The ratio of erythrocyte sedimentation rate to C-reactive protein is useful in distinguishing infection from flare in systemic lupus erythematosus patients presenting with fever.

Background Both C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) can be elevated in systemic lupus erythematosus (SLE) flare and infection, and are therefore of limited utility for distinguishing between the two conditions in febrile SLE patients. Methods A medical records review of hospitalizations (1997-2006) of SLE patients in the Michigan Lupus Cohort was performed. Eligible hospitalizations were those in which patients presented with a temperature of >100.3°F or with subjective fevers as a presenting complaint at admission. Detailed demographic, clinical, and laboratory data were collected. Multivariable logistic regression was used to examine the associations between ESR and CRP and the outcome of flare vs infection, adjusted for confounders. Results Among 557 SLE patients screened, there were 53 eligible hospitalizations (28 flares and 25 infections). Each unit increase in the ratio of ESR:CRP was associated with a 17% increase in the odds of fever being attributable to SLE flare compared to infection (OR 1.17, 95% CI 1.04, 1.31; p = 0.009), when adjusted for white blood cell count, SLE duration, sex, race, and age. ESR and CRP were not individually associated with flare vs infection when modeled with their ratio. Conclusions The ratio of ESR:CRP may provide diagnostic value beyond individual ESR and CRP levels in distinguishing flare vs infection in SLE patients presenting with fever.

Environmental exposures, epigenetic changes and the risk of lupus.

A dose-dependent combination of environmental exposures, estrogenic hormones and genetic predisposition is thought to be required for lupus to develop and flare, but how the environment modifies the immune system in genetically predisposed people is unclear. Current evidence indicates that environmental agents that inhibit DNA methylation can convert normal antigen-specific CD4+ T lymphocytes into autoreactive, cytotoxic, pro-inflammatory cells that are sufficient to cause lupus-like autoimmunity in animal models, and that the same changes in DNA methylation characterize CD4+ T cells from patients with active lupus. Environmental agents implicated in inhibiting T-cell DNA methylation include the lupus-inducing drugs procainamide and hydralazine, as well as diet, and agents causing oxidative stress, such as smoking, UV light exposure, and infections, which have been associated with lupus onset or disease activity. Other studies demonstrate that demethylated T cells cause only anti-DNA antibodies in mice lacking a genetic predisposition to lupus, but are sufficient to cause lupus-like autoimmunity in genetically predisposed mice and likely people, and that estrogens augment the disease. Collectively, these studies suggest that environmental agents that inhibit DNA methylation, together with lupus genes and estrogens or endocrine disruptors, combine in a dose-dependent fashion to cause lupus flares.

Folate receptor alpha (FRA) expression remains unchanged in epithelial ovarian and endometrial cancer after chemotherapy.

OBJECTIVE: Based on its expression profile, folate receptor alpha (FRA) is an attractive candidate for targeted diagnostics and therapeutics. However, applicability of these agents in residual or recurrent disease could be influenced by chemotherapy. We evaluated whether chemotherapy modified FRA expression in non-mucinous epithelial ovarian (EOC) and endometrial carcinoma (EC). METHODS: FRA staining was evaluated by immunohistochemistry, using MAb 26B3, in 81 patients (41 EOCs and 40 ECs) and 17 control tissues (5 benign ovarian cysts, 5 normal ovarian, and 7 normal endometrial tissues). Chemotherapy effect was evaluated in 42 patients (30 paired samples at primary and interval debulking surgery and 12 from primary and recurrent disease). FRA expression was assessed using a semi-quantitative staining algorithm, the M-score (range 0-50). RESULTS: Median difference in M-score between tumor and control samples was 27.5 for EOC (95% CI 10.0 to 45.0) and 6.7 for EC (95% CI -6.7 to 21.7). Paired samples from both primary and interval debulking surgery did not differ in FRA expression in EOC (median difference of M-score between paired samples of 0.0 [95% CI -2.6 to 2.6]). Recurrent EOC tumors reflected FRA status at diagnosis (median difference of M-score between paired samples of 3.3 [95% CI -7.0 to 13.6]). CONCLUSIONS: This study shows no significant difference in FRA expression after chemotherapy, strengthening the rationale for FRA targeted diagnostics and therapeutics in FRA expressing tumors, whether newly diagnosed or at recurrence.

Adjunctive GnRH-a treatment attenuates depletion of ovarian reserve associated with cyclophosphamide therapy in premenopausal SLE patients.

BACKGROUND: We measured antimullerian hormone (AMH), a marker of ovarian reserve, in women with lupus treated with cyclophosphamide (CYC) (group I), CYC plus gonadotropin-releasing hormone agonist (GnRH-a) (group II) or neither (group III). We hypothesized that AMH would be diminished in women exposed to CYC versus women receiving adjunctive GnRH-a treatment or no CYC exposure. METHODS: Forty-eight premenopausal lupus patients were retrospectively divided into three treatment groups: CYC alone (group I, n = 11), CYC + GnRH-a (group II, n = 10) and neither (group III, n = 27). Serum AMH levels between groups were compared using a nonparametric test (Wilcoxon rank-sum). Multiple linear regression adjusting for age was performed. RESULTS: AMH (ng/mL) levels at the last collection were significantly lower in group I versus group III (mean ± SD: 0.18 ± 0.20 group I vs 1.33 ± 1.59 group III; p = 0.015), and versus group II (mean ± SD: 0.86 ± 1.06; p = 0.018). When centered on age 30 years, average AMH levels for group I, group II and group III were 0.20, 0.44 and 1.00, respectively. When adjusted for age, AMH between all groups was significantly different (p<0.0001). CONCLUSION: Posttreatment AMH levels were significantly higher among patients receiving CYC + GnRH-a compared to CYC alone, suggesting that GnRH-a coadministration mitigates CYC-induced ovarian injury.

Effects of prasterone (dehydroepiandrosterone) on markers of cardiovascular risk and bone turnover in premenopausal women with systemic lupus erythematosus: a pilot study.

DHEA (dehydroepiandrosterone) is a weak androgen with proposed efficacy in the treatment of mild to moderate lupus, and possible beneficial effects on cardiovascular risk and bone mineral density. We hypothesized that treatment with 200 mg a day of Prasterone (DHEA) would improve pre-clinical measures of atherosclerosis: flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD), and circulating apoptotic endothelial cells (CD 146(AnnV +)), as well markers of bone metabolism. Thirteen premenopausal female patients with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)

Delayed lupus nephritis.

OBJECTIVE: To describe and analyse the clinical and immunological characteristics of a large series of patients with delayed lupus nephritis (LN). METHODS: A cross-sectional study was carried out. Patients with systemic lupus erythematosus (SLE) who developed renal involvement >or=5 years after the first manifestation(s) of the disease (delayed LN, n = 48) were compared with patients with SLE in whom LN developed within 5 years or less after SLE appeared (early-onset LN, n = 187). A control group, the no LN (NLN) group, comprised patients with longstanding SLE (duration of disease >10 years) who had never shown signs of renal involvement (n = 164). RESULTS: The group with delayed LN was positively associated with Sjögren's syndrome, lung involvement and antiphospholipid syndrome as compared with early LN. However, its renal clinical expression and histopathological patterns were similar to those of early-onset LN. The frequency of anti-dsDNA, anti-Sm and anti-RNP antibodies was higher in patients with LN than in the NLN group, as was the frequency of low complement levels. Jaccoud's arthropathy was a protective factor for nephritis. CONCLUSIONS: Delayed LN is not uncommon in patients with SLE. The identified risk factors might aid in its diagnosis and enhance the ability to identify patients at risk for this complication of SLE.

Prenatal Omega-3 Supplementation and Eczema Risk among Offspring at Age 36 Months.

BACKGROUND: Long-term follow-up was completed in 84 mother-infant pairs of 118 women who completed a randomized controlled trial of prenatal supplementation with EPA- or DHA-rich fish oil or soy oil placebo. The goal of this study was to determine whether prenatal omega-3 fatty acid supplementation protects offspring against development of early childhood allergies. METHODS AND FINDINGS: Assessment of childhood allergic/atopic disease among offspring at age 36 months was performed by maternal interview using the National Health Interview Survey (NHIS) questions for childhood digestive allergies, wheezing, eczema or skin allergy, and respiratory allergy. Multiple logistic regressions examined the association between prenatal supplementation and childhood outcomes, adjusted for covariates. Eczema was reported in 26/84 (31%) of offspring at age 36 months, and was significantly more prevalent in the omega-3 supplementation groups vs. placebo: EPA 13/31 (41.9%); DHA 10/26 (38.5%); placebo 3/27 (11.1%), p=0.019. Compared to placebo, EPA and DHA were associated with ≥5 times risk of offspring eczema [odds ratios (ORs): EPA 5.8 (95% CI 1.4-23.3); DHA 5.0 (95% CI 1.2-21.0)]. After adjusting for other potential risk factors (race, birth weight, vaginal/Cesarean delivery, and maternal eczema) the magnitudes of association for omega-3 supplementation increased: EPA OR 8.1 (95% CI 1.4-45.6); DHA OR 9.6 (95% CI 1.6-58.5). Maternal eczema was also significantly associated with offspring eczema in the adjusted model: OR 10.8 (95% CI 2.1-54.3). CONCLUSION: Contrary to our hypothesis, acids supplementation compared to soy oil was associated with a substantial increase in risk of childhood eczema. This association was not observed on childhood respiratory or digestive outcomes. It is unclear if these findings were driven by unfavorable effects of omega-3s, or whether there may have been unanticipated protective effects of the soy-based placebo with regards to eczema.

Histopathologic study of nine branch retinal vein occlusions.

Occlusions of nine branch retinal veins in eight eyes of seven patients were studied histopathologically by serial sections through the affected areas. Intravitreal neovascularization from the disc, retina, or both was noted in four eyes. Two additional eyes had intraretinal neovascularization (intraretinal microvascular abnormalities). Cystoid macular edema was present in five eyes. A fresh or recanalized thrombus was noted at the site of vein occlusion in all eyes. Inner ischemic atrophy of the retina was found distal to the area of occlusion in six of the nine affected quadrants of the eight eyes. Although the corresponding branch retinal arteries showed varying degrees of sclerosis (severe, three eyes; moderate, five eyes; and minimal, one eye), no definite thrombus was observed in any of them.

Risk assessment of drugs.

The value of risk-benefit analysis for drugs is outlined with emphasis on its special qualities compared with decisions on environmental agents, occupational risks and other societal risks. Consideration is given to the issue of risk perception and examples given of risk assessment in practice in Canada for Bendectin, isotretinoin, bovine somatropin (somatotrophin) and oral contraceptives. The changes in regulatory approaches for AIDS drugs are noted. It is suggested that an understanding of the risk-benefit balance should be incorporated into the drug evaluation process, perhaps eventually by the use of quality-of-life measures.

Effect of trisodium phosphate on biofilm and planktonic cells of Campylobacter jejuni, Escherichia coli O157: H7, Listeria monocytogenes and Salmonella typhimurium.

Trisodium phosphate (TSP) has been approved by the United States Department of Agriculture as a post-chill antimicrobial treatment for raw poultry. This study examines the effectiveness of TSP against planktonic (suspended) and biofilm (attached) cells of Campylobacter jejuni, Escherichia coli O157:H7, Listeria monocytogenes and Salmonella typhimurium at room temperature (RT) and 10 degrees C. At either temperature E. coli O157:H7 was the most sensitive to TSP treatments; 10(6) cfu/ml of planktonic or 10(5) cfu/cm2 of biofilm cells were eliminated by a 30 s treatment with 1% TSP. Campylobacter jejuni was slightly less sensitive. Listeria monocytogenes was the most resistant to the effect of TSP, requiring exposure to 8% TSP for 10 min (RT) or 20 min (10 degrees C) to reduce biofilm bacteria by at least one log. Biofilm cells of S. typhimurium and Listeria monocytogenes were more resistant than planktonic cells. Salmonella typhimurium was more sensitive to treatments using TSP at 10 degrees C than at RT. In contrast, L. monocytogenes was more resistant to TSP at 10 degrees C. Trisodium phosphate appears to be an effective treatment for reducing populations of C. jejuni, E. coli O157:H7 and S. typhimurium. This product has the potential to be used for reduction of bacterial counts on other food products besides raw poultry or on food and non-food contact surfaces.

The effects of prior growth as a biofilm on the virulence of Salmonella typhimurium for mice.

Relatively little is known about how growth as a biofilm affects the virulence of pathogenic bacteria. In this study, the virulence of Salmonella typhimurium grown as a biofilm, or as planktonic cells, was compared in mice. Increased numbers of colony forming units were recovered from the spleens of mice 5 days after i.p. injection with S. typhimurium grown as a biofilm, as compared with planktonic cells (P < 0.05). No significant difference in the CFU of S. typhimurium recovered from the liver was noted at the same time point, and no difference was noted in the CFU recovered from the spleen or liver at 5 days after i.v. or i.g. inoculation with 10(5) S. typhimurium. Nor were any differences noted at 7 days after i.p., i.v. or i.g. inoculation. Thus, any effect of growth as a biofilm has on the virulence of S. typhimurium seems to be limited to the first 5 days after i.p. inoculation.

Behavioral signs of central auditory processing disorder and attention deficit hyperactivity disorder.

Central auditory processing disorder (CAPD) and attention deficit hyperactivity disorder (ADHD) present overlapping symptomatology. Attention and listening problems, maladaptive behavior, distractibility, instruction-following difficulty, and increased time required to complete tasks appear on checklists purportedly characterizing behaviors exhibited by individuals with CAPD and ADHD. The present study compared audiologists' and pediatricians' rankings of 41 behavioral symptoms associated with ADHD and CAPD. Audiologists ranked the degree to which each item pertained to individuals with CAPD and pediatricians ranked the same items as related to ADHD. Item analysis revealed that only two of the most frequently cited behaviors were judged as characteristic of both disorders (i.e., inattention and distractibility). The majority of frequently cited behaviors were not seen as common to ADHD and CAPD.

The circadian clock in oral health and diseases.

Most physiological processes in mammals display circadian rhythms that are driven by the endogenous circadian clock. This clock is comprised of a central component located in the hypothalamic suprachiasmatic nucleus and subordinate clocks in peripheral tissues. Circadian rhythms sustain 24-hour oscillations of a large number of master genes controlling the correct timing and synchronization of diverse physiological and metabolic processes within our bodies. This complex regulatory network provides an important communication link between our brain and several peripheral organs and tissues. At the molecular level, circadian oscillations of gene expression are regulated by a family of transcription factors called "clock genes". Dysregulation of clock gene expression results in diverse human pathological conditions, including autoimmune diseases and cancer. There is increasing evidence that the circadian clock affects tooth development, salivary gland and oral epithelium homeostasis, and saliva production. This review summarizes current knowledge of the roles of clock genes in the formation and maintenance of oral tissues, and discusses potential links between "oral clocks" and diseases such as head and neck cancer and Sjögren's syndrome.

Density, calibre and ramification of muscle capillaries are altered in a mouse model of severe spinal muscular atrophy.

Spinal muscular atrophy (SMA) is traditionally described and characterised as a disease of the neuromuscular system. Recently, the vascular system has been implicated in SMA pathogenesis, but there are no reports on whether this impacts on skeletal muscle microvasculature. Using an established mouse model of severe SMA (Smn(-/-);SMN2(+/+)), we examined the capillary bed in three different skeletal muscles using quantitative imaging and western blotting in late symptomatic mice (P5). We found a dramatic (45%) decrease in the density of the capillary bed in all muscles examined compared to littermate controls at early and late symptomatic time points, and reduced expression of a key endothelial protein, PECAM-1. In addition, capillary calibre was increased by 50% in SMA mice while ramification of capillaries into muscle was reduced. Investigation of earlier developmental time points revealed identical changes at an early symptomatic time point (P3), but significantly, no difference at a pre-symptomatic time point (P1). These changes are likely to have considerable impact on the ability of the muscle capillary bed to deliver oxygen and remove metabolites from muscle and may therefore contribute to pathogenesis in SMA.

Plasma-enhanced synthesis of bactericidal quaternary ammonium thin layers on stainless steel and cellulose surfaces.

We have investigated bottom-up chemical synthesis of quaternary ammonium (QA) groups exhibiting antibacterial properties on stainless steel (SS) and filter paper surfaces via nonequilibrium, low-pressure plasma-enhanced functionalization. Ethylenediamine (ED) plasma under suitable conditions generated films rich in secondary and tertiary amines. These functional structures were covalently attached to the SS surface by treating SS with O 2 and hexamethyldisiloxane plasma prior to ED plasma treatment. QA structures were formed by reaction of the plasma-deposited amines with hexyl bromide and subsequently with methyl iodide. Structural compositions were examined by electron spectroscopy for chemical analysis and Fourier transform infrared spectroscopy, and surface topography was investigated with atomic force microscopy and water contact angle measurements. Modified SS surfaces exhibited greater than a 99.9% decrease in Staphylococcus aureus counts and 98% in the case of Klebsiella pneumoniae. The porous filter paper surfaces with immobilized QA groups inactivated 98.7% and 96.8% of S. aureus and K. pneumoniae, respectively. This technique will open up a novel way for the synthesis of stable and very efficient bactericidal surfaces with potential applications in development of advanced medical devices and implants with antimicrobial surfaces.