Leptospiral lipopolysaccharide dampens inflammation through upregulation of autophagy adaptor p62 and NRF2 signaling in macrophages.
Leptospira interrogans are pathogenic bacteria responsible for leptospirosis, a worldwide zoonosis. All vertebrates can be infected, and some species like humans are susceptible to the disease whereas rodents such as mice are resistant and become asymptomatic renal carriers. Leptospires are stealth bacteria that are known to escape several immune recognition pathways and resist killing mechanisms. We recently published that leptospires may survive intracellularly in and exit macrophages, avoiding xenophagy, a pathogen-targeting form of autophagy. Interestingly, the latter is one of the antimicrobial mechanisms often highjacked by bacteria to evade the host immune response. In this study we explored whether leptospires subvert the key molecular players of autophagy to facilitate infection. We showed in macrophages that leptospires triggered a specific accumulation of autophagy-adaptor p62 in puncta-like structures, without altering autophagic flux. We demonstrated that Leptospira-induced p62 accumulation is a passive mechanism depending on the leptospiral virulence factor LPS signaling via TLR4/TLR2. p62 is a central pleiotropic protein, also mediating cell stress and death, via the translocation of transcription factors. We demonstrated that Leptospira-driven accumulation of p62 induced the translocation of transcription factor NRF2, a key player in the anti-oxidant response. However, NRF2 translocation upon Leptospira infection did not result as expected in antioxydant response, but dampened the production of inflammatory mediators such as iNOS/NO, TNF and IL6. Overall, these findings highlight a novel passive bacterial mechanism linked to LPS and p62/NRF2 signaling that decreases inflammation and contributes to the stealthiness of leptospires.


A novel single domain bispecific antibody targeting VEGF and TNF-α ameliorates rheumatoid arthritis.
Anti-TNF-α therapy fails in 30% of patients, where TNF-α may not be the key causative factor in these patients. We developed a bispecific single-domain antibody block TNF-α and VEGF (V5-3).The experiments showed that V5-3 effectively activated proliferation and migration of RA-FLS and HUVEC, tube-forming role of HUVEC, and expression of inflammatory factors in vitro. Besides, the experiments indicated that the anti-RA activity of V5-3 was superior to Anbainuo in vivo. Application of V5-3 reduced the expression of inflammatory factors, extent of synovial inflammation and angiogenesis and attenuated the severity of autoimmune arthritis in collagen-induced arthritis (CIA) mice. Mechanistically, V5-3 suppressed p65, AKT and VEGFR2 phosphorylation, as well as production of TNF-α and VEGF in joint tissues. These results demonstrated that V5-3 displayed a superior effect of anti-RA, may be a new therapy to overcome the limitations of anti-TNF-α monoclonal antibody.


Transgenic overexpression of ADAM12 suppresses muscle regeneration and aggravates dystrophy in aged mdx mice.
Muscular dystrophies are characterized by insufficient restoration and gradual replacement of the skeletal muscle by fat and connective tissue. ADAM12 has previously been shown to alleviate the pathology of young dystrophin-deficient mdx mice, a model for Duchenne muscular dystrophy. The observed effect of ADAM12 was suggested to be mediated via a membrane-stabilizing up-regulation of utrophin, alpha7B integrin, and dystroglycans. Ectopic ADAM12 expression in normal mouse skeletal muscle also improved regeneration after freeze injury, presumably by the same mechanism. Hence, it was suggested that ADAM12 could be a candidate for nonreplacement gene therapy of Duchenne muscular dystrophy. We therefore evaluated the long-term effect of ADAM12 overexpression in muscle. Surprisingly, we observed loss of skeletal muscle and accelerated fibrosis and adipogenesis in 1-year-old mdx mice transgenically overexpressing ADAM12 (ADAM12(+)/mdx mice), even though their utrophin levels were mildly elevated compared with age-matched controls. Thus, membrane stabilization was not sufficient to provide protection during prolonged disease. Consequently, we reinvestigated skeletal muscle regeneration in ADAM12 transgenic mice (ADAM12(+)) after a knife cut lesion and observed that the regeneration process was significantly impaired. ADAM12 seemed to inhibit the satellite cell response and delay myoblast differentiation. These results discourage long-term therapeutic use of ADAM12. They also point to impaired regeneration as a possible factor in development of muscular dystrophy.


Insomnia and health-related quality of life in stroke.
Insomnia is a common complaint in stroke survivors. Insomnia after stroke is correlated with physical disability, dementia, anxiety, depression, and fatigue. However, the influence of insomnia following stroke on health-related quality of life (HRQoL) has not been investigated. The current study aimed to examine the effect of insomnia on HRQoL in stroke survivors 3 months after their index stroke over and above confounding variables. Three hundred and thirty-six patients were recruited from the acute stroke unit in a regional hospital in Hong Kong. Insomnia was ascertained by a single item on a locally validated, seven-item insomnia questionnaire. HRQoL was measured by the total score and the 12 domain scores of the Stroke Specific Quality of Life (SSQoL) scale. Demographic and clinical characteristics were obtained using the following scales: National Institutes of Health Stroke Scale (NIHSS), Barthel Index (BI), Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS). Forty-four percent of stroke survivors reported experiencing insomnia in the past month; they were more likely to be female and to have a higher GDS score. The insomnia group had significantly lower overall SSQoL, energy and thinking scores after adjusting for sex, BI, and GDS scores. The findings show that stroke survivors who experienced insomnia had a reduced overall HRQoL and were impaired in the energy and thinking domains of HRQoL. Early screening for sleep disturbance would be beneficial to prevent later development of post-stroke insomnia. Pharmacological and non-pharmacological interventions are suggested to improve HRQoL in stroke patients with insomnia.


Perceived psychosocial job stress and sleep bruxism among male and female workers.
Psychosocial job stress has been associated with sleep disturbances, but its association with sleep bruxism (SB), the stereotype movement disorder related to sleep, is not well understood. The aim of this epidemiological study was to examine the relationship between psychosocial job stress and SB. 1944 male and 736 female factory workers participated in this study (response rate 78.1%). Perceived job stress was evaluated with the Japanese version of the generic job stress questionnaire, which covered 13 job stress variables. SB was assessed by the question, 'Do you grind or clench your teeth during your sleep or has anyone in your family told you that you grind your teeth during your sleep?' Response options were 'never', 'seldom', 'sometimes' or 'often'. SB was considered present if the answer was 'sometimes' or 'often'. Overall, 30.9% of males and 20.2% of females reported SB. In males, workers with low social support from supervisors [odds ratio (OR) = 1.34, 95% confidence interval (CI) 1.08-1.68] or from colleagues (OR 1.47, 95% CI 1.17-1.83), and high depressive symptoms (OR 1.60, 95% CI 1.26-2.03) had a significantly increased risk of SB after controlling for confounders. By contrast, no significant association was found in females. We conclude that SB is weakly associated with some aspects of job stress in men but not in women among the Japanese working population.


The influence of atmosphere on the performance of pure-phase WZ and ZB InAs nanowire transistors.
We compare the characteristics of phase-pure MOCVD grown ZB and WZ InAs nanowire transistors in several atmospheres: air, dry pure N2 and O2, and N2 bubbled through liquid H2O and alcohols to identify whether phase-related structural/surface differences affect their response. Both WZ and ZB give poor gate characteristics in dry state. Adsorption of polar species reduces off-current by 2-3 orders of magnitude, increases on-off ratio and significantly reduces sub-threshold slope. The key difference is the greater sensitivity of WZ to low adsorbate level. We attribute this to facet structure and its influence on the separation between conduction electrons and surface adsorption sites. We highlight the important role adsorbed species play in nanowire device characterisation. WZ is commonly thought superior to ZB in InAs nanowire transistors. We show this is an artefact of the moderate humidity found in ambient laboratory conditions: WZ and ZB perform equally poorly in the dry gas limit yet equally well in the wet gas limit. We also highlight the vital role density-lowering disorder has in improving gate characteristics, be it stacking faults in mixed-phase WZ or surface adsorbates in pure-phase nanowires.


Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study.
To compare survival and toxicity in adult patients treated with low-dose (50.4 Gy/28 fractions) versus high-dose (64.8 Gy/36 fractions) localized radiation therapy (RT) for supratentorial low-grade astrocytoma, oligodendroglioma, and mixed oligoastrocytoma. From 1986 to 1994, 203 eligible/analyzable patients were randomized: 101 to low-dose RT, 102 to high-dose RT. Almost half were younger than 40 years, and 95% had grade 2 tumors. Histologic subtype was astrocytoma (or mixed oligo-astrocytoma with astrocytoma dominant) in 32% of patients and oligodendroglioma (or oligoastrocytoma with oligodendroglioma dominant) in 68%. Tumor diameter was less than 5 cm in 35% of patients, and 41% of tumors showed some degree of contrast enhancement. Extent of resection was gross total in 14% of patients, subtotal in 35%, and biopsy only in 51%. At the time of the present analysis, 83 patients (41%) are dead, and median follow-up is 6.43 years in the 120 who are still alive. Survival at 2 and 5 years is nonsignificantly better with low-dose RT; survival at 2 and 5 years was 94% and 72%, respectively, with low-dose RT and 85% and 64%, respectively, with high-dose RT (log rank P =.48). Multivariate analysis identified histologic subtype, tumor size, and age as the most significant prognostic factors. Survival is significantly better in patients who are younger than 40 years and in patients who have oligodendroglioma or oligo-dominant histology. Grade 3 to 5 radiation neurotoxicity (necrosis) was observed in seven patients, with one fatality in each treatment arm. The 2-year actuarial incidence of grade 3 to 5 radiation necrosis was 2.5% with low-dose RT and 5% with high-dose RT. This phase III prospective randomized trial of low- versus high-dose radiation therapy for adults with supratentorial low-grade astrocytoma, oligodendroglioma, and oligoastrocytoma found somewhat lower survival and slightly higher incidence of radiation necrosis in the high-dose RT arm. The most important prognostic factors for survival are histologic subtype, tumor size, and age. The study design of the ongoing intergroup trial in this population will be discussed.


Municipal solid waste compost application improves productivity, polyphenol content, and antioxidant capacity of Mesembryanthemum edule.
Organic wastes were successfully used as soil amendment to improve agrosystems productivity. Yet, the effectiveness of this practice to enhance plant antioxidant capacities has received little attention. Here, we assess the effect of municipal solid waste (MSW) compost (at 40 t ha(-1)) on growth, polyphenol contents and antioxidant activities of Mesembryanthemum edule. MSW compost application significantly increased the soil contents of carbon, nitrogen, calcium, phosphorus and potassium. This was associated with higher nutrient (N, P, and K) uptake, which likely led to the significant improvement of the plant biomass and relative growth rate (RGR) (+93% on average) as compared to the control. In the same way, the fertilizing effect of the added organic matter significantly enhanced the antioxidant potential M. edule, assessed by radical scavenging activity, iron reducing power and β-carotene bleaching capacity. This was associated with significantly higher antioxidant contents, mainly total phenols and flavonoids. Heavy metal (Pb, Cd, Cu, and Zn) concentrations were slightly increased upon compost application, but remained lower than phytotoxic values. Overall, our results point out that short-term MSW compost application at 40 t ha(-1) is efficient in enhancing the productivity together with the antioxidant potentiality of M. edule without any adverse environmental impact.


Relationship between prescribing of antibiotics and other medicines in primary care: a cross-sectional study.
High levels of antibiotic prescribing are a major concern as they drive antimicrobial resistance. It is currently unknown whether practices that prescribe higher levels of antibiotics also prescribe more medicines in general. To evaluate the relationship between antibiotic and general prescribing levels in primary care. Cross-sectional study in 2014-2015 of 6517 general practices in England using NHS digital practice prescribing data (NHS-DPPD) for the main study, and of 587 general practices in the UK using the Clinical Practice Research Datalink for a replication study. Linear regression to assess determinants of antibiotic prescribing. NHS-DPPD practices prescribed an average of 576.1 antibiotics per 1000 patients per year (329.9 at the 5th percentile and 808.7 at the 95th percentile). The levels of prescribing of antibiotics and other medicines were strongly correlated. Practices with high levels of prescribing of other medicines (a rate of 27 159.8 at the 95th percentile) prescribed 80% more antibiotics than low-prescribing practices (rate of 8815.9 at the 5th percentile). After adjustment, NHS-DPPD practices with high prescribing of other medicines gave 60% more antibiotic prescriptions than low-prescribing practices (corresponding to higher prescribing of 276.3 antibiotics per 1000 patients per year). Prescribing of non-opioid painkillers and benzodiazepines were also strong indicators of the level of antibiotic prescribing. General prescribing levels were a much stronger driver for antibiotic prescribing than other risk factors, such as deprivation. The propensity of GPs to prescribe medications generally is an important driver for antibiotic prescribing. Interventions that aim to optimise antibiotic prescribing will need to target general prescribing behaviours, in addition to specifically targeting antibiotics.


Deficiency in phosphorylase phosphatase activity despite elevated protein phosphatase type-1 catalytic subunit in skeletal muscle from insulin-resistant subjects.
Glycogen synthase is activated by protein phosphatase type-1 (PP-1). The spontaneous PP-1 activity accounts for only a small fraction of total PP-1 activity, which can be exposed by trypsin digestion of inhibitor proteins in the presence of Mn2+. We determined total PP-1 activity in muscle biopsies from insulin-sensitive and -resistant nondiabetic Pima Indians. Inhibitor-2 sensitive PP-1 represented 90% of total phosphatase activity. Spontaneous and total PP-1 activities were reduced in insulin resistant subjects (P less than 0.05-0.01), suggesting that the reduced PP-1 activity is not the result of inhibition by trypsin-labile phosphatase regulatory subunits. This difference was further investigated by Western blots using two different antibodies. An antibody raised against the rabbit muscle PP-1 catalytic subunit was used to analyze muscle extracts concentrated by DEAE-Sepharose adsorption. An antibody raised against a peptide derived from the COOH-terminal end of the PP-1 catalytic subunit was used to analyze crude muscle extracts. Both antibodies recognized a PP-1 catalytic subunit of approximately 33 kD, which unexpectedly was more abundant in insulin-resistant subjects (P less than 0.05-0.01). The increase in the tissue PP-1 protein content may be a response to compensate for the impairment in the enzyme activity.


Reducing prescribing error: competence, control, and culture.
Medication errors are probably the most prevalent form of medical error, and prescribing errors are the most important source of medication errors. In this article we suggest interventions are needed at three levels to improve prescribing: (1) improve the training, and test the competence, of prescribers; (2) control the environment in which prescribers perform in order to standardise it, have greater controls on riskier drugs, and use technology to provide decision support; and (3) change organisational cultures, which do not support the belief that prescribing is a complex, technical, act, and that it is important to get it right. Solutions involve overt acknowledgement of this by senior clinicians and managers, and an open process of sharing and reviewing prescribing decisions.


NAC Transcription Factor GmNAC12 Improved Drought Stress Tolerance in Soybean.
NAC transcription factors (TFs) could regulate drought stresses in plants; however, the function of NAC TFs in soybeans remains unclear. To unravel NAC TF function, we established that GmNAC12, a NAC TF from soybean (Glycine max), was involved in the manipulation of stress tolerance. The expression of GmNAC12 was significantly upregulated more than 10-fold under drought stress and more than threefold under abscisic acid (ABA) and ethylene (ETH) treatment. In order to determine the function of GmNAC12 under drought stress conditions, we generated GmNAC12 overexpression and knockout lines. The present findings showed that under drought stress, the survival rate of GmNAC12 overexpression lines increased by more than 57% compared with wild-type plants, while the survival rate of GmNAC12 knockout lines decreased by at least 46%. Furthermore, a subcellular localisation analysis showed that the GmNAC12 protein is concentrated in the nucleus of the tobacco cell. In addition, we used a yeast two-hybrid assay to identify 185 proteins that interact with GmNAC12. Gene ontology (GO) and KEGG analysis showed that GmNAC12 interaction proteins are related to chitin, chlorophyll, ubiquitin-protein transferase, and peroxidase activity. Hence, we have inferred that GmNAC12, as a key gene, could positively regulate soybean tolerance to drought stress.


Receiver operating characteristic (ROC) curves to identify birth weight cutoffs to predict overweight in Mexican school children.
To identify birth weight cutoffs to predict overweight in school children and adolescents from Chilpancingo, Mexico, in 2004. Six hundred and sixty-two male and female children between 5 and 13 years old were selected by probability sampling. Birth weight measures were extracted from vaccination cards. The school children's nutritional status was defined using specific body mass index (BMI) cutoffs according to sex and age. Predicting equations were built using linear regression models. Areas under the receiver operating characteristic (ROC) curves were calculated and two-graph (TG) ROC curves were plotted, respectively, to detect global accuracy and to identify birth weight cutoffs corresponding to the intersection of sensitivity and specificity curves. Overweight prevalence was higher in female (46%) than male school children (38.5%). Among adolescents, overweight prevalence was also higher in females (43.5%) than males (38.9%). BMI average and birth weight deciles showed a linear relation. Areas under ROC curves showed values > or = 78% in each stratum of sex and age, depicting a difference by sex in adolescents. TG-ROC curves showed that birth weight cutoffs were slightly higher in boys than in girls, and the sensitivity/specificity intersections were > or = 0.70. The study results showed that birth weight cutoffs can be used as overweight markers in childhood and adolescence, being useful as a screening strategy to detect risk groups.


Instability, laxity, and physical function in patients with medial knee osteoarthritis.
Studies have identified factors that contribute to functional limitations in people with knee osteoarthritis (OA), including quadriceps femoris muscle weakness, joint laxity, and reports of knee instability. However, little is known about the relationship among these factors or their relative influence on function. The purpose of this study was to investigate self-reported knee instability and its relationships with knee laxity and function in people with medial knee osteoarthritis (OA). Fifty-two individuals with medial knee OA participated in the study. Each participant was classified into 1 of 3 groups based on reports of knee instability. Limb alignment, knee laxity, and quadriceps femoris muscle strength (force-generating capacity) were assessed. Function was measured with the Knee Injury and Osteoarthritis Outcome Score (KOOS) and a stair-climbing test (SCT). Group differences were detected with one-way analyses of variance, and relationships among variables were assessed with the Eta(2) statistic and hierarchical regression analysis. There were no differences in alignment, laxity, or strength among the 3 groups. Self-reported knee instability did not correlate with medial laxity, limb alignment, or quadriceps femoris muscle strength. Individuals reporting worse knee instability scored worse on all subsets of the KOOS. Self-reported knee instability scores significantly contributed to the prediction of all measures of function above that explained by quadriceps femoris muscle force, knee laxity, and alignment. Neither laxity nor alignment contributed to any measure of function. Self-reported knee instability is a factor that is not directly associated with knee laxity and contributes to worse function. Further research is necessary to delineate the factors that contribute to self-reported knee instability and reduced function in this population.


A tricotage-like failure of nanographene.
The response of a nanographene sheet to external stresses was considered in terms of a mechanochemical reaction. The quantum chemical realization of the approach was based on the coordinate-of-reaction concept for the purpose of introducing a mechanochemical internal coordinate (MIC) that specifies a deformational mode. The related force of response is calculated as the energy gradient along the MIC, while the atomic configuration is optimized over all of the other coordinates under the MIC constant-pitch elongation. The approach is applied to the benzene molecule and (5,5) nanographene. A drastic anisotropy in the microscopic behavior of both objects under elongation along a MIC was observed when the MIC was oriented either along or normally to the C-C bond chain. Both the anisotropy and the high stiffness of the nanographene originate from the response of the benzenoid unit to stress.


Non-ST Elevation Acute Coronary Syndromes: A Comprehensive Review.
Non-ST elevation-acute coronary syndrome (NSTE-ACS) includes NSTE myocardial infarction and unstable angina. This patient population forms approximately two-thirds of all hospital admissions for ACS in the United States each year and is associated with an in-hospital mortality of 5%. NSTE-ACS is primarily due to an acute change in the supply and demand balance of coronary perfusion and myocardial oxygen consumption, because of the significant coronary artery obstruction presenting as plaque rupture or erosion. Nevertheless, nonobstructive causes may lead to that same phenomenon by excessive myocardial oxygen demand or reduced coronary supply from hypotension, anemia, or sepsis, including transient coronary vasospasm and endocardial dysfunction. The recent clinical application of high-sensitivity troponin biomarker assays and computer tomography angiography shows promise for improving the diagnosis and the risk stratification of patients with angina symptoms. Implementation of recent updates to the American College of Cardiology/American Heart Association (ACC/AHA) guidelines on NSTE-ACS, especially regarding the selection and duration of antiplatelet therapy, have led to improvement in management and outcomes of this disease. Additionally, new adjunctive therapies and approaches to diagnosis and treatment are discussed. Despite the progress made in recent years in the diagnosis and management of NSTE-ACS, morbidity remains high and mortality is significant. Such a fact suggests that future research targeting prevention, early diagnosis, and intervention in these patients is warranted. This article provides a detailed overview of the most recent information on the pathophysiology, diagnosis, treatment, and prognosis of NSTE-ACS.


Heparin-induced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests.
Laboratory confirmation of heparin-induced thrombocytopenia (HIT) is based on detection of heparin-dependent platelet-activating antibodies. Platelet factor 4 (PF4)/heparin enzyme-immunoassays (EIA) are a widely available surrogate for platelet-activating antibodies. Defining the optical density (OD) reactivity profiles of a PF4/heparin EIA in reference subject and patient populations and the correlation of the EIA results (expressed in OD units) with the prevalence of platelet-activating antibodies. Using quantile regression we determined the 97.5th percentile of PF4/heparin-immunoglobulin G (IgG) EIA reactivities in non-heparin-treated individuals [blood donors (n = 935)] and patients before heparin therapy (n = 1207). In patients with suspected HIT, we compared the correlation of EIA-IgG reactivities (Greifswald laboratory; n = 2821) and the heparin-induced platelet activation assay (HIPA) with the correlation of reactivities of another EIA-IgG (McMaster laboratory; n = 1956) with the serotonin-release assay (SRA). PF4/heparin-IgG EIA OD reactivities had a lower OD 97.5th percentile in blood donors compared with patient groups before heparin treatment (P < 0.001). The percentage of sera testing positive in the functional assays strongly correlated with PF4/heparin-IgG EIA OD reactivities in both laboratories with very similar results (correlation coefficient > 0.9) when normalized OD ranges (maximum OD divided by 10) were used instead of absolute OD values. Results of PF4/heparin-IgG EIA should not be reported as only positive or negative as there is no single acceptable cut-off value. Instead, reporting PF4/heparin-IgG EIA OD results in ranges allows for risk-stratified prediction for presence of platelet-activating antibodies. Use of normalized OD ranges permits a standardized approach for inter-laboratory comparisons.


Structure and function of cis-prenyl chain elongating enzymes.
All carbon skeletons of isoprenoids, whose chain lengths vary widely from geranyl diphosphate (C10) to natural rubber (C>10,000), are synthesized by sequential condensation of isopentenyl diphosphate with an allylic diphosphate through catalytic functions of a group of enzymes commonly called "prenyltransferases." Prenyltransferases are classified into two major groups, trans- or (E)-prenyltransferases and cis- or (Z)-prenyltransferases, according to the geometry of the prenyl chain units in the products. From the year 1987, many genes encoding trans-prenyltransferases were cloned and clearly characterized. In contrast, the structure and detailed mechanism of cis-prenyltransferase was completely unknown until the identification of a gene encoding the undecaprenyl diphosphate (UPP) synthase from Micrococcus luteus B-P 26 in 1998. Not only the primary but also the tertiary structure of the UPP synthase is quite different from that of the trans-prenyltransferases. Multiple alignment of the primary structures of cis-prenyltransferases identified from various organisms reveals five highly conserved regions. Site-directed mutagenesis of the conserved amino acid residues in UPP synthases based on the crystal structure has elucidated the basic catalytic mechanisms. Moreover, comparison of the structures of short-, medium-, and long-chain cis-prenyltransferases reveals important amino acid residues for product chain length determination, which enabled us to understand the regulation mechanism of the ultimate chain length among cis-prenyltransferases.


Antagonism of the Prokineticin System Prevents and Reverses Allodynia and Inflammation in a Mouse Model of Diabetes.
Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is associated with neuroinflammation-related events that participate in pain generation and chronicization. Prokineticins are a new family of chemokines that has emerged as critical players in immune system, inflammation and pain. We investigated the role of prokineticins and their receptors as modulators of neuropathic pain and inflammatory responses in experimental diabetes. In streptozotocin-induced-diabetes in mice, the time course expression of prokineticin and its receptors was evaluated in spinal cord and sciatic nerves, and correlated with mechanical allodynia. Spinal cord and sciatic nerve pro- and anti-inflammatory cytokines were measured as protein and mRNA, and spinal cord GluR subunits expression studied. The effect of preventive and therapeutic treatment with the prokineticin receptor antagonist PC1 on behavioural and biochemical parameters was evaluated. Peripheral immune activation was assessed measuring macrophage and T-helper cytokine production. An up-regulation of the Prokineticin system was present in spinal cord and nerves of diabetic mice, and correlated with allodynia. Therapeutic PC1 reversed allodynia while preventive treatment blocked its development. PC1 normalized prokineticin levels and prevented the up-regulation of GluN2B subunits in the spinal cord. The antagonist restored the pro-/anti-inflammatory cytokine balance altered in spinal cord and nerves and also reduced peripheral immune system activation in diabetic mice, decreasing macrophage proinflammatory cytokines and the T-helper 1 phenotype. The prokineticin system contributes to altered sensitivity in diabetic neuropathy and its inhibition blocked both allodynia and inflammatory events underlying disease.


Serial LPS without serial imaging in idiopathic intracranial hypertension: a lesson learned.
With obscure etiology, confusing terminology, and controversial management, idiopathic intracranial hypertension (IIH), most commonly known as benign intracranial hypertension, remains a common and challenging clinical problem of the general and neurological practice. The authors present a case of a patient who was diagnosed with IIH and treated with serial lumbar punctures for 4 years prior to her final diagnosis of a large intracranial tumor. This case emphasizes that IIH, an enigmatic disease that affects young females and can potentially lead to blindness, should be diagnosed after an exhausting exclusion of secondary causes of intracranial hypertension.


Is there an association between inappropriate prescription drug use and adherence in discharged elderly patients?
Inappropriate prescription drug (IPD) use is very common among older patients. However, its impact on medication continuity and adherence after hospitalization has not been researched, with little known regarding readmissions and mortality. To investigate the prevalence and clinical characteristics of patients discharged with IPDs and examine whether use of these drugs is related to medication continuity and adherence 1 month postdischarge as well as to readmissions and mortality 3 months postdischarge. Clinical and demographic data, postdischarge medication modification, and adherence were prospectively obtained on interview of 212 unselected elderly (aged > or = 65 y) patients or, if necessary, their caregivers. Nonadherence was defined as the percentage of drug doses less than or equal to 70% or greater than or equal to 110%. Medication appropriateness was assessed retrospectively using the Beers' criteria. Use of IPDs occurred in 43.5% and 44.4% of patients on admission and discharge, respectively. At discharge, the numbers of IPDs and prescribed drugs were correlated (R = 0.39; p < 0.01). No relationship was found between IPDs at discharge and age, sex, functional and cognitive status, number of chronic diseases, and reason for admission. Sixty percent of patients who were nonadherent to at least one drug had at least one IPD, compared with 37.4% of the adherent patients (p = 0.008). Nonadherence to at least one drug increased as the number of IPDs on discharge increased (p = 0.004). No relationship was found between IPD use and postdischarge medication modifications, readmissions, and mortality. A high number of hospitalized elderly patients are discharged with IPDs that are directly correlated with the number of prescribed drugs at discharge and postdischarge nonadherence. Further studies are needed to assess the impact of postdischarge IPD use on health outcome, and healthcare providers should work to decrease its prevalence.


Adverse Childhood Experiences and Chronic Disease Risk in the Southern Community Cohort Study.
We used the Southern Community Cohort Study of people residing in 12 states in the southeastern United States (n=38,200 participants) to examine associations between adverse childhood experiences (ACEs) and chronic disease risk. After adjustment for confounding, there were statistically significant positive associations for people reporting four or more ACEs relative to those reporting no ACEs, and this was true for all chronic diseases except hypertension. The most elevated risk was seen for depression when measured as a yes/no variable (odds ratio (OR) 2.84, 95% confidence interval (CI) 2.64-3.06) or when using the 10-item Center for Epidemiologic Student Depression (CESD) scale (OR 1.88, 95% CI 1.75-2.02). There were also statistically significant monotonic increases in risk with worsening ACE score for all chronic diseases except hypertension, cancer, and high cholesterol. The need to establish programs that build resilience during childhood is paramount for preventing chronic diseases that may result from childhood abuse, neglect, and household dysfunction.


Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis.
In patients with rheumatoid arthritis (RA), CD4(+)T cells hyperproliferate during clonal expansion, differentiating into cytokine-producing effector cells that contribute to disease pathology. However, the metabolic underpinnings of this hyperproliferation remain unclear. In contrast to healthy T cells, naïve RA T cells had a defect in glycolytic flux due to the up-regulation of glucose-6-phosphate dehydrogenase (G6PD). Excess G6PD shunted glucose into the pentose phosphate pathway, resulting in NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) accumulation and reactive oxygen species (ROS) consumption. With surplus reductive equivalents, RA T cells insufficiently activated the redox-sensitive kinase ataxia telangiectasia mutated (ATM), bypassed the G2/M cell cycle checkpoint, and hyperproliferated. Moreover, insufficient ATM activation biased T cell differentiation toward the T helper 1 (TH1) and TH17 lineages, imposing a hyperinflammatory phenotype. We have identified several interventions that replenish intracellular ROS, which corrected the abnormal proliferative behavior of RA T cells and successfully suppressed synovial inflammation. Thus, rebalancing glucose utilization and restoring oxidant signaling may provide a therapeutic strategy to prevent autoimmunity in RA.


Characteristics of Innovators Adopting a National Personal Health Record in Portugal: Cross-Sectional Study.
Personal health records (PHRs) are increasingly being deployed worldwide, but their rates of adoption by patients vary widely across countries and health systems. Five main categories of adopters are usually considered when evaluating the diffusion of innovations: innovators, early adopters, early majority, late majority, and laggards. We aimed to evaluate adoption of the Portuguese PHR 3 months after its release, as well as characterize the individuals who registered and used the system during that period (the innovators). We conducted a cross-sectional study. Users and nonusers were defined based on their input, or not, of health-related information into the PHR. Users of the PHR were compared with nonusers regarding demographic and clinical variables. Users were further characterized according to their intensity of information input: single input (one single piece of health-related information recorded) and multiple inputs. Multivariate logistic regression was used to model the probability of being in the multiple inputs group. ArcGis (ESRI, Redlands, CA, USA) was used to create maps of the proportion of PHR registrations by region and district. The number of registered individuals was 109,619 (66,408/109,619, 60.58% women; mean age: 44.7 years, standard deviation [SD] 18.1 years). The highest proportion of registrations was observed for those aged between 30 and 39 years (25,810/109,619, 23.55%). Furthermore, 16.88% (18,504/109,619) of registered individuals were considered users and 83.12% (91,115/109,619) nonusers. Among PHR users, 32.18% (5955/18,504) engaged in single input and 67.82% (12,549/18,504) in multiple inputs. Younger individuals and male users had higher odds of engaging in multiple inputs (odds ratio for male individuals 1.32, CI 1.19-1.48). Geographic analysis revealed higher proportions of PHR adoption in urban centers when compared with rural noncoastal districts. Approximately 1% of the country's population registered during the first 3 months of the Portuguese PHR. Registered individuals were more frequently female aged between 30 and 39 years. There is evidence of a geographic gap in the adoption of the Portuguese PHR, with higher proportions of adopters in urban centers than in rural noncoastal districts.


Influence of urea and guanidine hydrochloride on lysozyme stability and thermal denaturation; a correlation between activity, protein dynamics and conformational changes.
The effect of urea and guanidine hydrochloride (GuHCl) on lysozyme stability has been investigated using activity measurements, microcalorimetry and Raman spectroscopy in the low-frequency and amide I regions. Raman investigations on lysozyme dissolved in H(2)O and D(2)O in the presence of up to 10 M denaturants have revealed direct binding between the protein and both denaturants. The analysis of isotopic exchanges in the amide I region allows the identification of binding sites as hydrophilic and hydrophobic groups, respectively, for urea and GuHCl. The weak loss of activity of lysozyme in the presence of urea (∼15% maximum) is mainly assigned to a transformation of the tertiary structure corresponding to a molten globule state without unfolding of α-helix structures, in contrast to GuHCl which clearly induces conformational changes, associated with a larger loss of activity (40% maximum). The denaturing power of urea and guanidine hydrochloride on lysozyme has been related to the solvent and protein dynamics, reflecting direct interaction between denaturants and protein. It clearly appears that solvent dynamics control protein dynamics, and the significant hardening of the dynamics of GuHCl aqueous solutions is considered responsible for its important denaturing power. The comparison between the low-frequency spectra of solvents and lysozyme aqueous solutions in the absence and presence of different types of additives (urea, GuHCl, trehalose) reveals the Raman signature of the hydration water dynamics. This comparison points out the exclusion of trehalose around the protein surface.


A study of the transmission and structure of double stranded RNAs associated with the killer phenomenon in Saccharomyces cerevisiae.
Killer strains contain two double stranded RNAs, L and M. The M dsRNA appears to be necessary for production of a toxin and for resistance to that toxin. Mutant strains have been found that are defective in their ability to kill and in their resistance to toxin. These sensitive, non-killer strains have altered dsRNA composition. One class has no M dsRNA. Another class of sensitive, non-killers called suppressives has no M dsRNA but instead has smaller dsRNAscalledS. Indiploidsresulting from a cross of a wild-type killer by a suppressive the transmission of the M dsRNA is suppressed by the S dsRNA. When a suppressive is crossed by a strain with no M dsRNA, the diploids and all four meiotic spores have the S dsRNA characteristic of the parental suppressive strain. Suppressive strains do not suppress each other. Intercrosses between two different suppressives yields diploids with both parental S dsRNAs. These two S dsRNAs are transmitted to all 4 meiotic progeny. Another class of mutants has been found which is defective for one of the traits but retains the other. One type, temperature-sensitive killers, has a normal dsRNA composition but is unable to kill at 30 degrees. The other type, immunity-minus, has a complex dsRNA pattern. The immunity-minus strain is extremely unstable during mitotic growth and segregates several different types of non-killers. Analysis of the dsRNAs from wild type and the mutants by electron microscopy shows that the L, M, and S dsRNAs are linear. All strains regardless of killer phenotype appear to have the same size L dsRNA.


The measurement of radiation levels in Australian zircon milling plants.
The processing of zircon often involves grinding it to a fine powder known as zircon flour. As the resulting particles are small they may be inhaled if they become airborne and, since they contain some uranium and thorium, deliver radiation doses to workers. Theoretical estimates and measured radiation exposure in Australian zircon milling plants are reported in this paper. Theoretical doses, calculated in this work, indicate a potential maximum dose to workers of 5.5 mSv y(-1). Measured doses, based on normal work practices, vary in different plants from 0.66 mSv to 1.03 mSv y(-1) and suggest that in the dustiest Australian zircon milling plants the maximum dose would be of the order of 1 mSv y(-1). Measurements, which focused on the dustiest operations, indicate an upper limit of dose of about 3 mSv y(-1). Based on the theoretical and measured doses not exceeding 6 mSv y(-1), workers would not be designated as Category A workers, and probably would not be designated Category B workers, exceeding 1 mSv y(-1), under the guidelines of a EURATOM Directive.


Increased residual variance at developmental switch points: statistical artifact or indicator of exposed genotypic influence?
Discussing the organization of developmental switches, West-Eberhard (2003) proposed the use of regression residual plots to locate the neutral point of the switch, which is characterized by maximum genotypic influence on the resulting phenotype. However, statistical artifacts due to measurement error in nonlinear models might account for a substantial proportion of the increase of residuals variance at the switch point. Simulations based on field data show that increases in residual variance occur as artifacts when normal amounts of measurement error are present, even in absence of any genotypic variance. The results suggest that interpretation of nonlinear variation in thresold traits is problematic and requires considering this statistical effect. A method to estimate the weight of genotypic contribution to residual variance is proposed, and its assumptions and limitations are discussed.


Gastrodin reduces IL-1β-induced apoptosis, inflammation, and matrix catabolism in osteoarthritis chondrocytes and attenuates rat cartilage degeneration in vivo.
Therapeutics for osteoarthritis (OA) are intended to restore chondrocyte function and inhibit cell apoptosis. Previous studies have shown that gastrodin had anti-apoptotic and anti- inflammatory effects. However, little is known about whether gastrodin has protective effects against the processes of OA. We studied the potential effects of gastrodin on chondrocytes and the underlying mechanisms. Our results showed that gastrodin could prevent chondrocyte apoptosis induced by IL-1β. Additionally, gastrodin suppressed the nuclear factor kappa B (NF-κB) pathway, decreased the release of inflammatory mediators (IL-6, TNF-α), and reduced matrix catabolism in IL-1β-treated chondrocytes. Furthermore, gastrodin ameliorated rat cartilage degeneration in an OA model of knee joints in vivo, suggesting its potential as a candidate therapeutic for OA.


Relationships Between Distention-, Butyrate- and Pellet-Induced Stimulation of Peristalsis in the Mouse Colon.
Luminal factors such as short-chain fatty acids are increasingly recognized for playing a regulatory role in peristaltic activity. Our objective was to understand the roles of butyrate and propionate in regulating peristaltic activity in relation to distention-induced activities. Butyrate and propionate were perfused intraluminally under varying intraluminal pressures in murine colons bathed in Krebs solution. We used video recording and spatiotemporal maps to examine peristalsis induced by the intrinsic rhythmic colonic motor complex (CMC) as well as pellet-induced peristaltic reflex movements. The CMC showed several configurations at different levels of excitation, culminating in long distance contractions (LDCs) which possess a triangular shape in murine colon spatiotemporal maps. Butyrate increased the frequency of CMCs but was a much weaker stimulus than distention and only contributed to significant changes under low distention. Propionate inhibited CMCs by decreasing either their amplitudes or frequencies, but only in low distention conditions. Butyrate did not consistently counteract propionate-induced inhibition likely due to the multiple and distinct mechanisms of action for these signaling molecules in the lumen. Pellet movement occurred through ongoing CMCs as well as pellet induced peristaltic reflex movements and butyrate augmented both types of peristaltic motor patterns to decrease the amount of time required to expel each pellet. Butyrate is effective in promoting peristalsis, but only when the level of colonic activity is low such as under conditions of low intraluminal pressure. This suggests that it may play a significant role in patients with poor fiber intake, where there is low mechanical stimulation in the lumen.


The effect of agrochemicals on indicator bacteria densities in outdoor mesocosms.
Water bodies, which are monitored for microbial water quality by quantification of faecal indicator organisms (IOs), can contain various zoonotic pathogens contributed by livestock waste and other sources. Sediments can serve as reservoirs of IOs and other enteric microorganisms, including pathogens. Agrochemicals may influence the survival of these microorganisms in water bodies impacted by livestock waste by enhancing or reducing their survival. Complex, 1100 l, freshwater mesocosms containing leaf litter, zooplankton, periphyton, phytoplankton, and invertebrate and vertebrate animals were used to investigate the response of Escherichia coli and enterococci to agrochemicals. Replicate tanks were treated with atrazine, malathion, chlorothalonil and inorganic fertilizer, either alone at 1× or 2× their expected environmental concentrations (EECs) or in pair-wise combinations at their EECs. IOs inoculated in sediment (∼10⁴ cfu per 100 ml) were enumerated over 28 days. IOs generally declined over time, but manova revealed that addition of fertilizer and atrazine resulted in significantly greater IO densities. Malathion, chlorothalonil and agrochemical concentration (1× vs 2×) did not significantly affect IO densities and no significant interactions between agrochemicals were noted. The augmentation of IO densities in sediments by fertilizer and atrazine may impact their reliability as accurate predictors of water quality and human health risk, and indicates the need for a better understanding of the fate of IOs and enteric pathogens in sediments exposed to agrochemicals.


Carboxymethylcellulose from recycled newspaper in aqueous medium.
Recycled paper cellulose has some drawbacks, for example loss in mechanical strength, to use in paper industry alone. However, derivatives of cellulose can find applications in other industrial areas. Carboxymethylcellulose (CMC) is one of the most used cellulose derivatives and can be obtained by heterogeneous modification of cellulose. In general carboxymethylation of cellulose achieved in alkaline alcoholic dispersions. In this work modification of cellulose from recycled newspaper in aqueous alkaline solution was aimed. First cellulose was recovered from newspaper under oxidative alkaline conditions. Cellulose recovery was determined as 75-90% (w/w) of starting material. Carboxymethylation reactions were carried out to find optimum conditions for derivatization, changing concentrations of components and reaction temperature. Obtained CMC samples had a DS of 0.3-0.7% and 84-94% CMC content. As a result, carboxymethylation of cellulose from recycled newspaper was achieved in aqueous alkaline dispersion giving commercial grade CMC for industrial use.


Proteomic analysis in Giardia duodenalis yields insights into strain virulence and antigenic variation.
Giardia duodenalis is a protozoan parasite of the small intestine in vertebrates, including humans. Assemblage A of G. duodenalis is one of the two discrete subtypes that infects humans, and is considered a zoonotic assemblage. Two G. duodenalis Assemblage A strains BRIS/95/HEPU/2041 and BRIS/83/HEPU/106, constituting virulent and control strains respectively, were analyzed in one of the first comparative shotgun proteomic studies performed in this parasite. Protein extracts were prepared using a multiplatform approach with both an in-gel and in-solution sample preparation to enable us to assess the complementarity for future Giardia proteomic studies. Protein analysis revealed that BRIS/95/HEPU/2041 possessed a wider and more varied repertoire of variant surface proteins (VSPs), which are hypothesized to be involved in host adaptation, immune evasion, and virulence. A total of 35 VSPs were identified, with three common to both strains, six unique to BRIS/82/HEPU/106, and twenty-six unique to BRIS/95/HEPU/2041. Additionally, up to 25.6% of all differentially expressed proteins in BRIS/95/HEPU/2041 belonged to the VSP family, a trend not seen in the control BRIS/83/HEPU/106. Greater antigen variation in BRIS/95/HEPU/2041 may explain aspects of virulence phenotypes in G. duodenalis, with a highly diverse population capable of evading host immune responses.


Structural modifications of mitochondria-targeted chlorambucil alter cell death mechanism but preserve MDR evasion.
Multidrug resistance (MDR) remains one of the major obstacles in chemotherapy, potentially rendering a multitude of drugs ineffective. Previously, we have demonstrated that mitochondrial targeting of DNA damaging agents is a promising tool for evading a number of common resistance factors that are present in the nucleus or cytosol. In particular, mitochondria-targeted chlorambucil (mt-Cbl) has increased potency and activity against resistant cancer cells compared to the parent compound chlorambucil (Cbl). However, it was found that, due to its high reactivity, mt-Cbl induces a necrotic type of cell death via rapid nonspecific alkylation of mitochondrial proteins. Here, we demonstrate that by tuning the alkylating activity of mt-Cbl via chemical modification, the rate of generation of protein adducts can be reduced, resulting in a shift of the cell death mechanism from necrosis to a more controlled apoptotic pathway. Moreover, we demonstrate that all of the modified mt-Cbl compounds effectively evade MDR resulting from cytosolic GST-μ upregulation by rapidly accumulating in mitochondria, inducing cell death directly from within. In this study, we systematically elucidated the advantages and limitations of targeting alkylating agents with varying reactivity to mitochondria.


Awareness, Attitude and Knowledge Regarding Oral Health among Pregnant Women: A Comparative Study.
Pregnancy in a woman's life is associated with many physiological changes in the body due to alterations in the hormone levels. These altered hormonal levels are associated with many systemic diseases. The incidence of oral diseases in general and periodontal diseases in particular are higher in pregnant women, with gingivitis and periodontitis being the most common. Furthermore, it has been evidenced in literature that periodontal diseases are associated with adverse pregnancy outcomes such as preterm low birth weight and preeclampsia. The aim of this study was to evaluate the oral health knowledge among pregnant women visiting and not visiting a dental professional. The study was a survey-based one with a sample size of 260. The study population was divided into two groups based on their visits to a dentist. A questionnaire comprising 20 questions has been used to assess their awareness and attitude towards oral health. The awareness regarding oral health and association with adverse pregnancy outcomes among the study population was very low, irrespective of their dental visit. Furthermore, majority of the study population in neither of the groups were aware that dental treatment was safe during pregnancy. The results of the study clearly reflected that the awareness levels among the pregnant women regarding this association were low. Hence, more collective efforts are required from dental and medical professionals to improve the oral and periodontal health outcomes during pregnancy.


The effect of disturbances on milk production in cows.
Observations were made at the evening and morning milkings immediately before, and the corresponding milkings immediately after, cows had either been injected with tuberculin or disturbed by parties of visitors. At the evening milkings both types of disturbance reduced yield and solids-not-fat (SNF) and protein percentages, but the tuberculin tests increased, and the party visits decreased, the fat percentages. For all these parameters compensatory opposite results were obtained at the milkings the following mornings.


Distinct functions of the RNA polymerase σ subunit region 3.2 in RNA priming and promoter escape.
The σ subunit of bacterial RNA polymerase (RNAP) has been implicated in all steps of transcription initiation, including promoter recognition and opening, priming of RNA synthesis, abortive initiation and promoter escape. The post-promoter-recognition σ functions were proposed to depend on its conserved region σ3.2 that directly contacts promoter DNA immediately upstream of the RNAP active centre and occupies the RNA exit path. Analysis of the transcription effects of substitutions and deletions in this region in Escherichia coli σ(70) subunit, performed in this work, suggests that (i) individual residues in the σ3.2 finger collectively contribute to RNA priming by RNAP, likely by the positioning of the template DNA strand in the active centre, but are not critical to promoter escape; (ii) the physical presence of σ3.2 in the RNA exit channel is important for promoter escape; (iii) σ3.2 promotes σ dissociation during initiation and suppresses σ-dependent promoter-proximal pausing; (iv) σ3.2 contributes to allosteric inhibition of the initiating NTP binding by rifamycins. Thus, region σ3.2 performs distinct functions in transcription initiation and its inhibition by antibiotics. The B-reader element of eukaryotic factor TFIIB likely plays similar roles in RNAPII transcription, revealing common principles in transcription initiation in various domains of life.


Gradual decline in the age-adjusted in-hospital mortality rate from STEMI-related cardiogenic shock irrespective of cause, race or gender with persistent higher mortality rates in women despite multivariate adjustment.
Recent improvements in the care of critically ill patients with cardiogenic shock (CS) should be associated with improved outcomes. The goal of this study was to evaluate the trends of age-adjusted mortality rates for all-cause and ST-elevation myocardial infarction (STEMI)-related CS in the United States. The Nationwide Inpatient Sample (NIS) database was utilized to calculate the age-adjusted mortality rate of all-cause and STEMI-related CS from 1996 to 2006. We used specific ICD- 9 codes for CS and STEMI based on race and gender. We found a gradual decrease in mortality over the 10-year period in patients suffering from all causes or STEMI-related CS irrespective of gender and race with a persistently higher mortality rates in women and African Americans. However, after multivariate adjustment, only female gender remains associated with persistently higher mortality. The age-adjusted mortality rate from STEMI-related CS in women was 2.2% in 1996, with a gradual reduction to the lowest level of 1.7% in 2006 (P<.01). Likewise, the age-adjusted mortality rate from STEMI-related CS in men was 1.7% in 1996, which declined to the lowest level of 1.4% in 2006 (P<.01). Regardless of gender and race, age-adjusted in-hospital mortality is gradually declining in patients presenting with all causes or STEMI-related CS. However, as compared to men, women suffer from persistently higher mortality rates in the setting of STEMI-related CS despite multivariate adjustment.


Beyond rambling and trembling: effects of visual feedback on slow postural drift.
We explored one of the unusual predictions of the concept of back-coupling within the theoretical scheme of the control of posture and movement with setting referent coordinates for the effectors. This concept implies slow drifts of referent coordinates toward actual coordinates leading to unintentional drift in performance. During standing, such slow drifts may lead to a protective step or even a fall and, therefore, corrections are expected leading to body sway at frequencies under 0.1 Hz. Young healthy subjects stood on the force platform quietly for 60 s under two single-task conditions, with eyes open and closed, and two double-task conditions, matching an irrelevant muscle activation signal to a target (MATCH) and performing a subtraction task. The latter was performed with eyes open and closed. The rambling-trembling decomposition was applied to the displacements of the center of pressure in the anterior-posterior direction. Spectral analysis was used to quantify power within typical ranges for Tr and Rm, as well as for a slow Rm component (under 0.1 Hz) addressed as Drift. Closing eyes led to a significant increase in Rm and Tr, but no effects on Drift. Drift increased significantly in the MATCH task with no changes in Rm and a drop in Tr. No effects of the subtraction task were seen on Drift. Overall, our findings suggest that unintentional slow drift of referent body orientation towards the actual body orientation leads to Drift, a specific example of back-coupling reflected in postural sway. This observation can be also seen as an example of physiological minimization of activity of motoneurons. Natural visual feedback is used to avoid the COP drift and/or correct it quickly and effectively; this ability is compromised when vision is used for an unrelated task.


Identification of new biophysical markers for pathological ventricular remodelling in tachycardia-induced dilated cardiomyopathy.
Our aim was to identify biophysical biomarkers of ventricular remodelling in tachycardia-induced dilated cardiomyopathy (DCM). Our study includes healthy controls (N = 7) and DCM pigs (N = 10). Molecular analysis showed global myocardial metabolic abnormalities, some of them related to myocardial hibernation in failing hearts, supporting the translationality of our model to study cardiac remodelling in dilated cardiomyopathy. Histological analysis showed unorganized and agglomerated collagen accumulation in the dilated ventricles and a higher percentage of fibrosis in the right (RV) than in the left (LV) ventricle (P = .016). The Fourier Transform Infrared Spectroscopy (FTIR) 1st and 2nd indicators, which are markers of the myofiber/collagen ratio, were reduced in dilated hearts, with the 1st indicator reduced by 45% and 53% in the RV and LV, respectively, and the 2nd indicator reduced by 25% in the RV. The 3rd FTIR indicator, a marker of the carbohydrate/lipid ratio, was up-regulated in the right and left dilated ventricles but to a greater extent in the RV (2.60-fold vs 1.61-fold, P = .049). Differential scanning calorimetry (DSC) showed a depression of the freezable water melting point in DCM ventricles - indicating structural changes in the tissue architecture - and lower protein stability. Our results suggest that the 1st, 2nd and 3rd FTIR indicators are useful markers of cardiac remodelling. Moreover, the 2nd and 3rd FITR indicators, which are altered to a greater extent in the right ventricle, are associated with greater fibrosis.


Arterial blood supply of the normal human pituitary gland. An anatomical study.
A technique for the removal of sphenoid blocks from cadavers and for selective injection of the hypophyseal arteries of these specimens is described. Results of such injections are presented, with emphasis on the role of the inferior hypophyseal artery (IHA). The IHA was found to be the most important artery supplying the pituitary gland, and in particular, the structures involved in production, transportation, and storage of the antidiuretic hormone. The literature pertinent to the arterial blood supply of the normal pituitary gland is reviewed.


Aspartame: clinical update.
Since the introduction of aspartame into the American food supply in 1981, it has grown to become the most widely used and accepted artificial sweetener. However, recent published and unpublished reports of headaches, seizures, blindness, and cognitive and behavioral changes with long-term, high-dose aspartame may be cause for concern. Physician awareness of the present clinical and research status of aspartame is important.


Strong association between lung cancer and the AXIN2 polymorphism.
Accumulated evidence suggests that alterations due to mutations or genetic polymorphisms in the AXIN2 tumor suppressor gene, a component of the Wnt signaling pathway, contributes to carcinogenesis. The effect of the AXIN2 exon 1 148 C↷T polymorphism was recently investigated in a Japanese population, but has not been investigated in other populations. Additionally, other common polymorphisms of this gene have not been studied. In the present study, 8 polymorphisms of the AXIN2 gene, including exon 1 148 C↷T, were investigated in a Turkish population of 100 lung cancer patients using PCR-RFLP methods. For the exon 1 432 C↷T, exon 5 1365 G↷A, exon 5 1386 C↷T, intron 5 1712+19 G↷T, exon 7 2062 C↷T and intron 7 2141+73 G↷A single nucleotide polymorphisms of AXIN2, no significant association was found between the controls and the lung cancer patients. For exon 1 148 C↷T, a statistically significant association between the controls and lung cancer patients was found. For this region, lung cancer patients with the TT genotype showed a decreased risk [odds ratio (ORTT) 0.33, 95% confidence interval (CI) 0.12-0.89; p=0.032 (adjusted for age, gender and smoking status)] as compared with the controls with the CC genotype. Concerning histological tumor type, it has been found that exon 1 148 C↷T SNP is associated with a significant decreased risk in squamous cell carcinoma patients (ORTT 0.16; 95% CI 0.03-0.79; p=0.014). Male (ORTT 0.19; 95% CI 0.04-0.77; p=0.015) and smoker (ORTT 0.11; 95% CI 0.01-0.71; p=0.019) lung cancer patients with the TT genotype showed a decreased risk for the same region. Our results suggest that the risk of lung cancer in a Turkish population is related to polymorphisms of the AXIN2 gene.


Reduced chemical and electrical connections of fast-spiking interneurons in experimental cortical dysplasia.
Aberrant neural connections are regarded as a principal factor contributing to epileptogenesis. This study examined chemical and electrical connections between fast-spiking (FS), parvalbumin (PV)-immunoreactive (FS-PV) interneurons and regular-spiking (RS) neurons (pyramidal neurons or spiny stellate neurons) in a rat model of prenatal irradiation-induced cortical dysplasia. Presynaptic action potentials were evoked by current injection and the elicited unitary inhibitory or excitatory postsynaptic potentials (uIPSPs or uEPSPs) were recorded in the postsynaptic cell. In dysplastic cortex, connection rates between presynaptic FS-PV interneurons and postsynaptic RS neurons and FS-PV interneurons, and uIPSP amplitudes were significantly smaller than controls, but both failure rates and coefficient of variation of uIPSP amplitudes were larger than controls. In contrast, connection rates from RS neurons to FS-PV interneurons and uEPSPs amplitude were similar in the two groups. Assessment of the paired pulse ratio showed a significant decrease in synaptic release probability at FS-PV interneuronal terminals, and the density of terminal boutons on axons of biocytin-filled FS-PV interneurons was also decreased, suggesting presynaptic dysfunction in chemical synapses formed by FS-PV interneurons. Electrical connections were observed between FS-PV interneurons, and the connection rates and coupling coefficients were smaller in dysplastic cortex than controls. In dysplastic cortex, we found a reduced synaptic efficiency for uIPSPs originating from FS-PV interneurons regardless of the type of target cell, and impaired electrical connections between FS-PV interneurons. This expands our understanding of the fundamental impairment of inhibition in this model and may have relevance for certain types of human cortical dysplasia.


Spinal cord injury is accompanied by chronic progressive demyelination.
Preceding the development of therapeutic strategies for spinal cord injury is an identification of those pathological processes that might serve as therapeutic targets. Although demyelination has been documented as a secondary degenerative component of spinal cord injury in several species including humans, the extent of demyelination and its functional consequence remain unknown. In this report, we document the extent of demyelination and remyelination up to 450 days following contusive spinal cord injury in adult rats. The overall number of demyelinated axons peaked at 1 day post injury, declined by 7-14 days post injury, and then progressively increased up to 450 days post injury. Oligodendrocyte and Schwann cell remyelinated axons appeared by 14 days post injury. Although remyelinated axons were present from 14 to 450 days post injury, remyelination was incomplete, as indicated by the presence of demyelinated axons at every time point examined. These studies demonstrate for the first time that spinal cord injury is accompanied by chronic progressive demyelination, and they substantiate demyelination as a target for therapeutic intervention.


Stable incidence of primary systemic vasculitides over five years: results from the German vasculitis register.
To register all newly diagnosed patients with primary systemic vasculitides (PSV) in a large region in northern Germany. Between January 1, 1998 and December 31, 2002 all newly diagnosed cases of PSV were identified in a large mixed rural/urban northern German region consisting of 2,777,275 habitants in a population-based prospective study. The following sources were used: departments of all hospitals, including their outpatient clinics; all departments of pathology; and the reference immunologic labs serving the catchment area. During 5 years, 642 PSV patients were identified. The incidence rates for all PSV were between 40 and 54 cases per 1 million and per year. People at age 50 years and older had a 3-5-fold higher risk of developing PSV compared with those younger than 50 years. The incidence rates of antineutrophil cytoplasmic antibody (ANCA)-associated PSV (Wegener's granulomatosis [WG], microscopic polyangiitis [MPA], Churg-Strauss syndrome [CSS]) were between 9.5 and 16/million/year. WG occured 2-3 times more frequently than MPA or CSS. Results of a population-based vasculitis register over 5 years for the incidence of PSV among 2.78 million habitants in northern Germany revealed a stable incidence for all PSV. Compared with other European studies coming from small regions or referral centers, the incidence rates for ANCA-associated PSV were the same as in Norway, lower than those in United Kingdom, but higher than those in Spain.


[SURGICAL HAND WASHING: HANDSCRUBBING OR HANDRUBBING].
The importance of protocols for preoperative antisepsis of the hands is given by the risk of transferring bacteria from the hands of the surgical team to the patient during surgery and it is relationship with infection of surgical wound site (SSI). Careful surgical scrub reduces the number of bacteria on the skin, but does not eliminate them completely, remaining transient microorganisms on hands after the surgical scrub. There fore if micropuncture in surgical gloves occurs, the correct preoperative preparation of hands and double gloving will be essential to reduce the risk of bacterial transmission to patients. The protocols for surgical hand antisepsis are two: Surgical scrub with antiseptic soap (hand scrubbing). Surgical scrub by rubbing alcohol (handrubbing). The hand antisepsis by rubbing with an alcohol solution has proved to be significantly more effective compared to soap solutions. We must also see that in surgical hand antisepsis with soap, you must rinse them with water. And often hospitals' taps and keys are contaminated by Pseudomonas spp., including P. aeuinosa.


The IL-4 receptor alpha-chain cytoplasmic domain is sufficient for activation of JAK-1 and STAT6 and the induction of IL-4-specific gene expression.
The common gamma-chain (gamma(c)) is a functional component of the IL-4R, yet cells lacking gamma(c) are able to respond to IL-4. This has led to the suggestion that a surrogate gamma'-chain, which can interact with the IL-4R alpha chain to mediate signaling, is expressed on cells lacking gamma(c). An alternative possibility is that in the absence of gamma(c), the IL-4R alpha chain is able to transduce signals by homodimerization. To test this latter possibility, a chimeric receptor containing the extracellular domain of c-kit (the stem cell factor (SCF) receptor) and the cytoplasmic and transmembrane domains of the IL-4R alpha chain was generated. Treatment of cells expressing the chimeric receptor kit/IL-4R alpha with SCF induces activation of the IL-4R alpha-associated kinase JAK-1 and the transcription factor STAT6. However, tyrosine phosphorylation of JAK-3, which associates with gamma(c), is not induced by SCF in these cells. SCF-mediated ligation of kit/IL-4R alpha is sufficient to elicit IL-4-specific gene expression, including up-regulation of CD23 and synthesis of germ-line epsilon transcripts. In the T cell line CTLL2, ligation of kit/IL-4R alpha induces cellular proliferation. Finally, in JAK-1-deficient HeLa cells, STAT6 activation by IL-4 is completely abolished. Together, these data demonstrate that the IL-4R alpha cytoplasmic domain is sufficient to activate JAK-1 and STAT6 and to induce expression of IL-4 target genes, thus identifying a mechanism by which IL-4 signaling can proceed in the absence of JAK-3 and gamma(c).


Distribution and properties of beta-adrenergic receptors in human iris-ciliary body.
beta-Adrenergic receptors from the iris-ciliary body of human eyes removed shortly after death were studied using membranes prepared by isopycnic centrifugation of tissue homogenates. This procedure separates uveal melanin pigment from plasma membranes and reduces nonspecific binding of 125I-iodopindolol. The observed binding of 125I-iodopindolol was of high affinity (Kd = 78 +/- 6.6 pM), saturable, and fully reversible (t1/2 = 4.6 min). Scatchard plots were linear and revealed a Bmax of 134 +/- 20 fmol/mg of protein from the whole iris-ciliary body. The affinities of the receptors for a series of agonists and antagonists were determined. The order of potency for the inhibition of the binding of the radioligand by antagonists was ICI 118,551 greater than MK950 greater than propranolol greater than ICI 89,406 greater than metoprolol. This order of potency is characteristic of beta-adrenergic receptors of the beta 2 subtype. Preparations of iris-ciliary body were also subjected to microdissection prior to density gradient centrifugation to permit the study of beta-adrenergic receptors in the ciliary processes, ciliary body, and iris. Each of these regions was found to contain approximately one third of the total number of beta-adrenergic receptors in the human iris-ciliary body. The highest density of receptors was located in the ciliary processes (180 +/- 40 fmol/mg of protein), while the density of receptors in the iris (98 +/- 7.5 fmol/mg of protein) and ciliary body (less the processes) (42 +/- 17 fmol/mg of protein) was notably lower. Only beta 2-adrenergic receptors are detectable by competition experiments in the iris-ciliary body as a whole, or in the individual preparations of iris, ciliary processes, or ciliary body; however, microdissection and analysis of beta-adrenergic receptor subtypes in isolated ciliary muscle permitted detection of a small number of beta 1-adrenergic receptors. beta 1-Adrenergic receptors comprised about 10% of the total number of beta-adrenergic receptors in the whole iris-ciliary body. The finding that most of the beta-adrenergic receptors in the human iris-ciliary body are of the beta 2 subtype may be of significant therapeutic importance in the medical management of glaucoma.


Which retinal and extra-retinal information is crucial for circular vection?
In contradistinction to conventional wisdom, we propose that retinal image slip of a visual scene (optokinetic pattern, OP) does not constitute the only crucial input for visually induced percepts of self-motion (vection). Instead, the hypothesis is investigated that there are three input factors: 1) OP retinal image slip, 2) motion of the ocular orbital shadows across the retinae, and 3) smooth pursuit eye movements (efference copy). To test this hypothesis, we visually induced percepts of sinusoidal rotatory self-motion (circular vection, CV) in the absence of vestibular stimulation. Subjects were presented with three concurrent stimuli: a large visual OP, a fixation point to be pursued with the eyes (both projected in superposition on a semi-circular screen), and a dark window frame placed close to the eyes to create artificial visual field boundaries that simulate ocular orbital rim boundary shadows, but which could be moved across the retinae independent from eye movements. In different combinations these stimuli were independently moved or kept stationary. When moved together (horizontally and sinusoidally around the subject's head), they did so in precise temporal synchrony at 0.05 Hz. The results show that the occurrence of CV requires retinal slip of the OP and/or relative motion between the orbital boundary shadows and the OP. On the other hand, CV does not develop when the two retinal slip signals equal each other (no relative motion) and concur with pursuit eye movements (as it is the case, e.g., when we follow with the eyes the motion of a target on a stationary visual scene). The findings were formalized in terms of a simulation model. In the model two signals coding relative motion between OP and head are fused and fed into the mechanism for CV, a visuo-oculomotor one, derived from OP retinal slip and eye movement efference copy, and a purely visual signal of relative motion between the orbital rims (head) and the OP. The latter signal is also used, together with a version of the oculomotor efference copy, for a mechanism that suppresses CV at a later stage of processing in conditions in which the retinal slip signals are self-generated by smooth pursuit eye movements.


A rapid volume of interest-based approach of radiomics analysis of breast MRI for tumor decoding and phenotyping of breast cancer.
Recently, radiomics has emerged as a non-invasive, imaging-based tissue characterization method in multiple cancer types. One limitation for robust and reproducible analysis lies in the inter-reader variability of the tumor annotations, which can potentially cause differences in the extracted feature sets and results. In this study, the diagnostic potential of a rapid and clinically feasible VOI (Volume of Interest)-based approach to radiomics is investigated to assess MR-derived parameters for predicting molecular subtype, hormonal receptor status, Ki67- and HER2-Expression, metastasis of lymph nodes and lymph vessel involvement as well as grading in patients with breast cancer. A total of 98 treatment-naïve patients (mean 59.7 years, range 28.0-89.4) with BI-RADS 5 and 6 lesions who underwent a dedicated breast MRI prior to therapy were retrospectively included in this study. The imaging protocol comprised dynamic contrast-enhanced T1-weighted imaging and T2-weighted imaging. Tumor annotations were obtained by drawing VOIs around the primary tumor lesions followed by thresholding. From each segmentation, 13.118 quantitative imaging features were extracted and analyzed with machine learning methods. Validation was performed by 5-fold cross-validation with 25 repeats. Predictions for molecular subtypes obtained AUCs of 0.75 (HER2-enriched), 0.73 (triple-negative), 0.65 (luminal A) and 0.69 (luminal B). Differentiating subtypes from one another was highest for HER2-enriched vs triple-negative (AUC 0.97), followed by luminal B vs triple-negative (0.86). Receptor status predictions for Estrogen Receptor (ER), Progesterone Receptor (PR) and Hormone receptor positivity yielded AUCs of 0.67, 0.69 and 0.69, while Ki67 and HER2 Expressions achieved 0.81 and 0.62. Involvement of the lymph vessels could be predicted with an AUC of 0.8, while lymph node metastasis yielded an AUC of 0.71. Models for grading performed similar with an AUC of 0.71 for Elston-Ellis grading and 0.74 for the histological grading. Our preliminary results of a rapid approach to VOI-based tumor-annotations for radiomics provides comparable results to current publications with the perks of clinical suitability, enabling a comprehensive non-invasive platform for breast tumor decoding and phenotyping.


Speed and temperature dependences of mechanotransduction in afferent fibers recorded from the mouse saphenous nerve.
Here we have systematically characterized the stimulus response properties of mechanosensitive sensory fibers in the mouse saphenous nerve. We tested mechanoreceptors and nociceptors with defined displacement stimuli of varying amplitude and velocity. For each sensory afferent investigated we measured the mechanical latency, which is the delay between the onset of a ramp displacement and the first evoked spike, corrected for conduction delay. Mechanical latency plotted as a function of stimulus strength was very characteristic for each receptor type and was very short for rapidly adapting mechanoreceptors (<11 ms) but very long in myelinated and unmyelinated nociceptors (49-114 ms). Increasing the stimulus speed decreased mechanical latency in all receptor types with the notable exception of C-fiber nociceptors, in which mean mechanical latency was not reduced less, similar100 ms, even with very fast ramp stimuli (2,945 microm/s). We examined stimulus response functions and mechanical latency at two different temperatures (24 and 32 degrees C) and found that stimulus response properties of almost all mechanoreceptors were not altered in this range. A notable exception to this rule was found for C-fibers in which mechanical latency was substantially increased and stimulus response functions decreased at lower temperatures. We calculated Q(10) values for mechanical latency in C-fibers to be 5.1; in contrast, the Q(10) value for conduction velocity for the same fibers was 1.4. Finally, we examined the effects of short-term inflammation (2-6 h) induced by carrageenan on nociceptor and mechanoreceptor sensitivity. We did not detect robust changes in mechanical latency or stimulus response functions after inflammation that might have reflected mechanical sensitization under the conditions tested.


Automated Bright Field Segmentation of Cells and Vacuoles Using Image Processing Technique.
Understanding the mechanisms and other variants of programmed cell death will help provide deeper insight into various disease processes. Although complex procedures are required to distinguish each type of cell death, the formation of vacuoles is one of the important features in some process of cell death under different conditions. Thus, monitoring and counting the number of vacuoles and the ratio of cells with vacuoles is a commonly used method to indicate and quantify the efficacy of the therapy. Several studies have shown that image processing can provide a quick, convenient and precise mean of performing cell detection. Hence, this study uses an image processing technique to detect and quantify vacuolated cells without the need for dyes. The system both counts the number of vacuolated cells and determines the ratio of cells with vacuoles. The performance of the proposed image processing system was evaluated using 38 images. It has been shown that a strong correlation exists between the automated counts and the manual counts. Furthermore, the absolute percentage errors between automated counts and manual counts for cell detection and vacuolated cell detection using data pooled from all images are 3.61 and 3.33%, respectively. A user-friendly graphical user interface (GUI) is also developed and freely available for download, providing researchers in biomedicine with a more convenient instrument for vacuolization analysis.


Cystic Renal Oncocytoma and Tubulocystic Renal Cell Carcinoma: Morphologic and Immunohistochemical Comparative Study.
Renal oncocytoma (RO) may present with a tubulocystic growth in 3% to 7% of cases, and in such cases its morphology may significantly overlap with tubulocystic renal cell carcinoma (TCRCC). We compared the morphologic and immunohistochemical characteristics of these tumors, aiming to clarify the differential diagnostic criteria, which facilitate the discrimination of RO from TCRCC. Twenty-four cystic ROs and 15 TCRCCs were selected and analyzed for: architectural growth patterns, stromal features, cytomorphology, ISUP nucleolar grade, necrosis, and mitotic activity. Immunohistochemical panel included various cytokeratins (AE1-AE3, OSCAR, CAM5.2, CK7), vimentin, CD10, CD117, AMACR, CA-IX, antimitochondrial antigen (MIA), EMA, and Ki-67. The presence of at least focal solid growth and islands of tumor cells interspersed with loose stroma, lower ISUP nucleolar grade, absence of necrosis, and absence of mitotic figures were strongly suggestive of a cystic RO. In contrast, the absence of solid and island growth patterns and presence of more compact, fibrous stroma, accompanied by higher ISUP nucleolar grade, focal necrosis, and mitotic figures were all associated with TCRCC. TCRCC marked more frequently for vimentin, CD10, AMACR, and CK7 and had a higher proliferative index by Ki-67 (>15%). CD117 was negative in 14/15 cases. One case was weakly CD117 reactive with cytoplasmic positivity. All cystic RO cases were strongly positive for CD117. The remaining markers (AE1-AE3, CAM5.2, OSCAR, CA-IX, MIA, EMA) were of limited utility. Presence of tumor cell islands and solid growth areas and the type of stroma may be major morphologic criteria in differentiating cystic RO from TCRCC. In difficult cases, or when a limited tissue precludes full morphologic assessment, immunohistochemical pattern of vimentin, CD10, CD117, AMACR, CK7, and Ki-67 could help in establishing the correct diagnosis.


Endogenous thrombopoietin levels during the clinical management of acute myeloid leukaemia.
Thrombocytopenia represents a major problem in the management of acute myeloid leukaemia (AML). The data regarding the alterations of endogenous thrombopoietin (TPO) regulation during the clinical course of AML are limited. The aim of this study was to investigate endogenous TPO dynamics in association with platelets during the clinical course of AML. We serially measured both TPO and platelets concurrently over the entire treatment period of newly diagnosed patients receiving both remission induction and consolidation chemotherapies. The median concentration of TPO in AML patients at the initial diagnosis was 469.71 pg/ml and increased significantly during the aplastic period due to remission induction chemotherapy (median: 1085.33 pg/ml) but then decreased to a level (median: 45.26 pg/ml) encountered in the healthy control subjects (median: 56.90 pg/ml). In the cytopenic period due to consolidation treatment, TPO level again increased significantly to a high level (median: 891.38 pg/ml) during the platelet nadir, but decreased toward normal (median: 100.75 pg/ml) after the thrombocytopenic period had elapsed. In conclusion, endogenous TPO levels exhibit an inverse fluctuation in relation to platelet counts during the clinical course of AML. Pharmacological stimulation of thrombopoiesis in AML with novel molecules, including the recombinant thrombopoietins and the small peptide agonists, should be based on a critical administration strategy that must consider the endogenous levels of TPO. TPO levels in distinct AML disease states may explain the unsuccessful recombinant TPO trials and could help to design better strategies for 'pharmacological stimulation of thrombopoiesis' in AML.


[Number needed to treat: a useful tool for estimating the effectiveness of a treatment].
The concepts developed in evidence-based medicine, together with clinical experience, are the major principles on which clinical decisions are made. One of the concepts is number needed to treat (NNT), which means the number of patients who have to be treated either to prevent one additional unfavourable outcome or to achieve one additional favourable outcome. The NNT is dependent on the baseline risk (the risk of occurrence at baseline): the higher the baseline risk, the lower will be the NNT (which is more favourable). In contrast, the relative risk reduction is fairly independent of the baseline risk. NNT and number needed to harm provide numerical arguments for deciding whether a particular treatment does more good than harm.


Biocatalytic synthesis of polycatechols from toxic aromatic compounds.
A process is described in which toxic aromatic compounds are converted by toluene dioxygenase and in turn toluene cis-dihydrodiol dehydrogenase to catechols which are further polymerized by peroxidase-catalyzed oxidation producing polycatechols. Three approaches for obtaining catechols were employed: (1) addition of halogenated aromatics to P. putida F1, resulting in the accumulation of halogenated catechols; (2) inhibition of catechol 2,3-dioxygenase of P. putida F1 by known aromatic and aliphatic inhibitors; and (3) overexpression of toluene dioxygenase and toluene cis-dihydrodiol dehydrogenase genes in E. coli JM109. The process is suitable for producing novel catechols that upon oxidation may yield polymers with unique properties, presenting a tool for producing tailor-made biopolymers. Formation of 3-chlorocatechol from chlorobenzene, 3,4-dichlorocatechol from 1,2-dichlorobenzene, and catechol from benzene and their subsequent oxidation and polymerization was demonstrated. Oxidation of catechol yielded polymers with molecular weights of up to 4000 Daltons. Their apparently high water solubility eliminates the need for water-miscible solvents. In aqueous solution oxidation of catechols was rapid, yet the presence of 20%, 30%, and 40% ethanol, resulted in a rate decrease of 31%, 95%, and 93%, respectively. The advantage is that significantly less peroxidase is required for performing the reactions if miscible solvents are not employed. Furthermore, water-soluble polymers may be desirable for many applications.


A case of Graves' disease associated with painful thyroiditis.
We report on a 61-year-old woman with untreated Graves' disease associated with painful thyroiditis. On examination, the left lobe of the thyroid gland was firm and tender but the right lobe was not. A diagnosis of Graves' disease was made based on the results of thyroid function tests including the percentage of thyroidal radioactive iodine uptake (RAIU) and the presence of thyroid-stimulating antibodies (TSAb). However, ultrasonogram results and inflammatory findings (C-reactive protein concentration and erythrocyte sedimentation rate) also indicated the presence of inflammation in the thyroid gland. She was first treated with aspirin, and later with prednisolone. Her clinical course was similar to that in cases of subacute thyroiditis, but neither her HLA type nor aspiration cytology findings indicated the type of thyroiditis. With the resolution of the thyroiditis, her serum levels of thyroid hormone and TSAb decreased, although RAIU increased. Finally, she became euthyroid without antithyroid drug treatment. The serum levels of antithyroid antibodies, TSH-binding inhibitor immunoglobulins (TBII) and TSAb increased transiently and then decreased during the course of the illness, indicating that the mechanism(s) of the production and/or degradation of TBII and TSAb is similar to that for antithyroid antibodies in the present case. The present findings also indicate that remission may occur in some patients with Graves' disease after painful thyroiditis is resolved.


Definition of Barrett's oesophagus.
Barrett's oesophagus is the eponym applied to the columnar epithelium-lined lower oesophagus. In 1976, Paull et al. described three types of columnar epithelia lining the distal oesophagus: a junctional or cardiac-type epithelium, a gastric fundic-type epithelium and a distinctive type of intestinal metaplasia referred to as specialized columnar epithelium. Even the normal oesophagus can be lined by 2 cm of columnar epithelium. To avoid the problem of false-positive diagnoses, arbitrary criteria for the extent of oesophageal columnar lining necessary to include patients in studies of Barrett's oesophagus were established in the early 1980s. The latter criteria require a circumferential segment of columnar lined epithelium of 2 or 3 cm in length. There are, however, a number of technical and conceptual problems related to this approach. The traditional definition excludes shorter segments and tongues of columnar lined epithelium. Only the specialized columnar epithelium defined by intestinal type goblet cells carries an inherent risk of malignancy. Therefore, a number of investigators currently define Barrett's oesophagus as any amount of columnar mucosa in the lower esophagus that has histologic evidence of goblet cells (highlighted in biopsies using the alcian blue pH 2.5 stain). Recently, short segments of specialized intestinal metaplasia in the distal oesophagus ("short segment Barrett's oesophagus") have attracted considerable attention. It has also become clear that intestinal metaplasia can occur at a normally located gastro-oesophageal junction. The etiology and clinical significance (in terms of possible relationship to the adenocarcinoma of the cardia) of this "intestinal metaplasia of the gastric cardia" and its potential relationship to Barrett's oesophagus are not yet completely understood.


Distribution of mouse mammary tumour virus antigens in RIII mice as detected by immunofluorescence on tissue sections and by immunoassays in sera and organ extracts.
Organs of RIII mice at various physiological stages were tested for mouse mammary tumour virus (MMTV) antigen expression. Indirect immunofluorescence was used with three monospecific antisera to localize one envelope glycoprotein, gp47, and two core proteins, p28 and p8. These virus-specific antigens gave characteristic fluorescent patterns in the mammary tissues and were also detected in thymus and salivary gland sections of some mice. The amounts of antigens gp47 and p28 were measured by immunoassay in sera and organ extracts of corresponding samples of mice. Sera of mice of both sexes contained virus antigens from the suckling age onwards. Although ingested virus could be traced in suckling mice, weanlings were characterized by the absence of virus expression except in lymph nodes. This location points to the possible role of lymphoid tissue in producing the antigens of the blood and in disseminating the infection. In adult animals, virus antigens were present in salivary glands, digestive tract, lymph nodes, male genital organs and female mammary glands. Antigen expression, even found in the mammary glands of virgin mice, was strikingly increased by pregnancy, lactation and (or) ageing, the highest values being found in mammary tumours. The results for milk-borne MMTV infection in RIII mice are compared with those obtained previously in Swiss albino mice.


Transrectal needle aspiration versus transperineal needle biopsy in diagnosis of carcinoma of prostate.
Transrectal needle aspiration of the prostate was compared to transperineal biopsy in 28 patients with suspected carcinoma of the prostate. This technique was found to have a high sensitivity and specificity for diagnosing carcinoma of the prostate, and no complications were seen. The addition of Nuclear Flow DNA analysis may give further prognostic information from needle aspiration and core biopsy specimens. Transrectal needle aspiration of the prostate is a safe, inexpensive, and accurate method of diagnosing carcinoma of the prostate.


Pathways of change: Predicting the effects of fire on flammability.
Impacts of wildfire on humans are increasing as urban populations continue to expand into fire prone landscapes. Effective fire risk management can only be achieved if we understand and quantify how ecosystems change in response to fire and how these changes affect flammability. However, there have been limited studies to this effect with the dominant paradigm being the assumption that recently burnt vegetation is less flammable than older vegetation. To better quantify changes in flammability, we first need to quantify trajectories of changes in response to fire within individual vegetation communities. Second, we need to examine the extent to which these changes alter flammability. Here, we quantify the flammability pathways with increasing time since fire for five vegetation communities in south-eastern Australia. A total of 116 sites were measured across a range of heathland, woodland and forest ecosystems. Flammability was measured using an ecological point based mechanistic fire behaviour model that estimates three measures of flammability relevant to both fire management and research. Predicted changes in flammability varied between vegetation types with heathland and wet forests generally increasing in flammability with time since fire and tall mixed, foothills and forby forests decreasing or showing limited changes with time since fire. Variations in flammability pathways suggest fire management activities that alter fuel structure, such as prescribed burning, may only reduce flammability in a limited set of ecosystems. Incorporating these results into a landscape analysis will improve the quantification of fire risk.


Better Parenting through Biomedical Modification: A Case for Pluralism, Deference, and Charity.
In this paper, I will argue that the moral assessment of the prenatal selection and postnatal modification biotechnologies requires a nuanced approach, which pays close attention to the variety of sometimes conflicting parental roles and reasons involved in decisions for and against their use. I will focus on several related but distinct reasons that parents have, or give, for modifying existing children or selecting future children. Many of these reasons are expressed in terms of more effective parenting. Because there is a plurality of legitimate parental goals, I will conclude that assessing parental interventions requires us to adjudicate conflicts or tradeoffs among those goals.


Postpartum acute hemolytic transfusion reactions associated with anti-Lea in two pregnancies complicated by preeclampsia.
Lewis blood group antibodies, which are mostly naturally occurring and considered clinically insignificant, have rarely been documented as a cause of acute hemolytic transfusion reactions (AHTRs). This report presents two cases of AHTRs caused by anti-Lea occurring in postpartum black females (one group B, one group AB) whose pregnancies were complicated by preeclampsia. Neither anti-Lea was detected by automated solid-phase red cell adherence technology in pre-transfusion testing. Therefore, red blood cell units, compatible by electronic crossmatch, were issued and transfused. The subsequent transfusion reactions were characterized by acute intravascular hemolysis, evidenced by both clinical and laboratory criteria. These two cases demonstrate that, even when least anticipated, hemolytic transfusion reactions may occur. As expected, neither live-born neonate was affected by hemolytic disease of the fetus and newborn. Because both transfusion reactions occurred in non-group O, postpartum black females with pregnancies complicated by preeclampsia, possible links between in vivo hemolytic anti-Lea, non-group O pregnant black females, and preeclampsia may require additional investigation.


Osteochondritis dissecans with subchondral bone cyst of the femoral condyle: a novel surgical technique of treatment.
Osteochondritis dissecans (OCD) with a large subchondral bone cyst (SBC) is not common. The treatment of this lesion may be unsuccessful with conventional techniques. A novel surgical technique is described for the treatment of OCD with SBC of the femoral condyle. Modified osteochondral multiple autograft transfer following extraarticular curettage and bone grafting of SBC is a promising technique.