Evaluation of sulphasalazine in the treatment of spondyloarthropathies.
Sulphasalazine has been shown to have an effect in patients with spondyloarthropathies, but the clinical indication for its use is controversial and its long term effect has not yet been evaluated. Treatment with sulphasalazine was analysed retrospectively in a group of 372 patients with a wide range of spondyloarthropathies to determine subsets of patients showing differential effects of the drug. One hundred and one patients received sulphasalazine at a mean daily dose of 2 g (ankylosing spondylitis, 54 patients; psoriatic arthritis, 21 patients; reactive arthritis, four patients; arthritis related to inflammatory bowel disease, six patients; undifferentiated spondyloarthropathy, 16 patients). A comparison between treated and untreated patients suggests that only patients with active and severe disease were treated whatever the precise diagnosis or the amount of axial disease in the spondyloarthropathy. After six months of treatment improvement was noted in 59 patients unrelated to their subgroup or amount of axial disease. After a mean follow up of 20 months, 37 patients were still receiving treatment, 33 had discontinued the drug because of inefficacy, 14 because of side effects, six because of remission of the disease, and 11 for other reasons. Comparison between the beginning and end of treatment showed a statistically significant decrease in morning stiffness, erythrocyte sedimentation rate, and daily dose of non-steroidal anti-inflammatory drugs (NSAIDs). It is concluded that: (a) a low percentage of patients with spondyloarthropathy have active disease requiring treatment with sulphasalazine despite the use of NSAIDs (27% in this study); (b) in this subgroup of patients sulphasalazine seems to be of clinically relevant benefit in 59%; and (c) this benefit does not seem to be correlated with either the precise diagnosis of spondyloarthropathy or the amount of axial disease.


Androgenetic alopecia and coronary artery disease in women.
The meaningful association of androgenetic alopecia (AGA) and coronary artery disease (CAD) in men has been documented, but few studies, if any, have focused on this association in women. This study was carried out on 106 women under the age 55, who completed angiography procedures for diagnosis of coronary artery disease. The aim of study was to assess the relationship between androgenetic alopecia and coronary heart disease in women. The clinical and paraclinical information was obtained by personal interview, physical examination, and review of patients' files. Androgenetic alopecia in the patients was assessed blindly by a dermatologist, using Ludwig's baldness grading system (I to III). According to the angiographic studies, 51 cases had CAD and 55 subjects did not. On the other hand, 21 patients had female AGA (Grade I, 15; Grade II, 3; Grade III, 3 cases). The correlation of AGA and CAD, AGA and previous history of myocardial infarction, and graying of hair and CAD were statistically significant (p < 0.05), after adjustment of data for differences in age. These data support the hypothesis that female AGA, like male pattern baldness, is associated with CAD in women under the age 55.


Composite and shaped pulses for efficient and robust pumping of disconnected eigenstates in magnetic resonance.
Hyperpolarization methods, which can enhance nuclear spin signals by orders of magnitude, open up important new opportunities in magnetic resonance. However, many of these applications are limited by spin lattice relaxation, which typically destroys the hyperpolarization in seconds. Significant lifetime enhancements have been found with "disconnected eigenstates" such as the singlet state between a pair of nearly equivalent spins, or the "singlet-singlet" state involving two pairs of chemically equivalent spins; the challenge is to populate these states (for example, from thermal equilibrium magnetization or hyperpolarization) and to later recall the population into observable signal. Existing methods for populating these states are limited by either excess energy dissipation or high sensitivity to inhomogeneities. Here we overcome the limitations by extending recent work using continuous-wave irradiation to include composite and adiabatic pulse excitations. Traditional composite and adiabatic pulses fail completely in this problem because the interactions driving the transitions are fundamentally different, but the new shapes we introduce can move population between accessible and disconnected eigenstates over a wide range of radio-frequency (RF) amplitudes and offsets while depositing insignificant amounts of power.


Taxonomic identity, phylogeny, climate and soil fertility as drivers of leaf traits across Chinese grassland biomes.
Although broad-scale inter-specific patterns of leaf traits are influenced by climate, soil, and taxonomic identity, integrated assessments of these drivers remain rare. Here, we quantify these drivers in a field study of 171 plant species in 174 sites across Chinese grasslands, including the Tibetan Plateau, Inner Mongolia, and Xinjiang. General linear models were used to partition leaf trait variation. Of the total variation in leaf traits, on average 27% is due to taxonomic or phylogenetic differences among species within sites (pure species effect), 29% to variation among sites within species (pure site effect), 38% to joint effects of taxonomic and environmental factors (shared effect), and 6.2% to within-site and within-species variation. Examining the pure site effect, climate explained 7.8%, soil explained 7.4%, and climate and soil variables together accounted for 11%, leaving 18% of the inter-site variation due to factors other than climate or soil. The results do not support the hypothesis that soil fertility is the "missing link" to explain leaf trait variation unexplained by climatic factors. Climate- and soil-induced leaf adaptations occur mostly among species, and leaf traits vary little within species in Chinese grassland plants, despite strongly varying climate and soil conditions.


Association of kidney function with changes in the endothelial surface layer.
ESRD is accompanied by endothelial dysfunction. Because the endothelial glycocalyx (endothelial surface layer) governs interactions between flowing blood and the vessel wall, perturbation could influence disease progression. This study used a novel noninvasive sidestream-darkfield imaging method, which measures the accessibility of red blood cells to the endothelial surface layer in the microcirculation (perfused boundary region), to investigate whether renal function is associated with endothelial surface layer dimensions. Perfused boundary region was measured in control participants (n=10), patients with ESRD (n=23), participants with normal kidney function after successful living donor kidney transplantation (n=12), and patients who developed interstitial fibrosis/tubular atrophy after kidney transplantation (n=10). In addition, the endothelial activation marker angiopoietin-2 and shed endothelial surface layer components syndecan-1 and soluble thrombomodulin were measured using ELISA. Compared with healthy controls (1.82 ± 0.16 µm), ESRD patients had a larger perfused boundary region (+0.23; 95% confidence interval, 0.46 to <0.01; P<0.05), which signifies loss of endothelial surface layer dimensions. This large perfused boundary region was accompanied by higher circulating levels of syndecan-1 (+57.71; 95% confidence interval, 17.38 to 98.04; P<0.01) and soluble thrombomodulin (+12.88; 95% confidence interval, 0.29 to 25.46; P<0.001). After successful transplantation, the perfused boundary region was indistinguishable from healthy controls (without elevated levels of soluble thrombomodulin or syndecan-1). In contrast, however, patients who developed interstitial fibrosis and tubular atrophy showed a large perfused boundary region (+0.36; 95% confidence interval, 0.09 to 0.63; P<0.01) and higher levels of endothelial activation markers. In addition, a significant correlation between perfused boundary region, angiopoietin-2, and eGFR was observed (perfused boundary region versus GFR: Spearman's ρ=0.31; P<0.05; perfused boundary region versus angiopoietin-2: Spearman's ρ=-0.33; P<0.05). Reduced renal function is strongly associated with low endothelial surface layer dimensions. After successful kidney transplantation, the endothelial surface layer is indistinguishable from control.


Endocannabinoids and fatty acid amides in cancer, inflammation and related disorders.
The long history of the medicinal use of Cannabis sativa and, more recently, of its chemical constituents, the cannabinoids, suggests that also the endogenous ligands of cannabinoid receptors, the endocannabinoids, and, particularly, their derivatives may be used as therapeutic agents. Studies aimed at correlating the tissue and body fluid levels of endogenous cannabinoid-like molecules with pathological conditions have been started and may lead to identify those diseases that can be alleviated by drugs that either mimic or antagonize the action of these substances, or modulate their biosynthesis and degradation. Hints for the therapeutic applications of endocannabinoids, however, can be obtained also from our previous knowledge of marijuana medicinal properties. In this article, we discuss the anti-tumor and anti-inflammatory activity of: (1) the endocannabinoids anandamide (arachidonoylethanolamide) and 2-arachidonoyl glycerol; (2) the bioactive fatty acid amides palmitoylethanolamide and oleamide; and (3) some synthetic derivatives of these compounds, such as the N-acyl-vanillyl-amines. Furthermore, the possible role of cannabimimetic fatty acid derivatives in the pathological consequences of cancer and inflammation, such as cachexia, wasting syndrome, chronic pain and local vasodilation, will be examined.


Modeling metabolic syndrome and its association with cognition: the Northern Manhattan study.
Metabolic syndrome (MetS) is a clustering of vascular risk factors and is associated with increased risk of cardiovascular disease. Less is known about the relationship between MetS and cognition. We examined component vascular risk factors of MetS as correlates of different cognitive domains. The Northern Manhattan Study (NOMAS) includes 1290 stroke-free participants from a largely Hispanic multi-ethnic urban community. We used structural equation modeling (SEM) to model latent variables of MetS, assessed at baseline and an average of 10 years later, at which time participants also underwent a full cognitive battery. The two four-factor models, of the metabolic syndrome (blood pressure, lipid levels, obesity, and fasting glucose) and of cognition (language, executive function, psychomotor, and memory), were each well supported (CFI=0.97 and CFI=0.95, respectively). When the two models were combined, the correlation between metabolic syndrome and cognition was -.31. Among the metabolic syndrome components, only blood pressure uniquely predicted all four cognitive domains. After adjusting for age, gender, race/ethnicity, education, smoking, alcohol, and risk factor treatment variables, blood pressure remained a significant correlate of all domains except memory. In this stroke-free race/ethnically diverse community-based cohort, MetS was associated with cognitive function suggesting that MetS and its components may be important predictors of cognitive outcomes. After adjusting for sociodemographic and vascular risk factors, blood pressure was the strongest correlate of cognitive performance. Findings suggest MetS, and in particular blood pressure, may represent markers of vascular or neurodegenerative damage in aging populations.


The influence of formulation and manufacturing process parameters on the characteristics of lyophilized orally disintegrating tablets.
Gelatin is a principal excipient used as a binder in the formulation of lyophilized orally disintegrating tablets. The current study focuses on exploiting the physicochemical properties of gelatin by varying formulation parameters to determine their influence on orally disintegrating tablet (ODT) characteristics. Process parameters, namely pH and ionic strength of the formulations, and ball milling were investigated to observe their effects on excipient characteristics and tablet formation. The properties and characteristics of the formulations and tablets which were investigated included: glass transition temperature, wettability, porosity, mechanical properties, disintegration time, morphology of the internal structure of the freeze-dried tablets, and drug dissolution. The results from the pH study revealed that adjusting the pH of the formulation away from the isoelectric point of gelatin, resulted in an improvement in tablet disintegration time possibly due to increase in gelatin swelling resulting in greater tablet porosity. The results from the ionic strength study revealed that the inclusion of sodium chloride influenced tablet porosity, tablet morphology and the glass transition temperature of the formulations. Data from the milling study showed that milling the excipients influenced formulation characteristics, namely wettability and powder porosity. The study concludes that alterations of simple parameters such as pH and salt concentration have a significant influence on formulation of ODT.


Inferior Vena Cava Ultrasonography before General Anesthesia Can Predict Hypotension after Induction.
Hypotension is a common side effect of general anesthesia induction, and when severe, it is related to adverse outcomes. Ultrasonography of inferior vena cava (IVC) is a reliable indicator of intravascular volume status. This study investigated whether preoperative ultrasound IVC measurements could predict hypotension after induction of anesthesia. One hundred four adult patients, conforming to American Society of Anesthesiologists physical status I to III, scheduled for elective surgery after general anesthesia were recruited. Maximum IVC diameter (dIVCmax) and collapsibility index (CI) were measured preoperatively. Before induction, mean blood pressure (MBP) was recorded. After induction, MBP was recorded for 10 min after intubation. Hypotension was defined as greater than 30% decrease in MBP from baseline or MBP less than 60 mmHg. Receiver operating characteristic curve analysis with gray zone approach and regression analyses were used. IVC scanning was unsuccessful in 13.5% of patients. Data from 90 patients were analyzed. After induction, 42 patients developed hypotension. Areas (95% confidence interval) under the curves were 0.90 (0.82 to 0.95) for CI and 0.76 (0.66 to 0.84) for dIVCmax. The optimal cutoff values were 43% for CI and 1.8 cm for dIVCmax. The gray zone for CI was 38 to 43% and included 12% of patients and that for dIVCmax was 1.5 to 2.1 cm and included 59% of patients. After adjusting for other factors, it was found that CI was an independent predictor of hypotension with the odds ratio of 1.17 (1.09 to 1.26). CI was also positively associated with a percentage decrease in MBP (regression coefficient = 0.27). Preoperative ultrasound IVC CI measurement was a reliable predictor of hypotension after induction of general anesthesia, wherein CI greater than 43% was the threshold.


Dopaminergic challenges in social anxiety disorder: evidence for dopamine D3 desensitisation following successful treatment with serotonergic antidepressants.
Serotonergic antidepressants (SSRIs) are first-line treatments for social anxiety disorder [SAnD], though there is evidence of dopaminergic system dysfunction. Twenty subjects with DSM-IV SAnD, untreated (n = 10) and SSRI-remitted DSM-IV SAnD (n = 10), were administered a single dose of 1) a dopamine agonist (pramipexole 0.5 mg) and 2) a dopamine antagonist (sulpiride 400 mg), followed by anxiogenic challenges (verbal tasks and autobiographical scripts) in a double-blind crossover design, the two test days being one week apart. Anxiety symptoms were measured by self-reported changes in Visual Analogue Scales, specific SAnD scales and anxiety questionnaires. Plasma levels of prolactin were obtained. Untreated SAnD subjects experienced significant increases in anxiety symptoms following behavioural challenges after either sulpiride or pramipexole. Following remission with SSRIs, the socially anxiogenic effect of behavioural provocation was significantly attenuated under pramipexole, whereas under sulpiride effects remained significantly elevated. There appears to be instability of the dopamine system under behavioural stress in social anxiety subjects that is only partly rectified by successful treatment with an SSRI, which may induce a desensitisation of postsynaptic dopamine D(3) receptors.


System for Observing Staff Promotion of Activity and Nutrition (SOSPAN).
Frontline-staff are critical to achieving policies related to child physical activity and nutrition (PAaN) in out-of-school-time programs (OSTP). Recent policies call upon staff to demonstrate behaviors related to PAaN. Currently, no instrument exists to measure these behaviors. This study fills the gap between policy mandates and staff behaviors by describing the development of the System for Observing Staff Promotion of Activity and Nutrition (SOSPAN) in OSTP. SOSPAN items were aligned with existing OSTP policies. Reliability and validity data of SOSPAN were collected across 8 OSTP: 4 summer day camps and 4 afterschool programs. Validity of SOSPAN staff behaviors/management of PA was established using the percent of children active measured concurrently via direct observation. A total of 6437 scans were performed. Interrater percent agreement ranged from 74%-99% across PAaN behaviors. Children's activity was associated with staff facilitative behaviors/management, such as playing with the children and providing 2 or more activities for children to choose, while prohibitive behaviors/management, such as waiting in line were related to increased sedentary behavior. Staff nutrition behaviors were observed in less than 0.6% of scans. SOSPAN is a reliable and valid tool to assess staff behaviors/management of PAaN in OSTPs.


Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation.
An accumulating body of evidence suggests that endocannabinoids and cannabinoid receptors type 1 and 2 (CB(1), CB(2)) play a significant role in physiologic and pathologic processes, including cognitive and immune functions. While the addictive properties of marijuana, an extract from the Cannabis plant, are well recognized, there is growing appreciation of the therapeutic potential of cannabinoids in multiple pathologic conditions involving chronic inflammation (inflammatory bowel disease, arthritis, autoimmune disorders, multiple sclerosis, HIV-1 infection, stroke, Alzheimer's disease to name a few), mainly mediated by CB(2) activation. Development of CB(2) agonists as therapeutic agents has been hampered by the complexity of their intracellular signaling, relative paucity of highly selective compounds and insufficient data regarding end effects in the target cells and organs. This review attempts to summarize recent advances in studies of CB(2) activation in the setting of neuroinflammation, immunomodulation and HIV-1 infection.


Mobile phone use, blood lead levels, and attention deficit hyperactivity symptoms in children: a longitudinal study.
Concerns have developed for the possible negative health effects of radiofrequency electromagnetic field (RF-EMF) exposure to children's brains. The purpose of this longitudinal study was to investigate the association between mobile phone use and symptoms of Attention Deficit Hyperactivity Disorder (ADHD) considering the modifying effect of lead exposure. A total of 2,422 children at 27 elementary schools in 10 Korean cities were examined and followed up 2 years later. Parents or guardians were administered a questionnaire including the Korean version of the ADHD rating scale and questions about mobile phone use, as well as socio-demographic factors. The ADHD symptom risk for mobile phone use was estimated at two time points using logistic regression and combined over 2 years using the generalized estimating equation model with repeatedly measured variables of mobile phone use, blood lead, and ADHD symptoms, adjusted for covariates. The ADHD symptom risk associated with mobile phone use for voice calls but the association was limited to children exposed to relatively high lead. The results suggest that simultaneous exposure to lead and RF from mobile phone use was associated with increased ADHD symptom risk, although possible reverse causality could not be ruled out.


Unsupervised Common Spatial Patterns.
The common spatial pattern (CSP) method is a dimensionality reduction technique widely used in brain-computer interface (BCI) systems. In the two-class CSP problem, training data are linearly projected onto directions maximizing or minimizing the variance ratio between the two classes. The present contribution proves that kurtosis maximization performs CSP in an unsupervised manner, i.e., with no need for labeled data, when the classes follow Gaussian or elliptically symmetric distributions. Numerical analyses on synthetic and real data validate these findings in various experimental conditions, and demonstrate the interest of the proposed unsupervised approach.


Corneal graft rejection 10 years after penetrating keratoplasty in the cornea donor study.
The aim of this study was to assess the effect of donor and recipient factors on corneal allograft rejection and evaluate whether a rejection event was associated with graft failure. One thousand ninety subjects undergoing penetrating keratoplasty for a moderate risk condition (principally Fuchs dystrophy or pseudophakic corneal edema) were followed for up to 12 years. Associations of baseline recipient and donor factors with the occurrence of a rejection event were assessed in univariate and multivariate proportional hazards models. Among 651 eyes with a surviving graft at 5 years, the 10-year graft failure (±99% confidence interval) rates were 12% ± 4% among eyes with no rejection events in the first 5 years, 17% ± 12% in eyes with at least 1 probable, but no definite rejection event, and 22% ± 20% in eyes with at least 1 definite rejection event. The only baseline factor significantly associated with a higher risk of definite graft rejection was a preoperative history of glaucoma, particularly when previous glaucoma surgery had been performed and glaucoma medications were being used at the time of transplant (10-year incidence 35% ± 23% compared with 14% ± 4% in eyes with no history of glaucoma/intraocular pressure treatment, P = 0.008). Patients who experienced a definite rejection event frequently developed graft failure raising important questions as to how we might change acute and long-term corneal graft management. Multivariate analysis indicated that previous use of glaucoma medications and glaucoma filtering surgery was a significant risk factor related to a definite rejection event.


Comparison between shear wave dispersion magneto motive ultrasound and transient elastography for measuring tissue-mimicking phantom viscoelasticity.
Several methods have been developed over the last several years to analyze the mechanical properties of soft tissue. Elastography, for example, was proposed to evaluate soft tissue stiffness in an attempt to reduce the need for invasive procedures, such as breast biopsies; however, its qualitative nature and the fact that it is operator-dependent have proven to be limitations of the technique. Quantitative shearwave- based techniques have been proposed to obtain information about tissue stiffness independent of the operator. This paper describes shear wave dispersion magnetomotive ultrasound (SDMMUS), a new shear-wave-based method in which a viscoelastic medium labeled with iron oxide nanoparticles is displaced by an external tone burst magnetic field. As in magnetomotive ultrasound (MMUS), SDMMUS uses ultrasound to detect internal mechanical vibrations induced by the interaction between a magnetic field and magnetic nanoparticles. These vibrations generated shear waves that were evaluated to estimate the viscoelastic properties of tissue-mimicking phantoms. These phantoms were manufactured with different concentrations of gelatin and labeled with iron oxide nanoparticles. The elasticity and viscosity obtained with SDMMUS agreed well with the results obtained by traditional ultrasound-based transient elastography.


Anomalous terahertz transmission in bow-tie plasmonic antenna apertures.
Arrays of subwavelength dipole bow-tie apertures are designed and characterized at terahertz frequencies. For an incident terahertz field perpendicular to the longer axis of the bow tie, a strong resonance enhancement, line narrowing, and a nonmonotonic frequency shift were observed with increasing length of the tapered bow-tie arms. Such characteristic behaviors primarily originate from localized surface plasmon resonances. In addition, with a decreasing aperture size, the contribution of localized plasmons becomes prominent due to an increase in plasmonic lifetime as the terahertz pulses strongly couple with the metallic surface surrounding the bow-tie apertures.


For the sake of others: reciprocal webs of obligation and the pursuit of transplantation as a caring act.
This article highlights reciprocal webs of care and moral obligations toward kin during transplantation, using an expansive notion of "care" to include both its obvious and more hidden forms. Evidence from 24 months of ethnographic fieldwork among transplant patients, their loved ones, and clinical personnel in the U.S. Midwest suggests that patients are simultaneously caregivers to others and are considered vital members of reciprocal webs of care without whom their kin networks could not effectively operate. Transplantation can become a person's main, perhaps only hope of fulfilling ongoing obligations to others, so pursuing a transplant becomes not a matter of choice, but rather a moral orientation. A potential implication of these findings is that rather quotidian and conventional (even if contested) notions of what kin ought to do and be for each other may be among the underpinnings of high-tech biomedical practices like transplantation.


Redefining the serotonergic system by genetic lineage.
Central serotonin-producing neurons are heterogeneous-differing in location, morphology, neurotoxin sensitivity and associated clinical disorders-but the underpinnings of this heterogeneity are largely unknown, as are the markers that distinguish physiological subtypes of serotonergic neurons. Here we redefined serotonergic subtypes on the basis of genetic programs that are differentially enacted in progenitor cells. We uncovered a molecular framework for the serotonergic system that, having genetic lineages as its basis, is likely to have physiological relevance and will permit access to genetically defined subtypes for manipulation.


Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner.
Hepatitis C virus (HCV) subverts host cholesterol metabolism for key processes in its lifecycle. How this interference results in the frequently observed, genotype-dependent clinical sequelae of hypocholesterolemia, hepatic steatosis, and insulin resistance (IR) remains incompletely understood. Hypocholesterolemia typically resolves after sustained viral response (SVR), implicating viral interference in host lipid metabolism. Using a targeted cholesterol metabolomic platform we evaluated paired HCV genotype 2 (G2) and G3 patient sera for changes in in vivo HCV sterol pathway metabolites. We compared HCV genotypic differences in baseline metabolites and following antiviral treatment to assess whether sterol perturbation resolved after HCV eradication. We linked these metabolites to IR and urine oxidative stress markers. In paired sera from HCV G2 (n = 13) and G3 (n = 20) patients, baseline sterol levels were lower in G3 than G2 for distal metabolites (7-dehyrocholesterol (7DHC) 0.017 versus 0.023 mg/dL; P(adj) = 0.0524, cholesterol 140.9 versus 178.7 mg/dL; P(adj) = 0.0242) but not the proximal metabolite lanosterol. In HCV G3, SVR resulted in increased levels of distal metabolites (cholesterol [Δ55.2 mg/dL; P(adj) = 0.0015], 7DHC [Δ0.0075 mg/dL; P(adj) = 0.0026], lathosterol [Δ0.0430 mg/dL P(adj) = 0.0405]). In contrast, lanosterol was unchanged after SVR (P = 0.9515). HCV G3, but not G2, selectively interferes with the late cholesterol synthesis pathway, evidenced by lower distal sterol metabolites and preserved lanosterol levels. This distal interference resolves with SVR. Normal lanosterol levels provide a signal for the continued proteolysis of 3-hydroxyl-3-methylglutaryl coenzyme A reductase, which may undermine other host responses to increase cholesterol synthesis. These data may provide a hypothesis to explain why hypocholesterolemia persists in chronic HCV infection, particularly in HCV G3, and is not overcome by host cholesterol compensatory mechanisms.


Use of complementary and alternative medicine for the treatment of genital herpes.
Conventional antiviral drugs have proven effectiveness for genital herpes; however, patients continue to use a variety of complementary and alternative medicine (CAM) treatments. Given that patients may be using these products, it is important that healthcare providers become familiar with the data regarding safety and efficacy. We have reviewed available scientific data on six commonly used treatments (echinacea, eleuthero, L-lysine, zinc, bee products and aloe). In addition, information about a number of other products is presented in tabular form. Currently, there are insufficient clinical data to be confident of the efficacy and safety of any of these products for the treatment of genital herpes. It is hoped that future clinical trials will be conducted with sufficient rigour to provide guidance to the patients using these products.


Relationships between xylem anatomy, root hydraulic conductivity, leaf/root ratio and transpiration in citrus trees on different rootstocks.
The aim of the study was to determine the extent in which leaf and whole plant transpiration (Tp) were influenced by root hydraulic conductance (K(r)), leaf to root ratio and leaf mass. Also, the relationships between the anatomic characteristics of roots and K(r) were investigated. To this end, 9-month-old seedlings of the citrus rootstocks Cleopatra mandarin (CM), Poncirus trifoliata (PT), and their hybrids Forner-Alcaide no 5 (FA-5) and Forner-Alcaide no 13 (FA-13) and 15-month-old trees of Valencia orange budded on these four rootstocks were tested. The hybrid FA-13 and PT had higher values of K(r) and leaf transpiration rates (E) than FA-5 and CM. There was a positive curvilinear correlation between E and K(r). Furthermore, E levels in the different types of plants decreased with increased leaf/root (L/R) ratios. Pruning of the roots and defoliation confirmed that transpiration rates were strongly influenced by the L/R ratio. However, variations in E because of differences in L/R ratios were less pronounced in trees budded on FA-13 and PT than on the other two rootstocks. In addition, there was a positive correlation between Tp and leaf biomass, although differences between rootstocks may be attributed to differences in K(r). The average lumen diameter of xylem vessels was greater in rootstocks with high K(r). Size of epidermal and hypodermal cells of fibrous roots may also restrict K(r).


Regional cerebral blood flow and cerebrovascular reactivity in IDDM.
To investigate both rCBF and cerebrovascular reactivity, evaluated as pre- and post-ACZ rCBF differences in a group of IDDM patients with differences in duration of disease and severity of complications. rCBF was measured by the 133Xenon inhalation method in 20 IDDM patients and in 15 healthy control subjects before and after an intravenous injection of ACZ, a carbonic anhydrase inhibitor commonly used to assess cerebrovascular reactivity. Basal global CBF (the mean of 32 regional values) was within the normal range in all patients but 1, who showed slight hyperperfusion; moreover, in 3 patients with long-lasting disease, some hypoperfused regions were found. ANOVA showed an inverse correlation between basal global CBF (P < 0.01) and duration of diabetes, but no correlation with Hb, MABP, serum glucose concentration, or GHb. Compared with control subjects, the percentage of global CBF increment after ACZ administration was significantly impaired in 4 patients and gave a borderline response in 2 patients; 4 of these poor ACZ responders had retinopathy, and 1 had suffered from a TIA. Duration of diabetes, Hb, MABP, serum glucose concentration, and GHb did not correlate with the percentage of post-ACZ global CBF changes, and did not differ among the 6 poor ACZ responders and the other diabetic patients or control subjects. These results confirm that global CBF is within the normal range in most IDDM patients, although it is significantly influenced by the duration of diabetes; pathophysiological correlates of the altered cerebrovascular reactivity need to be further investigated. rCBF measurements, before and after ACZ administration, seem to represent a safe and reliable tool for assessing cerebrovascular function in IDDM.


Quantifying the Feeding Periods Required by Corn Flea Beetles to Acquire and Transmit Pantoea stewartii.
The feeding periods required by corn flea beetles to acquire and transmit Pantoea stewartii were investigated in the Stewart's disease of corn pathosystem. To quantify the effect of acquisition feeding period on percentage of acquisition, field-collected corn beetles were allowed to feed for 6, 12, 24 36, 48, and 72 h on corn seedlings previously inoculated with a rifampicin- and nalidixic acid-restraint strain of P. stewartii. Acquisition of P. stewartii by corn flea beetles was considered positive if the rifampicin- and nalidixic acid-marked strain was recovered on selective media. To quantity the effect of transmission feeding period on percent transmission of P. stewartii by corn flea beetles, P. stewartii- infested corn flea beetles were allowed to feed on healthy corn seedlings for periods of 3, 6, 12, 24, 36, 48, and 72 h. After the appropriate transmission feeding period, leaf tissues surrounding the sites of feeding scars were cultured for the presence of the P. stewartii-marked strain. Transmission of P. stewartii was considered positive if the marked strain was recovered on selective media. Acquisition of P. stewartii occurred within 6 h and the percentage of corn flea beetles that had acquired P. stewartii after 72 h ranged from 68 to 94%. The change in P. stewartii acquisition by corn flea beetles (Y) with respect to acquisition feeding period (X) was best described by the Gompertz model, with R2 values ranging from 91 to 99%. The mean time for acquisition by 50% of the corn flea beetles was 36.5 ± 11.6 h. The minimum transmission feeding time required for corn flea beetles to transmit P. stewartii following a 48-h acquisition feeding period was less than 3 h. The percent transmission of P. stewartii by corn flea beetles was nearly 100% after a 48-h transmission feeding period and was 100% by 72 h. Among population growth models evaluated, the monomolecular model best described the relationship between percent transmission (Y) and transmission feeding periods (X), with R 2 values of up to 84%. However, a nonlinear form of the monomolecular model better quantified the relationship between percent transmission and transmission feeding period, because pseudo-R2 values ranged between 98.1 and 99.5%. The predicted transmission feeding time required for 50% of P. stewartii-infested corn flea beetles to transmit the pathogen was 7.6 ± 0.87 h. These results suggest that the corn flea beetle is a highly efficient vector that can quickly acquire and transmit P. stewartii, thereby requiring insecticide seed treatments and foliar insecticides that act quickly to prevent corn flea beetles from acquiring and transmitting P. stewartii to corn plants.


Neither 10- nor 14-Day Sequential Treatment is better than Standard Triple Therapy for Helicobacter Pylori Eradication.
Helicobacter pylori is a bacterial pathogen associated with chronic gastritis, peptic ulcer disease, gastric adenocarcinoma, and gastric mucosa associated lymphoid tissue lymphoma. Current treatment guidelines support a 7- to 14-day, triple-drug protocol consisting of a proton-pump inhibitor (PPI), clarithromycin, and either amoxicillin or an imidazole. The initial eradication rates for this regimen were 80 to 90%. Nevertheless its effectiveness has declined as the antibiotic resistance to clarithromycin and metronidazole has emerged. In Puerto Rico the reported resistance of H. pylori to clarithromycin is 16% and to metronidazole, 3.7%. Sequential therapy for H. pylori eradication, 5 days of treatment with a PPI and amoxicillin followed by 5 days of treatment with the PPI and 2 other antibiotics (clarithromycin and an imidazole), was introduced as an effective alternate regimen. This is a prospective clinical trial intended to compare the efficacy of first-line, standard 10-day tripledrug therapy with those of both 10- and 14-day sequential therapy in eradicating H. pylori at the San Juan Veterans Affairs Hospital in a population that is naïve to previous treatment. This was a prospective, open-label, randomized clinical trial. Based on the intention-to-treat analysis, the eradication rate was 83.7% (72 of 86 patients) in the standard triple-therapy group, 80.0% (68/85) in the 10- day sequential-therapy group, and 79.1% (68/86) in the 14-day sequential-therapy group. There were no significant statistical differences between the eradication rates among therapies. Sequential-therapy treatment regimens are not better than standard triple therapy for the eradication of H. pylori infection, regardless of the treatment duration.


Sub region-specific modulation of synchronous neuronal burst firing after a kainic acid insult in organotypic hippocampal cultures.
Excitotoxicity occurs in a number of pathogenic states including stroke and epilepsy. The adaptations of neuronal circuits in response to such insults may be expected to play an underlying role in pathogenesis. Synchronous neuronal firing can be induced in isolated hippocampal slices and involves all regions of this structure, thereby providing a measure of circuit activity. The effect of an excitotoxic insult (kainic acid, KA) on Mg2+-free-induced synchronized neuronal firing was tested in organotypic hippocampal culture by measuring extracellular field activity in CA1 and CA3. Within 24 hrs of the insult regional specific changes in neuronal firing patterns were evident as: (i) a dramatic reduction in the ability of CA3 to generate firing; and (ii) a contrasting increase in the frequency and duration of synchronized neuronal firing events in CA1. Two distinct processes underlie the increased propensity of CA1 to generate synchronized burst firing; a lack of ability of the CA3 region to 'pace' CA1 resulting in an increased frequency of synchronized events; and a change in the 'intrinsic' properties limited to the CA1 region, which is responsible for increased event duration. Neuronal quantification using NeuN immunoflurescent staining and stereological confocal microscopy revealed no significant cell loss in hippocampal sub regions, suggesting that changes in the properties of neurons within this region were responsible for the KA-mediated excitability changes. These results provide novel insight into adaptation of hippocampal circuits following excitotoxic injury. KA-mediated disruption of the interplay between CA3 and CA1 clearly increases the propensity to synchronized firing in CA1.


The Identification of Intrinsic Chloramphenicol and Tetracycline Resistance Genes in Members of the Bacillus cereus Group (sensu lato).
Bacillus toyonensis strain BCT-7112T (NCIMB 14858T) has been widely used as an additive in animal nutrition for more than 30 years without reports of adverse toxigenic effects. However, this strain is resistant to chloramphenicol and tetracycline and it is generally considered inadvisable to introduce into the food chain resistance determinants capable of being transferred to other bacterial strains, thereby adding to the pool of such determinants in the gastro-enteric systems of livestock species. We therefore characterized the resistance phenotypes of this strain and its close relatives to determine whether they were of recent origin, and therefore likely to be transmissible. To this end we identified the genes responsible for chloramphenicol (catQ) and tetracycline (tetM) resistance and confirmed the presence of homologs in other members of the B. toyonensis taxonomic unit. Unexpectedly, closely related strains encoding these genes did not exhibit chloramphenicol and tetracycline resistance phenotypes. To understand the differences in the behaviors, we cloned and expressed the genes, together with their upstream regulatory regions, into Bacillus subtilis. The data showed that the genes encoded functional proteins, but were expressed inefficiently from their native promoters. B. toyonensis is a taxonomic unit member of the Bacillus cereus group (sensu lato). We therefore extended the analysis to determine the extent to which homologous chloramphenicol and tetracycline resistance genes were present in other species within this group. This analysis revealed that homologous genes were present in nearly all representative species within the B. cereus group (sensu lato). The absence of known transposition elements and the observations that they are found at the same genomic locations, indicates that these chloramphenicol and tetracycline resistance genes are of ancient origin and intrinsic to this taxonomic group, rather than recent acquisitions. In this context we discuss definitions of what are and are not intrinsic genes, an issue that is of fundamental importance to both Regulatory Authorities, and the animal feed and related industries.


Integration of Complementary and Alternative Medicine Therapies into Primary-Care Pain Management for Opiate Reduction in a Rural Setting.
Opiates are no longer considered the best strategy for the long-term management of chronic pain. Yet, physicians have made many patients dependent on them, and these patients still request treatment. Complementary and alternative medicine (CAM) therapies have been shown to be effective, but are not widely available and are not often covered by insurance or available to the medically underserved. Group medical visits (GMVs) provided education about non-pharmacological methods for pain management and taught mindfulness techniques, movement, guided imagery, relaxation training, yoga, qigong, and t'ai chi. Forty-two patients attending GMVs for at least six months were matched prospectively with patients receiving conventional care. No one increased their dose of opiates. Seventeen people reduced their dose, and seven people stopped opiates. On a 10-point scale of pain intensity, reductions in pain ratings achieved statistical significance (p = 0.001). The average reduction was 0.19 (95% confidence interval [CI] 0.12-0.60; p = 0.01). The primary symptom improved on average by -0.42 (95% CI -0.31 to -0.93; p = 0.02) on the My Medical Outcome Profile, 2nd version. Improvement in the quality-of-life rating was statistically significant (p = 0.007) with a change of -1.42 (95% CI = -0.59 to -1.62). In conventional care, no patients reduced their opiate use, and 48.5% increased their dose over the two years of the project. GMVs that incorporated CAM therapies helped patients reduce opiate use. While some patients found other physicians to give them the opiates they desired, those who persisted in an environment of respect and acceptance significantly reduced opiate consumption compared with patients in conventional care. While resistant to CAM therapies initially, the majority of patients came to accept and to appreciate their usefulness. GMVs were useful for incorporating non-reimbursed CAM therapies into primary medical care.


GeneMerge--post-genomic analysis, data mining, and hypothesis testing.
GeneMerge is a web-based and standalone program written in PERL that returns a range of functional and genomic data for a given set of study genes and provides statistical rank scores for over-representation of particular functions or categories in the data set. Functional or categorical data of all kinds can be analyzed with GeneMerge, facilitating regulatory and metabolic pathway analysis, tests of population genetic hypotheses, cross-experiment comparisons, and tests of chromosomal clustering, among others. GeneMerge can perform analyses on a wide variety of genomic data quickly and easily and facilitates both data mining and hypothesis testing. GeneMerge is available free of charge for academic use over the web and for download from: http://www.oeb.harvard.edu/hartl/lab/publications/GeneMerge.html.


Genome-wide association analysis identifies resistance loci for bacterial blight in a diverse collection of indica rice germplasm.
Bacterial blight, which is caused by Xanthomonas oryzae pv. oryzae (Xoo), is one of the most devastating rice diseases worldwide. The development and use of disease-resistant cultivars have been the most effective strategy to control bacterial blight. Identifying the genes mediating bacterial blight resistance is a prerequisite for breeding cultivars with broad-spectrum and durable resistance. We herein describe a genome-wide association study involving 172 diverse Oryza sativa ssp. indica accessions to identify loci influencing the resistance to representative strains of six Xoo races. Twelve resistance loci containing 121 significantly associated signals were identified using 317,894 single nucleotide polymorphisms, which explained 13.3-59.9% of the variability in lesion length caused by Xoo races P1, P6, and P9a. Two hotspot regions (L11 and L12) were located within or nearby two cloned R genes (xa25 and Xa26) and one fine-mapped R gene (Xa4). Our results confirmed the relatively high resolution of genome-wide association studies. Moreover, we detected novel significant associations on chromosomes 2, 3, and 6-10. Haplotype analyses of xa25, the Xa26 paralog (MRKc; LOC_Os11g47290), and a Xa4 candidate gene (LOC_11g46870) revealed differences in bacterial blight resistance among indica subgroups. These differences were responsible for the observed variations in lesion lengths resulting from infections by Xoo races P1 and P9a. Our findings may be relevant for future studies involving bacterial blight resistance gene cloning, and provide insights into the genetic basis for bacterial blight resistance in indica rice, which may be useful for knowledge-based crop improvement.


Characterization of Melan-A reactive memory CD8+ T cells in a healthy donor.
Melan-A specific CD8+ T cells are thought to play an important role against the development of melanoma. Their in vivo expansion is often observed with advanced disease. In recent years, low levels of Melan-A reactive CD8+ T cells have also been found in HLA-A2 healthy donors, but these cells harbor naive characteristics and are thought to be mostly cross-reactive for the Melan-A antigen. Here, we report on a large population of CD8+ T cells reactive for the Melan-A antigen, identified in one donor with no evidence of melanoma. Interestingly, this population is oligoclonal and displays a clear memory phenotype. However, a detailed study of these cells indicated that they are unlikely to be directly specific for melanoma, so that their in vivo expansion may have been driven by an exogenous antigen. Screening of a Melan-A cross-reactive peptide library suggested that these cells may be specific for an epitope derived from a Mycobacterium protein, which would provide a further example of CD8+ T cell cross-reactivity between a pathogen antigen and a tumor antigen. Finally, we discuss potential perspectives regarding the role of such cells in heterologous immunity, by influencing the balance between protective immunity and pathology, e.g. in the case of melanoma development.


Perineal reconstruction with bilateral bilobed flap for cloacal-like defect after childbirth.
Fourth degree lacerations of the vaginal wall and perineum following childbirth can cause cloacal-like defects of the perineum. The loss of the anterior anal sphincter and resultant thinning of the perineum and rectovaginal septum can lead to fecal incontinence and difficulties with sexual activity. This article introduces a technique to combine repair of the anterior anal sphincter with reconstruction of the perineal body with bilateral pedicled bilobed flaps.


Birth characteristics and Wilms tumor in Minnesota.
Wilms tumor (WT) is a childhood kidney cancer with the highest rate of occurrence before the age of 2. Since it is rare, previous research has been limited and few risk factors have been established. We used a case-cohort design to examine the influence of birth characteristics on occurrence of WT in Minnesota. A total of 2,188 cases of cancer diagnosed in children aged 28 days to 14 years from 1988 to 2004 were identified using the Minnesota Cancer Surveillance System (MCSS). For each case, 4 children were randomly selected from Minnesota birth records during 1976-2004, frequency matched on birth year. Thus, a total of 8,752 children comprised the subcohort for the study, who in this analysis, served as comparison to the 138 cases of WT. Study variables included parental demographics, maternal pregnancy history and conditions and health and conditions of the child at birth. Associations with WT were assessed using hazard ratios (HR) and 95% confidence intervals (CI) calculated from stratified Cox regression models. We found an increased risk of WT for children who were large for gestational age compared to those average for gestational age and for children with congenital abnormalities. There was also an increased risk for children with a birth weight > 4,000 g compared to those with a birth weight between 2,500 and 4,000 g. All other factors examined showed no association with WT. This study contributes to the mounting evidence that children with large size at birth have an increased risk of WT.


Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction.
As compared with thrombolytic therapy, primary percutaneous transluminal coronary angioplasty (PTCA) in acute myocardial infarction reduces the rates of death, reinfarction, and stroke, but recurrent ischemia, restenosis, and reocclusion of the infarct-related artery remain problematic. When used in combination with PTCA, coronary stenting and platelet glycoprotein IIb/IIIa inhibitors may further improve outcomes. Using a 2-by-2 factorial design, we randomly assigned 2082 patients with acute myocardial infarction to undergo PTCA alone (518 patients), PTCA plus abciximab therapy (528), stenting alone with the MultiLink stent (512), or stenting plus abciximab therapy (524). Normal flow was restored in the target vessel in 94.5 to 96.9 percent of patients and did not vary according to the reperfusion strategy. At six months, the primary end point - a composite of death, reinfarction, disabling stroke, and ischemia-driven revascularization of the target vessel - had occurred in 20.0 percent of patients after PTCA, 16.5 percent after PTCA plus abciximab, 11.5 percent after stenting, and 10.2 percent after stenting plus abciximab (P<0.001). There were no significant differences among the groups in the rates of death, stroke, or reinfarction; the difference in the incidence of the primary end point was due entirely to differences in the rates of target-vessel revascularization (ranging from 15.7 percent after PTCA to 5.2 percent after stenting plus abciximab, P<0.001). The rate of angiographically established restenosis was 40.8 percent after PTCA and 22.2 percent after stenting (P<0.001), and the respective rates of reocclusion of the infarcted-related artery were 11.3 percent and 5.7 percent (P=0.01), both independent of abciximab use. At experienced centers, stent implantation (with or without abciximab therapy) should be considered the routine reperfusion strategy.


Packing is a key selection factor in the evolution of protein hydrophobic cores.
The energy derived from optimized van der Waals interactions in closely packed, folded proteins has been proposed to be of similar energetic magnitude to hydrophobicity in stabilizing the native state. If packing is this energetically important, it should influence the evolution of protein core sequences. To test this hypothesis, the occurrence of various amino acid side chains in the major hydrophobic core of staphylococcal nuclease and 42 homologous proteins was determined. Most such positions in this protein family are usually isoleucine, leucine, or valine. Previously we have constructed and measured the stabilities of 12 single, 44 double, 64 triple, and 32 quadruple mutants, representing all possible permutations of these three side chains at two overlapping sets of four positions in the core of staphylococcal nuclease. The stabilities and interaction energies of those mutants with various combinations of the most common, or consensus, sequence were compared to the stabilities of all other mutants. Mutants which had the consensus side-chain combinations were not necessarily the most stable, but usually were found to have the best interaction energies. In other words, these proteins were far more stable than would be predicted from simply summing the observed energetic effects of the component single mutations, apparently reflecting particularly favorable packing interactions that are possible for the most common side chains. An additional 12 mutants which tested possible alternate explanations of the results were constructed. The stabilities and interaction energies of these mutants also support the conclusion that packing is a crucial determinant guiding the sequence evolution of protein cores.


Debranching of pea starch using pullulanase and ultrasonication synergistically to enhance slowly digestible and resistant starch.
Pullulanase (P) and ultrasonication (U) were simultaneously applied to debranch pea starch to enhance slowly digestible starch (SDS) and resistant starch (RS) fractions in the debranched pea starch (DPS). A synergistic debranching effect was found under conditions of pullulanase (40 npun/g) and ultrasonication (100% amplitude in pulse mode, 1 min on followed by 9 min off), which produced 73.5% linear glucans, 18% SDS and 26% RS in the resulting DPS-PU after 6 h of debranching. Even when autoclaving the DPS-PU at 118 °C for 30 min, following cooldown, 11% SDS and 25% RS were retained in the DPS-PU, compared with 0% SDS and 12% RS in autoclaved native pea starch. The SDS fraction in autoclaved DPS-PU further increased to 16% while the RS content remained constant during 14 days of cold storage. In summary, DPS-PU is high in linear glucans, low in starch digestibility and has a thermally stable RS fraction.


Does safety make a difference in selecting the right TNF antagonist?
Tumor necrosis factor (TNF) antagonists are biologic response modifiers that have significantly improved the outcomes in patients with rheumatoid arthritis (RA). At this report, safety data were collected on approximately 271,000 patients administered infliximab (as of February 2002), 121,000 patients administered etanercept (as of December 2001), and on 2400 patients who received adalimumab in trials in connection with the regulatory approval process (approval granted December 2002 in the US and September 2003 in European Union). Infliximab and etanercept have predictable and manageable safety profiles, and preliminary data suggest that the profile of adalimumab is comparable. Safety issues involving the anti-TNF agents as a class include the risk of injection-site reactions or infusion-related reactions, infection (for example, serious, opportunistic, or tubercular), malignancy, autoimmunity, and demyelinating and neurologic disorders. Injection-site and infusion-related reactions are most often easily managed and rarely lead to discontinuation of therapy. Infections can be minimized or prevented by screening and careful monitoring and follow-up; most infections respond to appropriate medical treatment. More studies are needed to evaluate the occurrence of malignancies in patients with RA to determine the potential risk posed by therapy. Antibody formation can follow the administration of any biologic agent. Although demyelinating disease has been reported with anti-TNF agents, it is not clear whether a causal relationship exists. Overall, the anti-TNF agents are well tolerated and have demonstrated a favorable benefit-to-risk profile in patients with RA.


Raynaud's of the tongue following chemoradiation for squamous cell carcinoma of the oropharynx.
Raynaud's of the tongue following radiation alone or chemoradiotherapy (CRT) is a rare occurrence. The present study reports a case where typical symptoms and signs of Raynaud's phenomenon involving the tongue occurred ~18 months following CRT treatment in a 53-year-old female, who was a smoker prior to CRT with stage T2N2cM0 local-regional advanced stage IV oropharyngeal cancer. The patient was treated using cisplatin chemotherapy and intensity-modulated radiation with a dose of 70 Gray (Gy). The intermittent episodes of painful discoloration of the tongue were exacerbated due to the cold and emotional stress. No definite clinical or laboratory evidence of connective tissue disorder was identified. To the best of our knowledge, this is the first reported case of Raynaud's of the tongue following CRT without primary Raynaud's of the digits. The possible pathogenesis involving vascular and neural mechanism is discussed in the case report.


Collective instance-level gene normalization on the IGN corpus.
A high proportion of life science researches are gene-oriented, in which scientists aim to investigate the roles that genes play in biological processes, and their involvement in biological mechanisms. As a result, gene names and their related information turn out to be one of the main objects of interest in biomedical literatures. While the capability of recognizing gene mentions has made significant progress, the results of recognition are still insufficient for direct use due to the ambiguity of gene names. Gene normalization (GN) goes beyond the recognition task by linking a gene mention to a database ID. Unlike most previous works, we approach GN on the instance-level and evaluate its overall performance on the recognition and normalization steps in abstracts and full texts. We release the first instance-level gene normalization (IGN) corpus in the BioC format, which includes annotations for the boundaries of all gene mentions and the corresponding IDs for human gene mentions. Species information, along with existing co-reference chains and full name/abbreviation pairs are also provided for each gene mention. Using the released corpus, we have designed a collective instance-level GN approach using not only the contextual information of each individual instance, but also the relations among instances and the inherent characteristics of full-text sections. Our experimental results show that our collective approach can achieve an F-score of 0.743. The proposed approach that exploits section characteristics in full-text articles can improve the F-scores of information lacking sections by up to 1.8%. In addition, using the proposed refinement process improved the F-score of gene mention recognition by 0.125 and that of GN by 0.03. Whereas current experimental results are limited to the human species, we seek to continue updating the annotations of the IGN corpus and observe how the proposed approach can be extended to other species.


Airway branching patterns influence asbestos fiber location and the extent of tissue injury in the pulmonary parenchyma.
The degree to which various anatomic components of the lung influence the distribution of inhaled particles is not entirely clear. Therefore, we have studied the role intrapulmonary airways play in the localization of respired asbestos fibers and have correlated local asbestos fiber burden with tissue injury in rats following exposure to aerosolized chrysotile asbestos for 7 hours per day, 5 days per week for 12 months. Tissues arising from anatomically distinct pathways of the tracheobronchial tree were isolated by using microdissection. Adjacent tissue blocks from regions immediately distal to the last dissected airway were prepared for light microscopic evaluation or digested in hypochlorite solution to determine alveolar septal tissue density and asbestos fiber concentration respectively. These studies demonstrated regional differences in asbestos fiber number, size, and mass which were inversely related to airway pathlength and to bifurcation number along each airway path. Fiber burden within each region was found to be proportional to the relative degree of tissue injury present. These findings suggest that differences in tissue injury from region to region in the lungs following exposure to asbestos are a result of regional differences in the deposition and retention of these substances in the lungs. These airway characteristics which influence fiber deposition may also play an important role in the deposition and subsequent lung injury caused by other particulates and environmental pollutants.


Fetal research.
This article reviews some of the significant contributions of fetal research and fetal tissue research over the past 20 years. The benefits of fetal research include the development of vaccines, advances in prenatal diagnosis, detection of malformations, assessment of safe and effective medications, and the development of in utero surgical therapies. Fetal tissue research benefits vaccine development, assessment of risk factors and toxicity levels in drug production, development of cell lines, and provides a source of fetal cells for ongoing transplantation trials. Together, fetal research and fetal tissue research offer tremendous potential for the treatment of the fetus, neonate, and adult.


Consistent intensity inhomogeneity correction in water-fat MRI.
To quantitatively and qualitatively evaluate the water-signal performance of the consistent intensity inhomogeneity correction (CIIC) method to correct for intensity inhomogeneities Water-fat volumes were acquired using 1.5 Tesla (T) and 3.0T symmetrically sampled 2-point Dixon three-dimensional MRI. Two datasets: (i) 10 muscle tissue regions of interest (ROIs) from 10 subjects acquired with both 1.5T and 3.0T whole-body MRI. (ii) Seven liver tissue ROIs from 36 patients imaged using 1.5T MRI at six time points after Gd-EOB-DTPA injection. The performance of CIIC was evaluated quantitatively by analyzing its impact on the dispersion and bias of the water image ROI intensities, and qualitatively using side-by-side image comparisons. CIIC significantly ( P1.5T≤2.3×10-4,P3.0T≤1.0×10-6) decreased the nonphysiological intensity variance while preserving the average intensity levels. The side-by-side comparisons showed improved intensity consistency ( Pint≤10-6) while not introducing artifacts ( Part=0.024) nor changed appearances ( Papp≤10-6). CIIC improves the spatiotemporal intensity consistency in regions of a homogenous tissue type.


Carnitine palmitoyltransferase II deficiency: a clinical, biochemical, and molecular review.
Congenital deficiency of carnitine palmitoyltransferase (CPT) II has been known for at least 30 years now, and its phenotypic variability remains fascinating. Three distinct clinical entities have been described, the adult, the infantile, and the perinatal, all with an autosomal recessive inheritance pattern. The adult CPT II clinical phenotype is somewhat benign and requires additional external triggers such as high-intensity exercise before the predominantly myopathic symptoms are elicited. The perinatal and infantile forms involve multiple organ systems. The perinatal disease is the most severe form and is invariably fatal. The introduction of mass spectrometry to analyze blood acylcarnitine profiles has revolutionized the diagnosis of fatty acid oxidation disorders including CPT II deficiency. Its use in expanded neonatal screening programs has made presymptomatic diagnosis a reality. An increasing number of mutations are being identified in the CPT II gene with a distinct genotype-phenotype correlation in most cases. However, clinical variability in some patients suggests additional genetic or environmental modifiers. Herein, we present a new case of lethal perinatal CPT II deficiency with a rare missense mutation, R296Q (907G>A) associated with a previously described 25-bp deletion on the second allele. We review the clinical features, the diagnostic protocol including expanded neonatal screening, the treatment, and the biochemical and molecular basis of CPT II deficiency.


Dietary intake of anthocyanins and risk of cardiovascular disease: A systematic review and meta-analysis of prospective cohort studies.
Accumulating evidence suggests flavonoid intake is associated with reduced risk of non-communicable diseases. We aimed to systematically determine and quantify the potential association between dietary anthocyanin intake and risk of cardiovascular diseases (CVD). A systematic literature search of studies reporting anthocyanin intake and risk of fatal or nonfatal CVD was performed using SCOPUS, MEDLINE, CINAHL and Cochrane Library. The relative risk (RR) or hazard ratio (HR) of highest category of anthocyanin foods were pooled in a random-effects meta-analysis. Subgroup analysis were conducted to determine possible sources of heterogeneity. The meta-analysis suggested intake of dietary anthocyanins and reduced risk of CHD (RR = 0.91, 95% CI: 0.83, 0.99; I2 = 12.0, Ph = 0.337) and CVD mortality (RR = 0.92, 95% CI: 0.87, 0.97; I2 = 0.0, Ph = 0.584). However, there was no relationship between the intake of these compounds and reduced risk of MI, stroke or total CVD. Subgroup analysis determined reduced risk of CHD and CVD mortality was more prominent for anthocyanidin intake, as opposed to anthocyanin or berries. Our systematic review and meta-analysis provides evidence that anthocyanins, specifically anthocyanidins, reduce the risk of CHD and CVD mortality. Further randomized controlled trials on anthocyanin intake and CVD risk factors are needed to support these findings.


The evolutionary dynamics of canid and mongoose rabies virus in Southern Africa.
Two variants of rabies virus (RABV) currently circulate in southern Africa: canid RABV, mainly associated with dogs, jackals, and bat-eared foxes, and mongoose RABV. To investigate the evolutionary dynamics of these variants, we performed coalescent-based analyses of the G-L inter-genic region, allowing for rate variation among viral lineages through the use of a relaxed molecular clock. This revealed that mongoose RABV is evolving more slowly than canid RABV, with mean evolutionary rates of 0.826 and 1.676 x 10(-3) nucleotide substitutions per site, per year, respectively. Additionally, mongoose RABV exhibits older genetic diversity than canid RABV, with common ancestors dating to 73 and 30 years, respectively, and while mongoose RABV has experienced exponential population growth over its evolutionary history in Africa, populations of canid RABV have maintained a constant size. Hence, despite circulating in the same geographic region, these two variants of RABV exhibit striking differences in evolutionary dynamics which are likely to reflect differences in their underlying ecology.


Standing up in multiple sclerosis (SUMS): protocol for a multi-centre randomised controlled trial evaluating the clinical and cost effectiveness of a home-based self-management standing frame programme in people with progressive multiple sclerosis.
Multiple sclerosis (MS) is an incurable, unpredictable but typically progressive neurological condition. It is the most common cause of neurological disability in young adults. Within 15 years of diagnosis, approximately 50 % of affected people are unable to walk unaided, and over time an estimated 25 % depend on a wheelchair. Typically, people with such limited mobility are excluded from clinical trials. Severely impaired people with MS spend much of their day sitting, often with limited ability to change position. In response, secondary complications can occur including: muscle wasting, pain, reduced skin integrity, spasms, limb stiffness, constipation, and associated psychosocial problems such as depression and lowered self-esteem. Effective self-management strategies, which can be implemented relatively easily and cheaply within people's homes, are needed to improve or maintain mobility and reduce sedentary behaviour. However this is challenging, particularly in the latter stages of disease. Regular supported standing using standing frames is one potential option. SUMS is a pragmatic multi-centre randomised controlled trial evaluating use of Oswestry standing frames with blinded outcome assessment and full economic evaluation. Participants will be randomly allocated (1:1) to either a home-based, self-management standing programme (with advice and support) along with their usual care or to usual care alone. Those in the intervention group will be asked to stand for a minimum of 30 min three times weekly over 20 weeks. Each participant will be followed-up at 20 and 36 weeks post baseline. The primary clinical outcome is motor function, assessed using the Amended Motor Club Assessment. The primary economic endpoint is quality-adjusted life years. The secondary outcomes include measures of explanatory physical impairments, key clinical outcomes, and health-related quality of life. An embedded qualitative component will explore participant's and carer's experiences of the standing programme. This is the first large scale multi-centre trial to assess the clinical and cost effectiveness of a home based standing frame programme for people who are severely impaired by MS. If demonstrated to be effective and cost-effective, we will use this evidence to develop recommendations for a health service delivery model which could be implemented across the United Kingdom. ISRCTN69614598 DATE OF REGISTRATION: 3.2.16 (retrospectively registered).


Quality indicators for blogs and podcasts used in medical education: modified Delphi consensus recommendations by an international cohort of health professions educators.
Quality assurance concerns about social media platforms used for education have arisen within the medical education community. As more trainees and clinicians use resources such as blogs and podcasts for learning, we aimed to identify quality indicators for these resources. A previous study identified 151 potentially relevant quality indicators for these social media resources. To identify quality markers for blogs and podcasts using an international cohort of health professions educators. A self-selected group of 44 health professions educators at the 2014 International Conference on Residency Education participated in a Social Media Summit during which a modified Delphi consensus study was conducted to determine which of the 151 quality indicators met the a priori ≥90% inclusion threshold. Thirteen quality indicators classified into the domains of credibility (n=8), content (n=4) and design (n=1) met the inclusion threshold. The quality indicators that were identified may serve as a foundation for further research on quality indicators of social media-based medical education resources and prompt discussion of their legitimacy as a form of educational scholarship.


Cytogenetic Karyotype Analysis in Selected Species of the Erinaceidae Family.
Comparative analysis of the karyotype structure was made in two hedgehog species: the northern white-breasted hedgehog (Erinaceus roumanicus) and the African pygmy hedgehog (Atelerix albiventris). The cytogenetic analysis used differential staining techniques (DAPI, Ag-NOR, and C-banding/DAPI) and sequential QFQ/FISH banding with NOR20 and TEL20 probes which showed 45S rDNA and (TTAGGG)n repeat sequences, respectively, on hedgehog chromosomes. It was confirmed that the somatic cells of the hedgehogs have a constant number of chromosomes (2n = 48,XY). Differences were observed in the NOR number between the species. NORs were identified on three autosome pairs in the northern white-breasted hedgehog and on only two pairs in the African pygmy hedgehog. Chromosome analysis by C-banding/DAPI showed large segments of heterochromatin rich in A-T pairs on three autosome pairs in both the northern white-breasted and African pygmy hedgehogs. The heterochromatin segments encompassed large fragments of the longer arm of chromosome pairs 13, 14 and 20. The (TTAGGG)n repeat sequences on the hedgehog chromosomes were only observed in the terminal position of all the chromosomes in both species. Our observations provide new information on the level of diversity within the Erinaceidae family.


A rapid and concise setup for the fast screening of FRET pairs using bioorthogonalized fluorescent dyes.
One of the most popular means to follow interactions between bio(macro)molecules is Förster resonance energy transfer (FRET). There is large interest in widening the selection of fluorescent FRET pairs especially in the region of the red/far red range, where minimal autofluorescence is encountered. A set of bioorthogonally applicable fluorescent dyes, synthesized recently in our lab, were paired (Cy3T/Cy5T; Cy1A/Cy3T and Cy1A/CBRD1A) based on their spectral characteristics in order to test their potential in FRET applications. For fast elaboration of the selected pairs we have created a bioorthogonalized platform based on complementary 17-mer DNA oligomers. The cyclooctynylated strands were modified nearly quantitatively with the fluorophores via bioorthogonal chemistry steps, using azide- (Cy1; CBRD1) or tetrazine-modified (Cy3; Cy5) dyes. Reactions were followed by capillary electrophoresis using a method specifically developed for this project. FRET efficiencies of the fluorescent dye pairs were compared both in close proximity (5' and 3' matched) and at larger distance (5' and 5' matched). The specificity of FRET signals was further elaborated by denaturation and competition studies. Cy1A/Cy3T and Cy1A/CBRD1A introduced here as novel FRET pairs are highly recommended for FRET applications based on the significant changes in fluorescence intensities of the donor and acceptor peaks. Application of one of the FRET pairs was demonstrated in live cells, transfected with labeled oligos. Furthermore, the concise installation of the dyes allows for efficient fluorescence modification of any selected DNA strands as was demonstrated in the construction of Cy3T labeled oligomers, which were used in the FISH-based detection of Helicobacter pylori.


A functional ectopic vaginal anus: a rare clinical entity.
A case of functional ectopic vaginal anus is presented in a 20 years old girl. Patient complained of passage of stool through her vagina. She was continent and had no complaint of constipation. Her examination revealed imperforated anus with functional ectopic vaginal anus. Her surgery was performed in two stages. In first stage, anoplasty was performed at midpoint between the vulval and anal opening. The posterior vaginal wall was repaired in two layers and protective loop colostomy was made. In the second stage, after a period of 3 months loop colostomy was closed. Patient's recovery was smooth, she is not constipated and continent with Wexner score of 3. She was advised pelvic floor rehabilitation exercises.She improved within a month with Wexner score of zero.


Automated bacterial identification by angle resolved dark-field imaging.
We propose and demonstrate a dark-field imaging technique capable of automated identification of individual bacteria. An 87-channel multispectral system capable of angular and spectral resolution was used to measure the scattering spectrum of various bacteria in culture smears. Spectra were compared between various species and between various preparations of the same species. A 15-channel system was then used to prove the viability of bacterial identification with a relatively simple microscope system. A simple classifier was able to identify four of six bacterial species with greater than 90% accuracy in bacteria-by-bacteria testing.


Grooves to tubes: evolution of the venom delivery system in a Late Triassic "reptile".
Venom delivery systems occur in a wide range of extant and fossil vertebrates and are primarily based on oral adaptations. Teeth range from unmodified (Komodo dragons) to highly specialized fangs similar to hypodermic needles (protero- and solenoglyphous snakes). Developmental biologists have documented evidence for an infolding pathway of fang evolution, where the groove folds over to create the more derived condition. However, the oldest known members of venomous clades retain the same condition as their extant relatives, resulting in no fossil evidence for the transition. Based on a comparison of previously known specimens with newly discovered teeth from North Carolina, we describe a new species of the Late Triassic archosauriform Uatchitodon and provide detailed analyses that provide evidence for both venom conduction and document a complete structural series from shallow grooves to fully enclosed tubular canals. While known only from teeth, Uatchitodon is highly diagnostic in possessing compound serrations and for having two venom canals on each tooth in the dentition. Further, although not a snake, Uatchitodon sheds light on the evolutionary trajectory of venom delivery systems in amniotes and provide solid evidence for venom conduction in archosaur-line diapsids.


Functional State of Cells During their Life and on their Journey Toward Inactivity and Death: Search for Morphological Evidence in Thyroid Fine Needle Aspiration Smears.
Synthesis and storage of thyroglobulin as well as synthesis of thyroid hormones and their release into the circulation are important functions of thyroid, which were studied in fine needle aspiration (FNA) smears from thyroid lesions. Evidence of thyroglobulin synthesis was demonstrated in neoplastic and nonneoplastic follicular cells, especially in Hürthle cells, in the form of colloid inclusions. Whereas the pinocytic vesicles containing colloid at the luminal end of in nonneoplastic and neoplastic follicular cells indicated engulfment of colloid for synthesis of thyroid hormones (T3 and T4), the marginal vacuoles (MVs) (fire-flare appearance) at the basal aspects of follicular cells suggested their release on way to the interfollicular capillaries. The morphological evidence of secretary activity could also be demonstrated in medullary thyroid carcinoma (MTC) in the form of azurophilic granules, marginal vacuoles, and intracytoplasmic lumina (ICL) with secretions; the secretory material, likely to be amyloid, present in MTC cells, and their release to the extracellular space was confirmed by positive immunocytochemical staining for calcitonin. It was found that nuclear grooves and related intranuclear cytoplasmic inclusions (INCIs) in papillary thyroid carcinoma (PTC) possibly represent an initial step of a degenerative process leading to formation of inactive cerebriform nuclei. Based on observation regarding formation and release of precursor substances for psammoma bodies (PBs), it was also suggested that PBs may not represent a process of dystrophic calcification over infarcted/dead papillae but suggest an active biological process, which leads to inhibition of growth of neoplastic cells and acts as a barrier against spread of PTC.


CUDA compatible GPU cards as efficient hardware accelerators for Smith-Waterman sequence alignment.
Searching for similarities in protein and DNA databases has become a routine procedure in Molecular Biology. The Smith-Waterman algorithm has been available for more than 25 years. It is based on a dynamic programming approach that explores all the possible alignments between two sequences; as a result it returns the optimal local alignment. Unfortunately, the computational cost is very high, requiring a number of operations proportional to the product of the length of two sequences. Furthermore, the exponential growth of protein and DNA databases makes the Smith-Waterman algorithm unrealistic for searching similarities in large sets of sequences. For these reasons heuristic approaches such as those implemented in FASTA and BLAST tend to be preferred, allowing faster execution times at the cost of reduced sensitivity. The main motivation of our work is to exploit the huge computational power of commonly available graphic cards, to develop high performance solutions for sequence alignment. In this paper we present what we believe is the fastest solution of the exact Smith-Waterman algorithm running on commodity hardware. It is implemented in the recently released CUDA programming environment by NVidia. CUDA allows direct access to the hardware primitives of the last-generation Graphics Processing Units (GPU) G80. Speeds of more than 3.5 GCUPS (Giga Cell Updates Per Second) are achieved on a workstation running two GeForce 8800 GTX. Exhaustive tests have been done to compare our implementation to SSEARCH and BLAST, running on a 3 GHz Intel Pentium IV processor. Our solution was also compared to a recently published GPU implementation and to a Single Instruction Multiple Data (SIMD) solution. These tests show that our implementation performs from 2 to 30 times faster than any other previous attempt available on commodity hardware. The results show that graphic cards are now sufficiently advanced to be used as efficient hardware accelerators for sequence alignment. Their performance is better than any alternative available on commodity hardware platforms. The solution presented in this paper allows large scale alignments to be performed at low cost, using the exact Smith-Waterman algorithm instead of the largely adopted heuristic approaches.


Sexually coercive male chimpanzees sire more offspring.
In sexually reproducing animals, male and female reproductive strategies often conflict. In some species, males use aggression to overcome female choice, but debate persists over the extent to which this strategy is successful. Previous studies of male aggression toward females among wild chimpanzees have yielded contradictory results about the relationship between aggression and mating behavior. Critically, however, copulation frequency in primates is not always predictive of reproductive success. We analyzed a 17-year sample of behavioral and genetic data from the Kasekela chimpanzee (Pan troglodytes schweinfurthii) community in Gombe National Park, Tanzania, to test the hypothesis that male aggression toward females increases male reproductive success. We examined the effect of male aggression toward females during ovarian cycling, including periods when the females were sexually receptive (swollen) and periods when they were not. We found that, after controlling for confounding factors, male aggression during a female's swollen periods was positively correlated with copulation frequency. However, aggression toward swollen females was not predictive of paternity. Instead, aggression by high-ranking males toward females during their nonswollen periods was positively associated with likelihood of paternity. This indicates that long-term patterns of intimidation allow high-ranking males to increase their reproductive success, supporting the sexual coercion hypothesis. To our knowledge, this is the first study to present genetic evidence of sexual coercion as an adaptive strategy in a social mammal.


It's not going to be that fun: negative experiences can add meaning to life.
People seek to spend time in positive experiences, enjoying and savoring. Yet there is no escaping negative experiences, from the mundane (e.g. arguing) to the massive (e.g. death of a child). Might negative experiences confer a hidden benefit to well-being? We propose that they do, in the form of enhanced meaning in life. Research suggests that negative experiences can serve to boost meaning because they stimulate comprehension (understanding how the event fits into a broader narrative of the self, relationships, and the world), a known pillar of meaning in life. Findings on counterfactual thinking, reflecting on events' implications, and encompassing experiences into broad-based accounts of one's identity support the role of comprehension in contributing to life's meaning from unwanted, unwelcome experiences.


The Role of Inclusion Benefits in Ethics Committee Assessment of Research Studies.
The relationship between risks and benefits is central to the ethics of research involving human participants. Traditionally, to be ethically justifiable, risks should be reasonable in relation to anticipated benefits (if any) to subjects and to the potential social benefits resulting from research. This calculus is being further complicated by findings from an increasing number of social science studies that reveal that prospective and actual research participants frequently describe various types of inclusion benefits (for example, personal benefits such as access to or improved health care, increased knowledge about their disease or condition, and greater solidarity with the local community) as important to them. What is the ethical significance of such inclusion benefits, particularly those nonmedical in nature, for research ethics committees' risk-benefit assessment of research studies? We argue that, unless participants are clearly mistaken in their perceptions, ethics committees should take these types of inclusion benefits into account, and we suggest a few ways this might look in practice.


Factors determining inadequate hypoglycaemia during insulin tolerance testing (ITT) after pituitary surgery.
Some patients fail to achieve adequate hypoglycaemia following a standard dose of intravenous insulin during the insulin tolerance test (ITT). Persistent acromegaly or Cushing's disease may contribute to inadequate hypoglycaemia. Aim To identify factors that predict failure to achieve adequate hypoglycaemia during an ITT after pituitary surgery. We reviewed consecutive ITTs performed over a 10-year period in 76 patients following pituitary surgery. Analyses were performed to determine if body mass index (BMI), fasting blood glucose (FBG), cortisol, GH status or underlying diagnosis influenced the outcome. Adequate hypoglycaemia (blood glucose < 2.2 mmol/l) was not achieved in 33 patients (Group 1) following a standard dose of neutral insulin (0.1 units/kg); 43 patients (Group 2) achieved adequate hypoglycaemia. Group 1 had significantly higher BMI, FBG, baseline cortisol and peak cortisol concentrations than Group 2. Peak GH response was not different. Multiple regression analysis showed that FBG was the only independent predictor of adequate hypoglycaemia. An insulin dose of 0.2 units/kg achieved adequate hypoglycaemia in 80% of patients with FBG >or= 5.5 mmol/l. In patients with acromegaly or Cushing's disease, failure to achieve adequate hypoglycaemia was associated with persistent disease. FBG is an important determinant of the dose of insulin required to achieve adequate hypoglycaemia during an ITT in patients after pituitary surgery. A standard insulin dose of 0.1 U/kg is insufficient for adequate hypoglycaemia in patients with FBG > 5.5 mmol/l. Adequate response to a standard dose of insulin suggests a likelihood of cure of acromegaly or Cushing's disease after pituitary surgery.


Self-propelled round-trip motion of Janus particles in static line optical tweezers.
Controlled propulsion of microparticles and micromachines in fluids could revolutionize many aspects of technology, such as biomedicine, microfluidics, micro-mechanics, optomechanics, and cell biology. We report the self-propelled cyclic round-trip motion of metallo-dielectric Janus particles in static line optical tweezers (LOT). The Janus particle is a 5 μm-diameter polystyrene sphere half-coated with 3 nanometer thick gold film. Both experiment and theory show that this cyclic translational and rotational motion is a consequence of the collective and fine action of the gold-face orientation dependent propulsion optical force, the gradient optical force, and the spontaneous symmetry breaking induced optical torque in different regions of the LOT. This study indicates a novel way to propel and manipulate the mechanical motion of microscopic motors and machines wirelessly in fluid, air, or vacuum environments using a static optical field with a smartly designed non-uniform intensity profile allowing fully controlled momentum and angular momentum exchange between light and the particle.


Requirement for non-T cells in the generation of cytotoxic T lymphocytes in vitro. I. Use of nude mice as source of non-T cells.
The ability of small numbers of LN cells to produce cytotoxic lymphocytes on in vitro culture with allogeneic stimulator cells is greatly augmented by the addition of spleen cells from athymic nude mice. The possibility that the synergism is a result of improved culture conditions or a "feeder effect" is excluded. All cytotoxic cells found in these cultures are shown to be T cells and to arise from precursors contained in the LN-cell component. The nude spleen cell component appears to be providing a required non-T cell which has been lost from the LN component through dilution. Synergism between the two components can occur whether they are syngeneic or allogeneic provided that both can recognize the same alloantigens in the stimulator population.


Plasmodium falciparum proteome changes in response to doxycycline treatment.
The emergence of Plasmodium falciparum resistance to most anti-malarial compounds has highlighted the urgency to develop new drugs and to clarify the mechanisms of anti-malarial drugs currently used. Among them, doxycycline is used alone for malaria chemoprophylaxis or in combination with quinine or artemisinin derivatives for malaria treatment. The molecular mechanisms of doxycycline action in P. falciparum have not yet been clearly defined, particularly at the protein level. A proteomic approach was used to analyse protein expression changes in the schizont stage of the malarial parasite P. falciparum following doxycycline treatment. A comparison of protein expression between treated and untreated protein samples was performed using two complementary proteomic approaches: two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) and isobaric tagging reagents for relative and absolute quantification (iTRAQ). After doxycycline treatment, 32 and 40 P. falciparum proteins were found to have significantly deregulated expression levels by 2D-DIGE and iTRAQ methods, respectively. Although some of these proteins have been already described as being deregulated by other drug treatments, numerous changes in protein levels seem to be specific to doxycycline treatment, which could perturb apicoplast metabolism. Quantitative reverse transcription polymerase chain reaction (RT-PCR) was performed to confirm this hypothesis. In this study, a specific response to doxycycline treatment was distinguished and seems to involve mitochondrion and apicoplast organelles. These data provide a starting point for the elucidation of drug targets and the discovery of mechanisms of resistance to anti-malarial compounds.


Bulgaria health system review.
In the last 20 years, demographic development in Bulgaria has been characterized by population decline, a low crude birth rate, a low fertility rate, a high mortality rate and an ageing population. A stabilizing political situation since the early 2000s and an economic upsurge since the mid-2000s were important factors in the slight increase of the birth and fertility rates and the slight decrease in standardized death rates. In general, Bulgaria lags behind European Union (EU) averages in most mortality and morbidity indicators. Life expectancy at birth reached 73.3 years in 2008 with the main three causes of death being diseases of the circulatory system, malignant neoplasms and diseases of the respiratory system. One of the most important risk factors overall is smoking, and the average standardized death rate for smoking-related causes in 2008 was twice as high as the EU15 average. The Bulgarian health system is characterized by limited statism. The Ministry of Health is responsible for national health policy and the overall organization and functioning of the health system and coordinates with all ministries with relevance to public health. The key players in the insurance system are the insured individuals, the health care providers and the third party payers, comprising the National Health Insurance Fund, the single payer in the social health insurance (SHI) system, and voluntary health insurance companies (VHICs). Health financing consists of a publicprivate mix. Health care is financed from compulsory health insurance contributions, taxes, outofpocket (OOP) payments, voluntary health insurance (VHI) premiums, corporate payments, donations, and external funding. Total health expenditure (THE) as a share of gross domestic product (GDP) increased from 5.3% in 1995 to 7.3% in 2008. At the latter date it consisted of 36.5% OOP payments, 34.8% SHI, 13.6% Ministry of Health expenditure, 9.4% municipality expenditure and 0.3% VHI. Informal payments in the health sector represent a substantial part of total OOP payments (47.1% in 2006). The health system is economically unstable and health care establishments, most notably hospitals, are suffering from underfunding. Planning of outpatient health care is based on a territorial principle. Investment for state and municipal health establishments is financed from the state or municipal share in the establishments capital. In the first quarter of 2009, health workers accounted for 4.9% of the total workforce. Compared to other countries, the relative number of physicians and dentists is particularly high but the relative number of nurses remains well below the EU15, EU12 and EU27 averages. Bulgaria is faced with increased professional mobility, which is becoming particularly challenging. There is an oversupply of acute care beds and an undersupply of longterm care and rehabilitation services. Health care reforms after 1989 focused predominantly on ambulatory care and the restructuring of the hospital sector is still pending on the government agenda. Citizens as well as medical professionals are dissatisfied with the health care system and equity is a challenge not only because of differences in health needs, but also because of socioeconomic disparities and territorial imbalances. The need for further reform is pronounced, particularly in view of the low health status of the population. Structural reforms and increased competitiveness in the system as well as an overall support of reform concepts and measures are prerequisites for successful progress.


An exploration of the perceived changes in intimacy of patients' relationships following head and neck cancer.
This paper reports the experiences of former patients who have undergone a range of head and neck cancer treatments and their perceptions of the changes in intimacy experienced, as an individual and through their relationships with partners, family and friends. A diagnosis of head and neck cancer, subsequent surgical treatment and radiotherapy can lead to an altered quality of life. Whilst important developments have been made to improve the quality of life for this patient group from a functional perspective, psychosocial perspectives are much less understood. A qualitative study approach. Data were collected in 2007/2008 via interview using open-ended questions from a purposive sample of 16 participants who were at least one year post-treatment. A thematic analysis was employed to interpret the findings. Analysis of the data produced three broad themes. These were 'personal identity', 're-establishing social networks' and 'intimate relationships' and explored the person as an individual and their perceived changes to self-esteem and image. The perception of their altered position in society, the impact this has on their willingness to re-engage with society and the degree to which treatment can alter an individual's ability to resume former intimate relationships with family and partners. Patients' definitions of intimacy are multifaceted and related directly to the type of relationship that existed prior to treatment. The concerns and challenges faced by patients need to be addressed and support opportunities considered as part of the rehabilitation process. The paper gives insight for nurses and other healthcare professionals who are expected to provide effective emotional and therapeutic support for patients who have undergone treatment for head and neck cancer. Understanding of patient concerns and recognition of adaptive and coping strategies are essential for this practice.