Exhaled nitric oxide in children with asthma receiving Xolair (omalizumab), a monoclonal anti-immunoglobulin E antibody.
To evaluate the effect of a humanized monoclonal antibody to immunoglobulin E, omalizumab (Xolair, Novartis Pharmaceuticals, East Hanover, NJ; Genentech Inc, South San Francisco, CA), on airway inflammation in asthma, as indicated by the fractional concentration of exhaled nitric oxide (FE(NO)), a noninvasive marker of airway inflammation. Xolair was approved recently by the US Food and Drug Administration for moderate-to-severe allergic asthma in adolescents and adults. As an addendum at 2 sites to a randomized, multicenter double-blind, placebo-controlled trial, FE(NO) was assessed in children with allergic asthma over 1 year. There were 3 consecutive study periods: 1) stable dosing of inhaled beclomethasone dipropionate (BDP) when the dose was optimized (period of 16 weeks); 2) inhaled steroid-reduction phase (period of 12 weeks), during which BDP was tapered if subjects remained stable; and 3) open-label extension phase, during which subjects receiving placebo were switched to active omalizumab (period of 24 weeks). The primary outcome was area under the FE(NO) versus time curve (AUC) for adjusted FE(NO), defined as the ratio of FE(NO) at each time point compared with the value at baseline. Twenty-nine subjects participated and were randomized to omalizumab (n = 18) and placebo (n = 11) treatment groups in a 2:1 ratio dictated by the main study. There was a significant difference for age, resulting in a difference in absolute forced expiratory volume in 1 second but no difference in asthma severity based on the forced expiratory volume in 1 second percentage predicted. Baseline BDP dose was comparable between groups, as were baseline values of mean FE(NO) (active: 38.6 +/- 25.6 ppb; placebo: 52.7 +/- 52.9 ppb). The degree of BDP dose reduction during the steroid-reduction and open-label phases was equivalent between the omalizumab and placebo-treated groups; subjects in the omalizumab- and placebo-treated groups had reduced their BDP dose by an average of 51% and 60%, respectively, at the end of the steroid-reduction phase and by 68% and 94%, respectively, by the end of the open-label period. In the active and placebo groups, 44% and 27% and 75% and 73% of subjects had stopped use of inhaled corticosteroids at the end of the steroid-reduction and open-label phases, respectively. There was no significant difference between the active and placebo groups during the steroid-stable phase for AUC of adjusted nitric oxide (1.31 +/- 1.511 vs 1.45 +/- 0.736). However, during the steroid-reduction phase, the variability of adjusted FE(NO) in the placebo-treated group was greater than that of the omalizumab-treated group at most visits, with a significant difference between groups for AUC of adjusted nitric oxide (0.88 +/- 0.69 vs 1.65 +/- 1.06). FE(NO) fell from 82.1 +/- 55.6 ppm at the end of the steroid-reduction phase to 33.3 +/- 21.6 ppb at the end of the open-label period in the placebo group who were placed on active omalizumab. This decrease occurred while the mean dose of BDP remained very low. Analysis of FE(NO) over 52 weeks of omalizumab treatment in the active group demonstrated that there was a significant reduction from baseline to the end of the open-label period (41.9 +/- 29.0 to 18.0 +/- 21.8 ppb) despite a high degree of steroid reduction. In this preliminary study based on FE(NO), a noninvasive marker of airway inflammation, treatment with omalizumab may inhibit airway inflammation during steroid reduction in children with allergic asthma. The degree of inhibition of FE(NO) was similar to that seen for inhaled corticosteroids alone, suggesting an antiinflammatory action for this novel therapeutic agent in asthma. This is in keeping with recent evidence that omalizumab inhibits eosinophilic inflammation in induced sputum and endobronchial tissue.


A genome-wide RNAi screen identifies regulators of cholesterol-modified hedgehog secretion in Drosophila.
Hedgehog (Hh) proteins are secreted molecules that function as organizers in animal development. In addition to being palmitoylated, Hh is the only metazoan protein known to possess a covalently-linked cholesterol moiety. The absence of either modification severely disrupts the organization of numerous tissues during development. It is currently not known how lipid-modified Hh is secreted and released from producing cells. We have performed a genome-wide RNAi screen in Drosophila melanogaster cells to identify regulators of Hh secretion. We found that cholesterol-modified Hh secretion is strongly dependent on coat protein complex I (COPI) but not COPII vesicles, suggesting that cholesterol modification alters the movement of Hh through the early secretory pathway. We provide evidence that both proteolysis and cholesterol modification are necessary for the efficient trafficking of Hh through the ER and Golgi. Finally, we identified several putative regulators of protein secretion and demonstrate a role for some of these genes in Hh and Wingless (Wg) morphogen secretion in vivo. These data open new perspectives for studying how morphogen secretion is regulated, as well as provide insight into regulation of lipid-modified protein secretion.


One-stage transanal Soave pullthrough for Hirschsprung disease: a multicenter experience with 141 children.
The surgical management of Hirschsprung's disease (HD) has evolved from the original 3-stage approach to the recent introduction of minimal-access single-stage techniques. We reviewed the early results of the transanal Soave pullthrough from 6 of the original centers to use it. The clinical course of all children with HD undergoing a 1-stage transanal Soave pullthrough between 1995 and 2002 were reviewed. Children with a preliminary stoma or total colonic disease were excluded. There were 141 patients. Mean time between diagnosis and surgery was 32 days, and mean age at surgery was 146 days. Sixty-six (47%) underwent surgery in the first month of life. Forty-seven (33%) had the pathologic transition zone documented laparoscopically or through a small umbilical incision before beginning the anal dissection. Mean blood loss was 16 mL, and no patients required transfusion. Mean time to full feeding was 36 hours, mean postoperative hospital stay was 3.4 days, and 87 patients (62%) required only acetaminophen for pain. Early postoperative complications included perianal excoriation (11%), enterocolitis (6%), and stricture (4%). One patient died of congenital cardiac disease. Mean follow-up was 20 months; 81% had normal bowel function for age, 18% had minor problems, and 1% had major problems. Two patients required a second operation (twisted pullthrough, and residual aganglionosis). One patient developed postoperative adhesive bowel obstruction. To date, this report represents the largest series of patients undergoing the 1-stage transanal Soave pullthrough. This approach is safe, permits early feeding, causes minimal pain, facilitates early discharge, and presents a low rate of complications.


Assessing clinical outcomes: the community functioning of persons with serious mental illness.
The demand to measure the clinical outcomes of persons with serious mental illness in the community is growing; however, there is no consensus about how to do this task. This paper identifies challenges in measuring the outcomes of persons with serious mental illness and reviews selected instruments that measure the community functioning of this population. Papers in peer-reviewed psychiatric journals for the years 1986 to 1996 were reviewed to select instruments that measure two or more domains of community functioning and for which data on reliability and validity have been published. Selected instruments were evaluated, focusing on their format, content, item scoring, length, and original sample population. Challenges to measuring the community functioning of persons with serious mental illness include the multiplicity of domains that must be measured, the conflicting interests of various stakeholders involved in care, the limitations of self-report data, and other methodological problems. Nine instruments that met the study criteria were selected from the literature. Three are self-report instruments, and six are based on the report of an informant or independent rater. The instruments vary in length and in their original sample population. The content areas most consistently represented are self-care and social relationships. Life satisfaction, health status, psychiatric symptoms, and work skills are not consistently addressed. Individual instruments have additional limitations, including the absence of behavioral anchors for scale items and the lack of specificity to persons with serious mental illness. Effort should be directed toward sharing data across settings, measuring the effects of treatment interventions, and demonstrating the predictive validity of outcome data.


Hand-assisted laparoscopic live donor nephrectomy - initial experience.
The advantages of minimally invasive live donor nephrectomy have been well documented, with no adverse effect on graft function. Minimal access nephrectomy has now become the standard of care in many units. We have adopted the hand-assisted laparoscopic live donor (HALLDN) technique, and present our initial experience with the first 24 cases. HALLDNs were performed trans-peritoneally. Primary outcomes included total operative time, warm ischaemic time, time to discharge, and post-operative complications. Warm ischaemic time was measured from the time of clamping the renal artery to the time of perfusing the kidney on the back table. Mean total operative time was 143 minutes and mean warm ischaemic time was 188 seconds. A downward trend was displayed for operative times. Mean time to discharge was 60 hours. A right nephrectomy was performed in 2 cases. No surgical morbidity is reported. We describe 1 donor mortality. Our results compare favourably with those documented in the literature. Aberrant renal vascular anatomy had no adverse effect on operative or warm ischaemic times. HALLDN proved beneficial in patients with a high BMI. Surgical experience is vital when performing HALLDN. Overcoming the learning curve with an animal model is beneficial.


Using data-driven model-brain mappings to constrain formal models of cognition.
In this paper we propose a method to create data-driven mappings from components of cognitive models to brain regions. Cognitive models are notoriously hard to evaluate, especially based on behavioral measures alone. Neuroimaging data can provide additional constraints, but this requires a mapping from model components to brain regions. Although such mappings can be based on the experience of the modeler or on a reading of the literature, a formal method is preferred to prevent researcher-based biases. In this paper we used model-based fMRI analysis to create a data-driven model-brain mapping for five modules of the ACT-R cognitive architecture. We then validated this mapping by applying it to two new datasets with associated models. The new mapping was at least as powerful as an existing mapping that was based on the literature, and indicated where the models were supported by the data and where they have to be improved. We conclude that data-driven model-brain mappings can provide strong constraints on cognitive models, and that model-based fMRI is a suitable way to create such mappings.


Inactivation of Corynebacterium glutamicum NCgl0452 and the role of MgtA in the biosynthesis of a novel mannosylated glycolipid involved in lipomannan biosynthesis.
Mycobacterium tuberculosis PimB has been demonstrated to catalyze the addition of a mannose residue from GDP-mannose to a monoacylated phosphatidyl-myo-inositol mannoside (Ac(1)PIM(1)) to generate Ac(1)PIM(2). Herein, we describe the disruption of its probable orthologue Cg-pimB and the chemical analysis of glycolipids and lipoglycans isolated from wild type Corynebacterium glutamicum and the C. glutamicum::pimB mutant. Following a careful analysis, two related glycolipids, Gl-A and Gl-X, were found in the parent strain, but Gl-X was absent from the mutant. The biosynthesis of Gl-X was restored in the mutant by complementation with either Cg-pimB or Mt-pimB. Subsequent chemical analyses established Gl-X as 1,2-di-O-C(16)/C(18:1)-(alpha-d-mannopyranosyl)-(1-->4)-(alpha-d-glucopyranosyluronic acid)-(1-->3)-glycerol (ManGlcAGroAc(2)) and Gl-A as the precursor, GlcAGroAc(2). In addition, C. glutamicum::pimB was still able to produce Ac(1)PIM(2), suggesting that Cg-PimB catalyzes the synthesis of ManGlcAGroAc(2) from GlcAGroAc(2). Isolation of lipoglycans from C. glutamicum led to the identification of two related lipoglycans. The larger lipoglycan possessed a lipoarabinomannan-like structure, whereas the smaller lipoglycan was similar to lipomannan (LM). The absence of ManGlcA-GroAc(2) in C. glutamicum::pimB led to a severe reduction in LM. These results suggested that ManGlcAGroAc(2) was further extended to an LM-like molecule. Complementation of C. glutamicum::pimB with Cg-pimB and Mt-pimB led to the restoration of LM biosynthesis. As a result, Cg-PimB, which we have assigned as MgtA, is now clearly defined as a GDP-mannose-dependent alpha-mannosyltransferase from our in vitro analyses and is involved in the biosynthesis of ManGlcAGroAc(2).


Astrocyte-neuron lactate transport is required for long-term memory formation.
We report that, in the rat hippocampus, learning leads to a significant increase in extracellular lactate levels that derive from glycogen, an energy reserve selectively localized in astrocytes. Astrocytic glycogen breakdown and lactate release are essential for long-term but not short-term memory formation, and for the maintenance of long-term potentiation (LTP) of synaptic strength elicited in vivo. Disrupting the expression of the astrocytic lactate transporters monocarboxylate transporter 4 (MCT4) or MCT1 causes amnesia, which, like LTP impairment, is rescued by L-lactate but not equicaloric glucose. Disrupting the expression of the neuronal lactate transporter MCT2 also leads to amnesia that is unaffected by either L-lactate or glucose, suggesting that lactate import into neurons is necessary for long-term memory. Glycogenolysis and astrocytic lactate transporters are also critical for the induction of molecular changes required for memory formation, including the induction of phospho-CREB, Arc, and phospho-cofilin. We conclude that astrocyte-neuron lactate transport is required for long-term memory formation.


Tetradecanoyl phorbol acetate suppresses follicle-stimulating hormone-induced synthesis of the cholesterol side-chain cleavage enzyme complex in rat ovarian granulosa cells.
The effect of tetradecanoylphorbol acetate (TPA) on follicle-stimulating hormone (FSH)-induced synthesis of the cholesterol side-chain cleavage (SCC) enzyme complex was studied in rat ovarian granulosa cells cultured for 48 h in serum-free medium. Cell proteins were radiolabeled with [35S]methionine, followed by immunoprecipitation of cholesterol side-chain cleavage cytochrome P-450 (P-450SCC) as well as the iron-sulfur protein adrenodoxin. Polyacrylamide gel electrophoresis and fluorography of the immunoprecipitates showed that TPA, when added in combination with FSH (50 ng/ml) or dibutyryl cAMP (Bt2cAMP; 1 mM), suppressed the stimulatory effects of these compounds on the synthesis of the SCC components in a concentration-dependent fashion. The effect of TPA was accompanied by decreased progesterone formation and decreased cAMP accumulation. The structural analog of TPA, phorbol-4 alpha-didecanoate, which does not activate protein kinase C (Ca2+/phospholipid-dependent enzyme), had no effect on the FSH- or Bt2cAMP-stimulated synthesis of SCC and progesterone or on cAMP formation. In addition to inhibiting the synthesis of these proteins, TPA greatly reduced the FSH- and Bt2cAMP-induced increase in levels of mRNA encoding the precursor form of P-450SCC. It is concluded that the effect of the phorbol ester TPA to inhibit FSH-stimulated progesterone formation in cultured ovarian granulosa cells of the rat involves decreased synthesis of the components of the SCC enzyme complex due to reduced levels of mRNA encoding the precursor forms of these proteins. The results are indicative that TPA not only inhibits FSH-mediated stimulation of cAMP formation but also may block cAMP-mediated induction of SCC synthesis. It is postulated that the effects of TPA may reflect the physiological role of protein kinase C in the regulation of ovarian steroidogenesis.


Finite element method (FEM), mechanobiology and biomimetic scaffolds in bone tissue engineering.
Techniques of bone reconstructive surgery are largely based on conventional, non-cell-based therapies that rely on the use of durable materials from outside the patient's body. In contrast to conventional materials, bone tissue engineering is an interdisciplinary field that applies the principles of engineering and life sciences towards the development of biological substitutes that restore, maintain, or improve bone tissue function. Bone tissue engineering has led to great expectations for clinical surgery or various diseases that cannot be solved with traditional devices. For example, critical-sized defects in bone, whether induced by primary tumor resection, trauma, or selective surgery have in many cases presented insurmountable challenges to the current gold standard treatment for bone repair. The primary purpose of bone tissue engineering is to apply engineering principles to incite and promote the natural healing process of bone which does not occur in critical-sized defects. The total market for bone tissue regeneration and repair was valued at $1.1 billion in 2007 and is projected to increase to nearly $1.6 billion by 2014.Usually, temporary biomimetic scaffolds are utilized for accommodating cell growth and bone tissue genesis. The scaffold has to promote biological processes such as the production of extra-cellular matrix and vascularisation, furthermore the scaffold has to withstand the mechanical loads acting on it and to transfer them to the natural tissues located in the vicinity. The design of a scaffold for the guided regeneration of a bony tissue requires a multidisciplinary approach. Finite element method and mechanobiology can be used in an integrated approach to find the optimal parameters governing bone scaffold performance.In this paper, a review of the studies that through a combined use of finite element method and mechano-regulation algorithms described the possible patterns of tissue differentiation in biomimetic scaffolds for bone tissue engineering is given. Firstly, the generalities of the finite element method of structural analysis are outlined; second, the issues related to the generation of a finite element model of a given anatomical site or of a bone scaffold are discussed; thirdly, the principles on which mechanobiology is based, the principal theories as well as the main applications of mechano-regulation models in bone tissue engineering are described; finally, the limitations of the mechanobiological models and the future perspectives are indicated.


Speech perception performance as a function of stimulus pulse rate and processing strategy preference for the Cochlear Nucleus CI24RE device: relation to perceptual threshold and loudness comfort profiles.
Current cochlear implants can operate at high pulse rates. The effect of increasing pulse rate on speech performance is not yet clear. Habituation to low rates may affect the outcome. This paper presents the results of three subsequent studies using different experimental paradigms, applying the Nucleus CI24RE device, and conducted by ten European implant teams. Pulse rate per channel varied from 500 to 3500 pulses per second with ACE and from 1200 to 3500 pps with CIS strategy. The results showed that the first rate presented had little effect on the finally preferred rate. Lower rates were preferred. The effect of pulse rate on word scores of post-linguistic implantees was small; high rates tended to give lower scores. However, there were no significant differences between the word scores across subjects if collected at the individually preferred pulse rate. High pulse rates were preferred when the post-implantation threshold was low.


Aberration correction of zoom lenses using evolutionary programming.
A systematic approach for the aberration correction of zoom systems is presented. It is assumed that the powers and movements of the components of the zoom systems are known. Each component is considered as a system of thin lenses in contact. An evolutionary algorithm is developed to explore the multivariate hyperspace of design variables formed by spherical aberration, central coma, and longitudinal chromatic aberration of each component for infinite conjugate. The primary aberrations for each component at any zoom position are deduced from three central aberration coefficients of the component for infinite conjugate using conjugate shift formulas. Overall system aberrations of the zoom systems are determined by using stop shift formulas. In most of the zoom lens systems it is important to achieve stability in the primary aberrations of the system over the zoom range. This is facilitated by proper formulation of the merit function for the optimization process. Investigations have been carried out on four-component zoom lenses, and an ab initio structure of a four-component zoom lens is presented.


Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death.
Sound perception requires functional hair cell mechanotransduction (MET) machinery, including the MET channels and tip-link proteins. Prior work showed that uptake of ototoxic aminoglycosides (AG) into hair cells requires functional MET channels. In this study, we examined whether tip-link proteins, including Cadherin 23 (Cdh23), regulate AG entry into hair cells. Using time-lapse microscopy on cochlear explants, we found rapid uptake of gentamicin-conjugated Texas Red (GTTR) into hair cells from three-day-old Cdh23(+/+) and Cdh23(v2J/+) mice, but failed to detect GTTR uptake in Cdh23(v2J/v2J) hair cells. Pre-treatment of wildtype cochleae with the calcium chelator 1,2-bis(o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA) to disrupt tip-links also effectively reduced GTTR uptake into hair cells. Both Cdh23(v2J/v2J) and BAPTA-treated hair cells were protected from degeneration caused by gentamicin. Six hours after BAPTA treatment, GTTR uptake remained reduced in comparison to controls; by 24 hours, drug uptake was comparable between untreated and BAPTA-treated hair cells, which again became susceptible to cell death induced by gentamicin. Together, these results provide genetic and pharmacologic evidence that tip-links are required for AG uptake and toxicity in hair cells. Because tip-links can spontaneously regenerate, their temporary breakage offers a limited time window when hair cells are protected from AG toxicity.


Patient-specific insulin-resistance-guided infusion improves glycemic control in cardiac surgery.
Maintenance of appropriate capillary blood glucose in cardiovascular surgery patients has been associated with improved outcomes, including lower mortality. Interpatient variability in insulin resistance can make management difficult, leading to unexpected episodes of hypoglycemia and hyperglycemia. To improve postoperative glucose control at our institution, a patient-specific insulin-resistance-guided (IRG) protocol was developed. Prospective data were gathered on 100 consecutive cardiovascular surgery patients managed with our standard insulin infusion protocol and 100 patients managed using the IRG protocol. Clinical characteristics and glycemic indices were analyzed for the two groups. Primary endpoints included (1) percentage of time spent in the target range, (2) number of hypoglycemic and hyperglycemic episodes, (3) time to achievement of target blood glucose, and (4) the total daily dose of insulin required. The IRG protocol resulted in significant improvements, including increased percentage of time spent in the normoglycemic range (82.5% versus 65.8%, p < 0.001), reduced rate of hypoglycemic episodes (0.12 versus 0.99, p < 0.01), reduced rate of hyperglycemic episodes (capillary blood glucose >126 mg/dL: 4.8 versus 8.2, p < 0.01), and a reduced time to the first measurement in the target range. Total daily dose of insulin was mildly increased, but failed to reach statistical significance (92.48 versus 82.64 units, p = 0.32). Use of the IRG protocol led to improved glycemic indices while reducing episodes of hypoglycemia in both diabetic and nondiabetic patients. The ability to adjust a patient's insulin dosing based upon factors related to their insulin resistance results in improved blood glucose control and safety in cardiovascular surgery patients.


Teaching single-incision laparoscopic appendectomy in pediatric patients.
Laparoscopic appendectomy is accepted as the gold standard technique for the treatment of acute appendicitis. Recently single-incision laparoscopic surgery (SILS) was tried in the pediatric population and was shown to be both feasible and safe. We describe our early experience in teaching the SILS procedure for appendicitis in a large community hospital center surgical residency program. SILS appendectomy was performed in 40 consecutive patients with acute appendicitis who were admitted by a single surgeon from May 2011 to August 2011. All patients over the age of 4 y presenting with noncomplicated and complicated appendicitis (perforated) were offered SILS appendectomy. Execution of the technical aspects of 20 SILS operations done by 3 PGY III residents was evaluated. The average age of the patient was 11.1 y (range, 7 to 15). SILS was performed successfully in 19 out of 20 patients. Nineteen patients underwent emergent or urgent appendectomy, while 1 patient underwent an interval procedure. Nine patients were found to have perforated appendicitis, while the other 11 had noncomplicated acute appendicitis. One patient was converted to conventional 3-port laparoscopy due to difficulties during the procedure. The mean operative time was 73 min (range, 47 to 112). A significant learning curve to successfully execute the critical steps of the SILS procedure was noted in all residents evaluated. SILS technology appears promising for the treatment of acute appendicitis. However, its successful incorporation into surgical training programs will depend on the development of innovative simulation strategies.


Physicochemical and biological characterization of synthetic phosphatidylinositol dimannosides and analogues.
Native phosphatidylinositol mannosides (PIMs), isolated from the cell wall of Mycobacterium bovis, and synthetic PIM analogues have been reported to offer a variety of immunomodulating properties, including both suppressive and stimulatory activity. While numerous studies have examined the biological activity of these molecules, the aim of this research was to assess the physicochemical properties at a molecular level and correlate these characteristics with biological activity in a mouse model of airway eosinophilia. To accomplish this, we varied the flexibility and lipophilicity of synthetic PIMs by changing the polar headgroup (inositol- vs glycerol-based core) and the length of the acyl chains of the fatty acid residues (C0, C10, C16, and C18). A series of six phosphatidylinositol dimannosides (PIM2s) and phosphatidylglycerol dimannosides (PGM2s) were synthesized and characterized in this study. Langmuir monolayer studies showed that surface pressure-area (π-A) isotherms were greatly influenced by the length of the lipid acyl chains as well as the steric hindrance and volume of the headgroups. In aqueous solution, lipidated PIM2 and PGM2 compounds were observed to self-assemble into circular aggregates, as confirmed by dynamic light scattering and transmission electron microscopic investigations. Removal of the inositol ring but retention of the three-carbon glycerol unit maintained biological activity. We found that the deacylated PGM2, which did not show self-organization, had no effect on the eosinophil numbers but did have an impact on the expansion of OVA-specific CD4(+) Vα2Vβ5 T cells.


Human health effects associated with the commercial use of grunerite asbestos (amosite): Paterson, NJ; Tyler, TX; Uxbridge, UK.
Grunerite asbestos (amosite) has been shown in epidemiological and experimental animal studies to cause lung cancer, mesothelioma and pulmonary fibrosis commonly referred to as asbestosis. An overview of the human and experimental animal studies describing the health hazards of grunerite asbestos (amosite) is presented. Of the many human studies describing the health hazards of asbestos, only three factories using mainly, if not exclusively, grunerite asbestos (amosite) have been studied. The first is a series of reports on a cohort of 820 workers from a plant located in Paterson, NJ. Among this cohort, 18.7% died of lung cancer and 17 mesotheliomas occurred. The Paterson factory closed in 1954 and moved to Tyler, Texas where it operated until 1972. Among the 1130 former workers in the Tyler plant 6 mesotheliomas were reported with 15.8% lung cancer mortality. The third grunerite asbestos (amosite) exposed cohort was an insulation board manufacturing facility in Uxbridge, United Kingdom. Here 17.1% of the workers died of lung cancer and 5 mesotheliomas occurred. The lung content from 48 Uxbridge workers was analyzed by analytical transmission electron microscopy for mineral fibers. The relationship between grunerite asbestos (amosite) concentrations in the lung correlated with grades of fibrosis and asbestos bodies and was lower than the concentration found in the cases with malignant tumors. The lung cancer cases contained more grunerite asbestos (amosite) than mesothelioma cases, and in the cases of non-malignant disease the concentrations were still lower. In both types of malignancies the concentration of grunerite asbestos (amosite) was very high-over a billion fibers per gram of dried lung tissue. Occupational exposure to airborne concentrations of between 14 and 100 fibers of grunerite asbestos (amosite) per milliliter after 20 year latency causes marked increases in lung cancer, mesothelioma and pulmonary fibrosis (asbestosis).


All-optical clocked delay flip-flop using a single terahertz optical asymmetric demultiplexer-based switch: a theoretical study.
A flip-flop (FF) is a kind of latch and the simplest form of memory device, which stores various values either temporarily or permanently. Optical FF memories form a fundamental building block for all-optical packet switches in next-generation communication networks. An all-optical clocked delay FF using a single terahertz optical asymmetric demultiplexer-based interferometric switch is proposed and described. Numerical simulation results are also reported.


New insights into the advantages of ammonium as a winemaking nutrient.
Nitrogen limitation is the most common cause for stuck or sluggish fermentation in winemaking, and it is usually dealt with by supplementing grape juice with either ammonium salts or organic nutrients. These practices have a direct impact on both fermentation kinetics and the sensorial features of the final product. The aim of this work is to provide a detailed characterization of yeast physiology in response to ammonium supplementation during alcoholic fermentation. This is done by determining changes in metabolic rates on a high frequency basis, as a sensitive way to detect the impact of fermentation conditions on yeast physiology. Our results indicate that the choice of supplementation strategy has an impact on several enological parameters like fermentation length, volatile acidity, final glycerol content, and aroma profile. Interestingly, a higher proportion of ammonium relates with improved glycerol and volatile acidity, for the same global yeast assimilable nitrogen content. However, ammonium over-supplementation has a negative impact on quality related parameters, notably on volatile acidity and aroma complexity. Production kinetics and final content of several volatile compounds are also differentially influenced by standard or excess ammonium supplementation.


Bioavailable vitamin D levels are reduced and correlate with bone mineral density and markers of mineral metabolism in adults with nephrotic syndrome.
Blood levels of 25-hydroxyvitamin D [25(OH) D] are reduced in patients with nephrotic syndrome (NS). The lowering is thought to be due to urinary loss of vitamin D binding protein (DBP). A link between vitamin D deficiency and bone disease or markers of mineral metabolism has not yet been shown in NS. We hypothesized that alterations in bioavailable vitamin D levels might be linked to these abnormalities in NS. We measured circulating levels of 25(OH)D, 1,25-dihydroxyvitamin D [1,25(OH)2 D], DBP, serum albumin and intact parathyroid hormone (iPTH) in 106 adults with sporadic idiopathic NS and 40 healthy controls. Bioavailable vitamin D was calculated from previously validated formulae. Bone mineral density (BMD) was measured at left hip (neck of femur) by DEXA. Compared to healthy controls, total and bioavailable 25(OH)D levels were significantly reduced in patients with NS as compared to healthy controls. Among the nephrotic patients, BMD was positively correlated with bioavailable 25(OH)D (r = 0.358; P = 0.0002) but not with total 25(OH)D (r = 0.174; P = 0.079). Total 1,25(OH)2 D and bioavailable 1,25(OH)2 D did not correlate with BMD (r = 0.131; P = 0.206 and r = 0.107, P = 0.295). Bioavailable 25(OH)D levels showed a strong inverse correlation with iPTH on univariate (r = -0.457; P < 0.0001) and multivariate (β=-0.453, P < 0.0001) analyses. We conclude that bioavailable 25(OH)D is a better measure of vitamin D status with respect of BMD and mineral metabolism in patients of nephrotic syndrome.


The role of paracetamol in chronic pain: an evidence-based approach.
Chronic pain is a significant public health burden. Several international guidelines and influential reviews recommend the use of paracetamol (acetaminophen) as the first-line analgesic of choice for the management of chronic pain. These recommendations are based largely on the balance of evidence, which favorably demonstrates the efficacy, safety, and low cost of paracetamol relative to other analgesics.A decade ago, March et al suggested that because of the dangers associated with conventional nonsteroidal antiinflammatory (NSAID) use, particularly in the elderly, they should ideally not be used without an individual n-of-1 trial to show that they are more effective than paracetamol. Today, the results of our investigations into the individualization of pain management options continue to support this suggestion. Based on the data available to date, it still seems prudent to use NSAIDs only in those patients in whom there is good evidence of improved efficacy over paracetamol. In patients with chronic pain, paracetamol can play an important role as an NSAID sparer, with resultant benefits in terms of reduced adverse effects and cost savings.


Short time exposure to lipopolysaccharide is sufficient to activate human monocytes.
Very little is known about early events in LPS binding and about the duration of LPS exposure required to activate monocytes. In the present study, we have investigated the kinetics of LPS binding to human monocytes and the time of exposure required to trigger the synthesis of TNF-alpha. We directly followed the binding of FITC-labeled LPS to monocytes by flow cytometry or confocal laser microscopy. LPS was able to bind to the cell surface within 1 min of exposure, and was internalized within 5 min. Equilibrium was reached within 15 min at all but the lowest LPS concentration tested (10 ng/ml). Binding was dependent on the presence of LPS-binding protein, supplied either as a plasma component or in purified form, and inhibited by an anti-CD14 mAb (MY4). Polymyxin B, an inhibitor of LPS-mediated activation, essentially abrogated the LPS-binding protein- and CD14-dependent binding of LPS to monocytes. Using either the anti-CD14 mAb or polymyxin B to block further LPS binding, we found that 5 to 10 min of exposure was sufficient to trigger maximal TNF-alpha release. Similarly, monocytes washed after 5 to 15 min exposure to eliminate LPS also produced high levels of TNF-alpha transcripts without further presence of LPS in the medium. We conclude that a few minutes of exposure to physiologically relevant concentrations of LPS are sufficient to trigger both maximal binding and activation of monocytes.


Uptake and release of fluoride from fluoride-impregnated chewing sticks (miswaks) in vitro and in vivo.
The purpose was to investigate the uptake and release of fluoride (F) from F-impregnated chewing sticks (miswaks). In the first series, 3-cm-long pieces were impregnated in 1, 2, 3 and 4% NaF solutions for 3 h, 1 day and 3 days (10 pieces/test). There was a dose-response effect with respect to both impregnation time and the concentration of the F solution. In the second and third series, totally 40 miswak pieces were impregnated in 3% NaF for 1 day and 3 days; the outer layer (bark) was separated from the inner spongy part (pulp) and analyzed separately. F was released from both parts, but somewhat more was released from the bark than from the pulp; a plateau was reached at around 30 min. In vivo, 9 healthy subjects used three products for 2 min in a crossover design: (1) a miswak impregnated in 3% NaF for 1 day, (2) a miswak impregnated in 3% NaF for 3 days, and (3) 1 g of F toothpaste (containing 1,450 ppm F as NaF) on a toothbrush. The highest F concentration at the approximal area was obtained after using the miswak impregnated in 3% NaF for 3 days compared with the other products (p < 0.05 or p < 0.01). To conclude, NaF-impregnated miswaks produced a rapid release of F in vitro as well as in vivo and may be an interesting vehicle for home care use for caries prevention in countries where they are used regularly.


The Link Between Autonomic Nervous System and Rheumatoid Arthritis: From Bench to Bedside.
Neuronal stimulation is an emerging field of research focused on the management and treatment of various diseases through the reestablishment of physiological homeostasis. Electrical vagus nerve stimulation has recently been proposed as a revolutionary therapeutic option for rheumatoid arthritis (RA) in combination with or even as a replacement for conventional and biological drugs. In the past few years, disruption of the autonomic system has been linked to RA onset and activity. Novel research on the link between the autonomic nervous system and the immune system (immune-autonomics) has paved the way for the development of innovative RA management strategies. Clinical evidence supports this approach. Cardiovascular involvement, in terms of reduced baroreflex sensitivity and heart rate variability-derived indices, and mood disorders, common comorbidities in patients with RA, have been linked to autonomic nervous system dysfunction, which in turn is influenced by increased levels of circulating pro-inflammatory cytokines. This narrative review provides an overview of the autonomic nervous system and RA connection, discussing most of the common cardiac and mental health-related RA comorbidities and their potential relationships to systemic and joint inflammation.


Factors predicting outcome in malignant minor salivary gland tumors of the oropharynx.
to report our experience in the care of patients with minor salivary gland cancers occurring only in the oropharynx and to determine factors predictive of outcome. Retrospective analysis. memorial Sloan-Kettering Cancer Center. sixty-seven patients with malignant minor salivary gland tumors were identified from a preexisting database of patients with cancers of the oropharynx between January 1985 and December 2005. overall survival, disease-specific survival, and recurrence-free survival were calculated by the Kaplan-Meier method. Factors predictive of outcome were identified by univariate and multivariate analyses. the most common histologic types were mucoepidermoid carcinoma in 26 patients (39%), adenoid cystic carcinoma in 16 (24%), adenocarcinoma in 16 (24%), and malignant mixed tumor in 7 (10%). The tumors were located in the base of the tongue in 41 patients (61%), soft palate in 20 (30%), and tonsil in 6 (9%). With a median follow-up time of 86 months (range, 12-249 months), overall outcomes at 5 and 10 years were overall survival, 80% and 53%; disease-specific survival, 87% and 67%; and recurrence-free survival, 69% and 60%, respectively. Tumor recurred in 20 patients (34%); 12 of these patients had locoregional failure and 15 developed distant metastases. Multivariate analyses showed that clinical T stage, anatomic subsite, and margin status were independent predictors for overall survival; T stage and margin status were independent predictors for locoregional recurrence-free survival. clinical T stage, anatomic subsite, and margin status are independent predictors of outcome of patients with minor salivary gland cancers of the oropharynx.


Liver volume as a determinant of drug clearance in children and adolescents.
Many drugs eliminated by the liver exhibit age-related differences in systemic clearance, necessitating different dosage requirements in children and adults. However, the physiological basis for these age-related changes is not well defined, including the importance of liver size in determining systemic clearance. Therefore, magnetic resonance imaging was used to determine liver volume in pediatric and adolescent patients, in whom systemic clearance of three model substrates [lorazepam (0.03 mg/kg), antipyrine (10 mg/kg), and indocyanine green (ICG; 0.5 mg/kg)] was also determined. In 16 children (ages 3.3-18.8 years; 8 boys), liver volume ranged from 469 to 1640 ml (median 937), and was significantly related to age, body weight, and body surface area (BSA). Younger children had larger liver normalized to body weight (ml/kg), but there was no difference when liver volume was normalized to BSA (ml/m2). Unnormalized lorazepam and ICG clearances (ml/min) were significantly related to absolute liver volume (r2 = 50.2% and 31.4%, respectively), whereas unnormalized antipyrine clearance was not. Lorazepam, ICG, and antipyrine clearance normalized to BSA did not exhibit age-related changes, nor did lorazepam or ICG clearance normalized to body weight decreased significantly with increasing age (r2 = 36.9%, p=0.012), as did antipyrine clearance relative to liver volume. Thus, age-related changes in drug clearance and the importance of liver volume may differ based on the principal hepatic mechanisms involved in drug elimination.


An Explanation for Symmetry-Induced Isotopic Fractionation in Ozone
Application of a theory of nuclear symmetry-based reaction restrictions to the O2 + O --> O3 reaction provides a potential explanation for the symmetry-induced isotopic enrichment observed for laboratory and atmospherically produced O3. Within this theory, the rate of formation of O3 from collisions of O and isotopically homonuclear O2 depends on whether the O2 molecule is in an f (allowed) or an e (restricted) parity label state. The restriction can be relaxed by various potential energy surface coupling terms, and the assumption that approximately 78 percent of the restricted O2(e) levels produce O3 with the same efficiency as the allowed O2(f) levels can account for laboratory-observed isotopic fractionation. In particular, the theory explains the special enhanced formation of the completely asymmetric isotopomer 16O17O18O.


The Removal of Endo- and Enterotoxins From Bacteriophage Preparations.
The production of phages for therapeutic purposes demands fast, efficient and scalable purification procedures. Phage lysates have a wide range of impurities, of which endotoxins of gram-negative bacteria and protein toxins produced by many pathogenic bacterial species are harmful to humans. The highest allowed endotoxin concentration for parenterally applied medicines is 5 EU/kg/h. The aim of this study was to evaluate the feasibility of different purification methods in endotoxin and protein toxin removal in the production of phage preparations for clinical use. In the purification assays, we utilized three phages: Escherichia phage vB_EcoM_fHoEco02, Acinetobacter phage vB_ApiM_fHyAci03, and Staphylococcus phage vB_SauM_fRuSau02. The purification methods tested in the study were precipitation with polyethylene glycol, ultracentrifugation, ultrafiltration, anion exchange chromatography, octanol extraction, two different endotoxin removal columns, and different combinations thereof. The efficiency of the applied purification protocols was evaluated by measuring phage titer and either endotoxins or staphylococcal enterotoxins A and C (SEA and SEC, respectively) from samples taken from different purification steps. The most efficient procedure in endotoxin removal was the combination of ultrafiltration and EndoTrap HD affinity column, which was able to reduce the endotoxin-to-phage ratio of vB_EcoM_fHoEco02 lysate from 3.5 × 104 Endotoxin Units (EU)/109 plaque forming units (PFU) to 0.09 EU/109 PFU. The combination of ultrafiltration and anion exchange chromatography resulted in ratio 96 EU/109 PFU, and the addition of octanol extraction step into this procedure still reduced this ratio threefold. The other methods tested either resulted to less efficient endotoxin removal or required the use of harmful chemicals that should be avoided when producing phage preparations for medical use. Ultrafiltration with 100,000 MWCO efficiently removed enterotoxins from vB_SauM_fRuSau02 lysate (from 1.3 to 0.06 ng SEA/109 PFU), and anion exchange chromatography reduced the enterotoxin concentration below 0.25 ng/ml, the detection limit of the assay.


Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice.
A role for the gastro-intestinal tract in controlling bone remodeling is suspected since serum levels of bone remodeling markers are affected rapidly after a meal. Glucose-dependent insulinotropic polypeptide (GIP) represents a suitable candidate in mediating this effect. The aim of the present study was to investigate the effect of total inhibition of GIP signaling on trabecular bone volume, microarchitecture and quality. We used GIP receptor (GIPR) knockout mice and investigated trabecular bone volume and microarchitecture by microCT and histomorphometry. GIPR-deficient animals at 16 weeks of age presented with a significant (20%) increase in trabecular bone mass accompanied by an increase (17%) in trabecular number. In addition, the number of osteoclasts and bone formation rate was significantly reduced and augmented, respectively in these animals when compared with wild-type littermates. These modifications of trabecular bone microarchitecture are linked to a remodeling in the expression pattern of adipokines in the GIPR-deficient mice. On the other hand, despite significant enhancement in bone volume, intrinsic mechanical properties of the bone matrix was reduced as well as the distribution of bone mineral density and the ratio of mature/immature collagen cross-links. Taken together, these results indicate an increase in trabecular bone volume in GIPR KO animals associated with a reduction in bone quality.


Embolization of basal ganglia and thalamic arteriovenous malformations.
Basal ganglia and thalamic arteriovenous malformations (AVMs) show a poor natural history and have proven difficult to treat. We report the safety and efficacy of presurgical and preradiosurgical embolization of these deep central lesions and describe the contribution of embolization to multimodality treatment. Thirty-eight patients with basal ganglia and/or thalamic AVMs underwent embolization in a total of 69 sessions. Seven of the 38 patients (18.4%) presented with hemorrhage, and 23 of 38 (60.5%) exhibited neurological deficits before therapy. Thirty patients (78.9%) underwent embolization with a liquid adhesive (cyanoacrylate), and five of these patients also underwent embolization with polyvinyl alcohol. Five patients (13.2%) were treated with polyvinyl alcohol or polyvinyl alcohol and silk. One patient (2.6%) underwent embolization alone, 19 (50.0%) underwent embolization followed by radiosurgery, 5 (13.2%) underwent embolization plus microsurgical resection, and 13 (34.2%) patients were treated using all three modalities. Three patients did not undergo embolization because of the morphological features of the AVMs and poor endovascular access. The patients who underwent embolization achieved AVM volume reductions of 10 to 100% (mean, 49.7%). Fifteen patients (39.5%) achieved complete obliteration of their AVMs, one with embolization alone, three with embolization followed by radiosurgery, five with embolization plus microsurgical resection, and six with a combination of all three modalities. At the time of the last follow-up imaging session, embolization combined with radiosurgery (19 patients) yielded a mean volume reduction of 81.1%, and all three modalities (13 patients) yielded a mean reduction of 84.6%. Four permanent neurological deficits resulted from embolization (5.8% of procedures, 10.5% of patients). The embolization-related complication rate was higher in the earlier years (1984-1989) of this series. Endovascular embolization plays an important role in multimodality treatment of AVMs involving the basal ganglia and/or thalamus. Embolization can result in obliteration of a significant volume of the AVM and may allow complete obliteration of the AVM when combined with microsurgical resection and/or stereotactic radiosurgery.


Successful treatment of refractory mucosal leishmaniasis with pentoxifylline plus antimony.
Mucosal leishmaniasis is characterized by an intense inflammatory reaction and tissue damage with few parasites in the lesion. On the basis of previous observations that suggest a possible role of tumor necrosis factor alpha (TNF-alpha) in the pathology of this disease, an open-label study was performed to evaluate the efficacy of the treatment with an inhibitor of TNF-alpha (pentoxifylline) associated to antimony therapy in 10 patients with refractory mucosal leishmaniasis. Patients were treated with pentavalent antimony (20 mg per kilogram of body weight per day) plus orally administered pentoxifylline 400 mg 3 times daily for 30 days. Nine of 10 patients fulfilled the criteria for cure: they experienced complete reepithelization of the mucosal tissue 90 days after therapy and displayed no evidence of relapse at 1 year of follow-up. The TNF-alpha levels before therapy (776 +/- 342 pg/mL) fell to 94 +/- 57 pg/mL (P < 0.05) within 60 days after therapy. Our results indicate that pentoxifylline plus antimony therapy should be considered in all patients with mucosal leishmaniasis that is refractory to treatment.


Preventing carryover of peptides and proteins in nano LC-MS separations.
Sample carryover is a significant problem that occurs in high-performance liquid chromatography (HPLC) analysis. Carryover effects cannot be tolerated in any high-performance liquid chromatography-mass spectroscopy (HPLC-MS) separation system, and proteomics analysis must be performed in a separation system with virtually no carryover. Several procedures have been tested for effective and fast removal of interfering peptides and proteins originating from previous analyses in the HPLC system. We have developed and optimized a cleaning method for eliminating carryover caused by the autosampler and the trap column. The new washing method uses an injection of trifluoroethanol into the injection path and onto the trap column to remove strongly bound peptides and proteins, and it includes trifluoroethanol as an additional solvent in the chromatographic mobile phase for enhanced cleaning of the separation column. By application of this method, a significant reduction in carryover was achieved without any loss in the amount of proteins and peptides identified by MS.


Effect of running on anterior knee laxity in collegiate-level female athletes after anterior cruciate ligament reconstruction.
Agility running activities are commonly used in the latter stages of rehabilitation for anterior cruciate ligament (ACL) reconstruction. However, the effects of agility running on anterior knee laxity in these patients have not been examined. The purpose of this study was to examine changes in anterior knee laxity before and after 30 minutes of agility running exercise. Subjects (N = 9) were female athletes (mean age = 20.1 +/- 1.5 years; height = 171.7 +/- 10.4 cm; weight = 65.7 +/- 8.6 kg) with unilateral ACL reconstruction (central 1/3 patella tendon graft, postoperation range = 9-52 months, mean = 24.2 months). Measurements were made at 20 degrees and 90 degrees of knee flexion bilaterally with KT-1000 arthrometry (MEDmetric, San Diego, CA) and recorded in millimeters of displacement. Data were analyzed with an analysis of variance (ANOVA) with repeated measures (p < 0.05). Results showed no statistical differences between the ACL-reconstructed knee and the normal knee at 20 degrees and 90 degrees knee flexion. The authors conclude that the central 1/3 patella tendon graft performs comparable to the normal knee when stressed with agility running exercise; therefore, agility exercise is an appropriate, safe, short-term activity.


Sexual behavior of HIV-positive adults not accessing HIV treatment in Mombasa, Kenya: Defining their prevention needs.
HIV spread continues at high rates from infected persons to their sexual partners. In 2009, an estimated 2.6 million new infections occurred globally. People living with HIV (PLHIV) receiving treatment are in contact with health workers and therefore exposed to prevention messages. By contrast, PLHIV not receiving ART often fall outside the ambit of prevention programs. There is little information on their sexual risk behaviors. This study in Mombasa Kenya therefore explored sexual behaviors of PLHIV not receiving any HIV treatment. Using modified targeted snowball sampling, 698 PLHIV were recruited through community health workers and HIV-positive peer counsellors. Of the 59.2% sexually-active PLHIV, 24.5% reported multiple sexual partners. Of all sexual partners, 10.2% were HIV negative, while 74.5% were of unknown HIV status. Overall, unprotected sex occurred in 52% of sexual partnerships; notably with 32% of HIV-negative partners and 54% of partners of unknown HIV status in the last 6 months. Multivariate analysis, controlling for intra-client clustering, showed non-disclosure of HIV status (AOR: 2.38, 95%CI: 1.47-3.84, p < 0.001); experiencing moderate levels of perceived stigma (AOR: 2.94, 95%CI: 1.50-5.75, p = 0.002); and believing condoms reduce sexual pleasure (AOR: 2.81, 95%CI: 1.60-4.91, p < 0.001) were independently associated with unsafe sex. Unsafe sex was also higher in those using contraceptive methods other than condoms (AOR: 5.47, 95%CI: 2.57-11.65, p < 0.001); or no method (AOR: 3.99, 95%CI: 2.06-7.75, p < 0.001), compared to condom users. High-risk sexual behaviors are common among PLHIV not accessing treatment services, raising the risk of HIV transmission to discordant partners. This population can be identified and reached in the community. Prevention programs need to urgently bring this population into the ambit of prevention and care services. Moreover, beginning HIV treatment earlier might assist in bringing this group into contact with providers and HIV prevention services, and in reducing risk behaviors.


Application of a novel interferometric method to investigate the relation between lipid layer thickness and tear film thinning.
The lipid layer of the tear film forms a barrier to evaporation. Evaporation is a major cause of tear thinning between blinks and tear breakup. The purpose of this study was to investigate the relation between tear film thinning and lipid layer thickness before and after instillation of an emulsion eye drop. Fifty non-contact lens wearers were studied. Spectral interferometry was used to measure the thinning rate of the precorneal tear film for up to 19 seconds after a blink. Simultaneously, lipid layer thickness was measured based on an absolute reflectance spectrum. After a 2-minute recovery, the measurement was repeated. A drop of the lipid emulsion was then instilled; 15 minutes later, two interferometry measurements were performed similarly. A histogram of thinning rates was fitted by a bimodal distribution with narrow and broad peaks corresponding to slow and rapid thinning, respectively. The correlation between repeated thinning rate measurements was modest, but repeatability was considerably more significant when analyzed in terms of the slow/rapid dichotomy. Similarly, the correlation between thinning rate and lipid thickness was modest but was more evident when analyzed in terms of the slow/rapid dichotomy. Instillation of an emulsion eye drop significantly increased the thickness of the lipid layer but did not significantly alter the thinning rate. The proposed slow/rapid dichotomy of thinning rates presumably relates to a good/poor barrier to evaporation of the lipid layer. The imperfect correlation between thinning rate and lipid thickness indicates that other factors, such as the composition and structure of the lipid layer, are important (e.g., sufficient polar lipids may be needed to form good interface between nonpolar lipids and the aqueous layer).


Oral toxicity of a tocotrienol preparation in rats.
Tocotrienols are added as antioxidants to food. As there have been no reports of toxicological evaluation, a 13-week oral toxicity study was performed in Fischer 344 rats of both sexes at dose levels of 0 (group 1), 0.19 (group 2), 0.75 (group 3) and 3% (group 4) of a preparation in powdered diet. Suppression of body weight gain was observed in group 4 males. On hematological examination, significant decrease in mean corpuscular volume (MCV) was observed in all treated males. Platelets were significantly reduced in group 3 and 4 males. Hemoglobin concentration, MCV, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration were significantly decreased in group 3 and 4 females and hematocrit in group 4 females. On serum biochemical examination, increase in the albumin/globulin ratio (A/G) and alkaline phosphatase in all treated males, elevated alanine transaminase in group 4 of both sexes and increases in asparagine transaminase and gamma-glutamyl transaminase in group 4 females were observed. With regard to relative organ weights, liver weights in group 4 of both sexes and adrenal weights in all treated males demonstrated an increase, and ovary and uterus weights in group 4 females were reduced. Histopathologically, slight hepatocellular hypertrophy in group 3 and 4 males, and reduction of cytoplasmic vacuolation in the adrenal cortical region in group 4 males were observed. Because of pathological changes in male liver and hematological changes in females, the no-observed-adverse-effect level (NOAEL) was concluded to be 0.19% in the diet (120 mg/kg body weight/day for male rats and 130 mg/kg body weight/day for female rats). As a decrease in MCV, an increase in the A/G, elevation of alkaline phosphatase and increase in adrenal weight were observed in all treated males, a no-observed-effect level (NOEL) could not be determined in this examination.


Mechanical bone strength of the tibial resection surface at increasing distance from the joint line in total knee arthroplasty.
Few articles have addressed the bone strength of the proximal tibia. This study attempts to quantify the compressive strength of bone in the proximal tibia of human cadaveric knees at increasing distance from the joint surface. Sixteen fresh-frozen human cadaveric knees were tested. The proximal tibia was sequentially sectioned into 1-cm slices, starting 2 mm below the chondral surface of the medial tibial plateau. Four slices were obtained from each knee. Each slice was then loaded to failure under an axial load. The proximal slice of bone had a significantly higher average maximum load to failure than the more distal slices. The second, third, and fourth slices of bone withstood 77%, 61%, and 73% of the average load of the proximal slice, respectively. This study was designed to simulate how the proximal tibia is loaded under an uncemented tibial base plate after total knee arthroplasty. The results are in agreement with previous studies that have shown the proximal 1 cm of tibial bone to have the highest resistance to compressive loads. Previous studies on the bone strength of the proximal tibia have focused on more proximal portions of bone than the current study. This study demonstrates that the load to failure of tibial resection surface decreases significantly with increasing distance from the joint line until the 4th cm of bone beneath the joint line is encountered. This information may play a role in surgical decision making and implant design.


A Narrative Review on Contrast-Enhanced Ultrasound in Aortic Endograft Endoleak Surveillance.
Endovascular repair of abdominal aortic aneurysms have been performed successfully since 1991. However, 20% to 50% of these patients may develop an endoleak or continued aneurysmal sac expansion or perfusion despite stent graft coverage. Current recommendations suggest lifelong surveillance with computed tomographic angiography (CTA) at least 1 month after intervention and yearly after that. In select patients with a stable aneurysm sac on computed tomography performed 1 year after treatment, future screening could be performed with ultrasonography. However, color Doppler ultrasound can fail to detect as many as 31% of endoleaks. Contrast-enhanced ultrasound (CEUS) provides an alternative approach to excluded aneurysm sac follow-up imaging. The Society for Vascular Surgery notes a need for further research on the role of CEUS in endovascular aortic repair surveillance. The European Federation of Societies for Ultrasound in Medicine and Biology suggests that early results are promising. Meta-analyses report pooled sensitivities and specificities of CEUS compared with CTA for the detection of endoleak between 89% and 98% and 86% and 88%, respectively. Owing to the dynamic flow information it provides, CEUS may actually be more sensitive than CTA at detection and characterization in select circumstances. Challenges with adoption, patient selection, and operator dependency remain, but current and future research suggests a role for CEUS in endoleak surveillance.


High fat food increases gastric residence and thus thresholds for objective symptoms in allergic patients.
We have tested the hypothesis that high fat foods such as chocolate induce reduced rates of gastric emptying in comparison to lower fat foods and that this can impact uptake of allergens and subsequent reactions in allergic patients. In four volunteers, magnetic resonance imaging was used to measure gastric emptying of a series of nine doses of either dark chocolate bars containing 35% fat or a chocolate dessert containing 8% fat. Analysis showed a mean rate of decrease in gastric volume with an 8% fat dessert was 0.33 ± 0.09 mL/min compared to an average rate of increase in gastric volume of 0.09 ± 0.10 mL/min for the chocolate bars. In parallel, eight allergic patients were challenged for either peanut or hazelnut in the same two matrices and doses using a standardized protocol. A statistical analysis of the objective symptoms in the allergic patients showed that the chocolate bars gave a significantly higher threshold for objective symptoms than the dessert. Chocolate bars induced lower gastric emptying rates and in food challenges with allergic patients gave a higher threshold of elicitation for objective reactions than a dessert.


Correlation between nuptial colors and visual sensitivities tuned by opsins leads to species richness in sympatric Lake Victoria cichlid fishes.
Reproductive isolation that prevents interspecific hybridization between closely related coexisting species maintains sympatric species diversity. One of the reproductive isolations is mate choice based on color signals (breeding color perceived by color vision). This is well known in several animal taxa, yet little is known about its genetic and molecular mechanism. Lake Victoria cichlid fishes are thought to be an example of sympatric species diversity. In the species inhabiting different light environments in rocky shore, speciation by sensory drive through color signals has been proposed by analyses of the long wavelength-sensitive (LWS) opsin gene and the male nuptial coloration. However, the genetic and molecular mechanism of how diversity of sympatric species occurring in the same habitat is maintained remains unknown. To address this issue, we determined nucleotide sequences of eight opsins of six sympatric species collected from a sandy-muddy shore--an ideal model system for studying sympatric species. Among eight opsins, the LWS and RH1 alleles were diversified and one particular allele is dominant or fixed in each species, and we propose that this is due to natural selection. The functions of their LWS alleles were also diversified as shown by absorption measurements of reconstituted visual pigments. To analyze the relationship between nuptial coloration and the absorption of LWS pigments, we systematically evaluated and defined nuptial coloration. We showed that the coloration was species specific with respect to hue and significantly differentiated by the index values of hue (dominant wavelength: λ(d)). The λ(d) value of the male nuptial coloration correlated with the absorption of LWS pigments from all the species, suggesting that reproductive isolation through mate choice using color signals may prevent sympatric interspecific hybridization, thereby maintaining the species diversity in sympatric species in Lake Victoria.


Sticky gecko feet: the role of temperature and humidity.
Gecko adhesion is expected to be temperature insensitive over the range of temperatures typically experienced by geckos. Previous work is limited and equivocal on whether this expectation holds. We tested the temperature dependence of adhesion in Tokay and Day geckos and found that clinging ability at 12 degrees C was nearly double the clinging ability at 32 degrees C. However, rather than confirming a simple temperature effect, our data reveal a complex interaction between temperature and humidity that can drive differences in adhesion by as much as two-fold. Our findings have important implications for inferences about the mechanisms underlying the exceptional clinging capabilities of geckos, including whether performance of free-ranging animals is based solely on a dry adhesive model. An understanding of the relative contributions of van der Waals interactions and how humidity and temperature variation affects clinging capacities will be required to test hypotheses about the evolution of gecko toepads and is relevant to the design and manufacture of synthetic mimics.


Zebrafish in the study of early cardiac development.
Heart development is a complex process that involves cell specification and differentiation, as well as elaborate tissue morphogenesis and remodeling, to generate a functional organ. The zebrafish has emerged as a powerful model system to unravel the basic genetic, molecular, and cellular mechanisms of cardiac development and function. We summarize and discuss recent discoveries on early cardiac specification and the identification of the second heart field in zebrafish. In addition to the inductive signals regulating cardiac specification, these studies have shown that heart development also requires a repressive mechanism imposed by retinoic acid signaling to select cardiac progenitors from a multipotent population. Another recent advance in the study of early zebrafish cardiac development is the identification of the second heart field. These studies suggest that the molecular mechanisms that regulate the second heart field development are conserved between zebrafish and other vertebrates including mammals and provide insight into the evolution of the second heart field and its derivatives.


Social Media, Higher Education, and Community Colleges: A Research Synthesis and Implications for the Study of Two-Year Institutions.
The boundaries between on-line and "real-world" communities are rapidly deteriorating, particularly for the generation of young people whose lives are pervaded by social media. For this generation, social media exchanges are a primary means of communication, social engagement, information seeking, and possibly, a central component of their identity and community-building. Given these realities, postsecondary educators should begin to seriously explore the potential to intentionally and strategically harness the power of these revolutionary transformations in technology use to better serve the needs of students to enhance their success. Therefore, this review of books, academic journals, higher education news, research reports, individual blogs and other online media on the use of social media technology (SMT) in higher education provides a baseline sense of current uses nationally, providing a descriptive overview of the social media phenomenon. Additionally, the review clarifies how colleges and college students use SMT and also challenges assumptions in two areas: how institutions can best exploit social media's features and its impact on student outcomes. The review further provides a foundation to develop conceptual frameworks that would better capture the role and impact of SMT among colleges and college students, and community colleges in particular.


HR-pQCT for the Evaluation of Muscle Quality and Intramuscular Fat Infiltration in Ageing Skeletal Muscle.
Myosteatosis is the infiltration of fat in skeletal muscle during the onset of sarcopenia. The quantification of intramuscular adipose tissue (IMAT) can be a feasible imaging modality for the clinical assessment of myosteatosis, important for the early identification of sarcopenia patients and timely intervention decisions. There is currently no standardized method or consensus for such an application. The aim of this study was to develop a method for the detection and analysis of IMAT in clinical HR-pQCT images of the distal tibia to evaluate skeletal muscle during the ageing process, validated with animal and clinical experimentation. A pre-clinical model of ovariectomized (OVX) rats with known intramuscular fat infiltration was used, where gastrocnemii were scanned by micro-computed tomography (micro-CT) at an 8.4 μm isotropic voxel size, and the images were analyzed using our modified IMAT analysis protocol. IMAT, muscle density (MD), and muscle volume (MV) were compared with SHAM controls validated with Oil-red-O (ORO) staining. Furthermore, the segmentation and IMAT evaluation method was applied to 30 human subjects at ages from 18 to 81 (mean = 47.3 ± 19.2). Muscle-related parameters were analyzed with functional outcomes. In the animal model, the micro-CT adipose tissue-related parameter of IMAT% segmented at −600 HU to 100 HU was shown to strongly associate with the ORO-positively stained area (r = 0.898, p = 0.002). For the human subjects, at an adjusted threshold of −600 to −20 HU, moderate positive correlations were found between MV and MD (r = 0.642, p < 0.001), and between MV and IMAT volume (r = 0.618, p < 0.01). Moderate negative correlations were detected between MD and IMAT% (r = −0.640, p < 0.001). Strong and moderate associations were found between age and MD (r = −0.763, p < 0.01), and age and IMAT (r = 0.559, p < 0.01). There was also a strong correlation between IMAT% and chair rise time (r = 0.671, p < 0.01). The proposed HR-pQCT evaluation protocol for intramuscular adipose-tissue produced MD and IMAT results that were associated with age and physical performance measures, and were of good predictive value for the progression of myosteatosis or sarcopenia. The protocol was also validated on animal skeletal muscle samples that showed a good representation of histological lipid content with positive correlations, further supporting the clinical application for the rapid evaluation of muscle quality and objective quantification of skeletal muscle at the peripheral for sarcopenia assessment.


Plasmacytoid dendritic cells control dengue and Chikungunya virus infections via IRF7-regulated interferon responses.
Type I interferon (IFN-I) responses are critical for the control of RNA virus infections, however, many viruses, including Dengue (DENV) and Chikungunya (CHIKV) virus, do not directly activate plasmacytoid dendritic cells (pDCs), robust IFN-I producing cells. Herein, we demonstrated that DENV and CHIKV infected cells are sensed by pDCs, indirectly, resulting in selective IRF7 activation and IFN-I production, in the absence of other inflammatory cytokine responses. To elucidate pDC immunomodulatory functions, we developed a mouse model in which IRF7 signaling is restricted to pDC. Despite undetectable levels of IFN-I protein, pDC-restricted IRF7 signaling controlled both viruses and was sufficient to protect mice from lethal CHIKV infection. Early pDC IRF7-signaling resulted in amplification of downstream antiviral responses, including an accelerated natural killer (NK) cell-mediated type II IFN response. These studies revealed the dominant, yet indirect role of pDC IRF7-signaling in directing both type I and II IFN responses during arbovirus infections.


The Effect of Framing and Placement on Linkage Consent.
Numerous surveys link interview data to administrative records, conditional on respondent consent, in order to explore new and innovative research questions. Optimizing the linkage consent rate is a critical step toward realizing the scientific advantages of record linkage and minimizing the risk of linkage consent bias. Linkage consent rates have been shown to be particularly sensitive to certain design features, such as where the consent question is placed in the questionnaire and how the question is framed. However, the interaction of these design features and their relative contributions to the linkage consent rate have never been jointly studied, raising the practical question of which design feature (or combination of features) should be prioritized from a consent rate perspective. We address this knowledge gap by reporting the results of a placement and framing experiment embedded within separate telephone and Web surveys. We find a significant interaction between placement and framing of the linkage consent question on the consent rate. The effect of placement was larger than the effect of framing in both surveys, and the effect of framing was only evident in the Web survey when the consent question was placed at the end of the questionnaire. Both design features had negligible impact on linkage consent bias for a series of administrative variables available for consenters and non-consenters. We conclude this research note with guidance on the optimal administration of the linkage consent question.


Hematologic and serum biochemical reference ranges and an assessment of exposure to infectious diseases prior to translocation of the threatened western ringtail possum (Pseudocheirus occidentalis).
Health screening of animals before translocation is important to minimize the risk of pathogen transmission between sites and species. Reintroduction has been incorporated into management of the endangered western ringtail possum (Pseudocheirus occidentalis) to mitigate for habitat loss within the species' core range in southwestern Australia. Between November 2005 and March 2008 we screened 47 wild and 24 captive P. occidentalis and 68 sympatric common brushtail possums (Trichosurus vulpecula hypoleucus) for infectious diseases that might compromise possum survival or fecundity at translocation sites. We found no evidence that infectious disease limits translocation success, and neither possum species showed evidence of infection with Salmonella spp., Toxoplasma gondii, Leptospira spp., or Chlamydophila spp. Antigen of Cryptococcus gattii was detected in one T. v. hypoleucus but was not of pathologic significance. Hematologic and serum biochemical reference ranges were determined for 81 wild and 24 captive P. occidentalis. Site differences were identified for red blood cell count, hemoglobin, albumin, urea, and globulin, suggesting that habitat quality or nutrient intake may vary among sites. Differences between wild and captive values were found for several parameters. These data are useful for health evaluations of injured P. occidentalis and the future monitoring of wild populations.


Apparent decreased risk of invasive bacterial disease after heterologous childhood immunization.
To investigate the possibility that there might be an increased risk of heterologous invasive bacterial disease after routine childhood immunization with measles, mumps, and rubella vaccine live; diphtheria and tetanus toxoids and pertussis vaccine; and oral poliovirus vaccine live, a case-control study was conducted within the Kaiser Permanente Northern California pediatric population. Contrary to the premise, an apparent protective effect against invasive bacterial disease was detected after all childhood vaccinations. However, when adjustment was made for frequency of well-care visits and day-care attendance, no significant relationship was seen between receipt of routine childhood immunizations and risk of invasive heterologous bacterial disease for any individual vaccine, although a statistically significant protective effect was detected within 1 or 3 months after the receipt of any vaccine. Since a decreased risk of invasive bacterial disease was also noted to be related to the receipt of routine well-child pediatric care, other preventive health care measures may be responsible for the apparent immunization protective effect.


The conserved foot domain of RNA pol II associates with proteins involved in transcriptional initiation and/or early elongation.
RNA polymerase (pol) II establishes many protein-protein interactions with transcriptional regulators to coordinate different steps of transcription. Although some of these interactions have been well described, little is known about the existence of RNA pol II regions involved in contact with transcriptional regulators. We hypothesize that conserved regions on the surface of RNA pol II contact transcriptional regulators. We identified such an RNA pol II conserved region that includes the majority of the "foot" domain and identified interactions of this region with Mvp1, a protein required for sorting proteins to the vacuole, and Spo14, a phospholipase D. Deletion of MVP1 and SPO14 affects the transcription of their target genes and increases phosphorylation of Ser5 in the carboxy-terminal domain (CTD). Genetic, phenotypic, and functional analyses point to a role for these proteins in transcriptional initiation and/or early elongation, consistent with their genetic interactions with CEG1, a guanylyltransferase subunit of the Saccharomyces cerevisiae capping enzyme.


Osteoporosis in elderly men and women: effects of dietary calcium, physical activity, and body mass index.
Dietary calcium intake and physical activity are considered practical measures for prevention of osteoporosis. However, their associations with bone mineral density (BMD) in the elderly are not clear. The present study examined the association between osteoporosis and these two factors in relation to body mass index (BMI) in a cross-sectional, epidemiological study involving 1075 women and 690 men, aged 69 +/- 6.7 years (mean +/- SD). Dietary calcium intake (median of 580 mg/day) was inversely related to age (p = 0.01), positively related to physical activity index (PAI) (p = 0.01), femoral neck BMD (p = 0.01) in women, and higher lumbar spine (p = 0.003) and femoral neck BMD (p = 0.03) in men. Quadriceps strength was negatively associated with age (p < 0.0001) and positively related to BMI (p < 0.0001) and BMD (p < 0.0001) in both men and women. The PAI was associated with quadriceps strength (p < 0.0001) and femoral neck and lumbar spine BMD in women (p < 0.001) and with femoral neck BMD in men (p = 0.04); however, these associations were not significant after adjusting for age, BMI, quadriceps strength, and dietary calcium. Women in the top tertile of quadriceps strength (> or =23 kg) and dietary calcium intake (> or =710 mg/day) had 15% higher BMD than those in the lowest tertiles (< or =15 kg and < or =465 mg/day); the difference was comparable in men (11%). Among subjects with the lowest tertiles of BMI (< or =23 kg/m2 for women and < or =24 kg/m2 for men), quadriceps strength (< or =15 kg for women and < or =28 kg for men), and dietary calcium intake (< or =465 mg/day), 64% and 40% of women and men, respectively, were classified as having osteoporosis (based on a 2.5-SD reduction from the young-normal mean). The prevalence was only 12% in women and 1.5% in men among those in the highest tertiles of the three factors. Adequate dietary calcium intake and maintaining a physically active lifestyle in late decades of life could potentially translate into a reduction in the risk of osteoporosis and hence improve the quality and perhaps quantity of life in the elderly population.


Depression associated with dementia.
Depression and cognitive disorders, including dementia and mild cognitive impairment, are common disorders in old age. Depression is frequent in dementia, causing distress, reducing the quality of life, exacerbating cognitive and functional impairment and increasing caregiver stress. Even mild levels of depression can significantly add to the functional impairment of dementia patients and the severity of psychopathological and neurological impairments increases with increasing severity of depression. Depressive symptoms may be both a risk factor for, as well as a prodrome of dementia. Major depressive syndrome of Alzheimer's disease may be among the most common mood disorders of older adults. Treating depression is therefore a key clinical priority to improve the quality of life both of people with dementia as well as their carergivers. Nonpharmacological approaches and watchful waiting should be attempted first in patients who present with mild to moderate depression and dementia. In cases of severe depression or depression not able to be managed through nonpharmacological means, antidepressant therapy should be considered.


Characterization of antimicrobial resistance of Salmonella Newport isolated from animals, the environment, and animal food products in Canada.
Multi-drug-resistant (MDR) Salmonella enterica serovar Newport strains are increasingly isolated from animals and food products of animal origin and have caused septicemic illness in animals and humans. The purpose of this study was to determine the occurrence and the epidemiologic, phenotypic, and genotypic characteristics of S. Newport of animal origin that may infect humans, either via the food chain or directly. During the 1993-2002 period, the Office International des Epizooties Reference Laboratory for Salmonellosis in Guelph, Ontario, received 36 841 Salmonella strains for serotyping that had been isolated from animals, environmental sources, and food of animal origin in Canada. Of these, 119 (0.3%) were S. Newport. Before 2000, none of 49 S. Newport strains was resistant to more than 3 antimicrobials. In contrast, between January 2000 and December 2002, 35 of 70 isolates, primarily of bovine origin, were resistant to at least 11 antimicrobials, including the extended-spectrum cephalosporins. The blaCMY-2', flo(st'), strA, strB, sulII, and tetA resistance genes were located on plasmids of 80 to 90 MDa that were self-transmissible in 25% of the strains. Conserved segments of the integron 1 gene were found on the large MDR-encoding plasmids in 3 of 35 strains additionally resistant to gentamicin and spectinomycin or to spectinomycin, sulfamethoxazole-trimethoprim, and trimethoprim. Resistance to kanamycin and neomycin was encoded by the aphA-1 gene, located on small plasmids (2.3 to 6 MDa). The increase in bovine-associated MDR S. Newport infections is cause for concern since it indicates an increased risk of human acquisition of the infection via the food chain.


MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19.
The SARS-CoV-2 virus responsible for the COVID-19 pandemic has generated an explosion of interest both in the mechanisms of infection leading to dissemination and expression of this disease, and in potential risk factors that may have a mechanistic basis for disease propagation or control. Vitamin D has emerged as a factor that may be involved in these two areas. The focus of this article is to apply our current understanding of vitamin D as a facilitator of immunocompetence both with regard to innate and adaptive immunity and to consider how this may relate to COVID-19 disease. There are also intriguing potential links to vitamin D as a factor in the cytokine storm that portends some of the most serious consequences of SARS-CoV-2 infection, such as the acute respiratory distress syndrome. Moreover, cardiac and coagulopathic features of COVID-19 disease deserve attention as they may also be related to vitamin D. Finally, we review the current clinical data associating vitamin D with SARS-CoV-2 infection, a putative clinical link that at this time must still be considered hypothetical.


Reducing cognitive vulnerability to depression: a preliminary investigation of MEmory Specificity Training (MEST) in inpatients with depressive symptomatology.
Reduced specificity of autobiographical memory retrieval represents an enduring vulnerability factor for depression. The present study is a preliminary evaluation of a newly developed group-based intervention program to increase specificity of memory retrieval. The MEmory Specificity Training (MEST) was administered on a weekly basis for 4 consecutive weeks to 10 inpatients with depressive symptomatology. Whereas earlier studies found that memory specificity does not improve following treatment as usual, the present results showed that participants' retrieval style became significantly more specific following MEST. These results suggest that the MEST may offer a potential and promising intervention to tackle a core cognitive process involved in depression and depressive vulnerability.


Two-step-only quadrature phase-shifting digital holography.
Conventional methods of quadrature phase-shifting holography require two holograms and either intensity distribution of the reference wave or that of the object wave to reconstruct an original object without the zero order and the twin-image noise in an on-axis holographic recording setup. We present a technique called two-step-only quadrature phase-shifting holography in which solely two quadrature-phase holograms are required. Neither reference-wave intensity nor an object-wave intensity measurement is needed in the technique.


Butyrate enema therapy stimulates mucosal repair in experimental colitis in the rat.
The short chain fatty acid (SCFA) butyrate provides energy for colonocytes, stimulates colonic fluid and electrolyte absorption and is recognised as an effective treatment for multiple types of colitis. To examine the impact of butyrate enema therapy on the clinical course, severity of inflammation, and SCFA stimulated Na+ absorption in a chronic experimental colitis. Distal colitis was induced in rats with a trinitrobenzenesulphonic acid (TNBS) enema. Five days after induction, rats were divided into groups to receive: no treatment, saline enemas, or 100 mM Na-butyrate enemas daily. On day 24, colonic damage score and tissue myeloperoxidase (MPO) activity were evaluated. Colon was mounted in Ussing chambers and Na+ transport and electrical activities were measured during a basal period and after stimulation with 25 mM butyrate. In the untreated and the saline enema treated TNBS groups, diarrhoea and extensive colonic damage were seen, associated with increased tissue MPO activities and absent butyrate stimulated Na+ absorption. In contrast, in the butyrate enema treated TNBS group, diarrhoea ceased, colonic damage score improved, and tissue MPO activity as well as butyrate stimulated Na+ absorption recovered to control values. Butyrate enema therapy stimulated colonic repair, as evidenced by clinical recovery, decreased inflammation, and restoration of SCFA stimulated electrolyte absorption.


Accumulation of heavy metals by intestinal helminths in fish: an overview and perspective.
Intestinal helminths of fish are of increasing interest as potential bioindicators for heavy metal contamination in aquatic habitats. Among these parasites cestodes and acanthocephalans in particular have an enormous heavy metal accumulation capacity exceeding that of established free living sentinels. Metal concentrations several thousand times higher in acanthocephalans than in host tissues were described from field and laboratory studies. Whereas larval stages inside their intermediate hosts are not able to take up high quantities of metals, young worms begin to take up metals immediately after infection of the final host. After four to five weeks of exposure, the parasites reach a steady-state concentration orders of magnitude higher than the ambient water level. Thus, acanthocephalans are not only very effective in taking up metals, but they can also respond very rapidly to changes in environmental exposure. The mechanism which enable acanthocephalans to take up metals from the intestinal lumen of the host appears to be based on the presence of bile acids, which form organo-metallic complexes that are easily absorbed by the worms due to their lipophilicity. Investigations of the environmental conditions affecting metal uptake have shown that the parasites are more consistent and reliable indicators for metal pollution than the host tissues as metal levels of the latter are much more dependent on the water chemistry. Thus, after some years of research on the uptake of metals by acanthocephalans and on the factors affecting metal accumulation in intestinal parasites it should be asked if acanthocephalans meet the criteria commonly accepted for sentinels. If parasites can be considered as promising sentinels, we need reasons for the establishment of 'new' indicators. Therefore, this review summarises the present knowledge about parasites as bioindicators and compares the accumulation properties of parasites and established free living indicators. Finally, this review presents possible answers to the question why it could be advantageous to have new and even more sensitive indicators for environmental monitoring purposes.


Philometrid nematodes (Philometridae) from marine fishes off the northern coast of Australia, including three new species.
Based on light and scanning electron microscopical studies, the following nine species of Philometridae (Nemaoda: Dracunculoidea) are described from female worms parasitizing marine perciform fishes belonging to six families off the northern coast Australia (near Darwin): Philometra australiensis sp. n. from the swimbladder of the king threadfin Polydactylus macrochir (Günther) (Polynemidae); P. epinepheli Dewi et Palm, 2013 from the operculum of the orange-spotted grouper Epinephelus coioides (Hamilton) (Serranidae); Philometra johnii Moravec et Ali, 2013 from the gonad of the croaker Johnius sp. (Sciaenidae); P. macrochiri sp. n. from the sensory fin of P. macrochir; P. zabidii sp. n. from the ovary of the ninespine batfish Zabidius novemaculatus (McCulloch) (Ephippidae); Philometra sp. 1 and Philometra sp. 2 from the ovary of the Spanish flag snapper Lutjanus carponotatus (Richardson) (Lutjanidae) and the silver grunt Pomadasys argenteus (Forsskål) (Haemulidae), respectively; Philometroides eleutheronemae Moravec et Manoharan, 2013 from the ovary of the fourfinger threadfin Eleutheronema tetradactylum (Shaw) (Polynemidae); and Spirophilometra endangae Dewi et Palm, 2013 from the pectoral fins of E. coioides. The new species P. australiensis is characterized mainly by the structure of the cephalic end, 14 minute cephalic papillae, absence of caudal projections and body length of gravid female (67 mm), P. macrochiri by the presence of a conspicuously large anterior oesophageal bulb, 14 very small cephalic papillae and the truncated posterior end of body without any caudal projections, whereas P. zabidii is characterized by the presence of distinct caudal projections, the number (14) and larger size and arrangement of cephalic papillae, a poorly developed anterior oesophageal inflation, the body length (114 mm) and the host family (Ephippidae). All above-mentioned species were recorded from Australian waters for the first time.


Eco-epidemiological study of an endemic Chagas disease region in northern Colombia reveals the importance of Triatoma maculata (Hemiptera: Reduviidae), dogs and Didelphis marsupialis in Trypanosoma cruzi maintenance.
In Colombia, Rhodnius prolixus and Triatoma dimidiata are the main domestic triatomine species known to transmit T. cruzi. However, there are multiple reports of T. cruzi transmission involving secondary vectors. In this work, we carried out an eco-epidemiological study on Margarita Island, located in the Caribbean region of Colombia, where Chagas disease is associated with non-domiciliated vectors. To understand the transmission dynamics of Trypanosoma cruzi in this area, we designed a comprehensive, multi-faceted study including the following: (i) entomological evaluation through a community-based insect-surveillance campaign, blood meal source determination and T. cruzi infection rate estimation in triatomine insects; (ii) serological determination of T. cruzi prevalence in children under 15 years old, as well as in domestic dogs and synanthropic mammals; (iii) evaluation of T. cruzi transmission capacity in dogs and Didelphis marsupialis, and (iv) genetic characterization of T. cruzi isolates targeting spliced-leader intergene region (SL-IR) genotypes. Out of the 124 triatomines collected, 94% were Triatoma maculata, and 71.6% of them were infected with T. cruzi. Blood-meal source analysis showed that T. maculata feeds on multiple hosts, including humans and domestic dogs. Serological analysis indicated 2 of 803 children were infected, representing a prevalence of 0.25%. The prevalence in domestic dogs was 71.6% (171/224). Domestic dogs might not be competent reservoir hosts, as inferred from negative T. cruzi xenodiagnosis and haemoculture tests. However, 61.5% (8/13) of D. marsupialis, the most abundant synanthropic mammal captured, were T. cruzi-positive on xenodiagnosis and haemocultures. This study reveals the role of peridomestic T. maculata and dogs in T. cruzi persistence in this region and presents evidence that D. marsupialis are a reservoir mediating peridomestic-zoonotic cycles. This picture reflects the complexity of the transmission dynamics of T. cruzi in an endemic area with non-domiciliated vectors where active human infection exists. There is an ongoing need to control peridomestic T. maculata populations and to implement continuous reservoir surveillance strategies with community participation.


A "health commons" approach to oral health for low-income populations in a rural state.
Oral health needs are urgent in rural states. Creative, broad-based, and collaborative solutions can alleviate these needs. "Health commons" sites are enhanced, community-based, primary care safety net practices that include medical, behavioral, social, public, and oral health services. Successful intervention requires a comprehensive approach, including attention to enhancing dental service capacity, broadening the scope of the dental skills of locally available providers, expanding the pool of dental providers, creating new interdisciplinary teams in enhanced community-based sites, and developing more comprehensive oral health policy. By incorporating oral health services into the health commons primary care model, access for uninsured and underserved populations is increased. A coalition of motivated stakeholders includes community leaders, safety net providers, legislators, insurers, and medical, dental, and public health providers.


Single-molecule spectroscopy of the unexpected collapse of an unfolded protein at low pH.
The dimensions of intrinsically disordered and unfolded proteins critically depend on the solution conditions, such as temperature, pH, ionic strength, and osmolyte or denarurant concentration. However, a quantitative understanding of how the complex combination of chain-chain and chain-solvent interactions is affected by the solvent is still missing. Here, we take a step towards this goal by investigating the combined effect of pH and denaturants on the dimensions of an unfolded protein. We use single-molecule fluorescence spectroscopy to extract the dimensions of unfolded cold shock protein (CspTm) in mixtures of the denaturants urea and guanidinium chloride (GdmCl) at neutral and acidic pH. Surprisingly, even though a change in pH from 7 to 2.9 increases the net charge of CspTm from -3.8 to +10.2, the radius of gyration of the chain is very similar under both conditions, indicating that protonation of acidic side chains at low pH results in additional hydrophobic interactions. We use a simple shared binding site model that describes the joint effect of urea and GdmCl, together with polyampholyte theory and an ion cloud model that includes the chemical free energy of counterion interactions and side chain protonation, to quantify this effect.