-unique curriculum. Results Since implementation, the curriculum has had 100% satisfaction on the part of the faculty and 80% to 100% on the part of the residents, as measured by annual review surveys. Although resident professionalism scores on evaluations did not change significantly, the number of adverse actions because of professionalism lapses has decreased steadily in the 4 years since inception, and the program has been without any such actions for the past 18 months. Conclusions Our novel transitional residency professionalism curriculum has been successful in a military residency program.

AimThe primary objective of this study was to determine whether adults with a chronic illness within a primary care setting who received a rehabilitation intervention in this setting showed greater improvement in health status and had fewer hospital admissions and emergency room visits compared with adults who do not receive the intervention.BackgroundMore than half of Canadians (16 million people) live with chronic illness. Persons with chronic illness in primary care, especially older persons who are most at risk for functional decline, are currently not receiving effective management.MethodsA randomized controlled trial was used. A rehabilitation multi-component intervention was delivered by a physiotherapist (PT) and occupational therapist in a primary care setting and included collaborative goal setting for rehabilitation needs, a six-week chronic disease self-management (SM) workshop, referral to community programs and a web-based education programme.FindingsThree hundred and three patients participated, n = 152 intervention group and n = 151 in the control group. There was a significant difference between the groups for planned hospital days (F = 6.3, P = 0.00) with an adjusted difference 0.60 day per person, and increased satisfaction with rehabilitation services however no difference on health status or emergency room visits. This rehabilitation intervention which had a strong SM component prevented planned hospitalizations that resulted in a conservative estimated cost saving from reduced hospitalizations of $65 000. Future research needs to examine which patient groups with chronic illness show positive responses to rehabilitation and self-management.

Early stroke in the premature infant has rarely been described. Presented here are the cases of 23 infants, born between 23 and 35 weeks gestational age, with focal arterial ischemic stroke occurring before 44 weeks gestational age. Ten (43%) were male. Five children (22%) were half of a twin pair; no co-twin died. The most commonly affected territory was the middle cerebral artery territory. Three children with extreme prematurity (or =26 weeks) had cerebellar infarcts. Twelve children had unilateral or bilateral intraventricular hemorrhages (grade 3 or higher in 8 of the 12). Twelve children had white matter injury: periventricular leukomalacia, hypoxic-ischemic encephalopathy, or both. Most children had multiple comorbidities, and the median neonatal intensive care unit stay was 63 days (range, 14-365). One child died in the neonatal intensive care unit (age 123 days). All 22 survivors were left with disabilities. Seventeen (77%) had cerebral palsy, 10 (45%) had epilepsy, and 17 (77%) had cognitive impairment. Arterial ischemic stroke appears to add to the neurologic disabilities commonly associated with prematurity.

Galactomannan biosynthesis in legume seed endosperms involves two Golgi membrane-bound glycosyltransferases, mannan synthase and galactomannan galactosyltransferase (GMGT). GMGT specificity is an important factor regulating the distribution and amount of (1→6)-α-galactose (Gal) substitution of the (1→4)-β-linked mannan backbone. The model legume Lotus japonicus is shown now to have endospermic seeds with endosperm cell walls that contain a high-Gal galactomannan (mannose [Man]/Gal = 1.2-1.3). Galactomannan biosynthesis in developing L. japonicus endosperms has been mapped, and a cDNA encoding a functional GMGT has been obtained from L. japonicus endosperms during galactomannan deposition. L. japonicus has been transformed with sense, antisense, and sense/antisense (“hairpin loop”) constructs of the GMGT cDNA. Some of the sense, antisense, and sense/antisense transgenic lines exhibited galactomannans with altered (higher) Man/Gal values in their (T1 generation) seeds, at frequencies that were consistent with posttranscriptional silencing of GMGT. For T1 generation individuals, transgene inheritance was correlated with galactomannan composition and amount in the endosperm. All the azygous individuals had unchanged galactomannans, whereas those that had inherited a GMGT transgene exhibited a range of Man/Gal values, up to about 6 in some lines. For Man/Gal values up to 4, the results were consistent with lowered Gal substitution of a constant amount of mannan backbone. Further lowering of Gal substitution was accompanied by a slight decrease in the amount of mannan backbone. Microsomal membranes prepared from the developing T2 generation endosperms of transgenic lines showed reduced GMGT activity relative to mannan synthase. The results demonstrate structural modification of a plant cell wall polysaccharide by designed regulation of a Golgi-bound glycosyltransferase.

Galactomannans [(1→6)-α-d-galactose (Gal)-substituted (1→4)-β-d-mannans] are major cell wall storage polysaccharides in the endosperms of some seeds, notably the legumes. Their biosynthesis in developing legume seeds involves the functional interaction of two membrane-bound glycosyltransferases, mannan synthase (MS) and galactomannan galactosyltransferase (GMGT). MS catalyzes the elongation of the mannan backbone, whereas GMGT action determines the distribution and amount of Gal substitution. Fenugreek (Trigonella foenum-graecum) forms a galactomannan with a very high degree of Gal substitution (Man/Gal = 1.1), and its GMGT has been characterized. We now report that the endosperm cell walls of the tobacco (Nicotiana tabacum) seed are rich in a galactomannan with a very low degree of Gal substitution (Man/Gal about 20) and that its depositional time course is closely correlated with membrane-bound MS and GMGT activities. Furthermore, we demonstrate that seeds from transgenic tobacco lines that express fenugreek GMGT constitutively in membrane-bound form have endosperm galactomannans with increased average degrees of Gal substitution (Man/Gal about 10 in T1 generation seeds and about 7.5 in T2generation seeds). Membrane-bound enzyme systems from transgenic seed endosperms form galactomannans in vitro that are more highly Gal substituted than those formed by controls under identical conditions. To our knowledge, this is the first report of structural manipulation of a plant cell wall polysaccharide in transgenic plants via a biosynthetic membrane-bound glycosyltransferase.

The National Institute of Neurological Disorders and Stroke benchmark treatment time for acute ischemic stroke with intravenous rtPA door to needle time is 60 minutes or less. Hospitals identified as Primary Stroke Centers will be required to treat 50% of their patients who qualify for rtPA within that time frame. Acute stroke care requires the skills of a multidisciplinary stroke team with nursing playing a pivotal role in the emergency room setting, including meeting the benchmark for IV rtPA administration. Review of the literature reveals that nurses comprehend the importance of and have a desire to provide timely and quality acute stroke care but there may be barriers to achieving that end including; lack of proficiency with the NIH stroke screen assessment, other emergency department demands and staffing challenges that affect stroke care. As part of the ongoing process improvement program at our 180 bed primary stroke care center in rural northwestern Pennsylvania, we hypothesized a need for an emergency room stroke nurse facilitator to meet the 60 minute door to needle IV rtPA time. Our hospital treated an average of 14 patients per year with IV rtPA from 2010 to 2013. We used a sample population of 31 participants representing all those presenting to the emergency department qualifying for IV rtPA: 13 patients from January to November 2013 before starting the stroke nurse facilitator role, 18 patients from December 2013 to May 2014 after starting the stroke nurse facilitator role. Data was collected from Get with the Guidelines stroke data base. Results revealed that before starting the role of the stroke nurse facilitator, the average door to needle IV rtPA time was 68 minutes with mean time of 70 minutes. After starting the role of the stroke nurse facilitator the average IV rtPA door to needle time was 60 minutes with a mean time of 47 minutes. In conclusion, a stroke nurse facilitator appears to provide improvement of door to needle IV rtPA time in the emergency room setting. Our goal is to maintain the stroke nurse facilitator and follow outcomes to determine if this improvement is sustainable.

Introduction Functional gastrointestinal disorders (FGIDs) and FGID-related signs and symptoms have a fundamental impact on the psychosocial, physical and mental well-being of infants and their parents alike. Recent reviews and studies have indicated that FGIDs and related signs and symptoms may also have a substantial impact on the budgets of third-party payers and/or parents. The objective of this systematic review is to investigate these costs. Methods and analysis The population of interest is healthy term infants (under 12 months of age) with colic, regurgitation and/or functional constipation. Outcomes of interest will include the frequency and volume of reported treatments, the cost to third-party payers and/or parents for prescribed or over the counter treatments, visits to health professionals and changes in infant formula purchases, and the loss of income through time taken off work and out of pocket costs. Relevant studies will be identified by searching databases from 2005 onwards (including MEDLINE, EMBASE, PsycINFO, NEXIS, DARE, Health Technology Assessment database, National Health Service Economic Evaluation Database and others), conferences from the previous 3 years and scanning reference lists of eligible studies. Study selection, data extraction and quality assessment will be conducted by two independent reviewers and disagreements resolved in discussion with a third reviewer. Quality assessment will involve study design-specific checklists. Relevant studies will be summarised narratively and presented in tables. An overview of treatments and costs will be provided, with any geographical or other differences highlighted. An assessment of how the totals for cost differ across countries and elements that contribute to the differences will be generated. Ethics and dissemination This is a systematic review of published studies that will be submitted for publication to a peer-reviewed journal. Ethical committee approval is not required. Trial registration number CRD42016033119.

Summary Background Plexiform neurofibromas are slow-growing chemoradiotherapy-resistant tumours arising in patients with neurofibromatosis type 1 (NF1). Currently, there are no viable therapeutic options for patients with plexiform neurofibromas that cannot be surgically removed because of their proximity to vital body structures. We undertook an open-label phase 2 trial to test whether treatment with imatinib mesylate can decrease the volume burden of clinically significant plexiform neurofibromas in patients with NF1. Methods Eligible patients had to be aged 3–65 years, and to have NF1 and a clinically significant plexiform neurofibroma. Patients were treated with daily oral imatinib mesylate at 220 mg/m 2 twice a day for children and 400 mg twice a day for adults for 6 months. The primary endpoint was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data were analysed on an intention-to-treat basis; a secondary analysis was also done for those patients able to take imatinib mesylate for 6 months. This trial is registered with ClinicalTrials.gov, number NCT01673009. Findings Six of 36 patients (17%, 95% CI 6–33), enrolled on an intention-to-treat basis, had an objective response to imatinib mesylate, with a 20% or more decrease in tumour volume. Of the 23 patients who received imatinib mesylate for at least 6 months, six (26%, 95% CI 10–48) had a 20% or more decrease in volume of one or more plexiform tumours. The most common adverse events were skin rash (five patients) and oedema with weight gain (six). More serious adverse events included reversible grade 3 neutropenia (two), grade 4 hyperglycaemia (one), and grade 4 increases in aminotransferase concentrations (one). Interpretation Imatinib mesylate could be used to treat plexiform neurofibromas in patients with NF1. A multi-institutional clinical trial is warranted to confirm these results. Funding Novartis Pharmaceuticals, the Indiana University Simon Cancer Centre, and the Indiana University Herman B Wells Center for Pediatric Research.

Adults with periventricular nodular heterotopia (PNH) suffer from epilepsy and dyslexia but most have normal intelligence. It is not known whether PNH-related reading difficulty can be detected earlier in childhood, or whether associated behavioral problems are present. We studied 10 children with PNH, three of whom did not have seizures, and 10 matched controls with neuropsychological testing and parental rating instruments at two timepoints separated by about one year. Children with PNH performed significantly worse than controls on three tasks related to reading fluency. In addition, those with PNH showed significantly worse adaptive skills, and a measure of conduct problems significantly worsened over time. Mood and behavioral problems were reported more commonly, though not significantly so, in children with PNH. These findings demonstrate that reading dysfluency can be evident in children with nodular heterotopia, even in the absence of epilepsy, but also highlight difficulties with behavior in this population.

Whether currency devaluation promotes growth is an empirically open question. Coexistence of an undervalued currency and the world�s largest trade surplus alongside a booming economy makes China a unique case study. Using the bounds-testing approach to cointegration and error correction modeling proposed by Pesaran et al. (2001), we estimate a reduced form model for China. The findings suggest that devaluation of the Yuan is contractionary in the short run but expansionary in the long run.

Mesial temporal sclerosis (MTS) has been linked to prolonged febrile seizures. The sequence of changes in the temporal lobe/hippocampus following prolonged febrile seizures and status epilepticus is beginning to be elucidated. We obtained repeated magnetic resonance imaging (MRI) volumetric analysis of the hippocampi in a 23-month-old boy after a prolonged focal febrile seizure. Three days after a prolonged left focal febrile seizure, brain MRI showed increased T2 weighted signal and increased volume (swelling) of the right hippocampus. Repeat MRI 2 months later demonstrated sclerosis of the right hippocampus. Review of the literature shows four other children with prolonged focal seizures associated with the MRI sequence of temporal lobe swelling followed by sclerosis. All had left focal seizures followed by right MTS. Our patient demonstrates a shorter interval for the radiologic development of hippocampal sclerosis compared to other reports.

The current experimental model for galactomannan biosynthesis in membrane-bound enzyme systems from developing legume-seed endosperms involves functional interaction between a GDP-mannose (Man) mannan synthase and a UDP-galactose (Gal) galactosyltransferase. The transfer specificity of the galactosyltransferase to the elongating mannan chain is critical in regulating the distribution and the degree of Gal substitution of the mannan backbone of the primary biosynthetic product. Detergent solubilization of the galactosyltransferase of fenugreek (Trigonella foenum-graecum) with retention of activity permitted the partial purification of the enzyme and the cloning and sequencing of the corresponding cDNA with proof of functional identity. We now document the positional specificity of transfer of (14C)Gal from UDP-(14C)Gal to manno-oligosaccharide acceptors, chain lengths 5 to 8, catalyzed by the detergent-solubilized galactosyltransferase. Enzymatic fragmentation analyses of the labeled products showed that a single Gal residue was transferred per acceptor molecule, that the linkage was (1→6)-α, and that there was transfer to alternative Man residues within the acceptor molecules. Analysis of the relative frequencies of transfer to alternative Man residues within acceptor oligosaccharides of different chain length allowed the deduction of the substrate subsite recognition requirement of the galactosyltransferase. The enzyme has a principal recognition sequence of six Man residues, with transfer of Gal to the third Man residue from the nonreducing end of the sequence. These observations are incorporated into a refined model for enzyme interaction in galactomannan biosynthesis.

Galactomannan biosynthesis in vitro is catalysed by membrane preparations from developing fenugreek seed endosperms. Two enzymes interact: a GDP-mannose dependent (1--4)-beta-D-mannan synthase and a UDP-galactose dependent (1--6)-alpha-D-galactosyltransferase. The statistical distribution of galactosyl substituents along the mannan backbone, and the degree of galactose substitution of the primary product of galactomannan biosynthesis appear to be regulated by the specificity of the galactosyltransferase. We now report the detergent solubilisation of the fenugreek galactosyltransferase with retention of activity, the identification on gels of a putative 51 kDa galactosyltransferase protein, and the isolation, cloning and sequencing of the corresponding cDNA. The solubilised galactosyltransferase has an absolute requirement for added acceptor substrates. Beta-(1--4)-linked D-manno-oligosaccharides with chain lengths greater than or equal to 5 acted as acceptors, as did galactomannans of low to medium galactose-substitution. The putative galactosyltransferase cDNA encodes a 51282 Da protein, with a single transmembrane alpha helix near the N terminus. We have also confirmed the identity of the galactosyltransferase by inserting the cDNA in frame into the genome of the methylotrophic yeast Pichia pastoris under the control of an AOX promoter and the yeast alpha secretion factor and observing the secretion of galactomannan alpha-galactosyltransferase activity. Particularly high activities were observed when a truncated sequence, lacking the membrane-spanning helix, was expressed.

Membrane-bound enzymes from developing legume-seed endosperms catalyse galactomannan biosynthesis in vitro from GDP-mannose and UDP-galactose. A mannosyltransferase [mannan synthase] catalyses the extension of the linear (1→4)-β-linked d-mannan backbone towards the non-reducing end. A specific α-galactosyltransferase brings about the galactosyl-substitution of the backbone by catalysing the transfer of a (1→6)-α-d-galactosyl residue to an acceptor mannosyl residue at or close to the non-reducing terminus of the growing backbone. Labelled galactomannans with a range of mannose/galactose (Man/Gal) ratios were formed in vitro from GDP-[14C]mannose and UDP-[14C]galactose using membrane-bound enzyme preparations from fenugreek (Trigonella foenum-graecum L.), guar (Cyamopsis tetragonoloba (L.) Taub.) and senna (Senna occidentalis (L.) Link.), species which in vivo, form galactomannans with Man/Gal ratios of 1.1, 1.6 and 3.3 respectively. The labelled galactomannans were fragmented using a structure-sensitive endo-(1→4)-β-d-mannanase and the quantitative fragmentation data were processed using a computer algorithm which simulated the above model for galactomannan biosynthesis on the basis of a second-order Markov chain process, and also the subsequent action of the endo-mannanase. For each galactomannan data-set processed, the algorithm generated a set of four conditional probabilities required by the Markov model. The need for a second-order Markov chain description indicated that the galactomannan subsite recognition sequence of the galactosyltransferase must encompass at least three backbone mannose residues, i.e. the site of substitution and the two preceding ones towards the reducing end of the growing galactomannan chain. Data-sets from the three plant species generated three distinctly different sets of probabilities, and hence galactose-substitution rules. For each species, the maximum degree of galactose-substitution consistent with these rules was closely similar to that observed for the primary product of galactomannan biosynthesis in vivo. The data provide insight into the mechanism of action and the spatial organisation of membrane-bound polysaccharide synthases.

The major polysaccharide in tamarind seed is a galactoxyloglucan for which the ratios galactose:xylose:glucose are 1:2:25:2.8. A minor polysaccharide (2-3%) contains branched (1----5)-alpha-L-arabinofuranan and unbranched (1----4)-beta-D-galactopyranan features. Small-angle X-ray scattering experiments gave values for the cross-sectional radius of the polymer in aqueous solution that were typical of single-stranded molecules. Marked stiffness of the chain (C infinity 110) was deduced from static light-scattering studies and is ascribed partially to the restriction of the motion of the (1----4)-beta-D-glucan backbone by its extensive (approximately 80%) glycosylation. The rigidity of the polymer caused significant draining effects which heavily influenced the hydrodynamic behaviour. The dependence of "zero-shear" viscosity on concentration was used to characterise "dilute" and "semi-dilute" concentration regimes. The marked dependence on concentration in the "semi-dilute" region was similar to that for other stiff neutral polysaccharide systems, ascribed to "hyper-entanglements", and it is suggested that these may have arisen through a tenuous alignment of stiffened chains.

Our patient’s parents became concerned about a ridge on the back of his skull when he was 2 weeks old. He was otherwise healthy. Head CT demonstrated a normal skull but suggested sinovenous thrombosis; follow-up …