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All relevant data are within the paper and its Supporting information files., Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects a large number of people throughout the world. Anxiety, depression and fatigue are common symptoms of SLE that substantially contribute to decreased quality of life. This study investigates the interplay between physical and psychiatric manifestations of lupus. To this end, an SLE patient cohort was examined for correlations between clinical presentation, laboratory tests, and psychological indicators., BDP was funded by the Fulbright commission: Portugal, scholar program. Funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Purpose. Rheumatoid arthritis (RA) is an often debilitating autoinflammatory disease. Patients with rheumatoid arthritis are often troubled by co-occurring depression or other psychological manifestations. RA patients have a variety of treatment options available, including biologicals that inhibit cytokines or immune cells. If these cytokines influence the psychological symptoms, then the use of cytokine inhibitors should modulate these symptoms. Methods. A cohort of 209 individuals was recruited. This group included 82 RA patients, 22 healthy subjects, 32 depressed control subjects, and 73 subjects with systemic lupus erythematosus. Of the RA patients, 51% were on a biological therapeutic. ELISA was used to measure cytokine levels. A variety of psychological assessments were used to evaluate depression, anxiety, sleep, fatigue, and relationship status. Clinical values were obtained from medical records. Results. IL-10 concentration was associated with depressive symptoms in the RA patients, healthy controls, and the lupus patients. In the patients with primary depression, depressive symptoms were associated with IL-6 and TNF-alpha. In RA patients, Tocilizumab use was associated with decreased depressive symptoms. 14 RA patients who were not using biologicals began using them by a one-month follow-up. In these patients, there was no significant change to any value except for fatigue. Conclusions. A variety of both biological and social factors influences depressive symptoms in RA. IL-10 and IL-6 are likely to be involved, since IL-10 concentration was associated with depression and Tocilizumab decreased depressive symptoms in the RA patients. The roles of these cytokines are different in RA and lupus, as high IL-10 in RA is associated with increased depressive symptoms, but high IL-10 in the lupus patients is associated with decreased depression. IL-6 was also associated with depressive symptoms in the patients with primary depression. These results strongly indicate that disease activity, including cytokine levels, has a strong impact on depressive symptoms.

INTRODUCTION Pachyonychia congenita (PC) is a rare skin disorder caused by an autosomal dominant mutation in one of five genes encoding keratin (K6a, K6b, K6c, K16 or K17; each defining one PC subtype). Pain is a prominent symptom, but its severity and type are poorly characterized. METHODS In total, 35 genotyped US patients with PC consented to clinical assessment including the quality of life (QoL) questionnaire EQ-5D-3L, the Brief Pain Inventory (BPI) and painDETECT. Abbreviated quantitative sensory testing (QST) was also performed, and included mechanical detection threshold (MDT), mechanical pain threshold (MPT), wind-up pain ratio (WUR) and vibration detection threshold (VDT). RESULTS Significant pain in patients with PC was confirmed, as indicated by mean BPI severity and interference of 4.2 ± 1.7 and 4.4 ± 2.2, respectively, as well as QoL impairment, as indicated by mean EQ-5D index of 0.69 ± 0.18. PD identified neuropathic pain in 62% of patients, the remainder being nociceptive. The painDETECT score was most significantly related to EQ-5D index (R(2) = 0.26, P = 0.02). The K17 and K6a subtypes exhibited significantly worse QoL (0.584 and 0.613 respectively) than the K16 and K6b subtypes (P = 0.02). In QST analysis, abnormal pressure pain (assessed as MPT) was frequently observed, with more than half of patients with PC affected (54%), and 57% of patients with K17 also exhibiting abnormality in minimum touch threshold (assessed as MDT, P

For the last 50 years, research investigating the effect of emotions on scope of cognitive processing was based on models proposing that affective valence determined cognitive scope. More recently, our motivational intensity model suggests that this past work had confounded valence with motivational intensity. Research derived from this model supports the idea that motivational intensity, rather than affective valence, explains much of the variance emotions have on cognitive scope. However, the motivational intensity model is limited in that the empirical work has examined only positive affects high in approach and negative affects high in avoidance motivation. Thus, perhaps only approach-positive and avoidance-negative states narrow cognitive scope. The present research was designed to clarify these conceptual issues by examining the effect of anger, a negatively valenced approach-motivated state, on cognitive scope. Results revealed that anger narrowed attentional scope relative to a neutral state and that attentional narrowing to anger was similar to the attentional narrowing caused by high approach-motivated positive affects (Study 1). This narrowing of attention was related to trait approach motivation (Studies 2 and Study 3). Anger also narrowed conceptual cognitive categorization (Study 4). Narrowing of categorization related to participants' approach motivation toward anger stimuli. Together, these results suggest that anger, an approach-motivated negative affect, narrows perceptual and conceptual cognitive scope. More broadly, these results support the conceptual model that motivational intensity per se, rather than approach-positive and avoidance-negative states, causes a narrowing of cognitive scope.

OBJECTIVES: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease. METHODS: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084). RESULTS: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes. CONCLUSIONS: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry./n© 2015 American Academy of Neurology. Kristiina Rannikmäe is supported by the Edinburgh and Lothians Health Foundation REMIND Fund and Stroke Research and Amenities Endowments Fund; Cathie Sudlow is supported by the Scottish Funding Council; Gail Davies is supported by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1), BBSRC and Medical Research Council (MSRC). Tom Van Agtmael is supported by the Kidney Research UK project grant RP19/2012. Details of funding for the studies contributing to the ICH GWAS can be found in: Woo D, Falcone GJ, Devan WJ, et al. Meta-analysis of genome-wide association studies identifies 1q22 as a novel susceptibility locus for intracerebral hemorrhage. American Journal of Human Genetics 2014;pii: S0002-9297(14)00070-6. doi:10.1016/j.ajhg.2014.02.012. [Epub ahead of print]. Details of funding for the studies contributing to the ischaemic stroke GWAS can be found in: Traylor M, Farrall M, Holliday EG, et al. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies. Lancet Neurology 2012;11:951-962. Details of funding for the studies contributing to the WMH in ischaemic stroke GWAS can be found in: Adib-Samii P, Rost N, Traylor M, et al. 17q25 Locus Is Associated With White Matter Hyperintensity Volume in Ischaemic Stroke, But Not With Lacunar Stroke Status. Stroke 2013;44:1609-1615. Details of funding for the studies contributing to the WMH in population GWAS can be found in: Fornage M, Debette S, Bis JC, et al. Genome-Wide Association Studies of Cerebral White Matter Lesion Burden: The CHARGE Consortium. Annals of Neurology 2011;69:928-939. Martin Dichgans is supported by the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain); Guido J Falcone is supported by the NIH / NINDS grant P50NS061343; Chistopher D Anderson is supported by the American Brain Foundation Clinical Research Training Fellowship, NIH-NINDS K23NS086873, Massachusetts General Hospital Institute for Heart, Vascular, and Stroke Care SPARK award; Jonathan Rosand is supported by the NIH / NINDS grant R01NS059727.

Sepsis is strongly associated with patency of the ductus arteriosus (PDA) in critically ill newborns. Inflammation and the aminoglycoside antibiotics used to treat neonatal sepsis cause smooth muscle relaxation, but their contribution to PDA is unknown. We examined whether: 1) lipopolysaccharide (LPS) or inflammatory cytokines cause relaxation of the ex vivo mouse DA; 2) the aminoglycosides gentamicin, tobramycin, or amikacin causes DA relaxation; and 3) newborn infants treated with aminoglycosides have an increased risk of symptomatic PDA (sPDA). Changes in fetal mouse DA tone were measured by pressure myography in response to LPS, TNF-α, IFN-γ, macrophage-inflammatory protein 2, IL-15, IL-13, CXC chemokine ligand 12, or three aminoglycosides. A clinical database of inborn patients of all gestations was analyzed for association between sPDA and aminoglycoside treatment. Contrary to expectation, neither LPS nor any of the inflammatory mediators caused DA relaxation. However, each of the aminoglycosides caused concentration-dependent vasodilation in term and preterm mouse DAs. Pretreatment with indomethacin and N-(G)-nitro-L-arginine methyl ester did not prevent gentamicin-induced DA relaxation. Gentamicin-exposed DAs developed less oxygen-induced constriction than unexposed DAs. Among 488,349 infants who met the study criteria, 40,472 (8.3%) had sPDA. Confounder-adjusted odds of sPDA were higher in gentamicin-exposed infants, 32 wk. Together, these findings suggest that factors other than inflammation contribute to PDA. Aminoglycoside-induced vasorelaxation and inhibition of oxygen-induced DA constriction support the paradox that antibiotic treatment of sepsis may contribute to DA relaxation. This association was also found in newborn infants, suggesting that antibiotic selection may be an important consideration in efforts to reduce sepsis-associated PDA.

Epstein–Barr virus-induced gene 2 (EBI2) is an important chemotactic receptor that is involved in proper B-cell T-cell interactions. Epstein–Barr virus (EBV) has been shown to upregulate this gene upon infection of cell lines, but the timing and mechanism of this upregulation, as well as its importance to EBV infection, remain unknown. This work investigated EBV’s manipulation of EBI2 expression of primary naive B cells. EBV infection induces EBI2 expression resulting in elevated levels of EBI2 after 24 h until 7 days post-infection, followed by a dramatic decline (P=0.027). Increased EBI2 expression was not found in non-specifically stimulated B cells or when irradiated virus was used. The EBV lytic gene BRRF1 exhibited a similar expression pattern to EBI2 (R2 =0.4622). BRRF1-deficient EBV could not induce EBI2. However, B cells transduced with BRRF1 showed elevated expression of EBI2 (P=0.042), a result that was not seen with transduction of a different EBV lytic transfection factor, BRLF1. Based on these results, we conclude that EBI2 expression is directly influenced by EBV infection and that BRRF1 is necessary and sufficient for EBI2 upregulation during infection.

The National Blood Transfusion Service (NBTS) in England and Wales was established as a single entity in 1946 and operated as such for almost half a century. During those 50 years, the blood service in Wales, as in the rest of the UK, saw many technological and operational changes. The automation of donation testing, the introduction of successive layers of microbiological screening, the creation of the Tissue Typing Laboratory (later renamed the Welsh Transplantation and Immunogenetics Laboratory) and the development of information technology brought - over a relatively long period - highly significant improvements to an organisation that had begun life as an Emergency Medical Service. Differing funding and reporting arrangements for the Welsh and English blood services made little difference in practice, but the devolution of government following the 1997 referendum in Wales would have a profound influence. Four years before the Government of Wales Act (1998) was passed through the UK parliament, the National Blood Authority (NBA) assumed executive control of the English blood services but not the blood service in Wales. The Scottish National Blood Transfusion Service and the Northern Ireland Blood Transfusion Service had been created as independent organisations in 1946; thus, the scene was set for diversification between the four independent blood services, each operating in different political environments with different funding streams. The creation of the UK Blood Services Forum and its Joint Professional Advisory Committee in 1999 has, however, ensured consistency in professional matters. The blood transfusion service in Wales, in its new headquarters in Talbot Green, became known as the Welsh Blood Service (WBS), or Gwasanaeth Gwaed Cymru in Welsh, reporting for most of its life to the Velindre NHS Trust, part of NHS Wales. Considerable changes would impact the WBS in the 21st century. Social changes would mean that the role of recruitment and marketing would become ever more important, although the impact of this was lessened somewhat by a decreasing demand for blood following the Better Blood Transfusion initiatives. The Medicines and Healthcare Products Regulatory Agency found new powers and impetus after the so-called EU Blood Directive was transposed into British law, and the inspection regime became significantly more onerous, requiring more resources to be put in this area. A strategic review found that some parts of the service required extensive modernisation, such as the information technology system in use and the deployment of staff on the blood collection teams, and these matters were attended to. The review also prompted the Welsh Government to consider the question of blood supply to and blood collection in North Wales, which had been the remit of the Liverpool Centre since the establishment of the NBTS in 1946. The Welsh Government duly announced the creation of an all-Wales Blood Service, and finally, in May 2016, 70 years after its creation, the WBS took over responsibility for blood collection and blood provision in the whole of Wales.

Decades of research focusing on the neurophysiological underpinnings related to global-local processing of hierarchical stimuli have associated global processing with the right hemisphere and local processing with the left hemisphere. The current experiment sought to expand this research by testing the causal contributions of hemisphere activation to global-local processing. To manipulate hemisphere activation, participants engaged in contralateral hand contractions. Then, EEG activity and attentional scope were measured. Right-hand contractions caused greater relative left-cortical activity than left-hand contractions. Participants were more narrowly focused after left-hemisphere activation than after right-hemisphere activation. Moreover, N1 amplitudes to local targets in the left hemisphere were larger after left-hemisphere activation than after right-hemisphere activation. Consistent with past research investigating hemispheric asymmetry and attentional scope, the current results suggest that manipulating left (right) hemisphere activity enhanced local (global) attentional processing.

BACKGROUND Tandem mass spectrometry has been proposed as a method of diagnosing or predicting the development of common complex neonatal diseases. Our objective was to identify metabolites associated with common complications of prematurity. METHODS We performed a retrospective analysis of medical data and metabolite measurements from routine neonatal screening on 689 preterm (

Background Fabry disease (FD) is an X-linked lysosomal storage disorder frequently associated with cerebrovascular disease. In recent years, the prevalence of FD has been reported to be up to 4% in cryptogenic young stroke patients. However, there have been no population-based studies in unselected patients with transient ischaemic attack (TIA) or stroke across the full range of ages. Methods We determined the prevalence of FD mutations in consecutive patients from a population-based study of acute TIA or ischaemic stroke (Oxford Vascular Study). Analysis included amplifying of the α-galactosidase A gene by polymerase chain reaction, denaturing high-performance liquid chromatography (dHPLC) analysis and sequencing using standard automated sequencing protocols [Mutation Surveyor software (Softgenetics)] where the dHPLC indicated a possible mutation. Results Samples of 1046 consecutive patients (52% women; mean age 73.2 years; 15% age

Clinicians regularly transplant omental pedicles to repair a wide variety of injured tissues but the basic mechanism underlying this efficacious procedure is not understood. One possibility that has not been addressed is the ability of omentum to directly contribute regenerative cells to injured tissues. We hypothesized that if omental progenitor cells could be mobilized to incorporate into damaged tissue, the power of this therapy would be greatly expanded. Labeled omental grafts were transplanted into a murine carotid artery injury model. Selected grafts were treated with Thymosinβ4 prior to transplantation to investigate the effects of chemical potentiation on healing. We found treatment of grafts with Thymosinβ4 induced progenitor cells to fully integrate into the wall of injured vessels and differentiate into vascular smooth muscle. Myographic studies determined that arteries receiving Thymosinβ4-stimulated grafts were functionally indistinguishable from uninjured controls. Concurrent in vitro analyzes showed that Thymosinβ4 promoted proliferation, migration, and trans-differentiation of cells via AKT signaling. This study is the first to demonstrate that omentum can provide progenitor cells for repair, thus revealing a novel and naturally occurring source of vascular smooth muscle for use in cell-based therapies. Furthermore, our data show this system can be optimized with inducing factors, highlighting a more powerful therapeutic potential than that of its current clinical application. This is a paradigm-setting concept that lays the foundation for the use of chemical genetics to enhance therapeutic outcomes in a myriad of fields.

IntroductionDepression is a common companion of systemic lupus erythematosus that substantially contribute to patient's suffering and a decreased quality of life. The relationship between depressive symptoms and disease immune processes is not well understood.ObjectivesTo further understand the relationship between lupus and depression, a patient cohort was examined for correlations between clinical presentation, biological parameters and psychosocial evaluation.MethodsSeventy-two lupus patients were screened for depressive symptoms, clinically and psychologically characterized using a battery of instruments, including assessments for depression, anxiety, fatigue, pain and overall health. Scores from these assessments were correlated with lupus clinical profile and biological parameters namely the immune profile.ResultsForty-two percent of the patients had scores indicative of depression using the HADS Depression scale. Strong correlation was found between pain and depression. Moderate correlation was found between several lupus symptoms, such as mouth ulcers, rash, and arthritis, and psychological evaluation. There was low to moderate correlation between complement levels, C-reactive protein and psychological indicators, but no other lab tests correlated well with the psychological tests.ConclusionThe correlation of depressive symptoms, complement and C-reactive protein with depressive symptoms suggests that these may be mediated by disease activity and share pathophysiological mechanisms. The overall weakness of correlations with biological markers demonstrates that more specific tests need to be developed. The study of lupus associated depression may, furthermore clarify the role of immune dysfunction in the pathophysiology of this psychiatric disorder.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Objectives. The primary aim of this study was to estimate annual health care costs for biologic-naive patients with PsA in the UK. The relationship between disease severity, defined by physical limitations, and costs was also explored. Methods. This study utilized data from the British Society of Rheumatology Biologics Register (BSRBR) to develop a multivariate model estimating disease severity from parameters available in routine primary care data. The HAQ Disability Index was used to determine disease severity. This algorithm was then applied to routine data from The Health Improvement Network (THIN). Annual costs were estimated for drugs, contacts with a general practitioner and other health care professionals, tests, hospital outpatient attendances and inpatient admissions from a National Health Service perspective using official tariffs. The relationship between disease severity and health care costs was estimated using a generalized linear model. Results. Three hundred and fifty-six cases with PsA were identified in the BSRBR and 4492 in THIN. Total mean annual health care costs ranged from £11 to £20 782 with a mean of £1446 (S.D. £1756). When costs were sub-grouped by the predicted HAQ score, the mean annual observed costs ranged from £548 per person for the least severely affected (HAQ ≤1.2) to £4832 for the most severely affected (HAQ >2.6). Prescription costs and secondary care episodes accounted for more than a third of total care costs each (38 and 34%, respectively). When the relationship between disease severity and costs was examined, estimated HAQ was found to be a significant predictor of total health care costs. Conclusions. Treatment of people with PsA resulted in considerable financial costs and these costs varied markedly by disease severity.

Serologic association, cross-reactivity of select EBV-specific antibodies with SLE autoantigens, SLE-like autoimmunity after immunization with EBV peptides, increased EB viral load in SLE patients, and SLE-specific alterations in EBV humoral and cellular immunity implicate Epstein–Barr virus (EBV) in the development of systemic lupus erythematosus (SLE). To investigate SLE-specific differences in EBV gene expression, levels of eight EBV genes were compared between SLE patients and controls by using both ex vivo-infected and un-manipulated peripheral blood mononuclear cells (PBMCs). Expression levels of mRNA were significantly greater by Wilcoxen signed rank test in the ex vivo-infected SLE patient-derived cells for 4 of 8 EBV genes, including BLLF1, 3.2-fold (p

To evaluate the association between systemic inflammation, as measured by CRP, and all-cause mortality. To also evaluate the association between change in CRP status (sub-acute,or =10 mg/l and acute10 mg/l) and all-cause mortality.A cohort of patients was selected from The Health Improvement Network (THIN) data set of anonymized patient-level data from UK general practice. Patients were selected if they had a diagnosis of RA, psoriasis, AS or PsA. Survival was evaluated using Cox proportional hazards regression models (CPHMs).A total of 11 362 cases had at least one CRP measurement. Analysis grouped by each additional unit increase in log-CRP (range 1-6) across the observed range was associated with a 21% increase in the hazard ratio (HR) of death, after controlling for cardiovascular risk factors (P0.001). This observation was consistent in separate analysis of cases with either RA or psoriasis. Repeated CRP observations around 1 yr apart were recorded in 2802 subjects. After controlling for confounding factors, in cases whose CRP changed from sub-acute (or =10 mg/l) to acute (10 mg/l), the HR for death increased 2-fold (P0.001) relative to cases whose CRP remained sub-acute. In comparison, among those subjects whose CRP was reduced from acute to sub-acute, the HR was virtually identical to those who stayed sub-acute (P = 0.571).CRP level predicted all-cause mortality after standardization for traditional risk factors, as did change in CRP status from sub-acute to acute observed over 1 yr.

Using standard calculus, explicit formulas for the one-dimensional continuous and discrete homotopy operators are derived. It is shown that these formulas are equivalent to those in terms of Euler operators obtained from the variational complex. The continuous homotopy operator automates integration by parts on the jet space. Its discrete analogue can be used in applications where summation by parts is essential. Several examples illustrate the use of the homotopy operators. The calculus-based formulas for the homotopy operators are easy to implement in computer algebra systems such as Mathematica and Maple. The homotopy operators can be readily applied to the symbolic computation of conservation laws of nonlinear partial differential equations and differential-difference equations., Comment: Revised version: 13 pages, to be published in "Mathematics and Computers in Simulation", Special Issue on Nonlinear Waves: Computation and Theory, Fourth IMACS Int. Conf. on Nonlinear Evolution Equations and Wave Phenomena: Computation and Theory. Athens, GA, April 11-14, 2005

We evaluated the efficacy of a new pharmacokinetically enhanced formulation of amoxicillin/clavulanate (2,000/125 mg) twice daily for the treatment of acute bacterial rhinosinusitis (ABRS) caused by Streptococcus pneumoniae, particularly penicillin-resistant S pneumoniae (PRSP; penicillin minimum inhibitory concentrations [MICs]: ≥2 μ/ml. A total of 2,482 patients received study medication (safety population). Of these, 2,324 were clinically evaluable (efficacy population), and 1,156 of them had at least one pathogen isolated at screening (bacteriology population). S pneumoniae was isolated from 371 patients in the bacteriology population, including 37 with PRSP. Follow-up in the bacteriology population on days 17 through 28 revealed that amoxicillin/clavulanate therapy was successful in 345 of 371 patients with S pneumoniae infection (93.0%) and in 36 of 37 patients with PRSP infection (97.3%), including 7 of 8 patients (87.5%) whose amoxicillin/clavulanic acid MICs were 4/2 μg/ml or higher. Pharmacokinetically enhanced amoxicillin/clavulanate was generally well tolerated, as only 2.2% of patients withdrew because of adverse events. This agent represents a valuable new therapeutic option for the empiric treatment of ABRS, particularly in areas where antimicrobial-resistant pathogens (including β- lactamase–positive organisms) are prevalent, and for the treatment of patients who are at increased risk of infection with PRSP.

Systemic lupus erythematosus (SLE or lupus) is a complex disease with a multifactoral etiology, with genetic, hormonal, and environmental influences. Molecular mimicry as a result of viral infection may contribute to the development of lupus. The pattern of autoantibody development in lupus is consistent with initiation through molecular mimicry, as the initial autoantigenic epitopes that have been observed are limited and cross-reactive with viral proteins. Autoantibody specificity may then later diversify to other autoantigens through B-cell epitope spreading. Epstein-Barr virus (EBV) is an excellent candidate to be involved in molecular mimicry in lupus. EBV infection has been associated with lupus through serological and DNA studies. Infection with EBV results in the production of the viral protein Epstein-Barr virus nuclear antigen-1 (EBNA-1), antibodies against which cross-react with lupus-associated autoantigens, including Ro, Sm B/B', and Sm D1, in lupus patients. The immune response against EBV, and EBNA-1 in particular, differs among lupus patients and healthy controls, with controls maintaining a limited humoral response and failing to produce long-standing cross-reactive antibodies. We hypothesize that the humoral immune response to EBNA-1 in susceptible individuals leads to the generation of cross-reactive antibodies. Through the process of epitope spreading, these cross-reactive antibodies target additional, non-cross reactive autoepitopes, spread to additional autoantigens, and become pathogenic, leading eventually to clinical lupus. This paper reviews some of the current literature supporting roles for EBV exposure and epitope spreading in SLE.

A helical tomotherapy system is used in our clinic to deliver intensity-modulated radiation therapy (IMRT) treatments. Since this machine is designed to deliver IMRT treatments, the traditional field flatness requirements are no longer applicable. This allows the unit to operate without a field flatness filter and consequently the 400 mm wide fan beam is highly inhomogeneous in intensity. The shape of this beam profile is mapped during machine commissioning and for quality assurance purposes the shape of the beam profile needs to be monitored. The use of a commercial diode array for quality assurance measurements is investigated. Central axis beam profiles were acquired at different depths using solid water built-up material. These profiles were compared with ion chamber scans taken in a water tank to test the accuracy of the diode array measurements. The sensitivity of the diode array to variations in the beam profile was checked. Over a seven week period, beam profiles were repeatedly measured. The observed variations are compared with those observed with an on-board beam profile monitor. The diode measurements were in agreement with the ion chamber scans. In the high dose, low gradient region the average ratio between the diode and ion chamber readings was 1.000 +/- 0.005 (+/- 1 standard deviation). In the penumbra region the agreement was poorer but all diodes passed the distance to agreement (DTA) requirement of 2 mm. The trend in the beam profile variations that was measured with the diode array device was in agreement with the on-board monitor. While the calculated amount of variation differs between the devices, both were sensitive to subtle variations in the beam profile. The diode array is a valuable tool to quickly and accurately monitor the beam profile on a helical tomotherapy unit.

Gene therapy has been investigated in many aspects of plastic and reconstructive surgery. These areas ultimately involve various forms of tissue healing and the manipulation of bony and soft tissues to reconstruct defects secondary to neoplastic and congenital disorders and trauma. Most research has been limited to animal studies with the exception of clinical trials on the use of gene therapy in lower leg ulcer healing and as an adjunct to advanced recurrent squamous cell carcinoma of the head and neck. Overall, these preliminary studies have produced optimistic results. With the development of more efficient and safer delivery systems, the application of gene therapy in plastic surgery could become more widespread, especially in combination with tissue engineering technology.

The therapeutic outcomes model (TOM) provides a logical and consistent manner in which bacteriologic and clinical efficacy can be predicted and calculated. It not only allows antibiotics to be ranked in efficacy, it gives precise estimates of the magnitude of differences in efficacy, which is typically lacking in older antimicrobial guidelines. The TOM identifies the major variables that need to be considered in accurately estimating outcome and places those variables into the appropriate relationships and formulas so that outcomes will be automatically calculated. In the case of rhinosinusitis, the major variables are (1) likelihood of spontaneously resolving nonbacterial cause, (2) likelihood of nonresolving nonbacterial cause, (3) prevalence of subcauses (eg, different species of bacteria), (4) the spontaneous resolution rates of each subcause, (5) the antibacterial efficacy of the treatment (eg, antibiotic) against each of the subcauses, and (6) the compliance rate of the treatment recommended. Minor variables, such as prior antibiotic use, patient age, or bacterial vaccination status, affect the efficacy of a given agent by modifying the value of one or more of the major variables. The TOM is a superior mechanism for ranking and evaluating relative antibiotic efficacy than previous methodologies.

This study examined parents' awareness of their daughters' attitudes, beliefs, and feelings about their bodies. Sixty-six daughters aged 12–15 years completed the Stirling Eating Disorder Scale, a body figure rating scale, and made ratings of their shape and weight. They also completed a more comprehensive measure of body satisfaction, the Body Esteem Scale (BES). Mothers and fathers estimated their daughters' shape and weight, and completed the BES with instructions to complete the measure from their daughters' perspective. While there were few differences between mothers' and fathers' reports, parent–daughter congruence scores varied according to methodology and attribute measured. That is, parents' ratings of objective daughter characteristics on single-item rating scales were more congruent with daughters' self-reports than parents' estimates of daughters' feelings about their bodies using a more comprehensive measure. Greater discrepancies between parents' estimates of daughters' body esteem and daughters' self-reported body esteem were associated with greater body dissatisfaction in daughters.

OBJECTIVE: The primary objective of this study was to demonstrate the clinical and radiologic efficacy of 5 days compared with 7 days of gemifloxacin therapy in the treatment of acute bacterial rhinosinusitis (ABRS).STUDY DESIGN: In this prospective, double-blind, multicenter, parallel-group study, adult patients presenting with ABRS were randomized to receive gemifloxacin 320 mg once daily for either 5 days (n = 218) or 7 days (n = 203).RESULTS: For the primary efficacy end point, clinical response to therapy at follow-up, 5 days of therapy with gemifloxacin was as effective as 7 days of therapy (per-protocol population; treatment difference 0.44%; 95% confidence interval (CI), −6.54 to 7.41). Five and 7 days of treatment with gemifloxacin were well tolerated.CONCLUSION AND SIGNIFICANCE: The clinical efficacy of gemifloxacin 320 mg daily for 5 days is at least as good as the efficacy of gemifloxacin 320 mg daily for 7 days in the treatment of ABRS.

We evaluated the clinical effectiveness of variable courses of paracetamol on patent ductus arteriosus (PDA) closure and examined its effect on the in vitro term and preterm murine ductus arteriosus (DA).Neonates received one of the following three paracetamol regimens: short course of oral paracetamol (SCOP), long course of oral paracetamol (LCOP), and intravenous paracetamol (IVP) for 2-6 d. Pressure myography was used to examine changes in vasomotor tone of the preterm and term mouse DA in response to paracetamol or indomethacin. Their effect on prostaglandin synthesis by DA explants was measured by mass spectroscopy.Twenty-one preterm infants were included. No changes in PDA hemodynamics were seen in SCOP infants (n = 5). The PDA became less significant and eventually closed in six LCOP infants (n = 7). PDA closure was achieved in eight IVP infants (n = 9). On pressure myograph, paracetamol induced a concentration-dependent constriction of the term mouse DA, up to 30% of baseline (P0.01), but required1 µmol/l. Indomethacin induced greater DA constriction and suppression of prostaglandin synthesis (P0.05).The clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration. Paracetamol is less potent than indomethacin for constriction of the mouse DA in vitro.

The use of exogenous agents to stimulate the growth of new blood vessels into ischaemic tissue is a potentially revolutionary therapy in a wide variety of clinical specialties. Therapeutic angiogenesis research has been mostly confined to ischaemia of the heart and the lower limb. There has been relatively little research into the potential applications of the technique to plastic, reconstructive and burns surgery. In this paper, relevant published work is reviewed and potential applications of therapeutic angiogenesis to our specialty are considered.

Introduction: Autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis affect millions of people worldwide. Interferon regulatory factor 5 (IRF5) contains polymorphisms associated with these autoimmune diseases. Two of these functional polymorphisms are found upstream of the IRF5 gene. rs2004640, which is a single nucleotide polymorphism and the CGGGG insertion/deletion (indel) were studied. IRF5 uses four different promoters for its four first exons: 1A, 1B, 1C, and 1D. Each promoter was analyzed, including functional differences due to the autoimmune-risk polymorphisms. Results: IRF5 promoters were analyzed using ChIP-Seq data (ENCODE database) and the FactorBook database to define transcription factor binding sites. To verify promoter activity, the promoters were cloned into luciferase plasmids. Each construct exhibited luciferase activity. Exons 1A and 1D contain putative PU.1 and NFkB binding sites. Imiquimod, a Toll-like receptor 7 (TLR7) ligand, was used to activate these transcription factors. IRF5 levels were doubled after imiquimod treatment (p

In this article, an intergenerational dance program involving 21 children (mean age = 8 years, 6 months) and 15 older adults (mean age = 83 years, 7 months) is described. The children came from rural grade schools. The older adults came from intermediate care facilities. Such programs can have positive impact across psychomotor and cognitive domains. Information is provided for those interested in establishing an intergenerational dance program, including warm-up exercises, limitations and adaptations of participants, specific movement skill combinations, and relaxation/cool down exercises. Recommendations regarding teaching methods, processes and program duration are also presented.

The impact of modern medical techniques has given rise to an increasing survival of persons with disorders of consciousness including coma, the vegetative state, and the minimally conscious state. The numbers of pediatric and adolescent survivors of brain injury who remain vegetative or minimally conscious are not definitively known, and while these patients have received growing professional consideration, no specific standards of care exist. Pediatric and adolescent treatment recommendations are not differentiated from adult populations although some questions linger regarding the progression and outcome of the disorders in adults as compared to those in children. Kluge Children's Rehabilitation Center has initiated a Low Response and Treatment Protocol for Children Following Acquired Brain Injury to provide structure for diagnostic and therapeutic initiatives. Its single subject design is literature based, empirically driven, and peer recognized. Clinical classifications label a patient's emergence from coma as uncomplicated, complicated by confounding medical conditions, or neuropathic complicated emergence. Patients receiving the neuropathic designation are considered for pharmacological intervention. Beyond optimizing care for the enrolled patient, the protocol is established to provide (Giacino, 1995) an ongoing data store for future group analysis. Case 1 presents the course of treatment and recovery for a 16-year-old male, severely disabled due to an automobile accident. Medical complications are addressed and his failure to progress is deemed complicated neuropathic at 14 weeks post-injury. At 15 weeks post-injury, administration of Amantadine 100 mg bid shows improvements, with almost complete emergence after two weeks at an increased dose of 200 gm bid. Discontinuation at the family's request, approximately a year post-injury, is followed by a measurable loss of functional ability. The patient regained functioning after returning to the Amantadine schedule. Case 2 outlines the course of treatment and recovery for a nine-year-old boy, the victim of a near drowning. Investigation considerations influence the structure of the protocol and analysis of its results. While first a therapeutic tool based on single subject design, the protocol attempts to qualitatively manage various threats to establishing causal relationships between drug interventions and the noted outcomes. Systematic consideration of the single subject design for therapeutic benefit, as well as making a meaningful contribution to the existing evidence base, is suggested until class I evidence is compiled to produce well supported standards of care. Copyright © 2000 John Wiley & Sons, Ltd.

Sinusitis is a prevalent and costly disease that affects >14% of the population and accounts for >$2 billion in yearly healthcare costs. It is one of the most common conditions treated by primary care physicians. The multiple host and environmental factors that contribute to the pathogenesis of the disease and the lack of clear guidelines for diagnosis and treatment pose a challenge to effective management of the problem. The diagnosis of uncomplicated cases rests mainly on the history and clinical examination; attempts have been made to identify the most useful clinical predictors of acute bacterial sinusitis. Microbiologic and imaging studies are rarely performed during the initial assessment and are usually reserved for recurrent or refractory disease. Treatment involves drainage of the congested sinuses and elimination of pathogenic organisms. Although antimicrobial therapy hastens the resolution of symptoms of acute sinusitis, the need for antimicrobial therapy remains questionable, and its judicious use is challenged by the increase in antibiotic-resistant Haemophilus influenzae and Streptococcus pneumoniae, the organisms most commonly implicated in acute sinusitis. A lack of resolution or frequent recurrence of sinusitis warrants evaluation by a specialist.

The precise role of maxillary constriction in the pathophysiology of obstructive sleep apnea (OSA) is unclear. However, it is known that subjects with maxillary constriction have increased nasal resistance and resultant mouth-breathing, features typically seen in OSA patients. Maxillary constriction is also associated with alterations in tongue posture which could result in retroglossal airway narrowing, another feature of OSA. Rapid maxillary expansion (RME) is an orthodontic treatment for maxillary constriction which increases the width of the maxilla and reduces nasal resistance. The aim of this pilot study was to investigate the effect of rapid maxillary expansion in OSA. We studied 10 young adults (8 male, 2 female, mean age 27 +/- 2 [sem] years) with mild to moderate OSA (apnea/hypopnea index-AHI 19 +/- 4 and minimum SaO2 89 +/- 1%), and evidence of maxillary constriction on orthodontic evaluation. All patients underwent treatment with RME, six cases requiring elective surgical assistance. Polysomnography was repeated at the completion of treatment. Nine of the 10 patients reported improvements in snoring and hypersomnolence. There was a significant reduction in AHI (19 +/- 4 vs 7 +/- 4, p < 0.05) in the entire group. In seven patients, the AHI returned to normal (i.e., = < 5); only one patient showed no improvement. These preliminary data suggest that RME may be a useful treatment alternative for selected patients with OSA.

To the Editor .— In his commentary, “Why Don't Those Ear Drops Work for My Patients?”1 Isaacson presented his argument against the use of ototopical fluoroquinolones alone or in combination with a steroid as the first line of defense for the treatment of acute tube otorrhea in infants. He made several points to discount the use of these agents in pediatric patients with acute otitis media with tympanostomy tubes. However, rooted in the first sentence of the commentary was the fact that seems to lie at the epicenter of his concerns: “‘Topical Ciprofloxacin/Dexamethasone Is Superior to Oral Amoxicillin/Clavulanic Acid in Acute Otitis Media With Otorrhea Through Tympanostomy Tubes,’ [is] the latest in a series of pharmaceutical industry–funded articles… .” Isaacson's first critique of this article2 pertains to the study population. He stated that “[i]f one were trying to design a study to demonstrate the superiority of ototopical drops over oral antibiotics, the ideal population would be older children.” This statement directly contradicted his other criticism that “more than half of their subjects were >22 months of age.” In fact, 58% of the subjects in the study were

This article examines the adjustment problems and work strategies of female deputy sheriffs working in four county jails and three local adult detention centers. Semistructured interviews were conducted with 108 women deputies. The findings suggest that in their role as jail officers, women experience integration difficulties predominantly imposed on them by their male coworkers; these difficulties include gender stereotyping, role conflict, and differential performance expectations. This article explores the impact of and response to these work problems.

Distraction osteogenesis is a technique of new bone formation by the gradual separation of bony fragments. The method, although initially developed for limb lengthening, is now being applied in the treatment of craniofacial deformities. A number of principles have been established through careful scientific study to guide clinical practice, such as the ideal rate and rhythm of distraction, the need for periosteal preservation during bone division, a "latent period" of neutral fixation before, and a "consolidation period" after distraction. The technique is being applied in craniofacial surgery particularly for mandibular deformities and offers considerable advantages over previous methods such as osteotomy and inlay bone grafting. Donor site morbidity is avoided, the investing soft tissue envelope is concurrently expanded, and the magnitude of the procedure is less. However, the technique is still in its infancy and requires further modification and refinement before widespread acceptance as a treatment in mainstream craniofacial surgery. Problems with cutaneous scarring and socially undesirable external hardware, particularly in the pediatric population, have led to the emergence of intraoral miniature devices, with the ultimate goal of development of a multiplanar internal autodistractor. Furthermore, many principles well established in leg lengthening, such as the rate and rhythm of distraction, need to be reexamined and the parameters redefined with particular reference to the craniofacial skeleton. Distraction osteogenesis has an expanding role in craniofacial surgery.

ntibody identification depends upon testing a serum containing an antibody with an unknown specificity with red cells (RBCs) of several pheno

Rational antibiotic therapy for sinusitis is a difficult goal, made difficult by few satisfactory comparative trials with sufficient clinical power, the large numbers of therapeutic options, prescribing pressures from the pharmaceutical industry, and rapid changes in bacterial resistance patterns. Controversies exist about the relative need of antibiotics for uncomplicated disease, duration of therapy, and relative efficacy of various agents. Nonetheless, limited data support the notion of superior efficacy of more potent antimicrobials, and an analysis of in vitro activity versus tissue concentrations of the various antibiotics can predict efficacy of eradication of causative bacteria. Multidrug-resistant pneumococci render any algorithm for empiric antibiotic use problematic and prone to fail.