Globalization and health policy space: Introducing the WTOhealth dataset of trade challenges to national health regulations at World Trade Organization, 1995-2016.

Do international trade rules and agreements constrain health policy space? A multitude of global actors and institutions with different interests and power can shape national health policy, and trade rules provide one means through which to exert pressure on governments. Yet, the full scope of political pressure on health policy within the global trade regime is insufficiently understood, as previous research largely focussed on challenges to food, alcohol, and tobacco regulations and used small-N case studies. This potentially overlooks other domains of influence and we lack an understanding of quantitative trends and patterns therein. In this article we introduce a novel dataset, WTOhealth, comprising all challenges to national health regulations at the WTO Technical Barriers to Trade (TBT) Committee between 1995 and 2016. The dataset is based on 1496 pages of minutes from 71 TBT meetings. We describe how we developed this dataset and present an exploratory analysis of key patterns within the data. Our analysis shows that WTO members raised 250 trade challenges to health regulations between 1995 and 2016. 83.6% of challenges to low- or lower-middle income country (LMIC) members were raised by high-income countries (HICs). Many challenges centred on food (16.4% challenges), alcohol (10.4%), and tobacco (4.2%) policies, but a substantial proportion concerned other products, including toxic chemicals (9.1%), pharmaceuticals and medical devices (8.1%), machinery (7.8%), and motor vehicles (7.3%). This includes measures targeting medical device safety, increased access to pharmaceuticals, and reduced exposure to toxins harmful to both health and the environment. We further examine these challenges, finding that HIC members made claims with contentious scientific support. In short, diverse health regulations may be changed or delayed following contentious challenges at the TBT Committee. There is a need for further research investigating the nature and influence of WTO challenges to diverse health regulations.

Assessment and validation of a screening questionnaire for the diagnosis of pediatric bladder and bowel dysfunction.

INTRODUCTION: Pediatric bladder and bowel dysfunction (BBD) is a common problem in children. However, the current ability to diagnosis and quantify pediatric BBD is limited as only a few validated instruments exist. In addition, the current questionnaires are limited by their lack of psychometric processing and methods of validation. To address these issues, the authors developed a new questionnaire to objectively diagnose pediatric BBD symptoms. This study aimed to evaluate the performance of this newly devised objective instrument in diagnosing and quantifying the symptomatology of BBD in children. MATERIALS AND METHODS: An 18-item, 5-point questionnaire was developed using both a literature review and expert opinions. The total questionnaire score could range from 0 to 72. Questions were subgrouped into six symptom categories: (1) nocturnal enuresis, (2) lower urinary tract symptoms, (3) urinary holding, (4) infrequent urination, (5) bowel symptoms, and (6) daytime urinary incontinence. The questionnaire also assessed the degree of bother associated with the symptoms. Patients were divided into cases and controls, and these two groups were compared. DISCUSSION/RESULTS: A total of 1265 new patients (758 cases and 507 controls) completed the new BBD questionnaire. The mean age of the whole study cohort was 9.5 years (range, 3-19 years). The total mean questionnaire score was significantly higher at 23 (3-58) in the cases, compared with 8 (0-35) in the controls (p < 0.001) (Summary Figure). Reliability analysis of the 18-item instrument showed a Cronbach's alpha reliability coefficient of 0.80 for the scale. CONCLUSIONS: This new instrument provides a valid and reliable method for diagnosis of pediatric BBD and classification of patients into subcategories of BBD based on their specific symptoms.

Effect of obesity on aromatase inhibitor efficacy in postmenopausal, hormone receptor-positive breast cancer: a systematic review.

Aromatase inhibitors (AIs) decrease the production of oestrogen, decreasing stimulation of hormone receptor-positive breast cancer. Theoretically, AIs may be less effective in obese women, due to the greater quantity of aromatase in peripheral fatty tissue. We performed a systematic review to assess the effect of obesity on AI efficacy in breast cancer treatment. The review followed PRISMA guidelines. Studies included were interventional or observational studies with comparison groups, of postmenopausal women with hormone receptor-positive breast cancer on treatment with an AI, alone or in combination with other drugs, in which body mass index or another measure of obesity was recorded. Studies in all languages were included; if published as an abstract only, authors were contacted for further information. Outcome measures included overall survival, disease-free survival or time to progressive disease, survival from the start of therapy, mortality measures, local or distant recurrence of primary cancer and time to recurrence. Of 2,344 citations identified from five databases, eight studies met the criteria for inclusion; three randomised controlled trials and five retrospective cohort studies. Due to variability in study factors, it was not possible to perform a quantitative meta-analysis. However, the systematic review showed a trend towards a negative effect of obesity on AI efficacy. There is evidence of a negative effect of obesity on AI efficacy in postmenopausal hormone receptor-positive breast cancer, but the size of the effect cannot be assessed. More information is needed before clinical recommendations are made.

Adverse obstetrical outcomes after treatment of precancerous cervical lesions: a Belgian multicentre study.

OBJECTIVE: To assess the impact of cervical intraepithelial neoplasia (CIN) treatment on the risk of (spontaneous) preterm delivery (PD) and small for gestational age (SGA) at birth. DESIGN: A multicentre cohort study. SETTING: Maternity wards of four academic hospitals in Belgium. POPULATION: Ninety-seven exposed pregnant women (with a CIN treatment history) and 194 nonexposed pregnant women (without a history of CIN treatment). METHODS: A questionnaire and check of obstetrical files included socio-demographic characteristics, risk factors for PD, obstetrical history for all women and characteristics of the CIN treatment for exposed women. Pregnancy outcomes were recorded after delivery. The influence of previous treatment of CIN on pregnancy outcomes, adjusted for confounding variables, was assessed by Cox regression and lifetables (for the outcome gestational age at birth) and by logistic regression (for the outcomes PD and SGA at birth). MAIN OUTCOME MEASURES: Occurrence of PD and SGA at birth. RESULTS: Seventy-nine per cent of the women in the database were multiparous; 16.3% of women with a previous excisional treatment spontaneously delivered preterm, compared with 8.1% of unexposed women [odds ratio (OR), 2.19; 95% confidence interval (CI), 0.97-4.99]. When adjusting for confounding factors (ethnicity, HIV status, education, age, smoking and parity), the OR for PD was 2.33 (95% CI, 0.99-5.49). Excisional treatment did not have an impact on SGA at birth (OR, 0.94; 95% CI,0.41-2.15). The depth of the cone was >10 mm in 63.5% of the documented cases. Large cones, more than 10 mm deep, were associated with a significantly increased risk of PD (adjusted OR, 4.55; 95% CI, 1.32-15.65) compared with untreated women, whereas smaller cones (≤ 10 mm) were not significantly associated with PD (OR, 2.77; 95% CI, 0.28-27.59). The associations seen for PD with respect to the cone size did not hold for SGA at birth. CONCLUSIONS: There was an increased risk of (spontaneous) PD after excision of CIN, in particular when the cone depth exceeded 10 mm.

A new hypothesis of pathogenesis based on the divorce between mitochondria and their host cells: possible relevance for Alzheimer's disease.

On the basis of not only the endosymbiotic theory of eukaryotic cell organization and evolution but also of observations of transcellular communication via Tunneling NanoTubes (TNTs), the hypothesis is put forward that when mitochondria, which were once independently living prokaryote-like organisms, are subjected to detrimental genetic, toxic, or environmental conditions, including age-related endogenous factors, they can regress towards their original independent state. At that point, they can become potentially pathogenic intruders within their eukaryotic host cell. Because of the protoplasmic disequilibrium caused by an altered, or mutated, mitochondral population, certain host cells with a minimal capacity for self-renewal, such as dopaminergic neurons, risk a loss of function and degenerate. It is also proposed that altered mitochondria, as well as their mutated mtDNA, can migrate, via TNTs, into adjacent cells. In this way, neurodegenerative states are propagated between cells (glia and/or neurons) of the Central Nervous System (CNS) and that this leads to conditions such as Alzheimer's and Parkinson's disease. This proposal finds indirect support from observations on rotenone-poisoned glioblastoma cells which have been co-cultured with non-poisoned cells. Immunocytochemical techniques revealed that mitochondria, moving along the TNTs, migrated from the poisoned cells towards the healthy cells. It has also been demonstrated by means of immunocytochemistry that, in glioblastoma cell cultures, Amyloid Precursor Protein (APP) is present in TNTs, hence it may migrate from one cell to neighbouring cells. This datum may be of high relevance for a better understanding of Alzheimer's Disease (AD) since molecular, cellular, and animal model studies have revealed that the formation of amyloid beta (Abeta) and other derivatives of the APP are key pathogenic factors in AD, causing mitochondrial dysfunction, free radical generation, oxidative damage, and inflammation. Furthermore, the present data demonstrate the presence of alpha-synuclein (alpha-syn) within TNTs, hence a similar pathogenic mechanism to the one surmised for AD, but centred on alpha-syn rather than on Abeta, may play a role in Parkinson's Disease (PD). As a matter of fact, alpha-syn can enter mitochondria and interact with complex I causing respiratory deficiency and increased oxygen free radical production. In agreement with this view, it has been demonstrated that, in comparison with normal subjects, PD patients show a significant accumulation of alpha-syn at Substantia Nigra and Striatal level, predominantly associated with the inner mitochondrial membrane,. These observations suggest that potentially neuropathogenic proteins, such as Abeta and alpha-syn, can not only diffuse via the extracellular space but also move from cell to cell also via TNTs where they can cause mitochondrial damage and cell degeneration. A mathematical model (see Appendix) is proposed to simulate the pathogenic consequences of the migration of altered mitochondria and/or of their mtDNA via TNTs. The results of the present simulation is compatible with the proposal that mutated mitochondrial agents behave as though they were infectious particles migrating through a continuum of interconnected cells.

A case of pilomyxoid astrocytoma presenting with CSF rhinorrhoea in a 15-year-old.

We report a pilomyxoid astrocytoma (PMA) presenting with CSF rhinorrhoea in a 15-year-old. This uncommon, recently described entity typically presents in infancy with focal neurological or endocrine symptoms, has distinctive histologic features and displays a more aggressive behaviour than pilocytic astrocytoma (PA) with which it was previously classified.

Health related quality of life of patients with refractory angina before and one year after enrolment onto a refractory angina program.

OBJECTIVE: This study was designed to assess the impact of a refractory angina programme on the health related quality of life for patients with chronic refractory angina (CRA) one year following enrolment. DESIGN: A one year prospective audit. SETTING: Specialist refractory angina clinic at a tertiary cardiac referral centre. PATIENTS: 69 consecutive refractory angina patients referred to a regional refractory angina centre from 1/03/2001 to 1/09/2002. INTERVENTIONS: Pain treatment algorithm in accordance with the recommendations of the national refractory angina guideline committee. MAIN OUTCOME MEASURES: Improvements in quality of life indices were assessed using Seattle angina questionnaire (SAQ), and short form-12 (SF-12) with changes in mood determined using the hospital anxiety and depression (HAD) questionnaire. RESULTS: All dimensions of the SF-12 and SAQ were superior at one year with significant improvement seen with the mental component of SF-12 (p = 0.023), and four of the five SAQ domains, angina stability (p = 0.028), angina frequency (p=0.02), treatment satisfaction (p=0.001) and quality of life (p < 0.001). All the significant changes within the SAQ domains were large enough to be considered clinically relevant. At one year the anxiety and depression domains were significantly improved from baseline (p = 0.015, 0.018) with clinical anxiety levels falling significantly from 55% to 40%, a relative reduction of 28% (p = 0.008). CONCLUSIONS: Implementation of the national refractory angina guidelines in a prospective study of 69 consecutive CRA patients significantly improved health related quality of life status at one year.

Serum exposed to nanoparticle carbon black displays increased potential to induce macrophage migration.

OBJECTIVE: To assess whether fine and ultrafine particles (nanoparticles) have the capacity to activate factors in serum that would induce macrophage migration. This is a model previously reported to investigate complement activation by other respirable particles and fibres. METHOD: Foetal bovine serum was exposed to varying doses of fine and nanoparticle carbon black as well as the oxidant tert-butyl hydroperoxide (tBHP). The subsequent potential of the serum to induce macrophage migration was measured using a macrophage chemotaxis assay. RESULTS: Treatment of serum with 10 mg/ml of nanoparticle carbon black generated substances that induced a 1.8-fold increase in macrophage migration (P<0.001) compared with untreated serum. This effect was partially inhibited by antioxidant intervention. Serum treated with an equivalent mass of fine carbon black did not display any chemotactic potential. tBHP treatment of the serum did not result in the generation of macrophage chemotactic factors. CONCLUSIONS: High doses of nanoparticle carbon black have the capacity to cause chemotactic factor generation in serum, by a mechanism involving ROS generation, although ROS alone, in the form of tBHP are not adequate to generate chemotactic factors in serum.

[The general practitioner and screening reproductive age women]. / Le médecin généraliste et le dépistage chez la femme en âge de procréer.

All women in age of procreation might benefit of well established screening tests. The latter being conduct to identify, in this apparently healthy population, diseased or carrier women of an affection. This screening program might be realised by a general practitioner and must be encouraged. Actually, in Belgium, there is no national screening program for this population. Recommendations might be proposed for all screening tests that can be realised in preconceptual period. These concern screening of diseases which affect all women like cervical cancer, which might influence the pregnancy or infant outcome, like an infection or an hereditary disease, or which could be adversely affected by the pregnancy, like diabetes.

The cytoskeleton facilitates a three-dimensional symplasmic continuum in the long-lived ray and axial parenchyma cells of angiosperm trees.

The microtubule (MT), microfilament (MF) and myosin components of the cytoskeleton were studied in the long-lived ray and axial parenchyma cells of the secondary xylem (wood) and secondary phloem of two angiosperm trees, Aesculus hippocastanum L. (horse-chestnut) and Populus tremula L. x P. tremuloides Michx. (hybrid aspen), using indirect immunofluorescence localisation and transmission electron microscopy. MTs and MFs were bundled and oriented axially (parallel to the cell's long axis) within all parenchyma cell types after they had fully differentiated. Additionally, actin and myosin were immunolocalised at the thin-walled membranes of the pits, which linked cells in neighbouring files of both ray and axial parenchyma, and at the pits between axial and ray parenchyma cells themselves. Anti-callose antibody immunolocated the plasmodesmata at the pit membranes, and in the same pattern as that of anti-myosin. Ray cells are important symplasmic pathways between the xylem and the phloem throughout the life of trees. We hypothesise that the MT and MF components of the cytoskeleton in the ray and axial parenchyma cells are involved in the transport of materials within those cells, and, in association with the acto-myosin of plasmodesmata at pit fields, are also important in intercellular transport. Thus, the symplasmic coupling between ray cells, between axial parenchyma cells, and between axial parenchyma and ray cells represents an extensive three-dimensional communication pathway permeating the tree from the phloem through the cambium into the wood. We suggest that this cytoskeletal pathway has an important role in delivery of photosynthate, and mobilised reserves, to the actively dividing cambium, and in the movement of materials to sites of reserve deposition, principally within the wood. This pathway could also have an important role in co-ordinating developmental processes throughout the tree.

Endoscopic treatment of prepontine arachnoid cysts.

Prepontine (or suprasellar) arachnoid cysts are uncommon in clinical practice and experience in their management may therefore be limited. Symptomatic cysts usually present with features of hydrocephalus due to obstruction of the third ventricle and aqueduct, and occlusion or partial obstruction of both foramina of Monro. Several treatment techniques have been used including stereotactic aspiration, microsurgical excision and shunting, but the best method of treatment remains unclear and the role of endoscopy is not yet established. We report our experience in a series of seven patients who had endoscopic treatment for prepontine arachnoid cysts; five were children under 15 years old who presented with delayed development and/or enlarged heads. The two adult patients, both of whom had insertion of shunts as children, presented with headache and vomiting due to shunt blockage. All patients improved following endoscopic cyst fenestration. There was no operative morbidity and there have been no relapses to date. Endoscopic fenestration of prepontine arachnoid cysts appears to be an effective method of treatment.

Treatment limiting decisions in a neurosurgical unit.

In a previous paper on mortality audit we reported on the use of treatment limiting decisions (TLDs) in a neurosurgical unit in the year 1988. In this paper we compare the findings of a similar audit for 1997. It appears that our unit's policy of openly discussing all TLDs in patients who die had led to such decisions being made at a more appropriate stage in the patient's illness. Regular review of TLDs is probably helpful in increasing the confidence of clinicians to make these difficult decisions openly and timeously.

Total chemical synthesis and high-resolution crystal structure of the potent anti-HIV protein AOP-RANTES.

BACKGROUND: RANTES is a CC-type chemokine protein that acts as a chemoattractant for several kinds of leukocytes, playing an important pro-inflammatory role. Entry of human immunodeficiency virus-1 (HIV-1) into cells depends on the chemokine receptor CCR5. RANTES binds CCR5 and inhibits HIV-1 entry into peripheral blood cells. Interaction with chemokine receptors involves a distinct set of residues at the amino terminus of RANTES. This finding was utilized in the development of a chemically modified aminooxypentane derivative of RANTES, AOP-RANTES, that was originally produced from the recombinant protein using semisynthetic methods. RESULTS: AOP-RANTES has been produced by a novel total chemical synthesis that provides efficient, direct access to large amounts of this anti-HIV protein analog. The crystal structure of chemically synthesized AOP-RANTES has been solved and refined at 1.6 A resolution. The protein is a dimer, with the amino-terminal pentane oxime moiety clearly defined. CONCLUSIONS: Total chemical synthesis of AOP-RANTES provides a convenient method of producing the multi-milligram quantities of this protein needed to investigate the molecular basis of receptor binding and antiviral activity. This work provides the first truly high-resolution structure of a RANTES protein, although the structure of RANTES was known from previous nuclear magnetic resonance (NMR) determinations.

The influence of mannitol on renal function during and after open-heart surgery.

Mannitol is often included in the priming solution of the heart-lung machine used during cardiopulmonary bypass (CPB). This study was set up to evaluate the effect of different doses of mannitol on human patients. Patients receiving 10 g of mannitol (n = 18) had an increased diuresis only during the bypass period (mean time = 87 min) when compared with a control group (n = 19) who did not receive mannitol. Patients receiving 20 g of mannitol (n = 19) had a significantly greater diuresis than both the control group and the 10 g group and the diuresis continued on throughout the immediate postbypass period (total mean time approximately 3 h). Patients receiving 30 g of mannitol (n = 20) also had a significantly greater diuresis that continued on during the first hour in the intensive care unit (ICU) (total mean time approximately 4 h). After 6 h in the ICU, all three groups of mannitol-treated patients equally demonstrated a trend towards an increased diuresis over the control group, which became a significant increase by 12 h in the ICU (p = 0.001) despite indications that the mannitol had been cleared from the body. These results suggest that there is an improvement of renal function post-CPB if mannitol is included in the CPB prime which may be due to an amelioration of the ischaemic effects of bypass on the kidneys.

An economic argument in favour of endoscopic third ventriculostomy as a treatment for obstructive hydrocephalus.

This project was undertaken to examine the health resource implications of performing endoscopic third ventriculostomy as an alternative to CSF shunting in appropriate patients. We carried out a retrospective study of case records and X-rays of patients shunted de novo at the INS, Glasgow for the two year period 1990-1991. We identified all those patients who would have been suitable for endoscopic third ventriculostomy and examined the shunt complications and extra days in hospital required by these patients. A total of 150 new shunts was inserted during the two year period. Of these, 23 patients (15%)were judged suitable for endoscopic third ventriculostomy as an alternative to CSF shunting. Eight out of 23 patients required a total of 29 repeat operations and an extra 230 days in hospital due to shunt complications. Assuming an 80% success (shunt free) rate for endoscopic third ventriculostomy, we calculate that 9 operations and 74 bed days per year could be saved by using this technique. We conclude that in units undertaking a large number of CSF shunt insertions, investment in neuroendoscopic equipment, training, and expertise has the potential to release significant resources for other uses.

Complete disintegration of the microtubular cytoskeleton precedes its auxin-mediated reconstruction in postmitotic maize root cells.

The inhibitory action of 0.1 microM auxin (IAA) on maize root growth was closely associated with a rapid and complete disintegration of the microtubular (MT) cytoskeleton, as visualized by indirect immunofluorescence of tubulin, throughout the growth region. After 30 min of this treatment, only fluorescent spots were present in root cells, accumulating either around nuclei or along cell walls. Six h later, in addition to some background fluorescence, dense but partially oriented oblique or longitudinal arrays of cortical MTs (CMTs) were found in most growing cells of the root apex. After 24 h of treatment, maize roots had adapted to the auxin, as inferred from the slowly recovering elongation rate and from the reassembly of a dense and well-ordered MT cytoskeleton which showed only slight deviations from that of the control root cells. Taxol pretreatment (100 microM, 24 h) prevented not only the rapid auxin-mediated disintegration of the MT cytoskeleton but also a reorientation of the CMT arrays, from transversal to longitudinal. The only tissue to show MTs in their cells throughout the auxin treatment was the epidermis. Significant resistance of transverse CMT arrays in these cells towards auxin was confirmed using a higher auxin concentration (100 microM, 24 h). The latter auxin dose also revealed inter-tissue-specific responses to auxin: outer cortical cell files reoriented their CMTs from the transversal to longitudinal orientation, whereas inner cortical cell files lost their MTs. This high auxin-mediated response, associated with the swelling of root apices, was abolished with the pretreatment of maize root with taxol.

Point mutations in the herpes simplex virus type 1 Vmw110 RING finger helix affect activation of gene expression, viral growth, and interaction with PML-containing nuclear structures.

Herpes simplex virus type 1 immediate-early protein Vmw110 (also known as ICP0) has been implicated in the control of the balance between the lytic and latent states, but the precise mechanisms by which it exerts its effects are unknown. Vmw110 includes a characteristic zinc binding domain, termed the C3HC4 domain or RING finger, which is essential for its function. The solution structure of a related herpesvirus RING finger domain suggested that an amphipathic alpha helix might be an important functional component of the RING finger. In this paper, we show that the equivalent region of Vmw110 is important for virus growth in tissue culture and for the normal interaction of Vmw110 with nuclear structures which include the PML protein.