Critical Periods During Childhood and Adolescence: A Study of Adult Height Among Immigrant Siblings

We identify the ages that constitute critical periods in children's development towards their adult health status. For this we use data on families migrating into Sweden from countries that are mostly poorer, with less healthy conditions. Long-run health is proxied by adult height. The relation between siblings' ages at migration and their heights after age 18 allows us to estimate the causal effect of conditions at a certain age on adult height. Moreover, we compare siblings born outside and within Sweden. We apply fixed-effect methods to a sample of about 9,000 brothers. We effectively exploit that for siblings the migration occurs simultaneously in calendar time but at different developmental stages (ages). We find important critical periods at ages 5/6 and 9. The effects are stronger in families migrating from poorer countries but weaker if the mother is well-educated.developmental origins, fetal programming, age, height retardation, adult health, parental education, migration, early-life conditions

Critical periods during childhood and adolescence: a study of adult height among immigrant siblings

We identify the ages that constitute critical periods in children’s development towards their adult health status. For this we use data on families migrating into Sweden from countries that are poorer, with less healthy conditions. Long-run health is proxied by adult height. The relation between siblings’ ages at migration and their heights after age 18 allows us to estimate the causal effect of conditions at certain ages on adult height. Moreover, we compare siblings born outside and within Sweden. We apply fixed-effect methods to a sample of about 9,000 brothers. We effectively exploit that for siblings the migration occurs simultaneously in calendar time but at different developmental stages (ages). We find some evidence for a critical period at age 9. The effects are stronger in families migrating from poorer countries but weaker if the mother is well-educated.Early-life conditions; migration; parental education; adult health; height retardation; age; fetal programming; developmental origins

Morning versus evening dosing of desloratadine in seasonal allergic rhinitis: a randomized controlled study [ISRCTN23032971].

BACKGROUND: A circadian rhythm of symptoms has been reported in allergic rhinitis and some studies have shown the dosing time of antihistamines to be of importance for optimizing symptom relief in this disease. The objective of this study was to examine the efficacy of morning vs. evening dosing of the antihistamine desloratadine at different time points during the day. METHODS: Patients ≥ 18 years, with seasonal allergic rhinitis received desloratadine 5 mg orally once daily in the morning (AM-group) or evening (PM-group) for two weeks. Rhinorrhea, nasal congestion, sneezing and eye symptoms were scored morning and evening. Wilcoxon rank sum and 2-way ANOVA test were used. RESULTS: Six-hundred and sixty-three patients were randomized; 336 in the AM-group; 327 in the PM-group. No statistically significant differences were seen between the AM and PM group at any time points. In the sub-groups with higher morning or evening total symptom score no difference in treatment efficacy was seen whether the dose was taken 12 or 24 hours before the higher score time. There was a circadian variation in baseline total symptom score; highest during daytime and lowest at night. The circadian variation in symptoms was reduced during treatment. This reduction was highest for daytime symptoms. CONCLUSIONS: A circadian rhythm was seen for most symptoms being more pronounced during daytime. This was less apparent after treatment with desloratadine. No statistically significant difference in efficacy was seen whether desloratadine was given in the morning or in the evening. This gives the patients more flexibility in choosing dosing time

Betydelsen av kraftledningsgator, skogsbilvägar och naturbetesmarker för fjärilar i olika landskapstyper

I landskap dominerade av modernt jord- och skogsbruk är många arters livsmiljöer starkt fragmenterade vilket hotar deras långsiktiga överlevnad. Linjära element i landskapet antas kunna underlätta arters spridning och överlevnad i landskapet genom att fungera som spridningskällor och därmed minska de negativa effekterna av fragmenteringen. Kunskapen om i vilken utsträckning linjära landskapselement, som vägkanter och kraftledningsgator utgör spridningskällor (habitat som producerar överskott av individer) och/eller fungerar som funktionella spridningskorridorer är dålig. En av målsättningarna med denna undersökning var att undersöka om närhet till kraftledningsgator ökar art- och individrikedomen av fjärilar i andra biotoper. Vi gjorde detta genom att inventera fjärilar på 160 platser i 23 landskap i södra Sverige. I fjärilsinventeringen jämförde vi fjärilsfaunan i naturbetesmarker och skogsbilvägar på olika avstånd från kraftledningsgator. Dessutom jämförde vi fjärilsfaunan i kraftledningsgator (och naturbetesmarker och skogsbilvägar) i en gradient från relativt öppna landskap med jordbruksmark till skogsdominerade landskap. Vi gjorde även detaljerade studier av några arters rörelsemönster och beteende i några utvalda landskap (två i varje delstudie). Vi studerade i) flygbeteendet hos några utvalda arter i kraftledningsgator, betesmarker och längs vägar med syftet att analysera om andelen individer som uppvisade snabb flykt (spridning) och födosöksflykt skiljde sig mellan habitaten. Dessutom gjordes ii) experiment med utsläpp av fångade individer av ett urval av arter vid gränsen mellan en betesmark och andra habitat för att se om de föredrog att flyga genom betesmark, skog, ledningsgator eller åkermark. Kraftledningsgator tycktes fungera som spridningskälla för fjärilar i skogsbilvägar eftersom både art- och individrikedom var signifikant högre i skogsbilvägar och naturbetesmarker nära kraftledningsgator än i områden långt ifrån ledningsgatorna. Den positiva effekten av närheten till kraftledningsgator tycktes klinga av först vid avstånd på 700-800 m från ledningsgatorna, dvs kraftledningsgatorna hade en positiv effekt på fjärilsfaunan i områden som är mycket större än den areal de täcker. Dessutom var sammansättningen av arter liknande i områden nära och på avstånd från ledningsgatorna, vilket tyder på att ökningen i art- och individrikedom inte berodde på en ökning av arter som normalt inte förekommer i större omfattning på skogsbilvägarna och i naturbetesmarkerna. De analyser vi genomfört när det gäller rörelsemönster och beteenden de utvalda arterna tyder på att det är stor skillnad mellan olika arter, vissa arter (t.ex. pärlgräsfjäril) tycks använda ledningsgatorna för födosök (och därmed troligen också reproduktion), luktgräsfjäril kan enligt våra resultat möjligen också använda ledningsgatorna för spridningsflykt och skogsnätfjäril tycktes göra det. Det troliga är alltså att ledningsgatorna fungerar som spridningskorridorer för vissa arter, medan andra använder habitatet för reproduktion, vilket resulterar i att ledningsgatorna fungerar som spridningskällor (bra habitat) för närliggande habitat. Generellt ökade artrikedomen av fjärilar i naturbetesmarker och skogsbilvägar med ökande andel skog i landskapet. Skogslandskap innehåller mer alternativa habitat än landskap med mer åkermark. I motsats till våra förväntningar fann vi inga starka effekter av landskapets sammansättning (inom 1 km eller 6 km radie) för art- och individrikedom av fjärilar i ledningsgatorna. Detta indikerar att ledningsgatorna (till skillnad från de två andra habitaten) uppfyller kraven för ett flertal arter oavsett det omgivande landskapets sammansättning. I likhet med tidigare studier fann vi att ledningsgatorna var art- och individrikare än naturbetesmarker och skogsbilvägar, vilket bekräftar deras betydelse för fjärilsfaunan. Förutom att fokusera på ledningsgatornas roll som spridningskälla för fjärilar så utvärderade vi betydelsen av övriga habitatvariabler som t.ex. korridorernas bredd, markförhållanden och förekomst av träd och buskar för artrikedom av fjärilar i ledningsgator och skogsbilvägar. En faktor som var viktig för artrikedomen i dessa två habitat var korridorernas bredd (från <10m m i de smalaste vägarna – 200 m i de bredaste ledningsgatorna), vilket visar betydelsen av arealen öppet habitat i de studerade skogslandskapen. För skogsbilvägar kan den högre artrikedomen i breda vägar också bero på mikroklimatets betydelse (solsken och högre temperatur i breda vägar), vilket är en viktig faktor för fjärilar på nordliga latituder. I kraftledningsgator (25 – 200 m breda) är det troligt att den positiva effekten av korridorbredd, ända upp till 200 m, är en effekt av ökad habitatvariation som är kopplat till den större arealen öppet habitat. Andra faktorer som var korrelerat till artrikedomen i både skogsbilvägar och ledningsgator var mängd lövsly längs transekten och mängd lövträd i de omgivande brynen. Detta kan bero på att flera arter är beroende av det skydd som buskarna erbjuder, vissa arter är också knutna till buskar och träd under larvstadiet. Markförhållandena (t.ex. näringsinnehåll) kan också påverka artrikedomen positivt, och lövträd indikerar goda näringsförhållanden (med förekomst av örter) i annars näringsfattiga barrskogsområden. I ledningsgatorna var artrikedomen negativt korrelerad med mängden lövträd (kopplat till tid sedan röjning). Detta indikerar att mer frekvent röjning i ledningsgator med en artrik eller värdefull fjärilsfauna med fördel kan ske oftare än vart 6-8 år som nu är standard i de flesta ledningsgatorna. Artrikedomen var låg i ledningsgator med torr mark och en vegetation dominerad av ris, d.v.s. specifik skötsel för att gynna fjärilsfaunan bör fokusera på breda ledningsgator med frisk-fuktig mark och en gräs-ört vegetation med blommande växter

Biosynthesis of Promatrix Metalloproteinase-9/Chondroitin Sulphate Proteoglycan Heteromer Involves a Rottlerin-Sensitive Pathway

BACKGROUND: Previously we have shown that a fraction of the matrix metalloproteinase-9 (MMP-9) synthesized by the macrophage cell line THP-1 was bound to a chondroitin sulphate proteoglycan (CSPG) core protein as a reduction sensitive heteromer. Several biochemical properties of the enzyme were changed when it was bound to the CSPG. METHODOLOGY/PRINCIPAL FINDINGS: By use of affinity chromatography, zymography, and radioactive labelling, various macrophage stimulators were tested for their effect on the synthesis of the proMMP-9/CSPG heteromer and its components by THP-1 cells. Of the stimulators, only PMA largely increased the biosynthesis of the heteromer. As PMA is an activator of PKC, we determined which PKC isoenzymes were expressed by performing RT-PCR and Western Blotting. Subsequently specific inhibitors were used to investigate their involvement in the biosynthesis of the heteromer. Of the inhibitors, only Rottlerin repressed the biosynthesis of proMMP-9/CSPG and its two components. Much lower concentrations of Rottlerin were needed to reduce the amount of CSPG than what was needed to repress the synthesis of the heteromer and MMP-9. Furthermore, Rottlerin caused a minor reduction in the activation of the PKC isoenzymes δ, ε, θ and υ (PKD3) in both control and PMA exposed cells. CONCLUSIONS/SIGNIFICANCE: The biosynthesis of the proMMP-9/CSPG heteromer and proMMP-9 in THP-1 cells involves a Rottlerin-sensitive pathway that is different from the Rottlerin sensitive pathway involved in the CSPG biosynthesis. MMP-9 and CSPGs are known to be involved in various physiological and pathological processes. Formation of complexes may influence both the specificity and localization of the enzyme. Therefore, knowledge about biosynthetic pathways and factors involved in the formation of the MMP-9/CSPG heteromer may contribute to insight in the heteromers biological function as well as pointing to future targets for therapeutic agents

Nocturnal temperature controlled laminar airflow for treating atopic asthma: a randomised controlled trial

   Objective To determine whether environmental control using nocturnal temperature controlled laminar airflow (TLA) treatment could improve the quality of life of patients with persistent atopic asthma. &lt;br&gt; &lt;br&gt;Design Randomised, double-blind, placebo-controlled, parallel-group trial. &lt;br&gt; &lt;br&gt;Setting Nineteen European asthma clinics. &lt;br&gt; &lt;br&gt;Participants 312 patients aged 7-70 with inadequately controlled persistent atopic asthma. &lt;br&gt; &lt;br&gt;Main outcome measure Proportion of patients with an increase of &amp;gt;= 0.5 points in asthma quality of life score after 1 year of treatment. &lt;br&gt; &lt;br&gt;Results TLA devices were successfully installed in the bedrooms of 282 (90%) patients included in the primary efficacy analysis. There was a difference in treatment response rate between active (143 of 189, 76%) and placebo (56 of 92, 61%) groups, difference 14.8% (95% CI 3.1 to 26.5, p=0.02).(3) In patients aged &amp;gt;= 12, on whom the study was powered, the difference in response rate was similar-active 106 of 143 (74%), placebo 42 of 70 (60%), difference 14.1% (0.6 to 27.7, p=0.059). There was a difference between groups in fractional exhaled nitric oxide change of -7.1 ppb (-13.6 to -0.7, p=0.03). Active treatment was associated with less increase in cat-specific IgE than placebo. There was no difference in adverse event rates between treatment groups. &lt;br&gt; &lt;br&gt;Conclusion Inhalant exposure reduction with TLA improves quality of life, airway inflammation and systemic allergy in patients with persistent atopic asthma. TLA may be a treatment option for patients with inadequately controlled persistent atopic asthma.funding agencies|Airsonett AB||National Institute for Health Research||National Institute for Health Research Biomedical Research Centre||MRC||Asthma UK Centre in Allergic Mechanisms of Asthma||</p

Cancer-associated fibroblasts from human NSCLC survive ablative doses of radiation but their invasive capacity is reduced

&lt;p&gt;Background: Cancer-Associated Fibroblasts (CAFs) are significant components of solid malignancies and play central roles in cancer sustainability, invasion and metastasis. In this study we have investigated the invasive capacity and matrix remodelling properties of human lung CAFs after exposure to ablative doses of ionizing radiation (AIR), equivalent to single fractions delivered by stereotactic ablative radiotherapy (SART) for medically inoperable stage-I/II non-small-cell lung cancers.&lt;/p&gt; &lt;p&gt;Methods: CAFs were isolated from lung tumour specimens from 16 donors. Initially, intrinsic radiosensitivity was evaluated by checking viability and extent of DNA-damage response (DDR) at different radiation doses. The migrative and invasive capacities of CAFs were thereafter determined after a sub-lethal single radiation dose of 18 Gy. To ascertain the mechanisms behind the altered invasive capacity of cells, expression of matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) were measured in the conditioned media several days post-irradiation, along with expression of cell surface integrins and dynamics of focal contacts by vinculin-staining.&lt;/p&gt; &lt;p&gt;Results: Exposing CAFs to 1 × 18 Gy resulted in a potent induction of multiple nuclear DDR foci (&gt; 9/cell) with little resolution after 120 h, induced premature cellular senescence and inhibition of the proliferative, migrative and invasive capacity. AIR promoted MMP-3 and inhibited MMP-1 appearance to some extent, but did not affect expression of other major MMPs. Furthermore, surface expression of integrins α2, β1 and α5 was consistently enhanced, and a dramatic augmentation and redistribution of focal contacts was observed.&lt;/p&gt; &lt;p&gt;Conclusions: Our data indicate that ablative doses of radiation exert advantageous inhibitory effects on the proliferative, migratory and invasive capacity of lung CAFs. The reduced motility of irradiated CAFs might be a consequence of stabilized focal contacts via integrins.&lt;/p&gt

Cleavage of the urokinase receptor (uPAR) on oral cancer cells: Regulation by transforming growth factor - beta1 (TGF-beta1) and potential effects on migration and invasion

Source at https://doi.org/10.1186/s12885-017-3349-7 Background: Urokinase plasminogen activator (uPA) receptor (uPAR) is up-regulated at the invasive tumour front of human oral squamous cell carcinoma (OSCC), indicating a role for uPAR in tumour progression. We previously observed elevated expression of uPAR at the tumour-stroma interface in a mouse model for OSCC, which was associated with increased proteolytic activity. The tumour microenvironment regulated uPAR expression, as well as its glycosylation and cleavage. Both full-length- and cleaved uPAR (uPAR (II-III)) are involved in highly regulated processes such as cell signalling, proliferation, migration, stem cell mobilization and invasion. The aim of the current study was to analyse tumour associated factors and their effect on uPAR cleavage, and the potential implications for cell proliferation, migration and invasion. Methods: Mouse uPAR was stably overexpressed in the mouse OSCC cell line AT84. The ratio of full-length versus cleaved uPAR as analysed by Western blotting and its regulation was assessed by addition of different protease inhibitors and transforming growth factor - β 1(TGF- β 1). The role of uPAR cleavage in cell proliferation and migration was analysed using real-time cell analysis and invasion was assessed using the myoma invasion model. Results: We found that when uPAR was overexpressed a proportion of the receptor was cleaved, thus the cells presented both full-length uPAR and uPAR (II-III). Cleavage was mainly performed by serine proteases and urokinase plasminogen activator (uPA) in particular. When the OSCC cells were stimulated with TGF- β 1, the production of the uPA inhibitor PAI-1 was increased, resulting in a reduction of uPAR cleavage. By inhibiting cleavage of uPAR, cell migration was reduced, and by inhibiting uPA activity, invasion was reduced. We could also show that medium containing soluble uPAR (suPAR), and cleaved soluble uPAR (suPAR (II-III)), induced migration in OSCC cells with low endogenous levels of uPAR. Conclusions: These results show that soluble factors in the tumour microenvironment, such as TGF- β 1, PAI-1 and uPA, can influence the ratio of full length and uPAR (II-III) and thereby potentially effect cell migration and invasion. Resolving how uPAR cleavage is controlled is therefore vital for understanding how OSCC progresses and potentially provides new targets for therapy

Nordic Innovative Trials to Evaluate osteoPorotic Fractures (NITEP) Collaboration : The Nordic DeltaCon Trial protocol-non-operative treatment versus reversed total shoulder arthroplasty in patients 65 years of age and older with a displaced proximal humerus fracture: a prospective, randomised controlled trial

Introduction The proximal humerus fracture (PHF) is one of the most common fractures in the elderly. The majority of PHFs are treated non-operatively, while 15%-33% of patients undergo surgical treatment. Recent randomised controlled trial (RCT) and meta-analyses have shown that there is no difference in outcome between non-operative treatment and locking plate or hemi-arthroplasty. During the past decade, reverse total shoulder arthroplasty (RTSA) has gained popularity in the treatment of PHF, although there is a lack of RCTs comparing RTSA to non-operative treatment. Methods This is a prospective, single-blinded, randomised, controlled, multicentre and multinational trial comparing RTSA with non-operative treatment in displaced proximal humeral fractures in patients 65-85 years. The primary outcome in this study is QuickDASH-score measured at 2 years. Secondary outcomes include visual analogue scale for pain, grip strength, Oxford shoulder score, Constant score and the number of reoperations and complications. The hypothesis of the trial is that operative treatment with RTSA produces better outcome after 2 and 5 years measured with QuickDASH. Ethics and dissemination In this protocol, we describe the design, method and management of the Nordic DeltaCon trial. The ethical approval for the trial has been given by the Regional Committee for Medical and Health Research Ethics, Norway. There have been several examples in orthopaedics of innovations that result in failure after medium-term follow-ups. In order to prevent such failures and to increase our knowledge of RSTA, we feel a large-scale study of the effects of the surgery on the outcome that focuses on the complications and reoperations is warranted. After the trial 2-year follow-up, the results will be disseminated in a major orthopaedic publication.Peer reviewe