Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition

RIG-I is a viral RNA sensor that induces the production of type I interferon (IFN) in response to infection with a variety of viruses. Modification of RIG-I with K63-linked poly-ubiquitin chains, synthesised by TRIM25, is crucial for activation of the RIG-I/MAVS signalling pathway. TRIM25 activity is targeted by influenza A virus non-structural protein 1 (NS1) to suppress IFN production and prevent an efficient host immune response. Here we present structures of the human TRIM25 coiled-coil-PRYSPRY module and of complexes between the TRIM25 coiled-coil domain and NS1. These structures show that binding of NS1 interferes with the correct positioning of the PRYSPRY domain of TRIM25 required for substrate ubiquitination and provide a mechanistic explanation for how NS1 suppresses RIG-I ubiquitination and hence downstream signalling. In contrast, the formation of unanchored K63-linked poly-ubiquitin chains is unchanged by NS1 binding, indicating that RING dimerisation of TRIM25 is not affected by NS1

Seksueel overdraagbare aandoeningen, waaronder HIV, in Nederland in 2007

Net als in 2006 was chlamydia in 2007 de meest gediagnosticeerde bacterikle geslachtsziekte in de soacentra, vooral bij jongeren. Het percentage positieve chlamydiatesten nder heteroseksuele mannen en vrouwen daalde enigszins, voor het eerst sinds vier jaar (van 10,6% naar 10,1%). In 2006 stabiliseerde dit percentage bij mannen die seks hebben met mannen (MSM), en die trend zette door in 2007. Het percentage positieve gonorroe-, syfilis- en hivtesten nam net als voorgaande jaren af in 2007 (respectievelijk 2,4%, 0,9% en ,5%). Deze infecties werden het meest gediagnosticeerd bij MSM. In 2007 zijn er 306 nieuwe hivdiagnoses gesteld in de soacentra, ongeveer een derde van de 864 hivpositieven die dat jaar landelijk in de hivcentra zijn gemeld. Eind 2007 waren in totaal 14.019 personen in Nederland met hiv geregistreerd. Het aandeel van MSM onder de nieuw hivinfecties nam in 2007 verder toe. Net als eerdere jaren werd in de soacentra bij MSM die bekend zijn met hun positieve hivstatus vaak nog een andere geslachtsziekte gevonden (45%). In deze groep is sinds 2004 regelmatig LGV, een agressieve variant van chlamydia, en sinds 2007 hepatitis C gediagnosticeerd. Versterkte surveillance en innovatieve interventies zijn nodig om verdere verspreiding onder MSM en naar andere groepen te voorkomen. Onder bepaalde migrantengroepen in Nederland (onder andere afkomstig uit Suriname, de Nederlandse Antillen en Aruba) komen hiv, chlamydia, gonorroe en syfilis relatief vaker voor dan onder autochtone Nederlanders. Ook deze constatering vraagt om vernieuwende maatregelen die op de bevolkingsgroepen zijn toegespitst. De soacentra bieden soazorg aan hoogrisicogroepen. In 2007 hebben ruim 78.000 personen zich daar laten testen, een toename van 13% ten opzichte van 2006. Net als in 2006 was chlamydia in 2007 de meest gediagnosticeerde bacterikle geslachtsziekte in de soacentra, vooral bij jongeren. Het percentage positieve chlamydiatesten onder heteroseksuele mannen en vrouwen daalde enigszins, voor het eerst sinds vier jaar (van 10,6% naar 10,1%). In 2006 stabiliseerde dit percentage bij mannen die seks hebben met mannen (MSM), en die trend zette door in 2007. Het percentage positieve gonorroe-, syfilis- en hivtesten nam net als voorgaande jaren af in 2007 (respectievelijk 2,4%, 0,9% en 0,5%). Deze infecties werden het meest gediagnosticeerd bij MSM.In 2007, chlamydia was the most common bacterial sexually transmitted infection (STI) diagnosed in Dutch STI centres. Similar to previous years, infections were reported especially in young heterosexuals. The proportion of positive chlamydia tests among heterosexual men and women decreased slightly for the first time in four years (from 10.6% to 10.1%). In 2006, this proportion had stabilized in men who have sex with men (MSM) with the trend continuing in 2007. The positivity rate for gonorrhoea (2.4%), syphilis (0.9%) and HIV (0.5%) continued to decrease in 2007. These infections were most frequently diagnosed in MSM. In 2007, 306 new positive HIV cases were diagnosed in STI centres in the Netherlands. This number amounts to about one third of the total number of 864 positive HIV cases registered nationally. At the end of 2007, a total of 14,019 HIV cases in care were registered in the Netherlands. The proportion of MSM among new HIV cases rose further in 2007. In line with previous years, concurrent STIs were diagnosed very frequently among MSM visiting STI centres (45%) who had known HIV positive status. In this group of men, Lymphogranuloma Venereum (LGV) an aggressive type of chlamydia, has been reported frequently since 2004; this has also been the case for hepatitis C since 2007. In this group of men, strengthened surveillance and innovative interventions are warranted in order to prevent further transmission both among MSM and to other population groups. In some specific migrant groups in the Dutch population -- for example, people from Surinam, the Netherlands Antilles and Aruba -- HIV, chlamydia, gonorrhoea and syphilis are more common than in the autochthonous Dutch population. This indicates the need for targeted intervention by risk profile. The specialised STI centres in the Netherlands offer STI testing and care targeted at high risk groups. In 2007, approximately 78,000 people used this service amounting to a rise of 13% compared to 2006

Reduced renal length and volume 20 years after very preterm birth

Intrauterine growth retardation is presumed to be associated with decreased renal size and impaired renal function as a result of stunted kidney development and nephron deficit. To study whether very preterm birth also affects renal size at young adulthood, we sonographically measured bipolar kidney length and volume in 51 very premature individuals (<32 weeks of gestation), either small (SGA) or appropriate (AGA) for gestational age (22 SGA and 29 AGA), and 30 full-term controls 20 years after birth. Relative kidney length and volume were calculated. Both absolute and relative left kidney length and volume were significantly lower in SGA and AGA individuals, notably in women. Renal size did not differ between SGA and AGA individuals. In 70% of controls, the left kidney was larger than the right one compared with 40.9% in SGA [relative risk (RR) 1.7; 95% confidence interval (CI) 1.0−3.0] and 48.3% in AGA (RR 1.5; 95% CI 0.9−2.3) individuals. Renal structural anomalies were present in eight prematurely born participants only. Our data suggest that kidney growth is stunted after preterm birth, especially on the left side, and in the female gender

Very preterm birth is a risk factor for increased systolic blood pressure at a young adult age

Children born very prematurely who show intrauterine growth retardation (IUGR) are suggested to be at risk of developing high blood pressure as adults. Renal function may already be impaired by young adult age. To study whether very preterm birth affects blood pressure in young adults, we measured 24-h ambulatory blood pressure (Spacelabs™ 90207 device) and renin concentration in 50 very premature individuals (<32 weeks of gestation), either small (SGA) or appropriate (AGA) for gestational age (21 SGA, 29 AGA), and 30 full-term controls who all were aged 20 years at time of measurement. The mean (standard deviation) daytime systolic blood pressure in SGA and AGA prematurely born individuals, respectively, was 122.7 (8.7) and 123.1 (8.5) mmHg. These values were, respectively, 3.6 mmHg [95% confidence interval (CI) −0.9 to 8.0] and 4.2 mmHg (95% CI 0.4−8.0) higher than in controls [119.6 (7.6)]. Daytime diastolic blood pressure and nighttime blood pressure did not differ between groups. We conclude that individuals born very preterm have higher daytime systolic blood pressure and higher risk of hypertension at a young adult age

Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-α-based isolated hepatic perfusion

Isolated hepatic perfusion (IHP) with melphalan with or without tumour necrosis factor alpha (TNF-α) is currently performed in clinical trials in patients with hepatic metastases. Previous studies led to the hypothesis that the use of TNF-α in isolated limb perfusion causes specific destruction of tumour endothelial cells and thereby induces an increased permeability of tumour vasculature. However, whether TNF-α contributes to the therapeutic efficacy in IHP still remains unclear. In an in vivo rat liver metastas

How to select a chiropractor for the management of athletic conditions

<p>Abstract</p> <p>Background</p> <p>Chiropractors are an integral part of the management of musculoskeletal injuries. A considerable communication gap between the chiropractic and medical professions exists. Subsequently referring allopathic practitioners lack confidence in picking a chiropractic practitioner with appropriate management strategies to adequately resolve sporting injuries. Subsequently, the question is often raised: "how do you find a good chiropractor?".</p> <p>Discussion</p> <p>Best practice guidelines are increasingly suggesting that musculoskeletal injuries should be managed with multimodal active and passive care strategies. Broadly speaking chiropractors may be subdivided into "modern multimodal" or "classical" (unimodal) in nature. The modern multimodal practitioner is better suited to managing sporting injuries by incorporating passive and active care management strategies to address three important phases of care in the continuum of injury from the acute inflammation/pain phase to the chronic/rehabilitation phase to the injury prevention phase. In contrast, the unimodal, manipulation only and typically spine only approach of the classical practitioner seems less suited to the challenges of the injured athlete. Identifying what part of the philosophical management spectrum a chiropractor falls is important as it is clearly not easily evident in most published material such as Yellow Pages advertisements.</p> <p>Summary</p> <p>Identifying a chiropractic practitioner who uses multimodal treatment of adequate duration, who incorporates active and passive components of therapy including exercise prescription whilst using medical terminology and diagnosis without mandatory x-rays or predetermined treatment schedules or prepaid contracts of care will likely result in selection of a chiropractor with the approach and philosophy suited to appropriately managing athletic conditions. Sporting organizations and associations should consider using similar criteria as a minimum standard to allow participation in health care team selections.</p

Utilisation of sexual health services by female sex workers in Nepal

Background The Nepal Demographic Health Survey (NDHS) in 2006 showed that more than half (56%) of the women with sexually transmitted infections (STIs), including HIV, in Nepal sought sexual health services. There is no such data for female sex workers (FSWs) and the limited studies on this group suggest they do not even use routine health services. This study explores FSWs use of sexual health services and the factors associated with their use and non-use of services. Methods This study aimed to explore the factors associated with utilisation of sexual health services by FSWs in the Kathmandu Valley of Nepal, and it used a mixed-method approach consisting of an interviewer administered questionnaire-based survey and in-depth interviews. Results The questionnaire survey, completed with 425 FSWs, showed that 90% FSWs self-reported sickness, and (30.8%) reported symptoms of STIs. A quarter (25%) of those reporting STIs had never visited any health facilities especially for sexual health services preferring to use non-governmental clinics (72%), private clinics (50%), hospital (27%) and health centres (13%). Multiple regression analysis showed that separated, married and street- based FSWs were more likely to seek health services from the clinics or hospitals. In- depth interviews with 15 FSWs revealed that FSWs perceived that personal, structural and socio-cultural barriers, such as inappropriate clinic opening hours, discrimination, the judgemental attitude of the service providers, lack of confidentiality, fear of public exposure, and higher fees for the services as barriers to their access and utilisation of sexual health services. Conclusion FSWs have limited access to information and to health services, and operate under personal, structural and socio-cultural constraints. The ‘education’ to change individual behaviour, health worker and community perceptions, as well as the training of the health workers, is necessary

The impact of bone mineral density and disc degeneration on shear strength and stiffness of the lumbar spine following laminectomy

Purpose Laminectomy is a standard surgical procedure for elderly patients with symptomatic degenerative lumbar stenosis. The procedure aims at decompression of the affected nerves, but it also causes a reduction of spinal shear strength and shear stiffness. The magnitude of this reduction and the influence of bone mineral density (BMD) and disc degeneration are unknown. We studied the influence of laminectomy, BMD, and disc degeneration on shear force to failure (SFF) and shear stiffness (SS). Methods Ten human cadaveric lumbar spines were obtained (mean age 72.1 years, range 53-89 years). Laminectomy was performed either on L2 or L4, equally divided within the group of ten spines. BMD was assessed by dual X-ray absorptiometry (DXA). Low BMD was defined as a BMD value below the median. Intervertebral discs were assessed for degeneration by MRI (Pfirrmann) and scaled in mild and severe degeneration groups. Motion segments L2-L3 and L4-L5 were isolated from each spine. SFF and SS were measured, while loading simultaneously with 1,600 N axial compression. Results Low BMD had a significant negative effect on SFF. In addition, a significant interaction between low BMD and laminectomy was found. In the high BMD group, SFF was 2,482 N (range 1,678-3,284) and decreased to 1,371 N (range 940-1,886) after laminectomy. In the low BMD group, SFF was 1,339 N (range 909-1,628) and decreased to 761 N (range 561-1,221). Disc degeneration did not affect SFF, nor did it interact with laminectomy. Neither low BMD nor the interaction of low BMD and laminectomy did affect SS. Degeneration and its interaction with laminectomy did not significantly affect SS. Conclusions In conclusion, low BMD significantly decreased SFF before and after lumbar laminectomy. Therefore, DXA assessment may be an important asset to preoperative screening. Lumbar disc degeneration did not affect shear properties of lumbar segments before or after laminectomy. © 2012 Springer-Verlag

Using Intervention Mapping to develop a programme to prevent sexually transmittable infections, including HIV, among heterosexual migrant men

<p>Abstract</p> <p>Background</p> <p>There is little experience with carefully developed interventions in the HIV/STI prevention field aimed at adult heterosexual target groups in the Netherlands. The ability to apply intervention development protocols, like Intervention Mapping, in daily practice outside of academia, is a matter of concern. An urgent need also exists for interventions aimed at the prevention of STI in migrant populations in the Netherlands. This article describes the theory and evidence based development of HIV/STI prevention interventions by the Municipal Public Health Service Rotterdam Area (MPHS), the Netherlands, for heterosexual migrant men with Surinamese, Dutch-Caribbean, Cape Verdean, Turkish and Moroccan backgrounds.</p> <p>Methods</p> <p>First a needs assessment was carried out. Then, a literature review was done, key figures were interviewed and seven group discussions were held. Subsequently, the results were translated into specific objectives ("change objectives") and used in intervention development for two subgroups: men with an Afro-Caribbean background and unmarried men with a Turkish and Moroccan background. A matrix of change objectives was made for each subgroup and suitable theoretical methods and practical strategies were selected. Culturally-tailored interventions were designed and were pre-tested among the target groups.</p> <p>Results</p> <p>This development process resulted in two interventions for specific subgroups that were appreciated by both the target groups and the migrant prevention workers. The project took place in collaboration with a university center, which provided an opportunity to get expert advice at every step of the Intervention Mapping process. At relevant points of the development process, migrant health educators and target group members provided advice and feedback on the draft intervention materials.</p> <p>Conclusion</p> <p>This intervention development project indicates that careful well-informed intervention development using Intervention Mapping is feasible in the daily practice of the MPHS, provided that sufficient time and expertise on this approach is available. Further research should test the effectiveness of these interventions.</p

Anterior shear strength of the porcine lumbar spine after laminectomy and partial facetectomy

Degenerative lumbar spinal stenosis is the most common reason for lumbar surgery in patients in the age of 65 years and older. The standard surgical management is decompression of the spinal canal by laminectomy and partial facetectomy. The effect of this procedure on the shear strength of the spine has not yet been investigated in vitro. In the present study we determined the ultimate shear force to failure, the displacement and the shear stiffness after performing a laminectomy and a partial facetectomy. Eight lumbar spines of domestic pigs (7 months old) were sectioned to obtain eight L2–L3 and eight L4–L5 motion segments. All segments were loaded with a compression force of 1,600 N. In half of the 16 motion segments a laminectomy and a 50% partial facetectomy were applied. The median ultimate shear force to failure with laminectomy and partial facetectomy was 1,645 N (range 1,066–1,985) which was significantly smaller (p = 0.012) than the ultimate shear force to failure of the control segments (median 2,113, range 1,338–2,659). The median shear stiffness was 197.4 N/mm (range 119.2–216.7) with laminectomy and partial facetectomy which was significantly (p = 0.036) smaller than the stiffness of the control specimens (median 216.5, 188.1–250.2). It was concluded that laminectomy and partial facetectomy resulted in 22% reduction in ultimate shear force to failure and 9% reduction in shear stiffness. Although relatively small, these effects may explain why patients have an increased risk of sustaining shear force related vertebral fractures after spinal decompression surgery