Ultraviolet A radiation and COVID-19 deaths in the USA with replication studies in England and Italy.

BACKGROUND: Understanding factors impacting deaths from COVID-19 is of the highest priority. Seasonal variation in environmental meteorological conditions affects the incidence of many infectious diseases and may also affect COVID-19. Ultraviolet (UV) A (UVA) radiation induces release of cutaneous photolabile nitric oxide (NO) impacting the cardiovascular system and metabolic syndrome, both COVID-19 risk factors. NO also inhibits the replication of SARS-CoV2. OBJECTIVES: To investigate the relationship between ambient UVA radiation and COVID-19 deaths. METHODS: COVID-19 deaths at the county level, across the USA, were modelled in a zero-inflated negative-binomial model with a random effect for states adjusting for confounding by demographic, socioeconomic and long-term environmental variables. Only those areas where UVB was too low to induce significant cutaneous vitamin D3 synthesis were modelled. We used satellite-derived estimates of UVA, UVB and temperature and relative humidity. Replication models were undertaken using comparable data for England and Italy. RESULTS: The mortality rate ratio (MRR) in the USA falls by 29% [95% confidence interval (CI) 40% to 15%) per 100 kJ m-2 increase in mean daily UVA. We replicated this in independent studies in Italy and England and estimate a pooled decline in MRR of 32% (95% CI 48% to 12%) per 100 kJ m-2 across the three studies. CONCLUSIONS: Our analysis suggests that higher ambient UVA exposure is associated with lower COVID-19-specific mortality. Further research on the mechanism may indicate novel treatments. Optimized UVA exposure may have population health benefits.

What is the evidence for interactions between filaggrin null mutations and environmental exposures in the aetiology of atopic dermatitis? A systematic review.

BACKGROUND: Epidemiological studies indicate that gene-environment interactions play a role in atopic dermatitis (AD). OBJECTIVES: To review the evidence for gene-environment interactions in AD aetiology, focusing on filaggrin (FLG) loss-of-function mutations. METHODS: A systematic search from inception to September 2018 in Embase, MEDLINE and BIOSIS was performed. Search terms included all synonyms for AD and filaggrin/FLG; any genetic or epidemiological study design using any statistical methods were included. Quality assessment using criteria modified from guidance (ROBINS-I and Human Genome Epidemiology Network) for nonrandomized and genetic studies was completed, including consideration of power. Heterogeneity of study design and analyses precluded the use of meta-analysis. RESULTS: Of 1817 papers identified, 12 studies fulfilled the inclusion criteria required and performed formal interaction testing. There was some evidence for FLG-environment interactions in six of the studies (P-value for interaction ≤ 0·05), including early-life cat ownership, older siblings, water hardness, phthalate exposure, higher urinary phthalate metabolite levels (which all increased AD risk additional to FLG null genotype) and prolonged breastfeeding (which decreased AD risk in the context of FLG null genotype). Major limitations of published studies were the low numbers of individuals (ranging from five to 94) with AD and FLG loss-of-function mutations and exposure to specific environmental factors, and variation in exposure definitions. CONCLUSIONS: Evidence on FLG-environment interactions in AD aetiology is limited. However, many of the studies lacked large enough sample sizes to assess these interactions fully. Further research is needed with larger sample sizes and clearly defined exposure assessment. Linked Comment: Park and Seo. Br J Dermatol 2020; 183:411.

The epidemiological status of African swine fever in domestic swine herds in the Tavush Province region, Armenia.

KEEN The factors associated with the spread and persistence of African swine fever (ASF) in the Caucasus region remain to be fully identified. It is assumed that large naive populations of domestic free-ranging and wild pigs are critical to disease transmission and maintenance. Nonetheless, 11 years since its epidemic introduction into the region in 2007, ASF virus (ASFV) is still circulating, suggesting that an endemic cycle has been established based on contact between free-ranging domestic pigs and wild pigs, and that native Ornithodoros ticks probably serve as reservoirs for the virus. Therefore, research is required to gather information on the epidemiological status of ASF in the Caucasus region, focusing particularly on understanding modes of ASFV spread and persistence in this new virus environment. The authors established an ASFV survey targeting domestic pigs in the Tavush province of northern Armenia, an area of the country considered to be at high risk of disease incursion/occurrence. All tested samples collected for this survey were negative for ASF. The probability of observing no reactors by antibody enzyme-linked immunosorbent assay in a sample of this size (n = 1,506) from a population with an estimated disease prevalence of 1% is very low (< 0.0001). Therefore, it is possible but very unlikely for ASFV to be present among domestic pigs in the Tavush province region.

Les facteurs associés à la propagation de la peste porcine africaine (PPA) dans le Caucase et à sa persistance restent en grande partie à élucider. On suppose que la présence de populations naïves de porcs domestiques en liberté et de porcs sauvages joue un rôle déterminant dans la transmission et le maintien de la maladie. Néanmoins, 11 ans après son introduction épidémique dans la région en 2007, le virus de la peste porcine africaine (VPPA) est toujours présent, ce qui laisse penser qu'un cycle s'est installé à la faveur des contacts entre les porcs domestiques en liberté et les porcs sauvages, les tiques autochtones Ornithodoros faisant probablement office de réservoir viral. Des études sont donc nécessaires pour recueillir des informations sur le statut épidémiologique de la PPA dans le Caucase et plus particulièrement pour comprendre les modalités de la propagation et de la persistance du VPPA dans ce nouvel environnement. Les auteurs rapportent les résultats d'une enquête épidémiologique sur le VPPA conduite chez les porcs domestiques de la province du Tavush, au nord de l'Arménie, zone considérée comme présentant un risque élevé d'incursion et d'émergence de la maladie. Les échantillons prélevés à cette fin ont tous donné des résultats négatifs au test de détection de la PPA. La probabilité qu'un échantillon de cette taille (n = 1 506) ne donne aucune réaction positive à l'épreuve ELISA de détection d'anticorps dans une population pour laquelle la prévalence de la maladie est estimée à 1 % est extrêmement faible (< 0,0001). On peut en conclure que la présence du VPPA parmi les porcs domestiques de la région du Tavush est possible, mais très improbable.

Aún no están perfectamente identificados los factores que intervienen en la propagación y persistencia de la peste porcina africana (PPA) en la región del Cáucaso. Se presupone que la existencia de grandes poblaciones de cerdos salvajes y cerdos domésticos en libertad que no han estado expuestas previamente al patógeno es un factor crucial en la transmisión y el mantenimiento de la enfermedad. Sin embargo, 11 años después de su penetración epidémica en la región, en 2007, el virus de la PPA aún sigue en circulación, hecho que parece apuntar al establecimiento de un ciclo endémico mediado por el contacto entre cerdos domésticos en libertad y cerdos salvajes y también a la probable función de la garrapata autóctona Ornithodoros como reservorio del virus. Por consiguiente, es necesario investigar para reunir información sobre la situación epidemiológica de la PPA en la región del Cáucaso, procurando especialmente aprehender las modalidades de propagación y persistencia del virus en este nuevo entorno. Los autores estudiaron la presencia del virus de la PPA específicamente en cerdos domésticos de la provincia de Tavush, al norte de Armenia, una zona del país considerada muy expuesta al riesgo de incursión o manifestación de la enfermedad. Todas las muestras obtenidas y analizadas para el estudio dieron resultado negativo a la PPA. La probabilidad de no detectar con ELISA ningún ejemplar con anticuerpos en una muestra de tal tamaño (n = 1 506), tomada de una población con una prevalencia de la enfermedad que según los cálculos es del 1%, resulta ínfima (<0,0001). Es por lo tanto posible, pero harto improbable, que el virus de la PPA esté presente en los cerdos domésticos de la zona de la provincia de Tavush.

Intravenous dexamethasone fails to prolong psoas compartment block when assessed by objective pinprick sensory testing: a prospective, randomised, dose-dependent, placebo-controlled equivalency trial.

BACKGROUND: Recent studies have concluded that i.v. dexamethasone can prolong the duration of peripheral nerve blockade. We hypothesized that a 4 mg dose would equally prolong the duration of psoas compartment blocks (PCBs) when compared with 8 mg, and that both doses would prolong the duration when compared with placebo. METHODS: This was a prospective, randomized, placebo-controlled, dose-dependent, equivalency trial with 115 patients undergoing total hip arthroplasty. The patients received a PCB. Subsequently, 15 patients received i.v. normal saline (placebo), 50 patients received i.v. dexamethasone 4 mg, and 50 patients received i.v. dexamethasone 8 mg. The primary outcome was the duration in hours of PCB, determined by serial pinprick assessments. Secondary outcomes included pain scores, time to first analgesic, and opioid consumption. An intention-to-treat-analysis (ITA) and per-protocol analysis (PPA) were performed. RESULTS: The ITA showed that block duration in the 4 and 8 mg groups was equivalent [mean (standard deviation), 18.5 h (8.0) vs 18.1 h (7.1)]. However, neither group differed from placebo [19.6 h (6.7), (4 mg vs placebo), P=0.97; (8 mg vs placebo), P=0.77)]. Postoperative pain scores and opioid consumption were not different between groups. Time to first analgesic was not different between the 4 and 8 mg groups, or the 4 mg and placebo groups. The 8 mg group, however, had a longer time to first analgesic (median of 533 vs 432 min, P=0.047) when compared with placebo, although the significance was not observed in the PPA (P=0.058). CONCLUSIONS: I.V. dexamethasone did not prolong PCB when duration was objectively assessed, or decrease total opioid consumption. However, dexamethasone 8 mg prolonged the time to first analgesic. CLINICAL TRIAL REGISTRATION: NCT 02464176.

Active surveillance of African swine fever in domestic swine herds in Georgia, 2014.

Since its introduction to the Republic of Georgia in 2007, African swine fever virus (ASFV) has spread across the Caucasus region, the Russian Federation, and some Eastern European countries. It is assumed that large populations of naïve, domestic, free-ranging and wild pigs are vital to the transmission of the disease. Since its epidemic emergence in the region in 2007, ASFV has continued to circulate, which suggests that an endemic cycle has been established and is maintained by contact between free-ranging domestic pigs, wild pigs, and possibly native Ornithodoros ticks, the most likely reservoirs for the virus. In 2014, a survey was conducted across the Republic of Georgia to determine ASFV prevalence among domestic swine herds. All 1,231 samples collected for this survey tested negative for ASF. The probability of observing no reactors in a sample of this size (n = 1,231) from a population with an estimated disease prevalence of 1% is very low (<0.0001). Therefore, it is possible but very unlikely that ASFV was present among domestic swine during the span of this survey. These data suggest that, in 2014, domestic pig herds were not the source of the virus, and that the ASF endemic cycle may be supported by the circulation of ASFV among feral pigs, wild pigs, and possibly native Ornithodoros ticks.

Depuis son introduction en république de Géorgie en 2007, le virus de la peste porcine africaine s'est propagé dans toute la région du Caucase, dans la fédération de Russie et dans certains pays d'Europe orientale. On estime que la transmission de la maladie nécessite des populations naïves et nombreuses de porcs domestiques, élevés en liberté et sauvages. Depuis son émergence épizootique dans la région en 2007, le virus de la peste porcine africaine a continué de se propager, ce qui semble indiquer qu'un cycle d'endémicité s'est établi et se maintient par contact entre les porcs domestiques en liberté, les porcs sauvages, et vraisemblablement les tiques autochtone du genre Ornithodoros, le réservoir le plus probable du virus. Une enquête a été effectuée en 2014 sur tout le territoire de la république de Géorgie afin de déterminer la prévalence du virus de la peste porcine africaine au sein des troupeaux de porcs domestiques. La totalité des 1 231 échantillons prélevés à cette fin ont donné des résultats négatifs au test de détection de la peste porcine africaine. La probabilité qu'un échantillon de cette taille (n = 1 231) ne donne aucune réaction positive dans une population pour laquelle la prévalence de la maladie est estimée à 1 % est extrêmement faible (< 0,0001). Par conséquent, la présence du virus de la peste porcine africaine chez les porcs domestiques au cours de la période de l'étude est possible, mais très peu probable. Ces résultats suggèrent que le cheptel de porcs domestiques n'a pas été à l'origine du virus en 2014 et que le cycle d'endémicité de la maladie est davantage soutenu par la présence du virus chez les porcs féraux et sauvages ainsi que probablement chez les tiques autochtones du genre Ornithodoros.

Desde que en 2007 penetró en la República de Georgia, el virus de la peste porcina africana se ha extendido por toda la región del Cáucaso, la Federación de Rusia y algunos países de Europa Oriental. Se presupone que, para que haya transmisión de la enfermedad, se requieren grandes poblaciones de cerdos sin exposición previa, domésticos, criados en libertad y salvajes. Desde su aparición epidémica en la región, en 2007, el virus de la peste porcina africana ha seguido circulando, lo que lleva a pensar que se ha arraigado un ciclo endémico, mantenido por el contacto entre cerdos domésticos criados en libertad, cerdos salvajes y posiblemente garrapatas autóctonas del género Ornithodoros, que son los más probables reservorios del virus. En 2014 se llevó a cabo un estudio en toda la República de Georgia para determinar la prevalencia del virus en las piaras de cerdos domésticos. De las 1.231 muestras obtenidas al efecto, todas resultaron negativas para el virus de la peste porcina africana. La probabilidad de no encontrar ningún animal positivo en una muestra de ese tamaño (n = 1.231) de una población con una prevalencia de la enfermedad estimada en un 1% resulta extremadamente baja (<0,0001). Por lo tanto es posible, pero muy poco probable, que el virus de la peste porcina africana estuviera presente en cerdos domésticos durante el periodo cubierto por el estudio. Estos datos parecen indicar que, en 2014, las piaras de cerdos domésticos no eran la fuente del virus, y que tal vez el ciclo endémico de la peste porcina africana repose en la circulación del virus en cerdos asilvestrados y salvajes y, posiblemente, en garrapatas autóctonas del género Ornithodoros.

Afferent and efferent immunological pathways of the brain. Anatomy, function and failure.

Immunological privilege appears to be a product of unique lymphatic drainage systems for the brain and receptor-mediated entry of inflammatory cells through the blood-brain barrier. Most organs of the body have well-defined lymphatic vessels that carry extracellular fluid, antigen presenting cells, lymphocytes, neoplastic cells and even bacteria to regional lymph nodes. The brain has no such conventional lymphatics, but has perivascular pathways that drain interstitial fluid (ISF) from brain parenchyma and cerebrospinal fluid (CSF) from the subarachnoid space to cervical lymph nodes. ISF and solutes drain along narrow, ∼100 nm-thick basement membranes within the walls of cerebral capillaries and arteries to cervical lymph nodes; this pathway does not allow traffic of lymphocytes or antigen presenting cells from brain to lymph nodes. Although CSF drains into blood through arachnoid villi, CSF also drains from the subarachnoid space through channels in the cribriform plate of the ethmoid bone into nasal lymphatics and thence to cervical lymph nodes. This pathway does allow the traffic of lymphocytes and antigen presenting cells from CSF to cervical lymph nodes. Efferent pathways by which lymphocytes enter the brain are regulated by selected integrins on lymphocytes and selective receptors on vascular endothelial cells. Here we review: (1) the structure and function of afferent lymphatic drainage of ISF and CSF, (2) mechanisms involved in the efferent pathways by which lymphocytes enter the brain and (3) the failure of lymphatic drainage of the brain parenchyma with age and the role of such failure in the pathogenesis of Alzheimer's disease.

Effects of different shoeing conditions on equine cervical and back kinematics during walking and trotting on a soft surface.

There is a paucity of scientific data on the effect of shoeing on equine neck and back kinematics during locomotion over commonly used sand training surfaces. A better appreciation of how alterations at hoof-ground interface influence equine upper body movements is relevant for improving horse's health and performance. Our objectives were to determine the effects of different shoeing conditions on equine neck and back kinematics at walk and trot in straight line over sand. Two-dimensional kinematic video analysis was performed under seven shoeing conditions: front feet shod with aluminum shoes and hind feet with steel racehorse shoes (REFSHOD), front aluminum shoe and hind feet unshod (FORESHOD), front feet unshod and hind steel race shoes (HINDSHOD), all four feet unshod (UNSHOD), front feet shod in combination with hind egg bar shoes (hEGGBAR), hind wide toe shoes (hTOE) and hind reverse shoes (hREVERSE). Data indicated that joint angles in the cervicothoracic junction were four times more likely to be significantly affected by the shoeing condition than in the back and sacrum. FORESHOD largely modifies the kinematics in comparison to REFSHOD or UNSHOD, with respectively a 6-11±1-2° (P<0.001) increased cervicothoracic extension at walk and trot, and a 3-4±1° (P<0.05) increased thoracolumbar flexion at trot. In comparison to REFSHOD, hEGGBAR, hTOE and hREVERSE induce a 5-7±1-2° (P<0.05) increased cervicothoracic extension at trot and walk respectively, and UNSHOD induced cervicothoracic flexion at trot (6±2°, P<0.05). In conclusion, shoeing conditions impact equine neck and back position, which should be considered during clinical examination, rehabilitation and training.

Review: cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy.

Failure of elimination of proteins from the brain is a major feature in many neurodegenerative diseases. Insoluble proteins accumulate in brain parenchyma and in walls of cerebral capillaries and arteries. Cerebral amyloid angiopathy (CAA) is a descriptive term for amyloid in vessel walls. Here, we adopt the term protein elimination failure angiopathy (PEFA) to focus on mechanisms involved in the pathogenesis of a spectrum of disorders that exhibit both unique and common features of protein accumulation in blood vessel walls. We review (a) normal pathways and mechanisms by which proteins and other soluble metabolites are eliminated from the brain along 100- to 150-nm-thick basement membranes in walls of cerebral capillaries and arteries that serve as routes for lymphatic drainage of the brain; (b) a spectrum of proteins involved in PEFA; and (c) changes that occur in artery walls and contribute to failure of protein elimination. We use accumulation of amyloid beta (Aß), prion protein and granular osmiophilic material (GOM) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as examples of different factors involved in the aetiology and pathogenesis of PEFA. Finally, we discuss how knowledge of factors involved in PEFA may help to focus on new therapies for neurodegenerative diseases. When Aß (following immunotherapy) and prion protein are released from brain parenchyma they deposit in walls of cerebral capillaries and arteries; GOM in CADASIL accumulates primarily in artery walls. Therefore, the focus of therapy for protein clearance in neurodegenerative disease should perhaps be on facilitating perivascular elimination of proteins and reducing PEFA.

Randomized controlled study of a cosmetic treatment for mild acne.

BACKGROUND: Cosmetic products are not tested with the same rigour as medical treatments, but recent high-quality studies have shown significant reductions in changes of skin ageing with use of cosmetic antiageing products. AIM: To test whether a cosmetic 'anti-spot' two-step treatment containing a complex of seaweed-derived oligosaccharide and zinc would produce a significant improvement in mild acne. METHODS: A double-blind, vehicle-controlled trial of this treatment was performed for 8 weeks on 60 age-matched participants with mild acne. They were divided into two groups: 30 participants were treated with vehicle control and 30 with the active treatment containing a seaweed-derived oligosaccharide complexed with 0.1% zinc pyrrolidone. RESULTS: After 8 weeks, both groups had a reduction in comedones, papules and pustules, and this was significantly greater in the active than control group at 2, 4 and 8 weeks. CONCLUSIONS: Cosmetic products may offer some benefit for mild acne and still meet the requirements of the European Cosmetic Directive. In particular, the seaweed-derived oligosaccharide complexed with 0.1% zinc pyrrolidone used in this study produced a significant reduction in acne vs. a control treatment. Cosmetic companies should conduct blinded controlled trials of their product's efficacy and publish the results.

Pattern of skin disease in Ethiopian HIV-infected patients on combination antiretroviral therapy: A cross-sectional study in a dermatology referral hospital.

Background: More than 90% of human immunodeficiency virus (HIV)-infected patients will develop at least one type of skin disorder during the course of the disease. The prevalence and severity of skin disease commonly seen in HIV-infected patients has decreased in the era of combination antiretroviral therapy (cART). Few studies in Ethiopia have shown the magnitude of skin problems among adult patients on cART. The aim of this study is to describe the pattern of skin disease among adult patients who are on cART. Methods: Cross-sectional observational study at ALERT Hospital from April 2018 to November 2018. Patterns of clinically diagnosed skin diseases were summarized descriptively. Result: A total of 572 patients were evaluated. In total, 412 (72%) were female and the mean age of study participants was 40 (SD = 10.4). The median CD4 count at the time of diagnosis and start of cART were 178 (R 5-2000) and 168 cells/µl (R 5-1327), respectively. The mean duration of cART was 8 (SD = 3) years. 89.3% of patients were on first line and 7% on second line of cART regimen. Noninfectious inflammatory skin disorders (40.9%) were the most common concomitant diagnosis followed by infectious diseases (34.9%), infestation (7.7%), pigmentary disorders (6.3%) and cutaneous drug eruption (0.7%), respectively. Among the inflammatory skin disorders, 56.5% presented with eczema. One patient had Kaposi sarcoma. Conclusion: Noninfectious inflammatory skin disorders are the most common concomitant skin disease in HIV-infected patients, with eczema being most prevalent. Infectious skin diseases were also common presentations. In our study, AIDS-defining skin conditions were rare.

Arginase is overactive in psoriatic skin.

BACKGROUND: Psoriatic keratinocytes are poorly differentiated and hyperproliferative. Low concentrations of nitric oxide (NO) induce keratinocyte proliferation, while high concentrations induce differentiation. The NO-producing enzyme inducible NO synthase is overexpressed in psoriatic skin, but so is arginase. The overexpressed arginase competes for arginine, the common substrate for both enzymes, and may reduce NO production. OBJECTIVES: To determine whether arginase activity is elevated in psoriatic skin and whether exogenous NO will improve psoriatic plaques. METHODS: Tape strips were taken from healthy skin of eight control subjects and nonlesional skin of eight patients with psoriasis and L-arginine, L-citrulline and L-ornithine concentrations measured by high-performance liquid chromatography. In a second study, four psoriatic patients with a pair of similar symmetrical plaques were treated with an NO donor and vehicle control. Plaques were scored for size, erythema, induration and scaling at the start and after 6 weeks of treatment. RESULTS: Ornithine, the end-product of arginase, was at higher concentrations in nonlesional psoriatic than in healthy skin (mean +/- SEM 2.08 +/- 0.98 vs. 1.13 +/- 0.44 microg mg(-1) protein; P = 0.0002). Arginine, its substrate, was at lower concentrations. Topical application of an NO donor improved psoriatic plaques clinically [mean +/- SD reduction in severity from baseline score (100%) to 35% +/- 16% in active NO donor and to 93% +/- 10% in control]. CONCLUSIONS: Arginase is overactive in psoriatic skin, leading to a relative increase in the consumption of arginine. We therefore hypothesize a relative decrease in NO synthase-derived NO production. NO donors may be effective topical treatments for psoriasis.

Root canal debridement using manual dynamic agitation or the EndoVac for final irrigation in a closed system and an open system.

AIM: This study examined canal debridement efficacy by testing the null hypothesis that there is no difference between a 'Closed' and an 'Open' system design in smear layer and debris removal using either manual dynamic agitation or the EndoVac for irrigant delivery. METHODOLOGY: Forty teeth were divided into four groups and submitted to a standardized instrumentation protocol. Final irrigation was performed with either manual dynamic agitation or the EndoVac on groups of teeth with or without a sealed apical foramen. Smear and debris scores were evaluated using SEM and analysed using Cochran-Mantel-Haenszel statistic. RESULTS: The ability of manual dynamic agitation to remove smear layer and debris in a closed canal system was significantly less effective than in an open canal system and significantly less effective than the EndoVac (P<0.001). CONCLUSION: The null hypothesis was rejected; the presence of a sealed apical foramen adversely affected debridement efficacy when using manual dynamic agitation but not the EndoVac. Apical negative pressure irrigation is an effective method to overcome the fluid dynamics challenges inherent in closed canal systems.

Canal and isthmus debridement efficacies of two irrigant agitation techniques in a closed system.

AIM: To compare canal and isthmus debris debridement efficacies of the manual dynamic irrigation (MDI) and apical negative pressure (ANP) techniques in the mesial root of mandibular first molars with narrow isthmi, using a closed canal design. METHODOLOGY: Micro-computed tomography was employed to select 20 teeth, each containing a narrow isthmus. Each root was sealed at the apex with hot glue and embedded in polyvinylsiloxane to simulate a closed canal system. The teeth were submitted to a standardized instrumentation protocol. Final irrigation was performed with either the MDI or the ANP technique using the EndoVac system (N=10). Masson trichrome-stained sections were prepared from completely demineralized roots at 10 canal levels between 1 and 2.8mm of the anatomical apices. Areas occupied by canals and isthmus of each root and debris in the corresponding regions were digitized by the NIH Image J software and statistically analysed using two-way repeated measures anova. RESULTS: For the instrumented canals, there were no differences between the two groups (P=0.131) in the area occupied by debris at all canal levels (P=0.343). Conversely, for the isthmus, less debris was found in the ANP group (P<0.001) but no differences were seen in each group with respect to the 10 canal levels (P=0.352). CONCLUSION: Neither technique completely removed debris from the isthmus regions. However, the EndoVac system, which encompasses the ANP concept, removed considerably more debris from narrow isthmi in mandibular mesial roots.

The 3D anatomy of the cervical articular process joints in the horse and their topographical relationship to the spinal cord.

UNLABELLED: REASONS FOR STUDY: Detailed anatomy of the equine cervical articular process joints (APJs) has received little attention in the literature and yet disorders of this joint have been linked to spinal cord compression resulting in severe clinical signs such as ataxia and weakness. This study aimed to describe the 3D anatomy of the APJ in relation to the spinal cord in the horse. HYPOTHESIS: Artificial distension of the APJ causes the joint pouches to extend into the vertebral canal, with the potential for APJ effusion to cause spinal cord compressive disease. METHODS: Six cadaveric necks (C1-C7) of clinically normal horses were used in this study. Computed tomography scans of the cervical APJ were acquired after injection of a negative contrast agent to maximal distension. The resulting images were semi-automatically segmented using greyscale thresholding and reconstructed in 3D by polygonal surface meshing. The 3D reconstructions were used to assess the topographic anatomy of the APJ in relation to the spinal cord and to measure joint volume at each cervical vertebra in relation to vertebrae size. RESULTS: Joint volume varied significantly between joint location (P<0.0001) and was positively correlated to the vertebral site (from cranial to caudal) (r = 0.781, P<0.0001). After distension, the medial outpouch of the APJ extended towards the vertebral canal from a dorsolateral location but in none of the 6 horses was there apparent compression of the dura mater surrounding the spinal cord. There was no significant difference in the extent of medial outpouch at any vertebral level (P = 0.104). Flexion of the neck resulted in minor changes to the shape of the APJ but did not result in the medial outpouch encroaching any closer to the spinal cord. CONCLUSIONS: From this study, it appears that in the absence of any other soft tissue or bony changes an effusion of the APJ is unlikely to cause spinal cord compression. However, given that the APJ and spinal cord are in close approximation, in the presence of other anatomical changes, an effusion may have the potential to cause compression. POTENTIAL RELEVANCE: This study confirms that the APJ extend into the dorsolateral aspect of the vertebral canal in a ventromedial direction, suggesting that oblique myelographic views are recommended for the diagnosis of spinal cord compression when pathology of the APJ is suspected.

Cervical lymph nodes are found in direct relationship with the internal carotid artery: significance for the lymphatic drainage of the brain.

The brain has no conventional lymphatics, but solutes injected into it drain along artery walls and reach lymph nodes in the neck. This study seeks to identify cervical lymph nodes related to the human internal carotid artery (ICA) that could act as the first regional lymph nodes for the brain. Bilateral dissections were carried out on four embalmed human heads, from the level of the carotid bifurcation in the neck, to the base of the skull. Lymph nodes from every specimen were processed for histological examination. A total of 51 deep cervical lymph nodes were identified: 12 lymph nodes (confirmed by histological examination) were observed to be in direct relationship with the ICA. These lymph nodes were found within the carotid sheath and had average diameters of 13.5 x 4.8 mm. Solutes and interstitial fluid from the brain may drain along the walls of cerebral arteries and reach these lymph nodes. They may be sites of stimulation of immune responses against antigens from the brain.

Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism.

Glucocorticoids (GCs) are among the most important drugs for acute lymphoblastic leukaemia (ALL), yet despite their clinical importance, the exact mechanisms involved in GC cytotoxicity and the development of resistance remain uncertain. We examined the baseline profile of a panel of T-ALL cell lines to determine factors that contribute to GC resistance without prior drug selection. Transcriptional profiling indicated GC resistance in T-ALL is associated with a proliferative phenotype involving upregulation of glycolysis, oxidative phosphorylation, cholesterol biosynthesis and glutamate metabolism, increased growth rates and activation of PI3K/AKT/mTOR and MYC signalling pathways. Importantly, the presence of these transcriptional signatures in primary ALL specimens significantly predicted patient outcome. We conclude that in lymphocytes the activation of bioenergetic pathways required for proliferation may suppress the apoptotic potential and offset the metabolic crisis initiated by GC signalling. It is likely that the link between GC resistance and proliferation in T-ALL has not been fully appreciated to date because such effects would be masked in the context of current multiagent therapies. The data also provide the first evidence that altered expression of wild-type MLL may contribute to GC-resistant phenotypes. Our findings warrant the continued development of selective metabolic inhibitors for the treatment of ALL.

Wind-driven ocean currents and ekman transport.

Oceanographic Engineering of the Woods Hole Oceanographic Institution and the Massachusetts Institute of Technology, Woods Hole, MA 02543. Oceanographers have long sought to verify the theoretical Ekman transport relation, which predicts that a steady wind stress acting together with the Coriolis force will produce a transport of water to the right of the wind. In situ measurements of wind and ocean currents provide a detailed view of this phenomenon. By separating the wind-driven current from the measured total current and by averaging over a long record, it is found that the observed transport is consistent with theoretical Ekman transport to within about 10 percent. In this case the wind-driven transport is strongly surface trapped, with 95 percent occurring in the upper 25 meters as a result of fair summer weather.

Three-dimensional flow in the upper ocean.

Measurements made from the Research Platform FLIP provide some of the first direct observations of three-dimensional flow within the surface mixed layer of the ocean. Relatively narrow regions of downwelling flow were found within the mixed layer, in coincidence with bands of convergent surface flow. At mid-depth in the mixed layer, the downwelling flow had magnitudes of up to 0.2 meter per second and was accompanied by a downwind, horizontal jet of comparable magnitude. There is some evidence that these motions transport heat and phytoplankton within the mixed layer.

Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain.

A major feature of Alzheimer's disease is the accumulation of amyloid-beta peptide (Abeta) in the brain both in the form of plaques in the cerebral cortex and in blood vessel as cerebral amyloid angiopathy (CAA). Experimental models and human clinical trials have shown that accumulation of Abeta plaques can be reversed by immunotherapy. In this study, we hypothesized that Abeta in plaques is solubilized by antibodies generated by immunization and drains via the perivascular pathway, detectable as an increase in cerebrovascular Abeta. We have performed a follow up study of Alzheimer's disease patients immunized against Abeta42. Neuropathological examination was performed on nine patients who died between four months and five years after their first immunization. Immunostaining for Abeta40 and Abeta42 was quantified and compared with that in unimmunized Alzheimer's disease controls (n = 11). Overall, compared with these controls, the group of immunized patients had approximately 14 times as many blood vessels containing Abeta42 in the cerebral cortex (P<0.001) and seven times more in the leptomeninges (P = 0.013); among the affected blood vessels in the immunized cases, most of them had full thickness and full circumference involvement of the vessel wall in the cortex (P = 0.001), and in the leptomeninges (P = 0.015). There was also a significantly higher level of cerebrovascular Abeta40 in the immunized cases than in the unimmunized cases (cortex: P = 0.009 and leptomeninges: P = 0.002). In addition, the immunized patients showed a higher density of cortical microhaemorrhages and microvascular lesions than the unimmunized controls, though none had major CAA-related intracerebral haemorrhages. The changes in cerebral vascular Abeta load did not appear to substantially influence the structural proteins of the blood vessels. Unlike most of the immunized patients, two of the longest survivors, four to five years after first immunization, had virtually complete absence of both plaques and CAA, raising the possibility that, given time, Abeta is eventually cleared from the cerebral vasculature. The findings are consistent with the hypothesis that Abeta immunization results in solubilization of plaque Abeta42 which, at least in part, exits the brain via the perivascular pathway, causing a transient increase in the severity of CAA. The extent to which these vascular alterations following Abeta immunization in Alzheimer's disease are reflected in changes in cognitive function remains to be determined.

Dislocation resistance of ProRoot Endo Sealer, a calcium silicate-based root canal sealer, from radicular dentine.

AIM: To examine the dislocation resistance of three root canal sealers from radicular dentine with and without immersion in a simulated body fluid (SBF), using a modified push-out test design that produced simulated canal spaces of uniform dimensions under identical cleaning and shaping conditions. METHODOLOGY: Sixty single-rooted caries-free human canine teeth were used. Standardized simulated canal spaces were created using 0.04 taper ProFile instruments along the coronal, middle and apical thirds of longitudinal tooth slabs. Following NaOCl/ethylenediamine tetra-acetic acid cleaning, the cavities were filled with ProRoot Endo Sealer, AH Plus Jet or Pulp Canal Sealer. After setting, half of the cavities were tested with a fibre-optic light-illuminated push-out testing device. The rest were immersed in SBF for 4 weeks before push-out evaluation. Failure modes were examined with stereomicroscopy and field emission (FE)-scanning electron microscopy. RESULTS: Location of the sealer-filled cavities did not affect push-out strengths. ProRoot Endo Sealer exhibited higher push-out strengths than the other two sealers particularly after SBF storage (P < 0.001). Failure modes were predominantly adhesive and mixed for Pulp Canal Sealer and AH Plus Jet, and predominantly cohesive for ProRoot Endo Sealer. Spherical amorphous calcium phosphate-like phases that spontaneously transformed into apatite-like phases were seen in the fractured specimens of ProRoot Endo Sealer after SBF storage. CONCLUSIONS: When tested in bulk without a main core, both 'sealer type' and 'SBF storage' were significant in affecting push-out results. The ProRoot Endo Sealer demonstrated the presence of spherical amorphous calcium phosphate-like phases and apatite-like phases (i.e. ex vivo bioactivity) after SBF storage.