Social media use for occupational lung disease.
Social media have great impact on all aspects of life throughout the world. The utilization of social media for occupational lung disease, however, has been much more limited. This article summarizes recent literature concerning social media for occupational lung disease and identifies areas for additional use. Social media are used in six relevant areas: information dissemination, peer-to-peer communication, survey research data collection, participatory research and exposome data acquisition, assessing public concerns, and knowledge generation. There are very clear advantages for information dissemination from experts to workers and on a peer-to-peer basis, although variable credibility and accuracy concerns persist. For research, social media have been used for acquiring data posted for nonresearch purposes and for efficiently collecting information specifically for research. The benefits of efficiency, democracy, and very large data sources may counterbalance concerns about inadequate specification of recruitment strategies and limited control over data quality. The potential benefits of using social media for lung health-workplace interactions are much greater than the very limited current utilization.


Histomorphometric evaluation of bone regeneration using autogenous bone and beta-tricalcium phosphate in diabetic rabbits.
The mechanism of impaired bone healing in diabetes mellitus includes different tissue and cellular level activities due to micro- and macrovascular changes. As a chronic metabolic disease with vascular complications, diabetes affects a process of bone regeneration as well. The therapeutic approach in bone regeneration is based on the use of osteoinductive autogenous grafts as well as osteoconductive synthetic material, like a β-tricalcium phosphate. The aim of the study was to determine the quality and quantity of new bone formation after the use of autogenous bone and β-tricalcium phosphate in the model of calvarial critical-sized defect in rabbits with induced diabetes mellitus type I. The study included eight 4-month-old Chincilla rabbits with alloxan-induced diabetes mellitus type I. In all animals, there were surgically created two calvarial bilateral defects (diameter 12 mm), which were grafted with autogenous bone and β-tricalcium phosphate (n = 4) or served as unfilled controls (n = 4). After 4 weeks of healing, animals were sacrificed and calvarial bone blocks were taken for histologic and histomorphometric analysis. Beside descriptive histologic evaluation, the percentage of new bone formation, connective tissue and residual graft were calculated. All parameters were statistically evaluated by Friedman Test and post hock Wilcoxon Singed Ranks Test with a significance of p < 0.05. Histology revealed active new bone formation peripherally with centrally located connective tissue, newly formed woven bone and well incorporated residual grafts in all treated defects. Control samples showed no bone bridging of defects. There was a significantly more new bone in autogeonous graft (53%) compared with β-tricalcium phosphate (30%), (p < 0.030) and control (7%), (p < 0.000) groups. A significant difference was also recorded between β-tricalcium phosphate and control groups (p < 0.008). In the present study on the rabbit grafting model with induced diabetes mellitus type I, the effective bone regeneration of critical bone defects was obtained using autogenous bone graft. [Projekat Ministarstva nauke Republike Srbije, br. 175021].


Interlinked bistable mechanisms generate robust mitotic transitions.
The transitions between phases of the cell cycle have evolved to be robust and switch-like, which ensures temporal separation of DNA replication, sister chromatid separation, and cell division. Mathematical models describing the biochemical interaction networks of cell cycle regulators attribute these properties to underlying bistable switches, which inherently generate robust, switch-like, and irreversible transitions between states. We have recently presented new mathematical models for two control systems that regulate crucial transitions in the cell cycle: mitotic entry and exit, 1 and the mitotic checkpoint. 2 Each of the two control systems is characterized by two interlinked bistable switches. In the case of mitotic checkpoint control, these switches are mutually activating, whereas in the case of the mitotic entry/exit network, the switches are mutually inhibiting. In this Perspective we describe the qualitative features of these regulatory motifs and show that having two interlinked bistable mechanisms further enhances robustness and irreversibility. We speculate that these network motifs also underlie other cell cycle transitions and cellular transitions between distinct biochemical states.


Fischer-Tropsch diesel emulsions stabilised by microfibrillated cellulose and nonionic surfactants.
Water-in-diesel emulsion fuels have been prepared with a combination of sorbitan monolaurate and glycerol monooleate as emulsifier and with microfibrillated cellulose (MFC) of different hydrophilic/hydrophobic character as stabilizer. The MFC was treated with either octadecylamine or poly(styrene-co-maleic anhydride), resulting in very hydrophobic fibrils. The most stable emulsion was achieved with a combination of hydrophilic (untreated) and hydrophobic MFC and only minute amounts of the stabilizer gave a pronounced effect. Even with the optimized formulation the lifetime of the emulsion was shorter than previously reported when a conventional polymeric stabilizer was used, however. The water drop sizes in the emulsions were determined by three methods: optical images, light scattering, and NMR diffusometry. All three methods gave water drops sizes of ca 2 μm. The NMR diffusometry indicated that besides the micrometer-sized emulsion drops a significant fraction of the water is present in small droplets of micelle size. The chemical exchange of water between these two populations of pools is believed to be the reason for the relatively low stability of the system.


Investigation Of Obesity-Related Mortality Rates In Delaware.
As Delaware's adult obesity crisis continues to be a leading public health concern, we evaluated Delaware's 1999-2014 vital records to examine the association between obesity and mortality. We used the Delaware population death records from the Centers for Disease Control and Prevention (CDC) WONDER database and the Delaware Health Statistics Center (DHSC). Together with the vital records, we incorporated Microsoft Excel, SAS (Statistical Analysis System) and GIS (geographic information system) tools to analyze obesity influences from county residence, economic status, education, gender, and race. Using the 15-year (1999-2014) time span with the CDC WONDER database, we observed a statistically significant 28.7% increase in the age-adjusted Delaware obesity-related mortality rates (where obesity was a contributory factor). Furthermore, obesity influenced death counts in all three Delaware counties (New Castle, Kent, and Sussex). Kent County experienced the largest increase (66.0%), followed by New Castle County (47.4%), and Sussex County (25.2%). The DHSC mortality rates for all leading causes of death from 2000 to 2011 indicated relatively stable mortality rates for Delaware. However, using CDC WONDER data, the Delaware mortality rate for obesity as a single underlying cause in 2011 was 56.9% higher than mortality rate in 2000.


Consumption of ready-to-eat cereals (RTEC) among Malaysian children and association with socio-demographics and nutrient intakes - findings from the MyBreakfast study.
Background: The association between different types of breakfast meals and nutrient intakes has been studied to a lesser extent. Objective: This study compared nutrient intakes at breakfast and throughout the day between Malaysian children who consumed ready-to-eat cereals (RTEC) and those who did not. Methods: Anthropometric and dietary data for 1955 children aged 6-12 years from the MyBreakfast study were used in the analysis. Results: Overall, 18% of the children consumed RTEC at breakfast on at least one of the recall days. RTEC consumption was associated with younger age, urban areas, higher income and education level of parents. Among consumers, RTEC contributed 10% and 15% to daily intakes of calcium and iron respectively and ≥20% to daily intakes of vitamin C, thiamin, riboflavin and niacin. RTEC consumers had significantly higher mean intakes of vitamin C, thiamin, riboflavin, niacin, calcium, iron and sugar but lower intakes of fat and sodium than non-RTEC consumers at breakfast and for the total day. Conclusion: Consumption of fortified RTEC at breakfast was associated with lower fat and sodium intakes and higher intakes of several micronutrients both at breakfast and for the total day. However, total sugar intakes appeared to be higher.


A single spinal lesion arising from an intradural meningioma contiguous with an extradural lymphoma.
The authors describe here a unique case of contiguous, synchronous meningioma and lymphoma in the spinal column. Both tumors were present at the same vertebral level, one intradural and the other extradural. A patient presented with bilateral leg pain, acute weakness, and sensory loss in the lower extremities. Magnetic resonance imaging revealed an intradural mass at T6-7 with ambiguous boundaries relative to the thecal sac and compressing the spinal cord. The patient underwent resection of the epidural and intradural mass at T6-7. Histopathology revealed the epidural specimen to be a double-hit B-cell lymphoma and the intradural mass to be a transitional meningioma. Postoperatively, the patient did well, with an immediate return of strength and sensation. A postoperative MR image showed complete resection of the intradural mass. The authors suggest that biopsy may be prudent in patients with known systemic lymphoma presenting with a spinal lesion that has unclear boundaries relative to the thecal sac prior to commencing radiation and chemotherapy.


Local ecological knowledge and scientific data reveal overexploitation by multigear artisanal fisheries in the southwestern Atlantic.
In the last decades, a number of studies based on historical records revealed the diversity loss in the oceans and human-induced changes to marine ecosystems. These studies have improved our understanding of the human impacts in the oceans. They also drew attention to the shifting baseline syndrome and the importance of assessing appropriate sources of data in order to build the most reliable environmental baseline. Here we amassed information from artisanal fishermen's local ecological knowledge, fisheries landing data and underwater visual census to assess the decline of fish species in Southeastern Brazil. Interviews with 214 fishermen from line, beach seine and spearfishing revealed a sharp decline in abundance of the bluefish Pomatomus saltatrix, the groupers Epinephelus marginatus, Mycteroperca acutirostris, M. bonaci and M. microlepis, and large parrotfishes in the past six decades. Fisheries landing data from a 16-year period support the decline of bluefish as pointed by fishermen's local knowledge, while underwater visual census campaigns show reductions in groupers' abundance and a sharp population decline of the Brazilian endemic parrotfish Scarus trispinosus. Despite the marked decline of these fisheries, younger and less experienced fishermen recognized fewer species as overexploited and fishing sites as depleted than older and more experienced fishermen, indicating the occurrence of the shifting baseline syndrome. Here we show both the decline of multigear fisheries catches - combining anecdotal and scientific data - as well as changes in environmental perceptions over generations of fishermen. Managing ocean resources requires looking into the past, and into traditional knowledge, bringing historical baselines to the present and improving public awareness.


Primary pulmonary botryomycosis: case report.
A case is presented of pulmonary botryomycosis in a 61-year-old man with a massive right-side pulmonary infiltrate which looked like a tumor (on X-ray). Microscopic examination of a transbronchial biopsy specimen revealed chronic suppurative inflammation, which did not regress despite intensive antibiotic therapy for a period of two months. Histological analysis of specimens taken during surgery for hemoptysis revealed pulmonary botryomycosis. The disease was diagnosed on the basis of characteristic eosinophilic granules in which the bacteria are surrounded by protein material (Splendore-Hoeppli phenomenon). Pulmonary actinomycosis was excluded. The case demonstrates that pulmonary botryomycosis can have the appearance of a mass which resembles pulmonary carcinoma on X-ray, and may also be mistaken for pulmonary actinomycosis. For this reason, pulmonary botryomycosis, although rare, should be excluded during differential diagnosis of hemoptysis or pulmonary infiltrates.


Serum 25-hydroxyvitamin D3 and D2 and non-clinical psychotic experiences in childhood.
Non-clinical psychotic experiences are common and distressing. It has been hypothesized that early life vitamin D deficiency may be a risk factor for psychosis-related outcomes, but it is not known if circulating concentrations of 25-hydroxyvitamin D (25(OH)D) during childhood are associated with psychosis-related outcomes or whether the two different forms of 25(OH)D, (25(OH)D(3) and 25(OH)D(2), have similar associations with psychosis-related outcomes. We investigated the association between serum 25(OH)D(3) and 25(OH)D(2) concentrations and psychotic experiences in a prospective birth cohort study. Serum 25(OH)D(3) and 25(OH)D(2) concentrations were measured at mean age 9.8 years and psychotic experiences assessed at mean age 12.8 years by a psychologist (N = 3182). Higher 25(OH)D(3) concentrations were associated with lower risk of definite psychotic experiences (adjusted odds ratio: OR (95% confidence interval: CI) 0.85 (0.75-0.95)). Higher concentrations of 25(OH)D(2) were associated with higher risk of suspected and definite psychotic experiences (adjusted odds ratio: OR (95% confidence interval: CI) 1.26 (1.11, 1.43)). Higher 25(OD)D(2) concentrations were also weakly associated with definite psychotic experiences (adjusted OR (95% CI) 1.17 (0.96, 1.43), though with wide confidence intervals including the null value. Our findings of an inverse association of 25(OH)D(3) with definite psychotic experiences is consistent with the hypothesis that vitamin D may protect against psychosis-related outcomes.


LEUCOCYTIC SECRETIONS.
In the present condition of the technique of cultivation of tissues, the only possible way of studying leucocytic secretions was to grow colonies of leucocytes in a medium of known properties and to examine the modifications of these properties under the influence of the living cells. The method was far from perfect, because the secretions were mixed with serum and accumulated for 48 hours in a medium where they probably underwent partial destruction. But an approximate idea of certain of the qualities of the secretions, although not of their quantity, could be derived from the experiments. In the fluids extracted from the cultures, we attempted to detect the presence of the leucocytic secretions through their physiological effects on homologous and foreign cells. Two kinds of substances were sought, those which act on homologous cells, and those which destroy foreign erythrocytes. The secretion by leucocytes of substances necessary to the nutrition of other cells was considered as probable long ago. Renaut thought that the main function of the white blood corpuscles was to bring to the fixed cells of the tissues the food material which they need. While the existence of physiological relations between leucocytes and tissue cells could be considered as almost certain, their nature had remained practically unknown. It was probable, however, that the substances secreted by leucocytes were analogous to the growth-activating and unstable substances which are found in embryonic tissues, leucocytes, and certain adult tissues. When connective tissue was aseptically inflamed, or when an aseptic peritoneal exudate contained many leucocytes, aqueous extracts of both connective tissue and peritoneal exudate were found to have acquired the power of stimulating cell proliferation. These experiments showed that leucocytes could bring to the tissues some activating substances. But it remained to be ascertained whether leucocytes, while they are alive, could secrete similar substances either spontaneously or under the stimulus of a foreign factor. Leucocytes are supposed to be, as is well know, the origin of the substances which protect the organism against infection. Although the problem of the origin of alexin and antibodies has been investigated by many experimenters, it is not yet completely solved. It was of interest, therefore, to ascertain whether leucocytic secretions could increase the natural hemolytic effect of hen serum on sheep or rabbit erythrocytes, and whether these secretions would become more active under the influence of a foreign protein. The substances which destroy foreign cells are not necessarily different from those which act on homologous cells. The word substance is used for simplicity of description and may be taken as meaning only a given property of an unknown substrate. A comparison was made of certain properties of sera extracted after 48 hours incubation from media containing leucocytes and from media containing no leucocytes. The serum from the leucocytic cultures was always found to be more favorable to the growth of homologous fibroblasts than the serum from the culture media incubated without leucocytes. The natural hemolytic power of the serum on sheep erythrocytes was found to be increased in about SO per cent of the experiments. In other experiments, we found that when two culture media free of cells were placed, one in an incubator at +38 degrees C. and the other in a refrigerator at +5 degrees C. for 48 hours, the serum from the incubated medium partly lost its hemolytic action on sheep or rabbit erythrocytes, while that from the refrigerated medium remained normal; at the same time, the inhibiting action of the incubated medium on homologous fibroblasts had increased very much. This effect of incubation indicates that certain unstable constituents of serum are destroyed by heat. Then the changes found in the properties of the serum from cultures of leucocytes are due to the fraction of the activating substances which has not been destroyed by incubation at 38 degrees C. A quantitative study of the secretions is, therefore, impossible with the present technique, which can furnish only qualitative indications about the substances set free by the leucocytes. We have ascertained also whether a medium containing leucocytes and kept in the refrigerator undergoes any change under the influence of the cells while they are in a condition of latent life. Gabritschewski dishes with and without leucocytes were placed in a refrigerator at a temperature of about +5 degrees C. After 48 hours, the hemolytic power on sheep erythrocytes of the serum from the leucocytic cultures had increased slightly and its inhibiting action on the growth of homologous fibroblasts had decreased. Then certain substances favorable to the growth of homologous cells and toxic for heterologous cells were diffused by the leucocytes into their medium. But the action of these substances was weaker than in the case of the cultures kept in the incubator. This experiment showed that leucocytes under certain conditions diffuse alexin or natural hemolysins which originate from them at the same time as the substances which activate homologous cells. In other experiments, although leucocytes were frozen at -10 degrees C., treated with distilled water, or extracted with saline solution, they did not yield any hemolysin. To summarize: Leucocytes, cultivated in plasma, always secreted substances which increased the rate of growth of homologous cells. Less frequently, they set free substances which hemolyzed foreign erythrocytes. The growth-promoting substances are analogous to those contained in embryonic tissues, and probably represent some of the foodstuffs brought to fixed tissue cells by leucocytes. They may possess the function of rejuvenating cells which have ceased to multiply when the cicatrization of a wound or the repair of a fracture requires a resumption of tissue activity. According to this hypothesis, the leucocytes brought to the surface of a wound by the process of inflammation would not only oppose bacterial invasion, but also bring to the tissues the material necessary to cell multiplication. It seems that in some cases regeneration is started by substances brought to the tissues by other cells. Loeb thinks that in Tubularia, when endodermic cells gather at the end where a new polyp is about to be formed, the substances given off by these cells are responsible for polyp formation.(6) There may be an analogy between this phenomenon and the secretion by leucocytes of growth-activating substances at the surface of a wound. If we assume that leucocytes in vivo set free their secretions in the blood stream, certain variations of the growth-inhibiting action of normal serum can be better understood. The rate of proliferation of homologous fibroblasts is much slower in the serum of an old chicken than in that of a young one. When the serum is heated at 56 degrees and 70 degrees C. for (1/2) hour, it becomes still more inhibiting. A substance favorable to cell activity has disappeared. It is therefore permissible to suppose that the growth-inhibiting power of serum and its variations are due to the antagonistic action of two substances, one growth-promoting and thermolabile, and the other growth-inhibiting and thermostable, the activating substance being always weaker in its effect than the inhibiting one. We know that activating substances can be extracted from embryonic tissue, from muscle and gland tissues, and from leucocytes of the adult animal, and that they are thermolabile and very unstable. Leucocytic secretions seem to have some of the properties of leucocytic extracts. It is probable that the activating substances which disappear from the heated serum are secreted by leucocytes and other cells. An increase of these secretions, then, would diminish the inhibiting action of serum on homologous fibroblasts. On the contrary, a decrease of the secretions in the serum would increase its inhibiting effect on homologous cells. The strong inhibiting action of serum in old age would be due partly to a reduction in the amount and activity of the substances secreted by leucocytes and tissue cells in the humors of the organism. Leucocytes also secreted in vitro substances which were toxic for foreign cells. Although the results were not constant, the serum appeared to become slightly more hemolytic for sheep or rabbit erythrocytes, under the influence of the leucocytes. The hemolysis of rabbit corpuscles by hen serum is due, according to Hyde,(9) to a complex sensitizer alexin, and not merely to alexin, as Bordet thought. When a foreign protein was added to the culture medium, the leucocytic secretions increased, as was shown by the action on homologous fibroblasts of sera taken from cultures of leucocytes with and without casein. The presence in the medium of the cultures of leucocytes of only 0.1 per 1,000 casein did not markedly modify the action of their serum on the proliferation of fibroblasts. When the concentration of casein in the leucocyte cultures reached 1 per 1,000, the growth of chicken fibroblasts in the serum extracted from the Gabritschewski dishes became more rapid. But there was no parallel increase of the hemolytic action of the serum upon sheep erythrocytes. We found that chicken serum containing 0.1 per 1,000 casein was barely toxic for homologous fibroblasts, while it became markedly inhibiting when the casein concentration reached 1 per 1,000. Probably, there is a relation between the toxicity of the medium, the increase of leucocytic secretions, and the time of the increase. The change brought about by casein in the equilibrium of the system composed of the cells and their medium determines the secretion by the leucocytes of substances which increase the activity of homologous cells and oppose the inhibiting effect of the foreign proteins. (ABSTRACT TRUNCATED)


Quantification of biological network perturbations for mechanistic insight and diagnostics using two-layer causal models.
High-throughput measurement technologies such as microarrays provide complex datasets reflecting mechanisms perturbed in an experiment, typically a treatment vs. control design. Analysis of these information rich data can be guided based on a priori knowledge, such as networks or set of related proteins or genes. Among those, cause-and-effect network models are becoming increasingly popular and more than eighty such models, describing processes involved in cell proliferation, cell fate, cell stress, and inflammation have already been published. A meaningful systems toxicology approach to study the response of a cell system, or organism, exposed to bio-active substances requires a quantitative measure of dose-response at network level, to go beyond the differential expression of single genes. We developed a method that quantifies network response in an interpretable manner. It fully exploits the (signed graph) structure of cause-and-effect networks models to integrate and mine transcriptomics measurements. The presented approach also enables the extraction of network-based signatures for predicting a phenotype of interest. The obtained signatures are coherent with the underlying network perturbation and can lead to more robust predictions across independent studies. The value of the various components of our mathematically coherent approach is substantiated using several in vivo and in vitro transcriptomics datasets. As a proof-of-principle, our methodology was applied to unravel mechanisms related to the efficacy of a specific anti-inflammatory drug in patients suffering from ulcerative colitis. A plausible mechanistic explanation of the unequal efficacy of the drug is provided. Moreover, by utilizing the underlying mechanisms, an accurate and robust network-based diagnosis was built to predict the response to the treatment. The presented framework efficiently integrates transcriptomics data and "cause and effect" network models to enable a mathematically coherent framework from quantitative impact assessment and data interpretation to patient stratification for diagnosis purposes.


Risk factors for late-life insomnia in a representative general practice sample.
Insomnia is widely reported and widely treated in general practice, yet relatively little research has focused on the natural history of the condition in primary care settings. As a result, there is at present little information to enable clinicians to assess insomnia risk, or anticipate outcomes in older general practice populations. To estimate, using 8-year longitudinal data, the risk of insomnia onset associated with selected health and lifestyle factors. Survivors from a nationally representative sample (n = 1042) of elderly people originally interviewed in 1985 were reassessed in 1989 (n = 690) and 1993 (n = 410). At the first follow up in 1989, 84 new cases of insomnia were identified (a weighted incidence rate per person per year at a risk of 3.1%; 95% CI = 2.7-3.5). In logistic regression analyses controlling for age and sex, the risk of insomnia onset was then assessed in relation to the selected factors. Three factors assessed in 1985 were significantly and independently related to incident insomnia: psychometric ratings consistent with depressed mood odds ratio (OR) = 4.41; 95% CI = 3.32-5.43); health index scores indicating lower physical health status (OR = 1.19; 95% CI = 1.06-1.31 per unit change in scale score); and moderate and low levels of physical activity (OR = 1.91 and 2.14; 95% CI = 1.91-3.62 and 2.14-3.64 respectively). However, although depressed mood represented a major risk factor, the most likely source of risk was physical rather than mental ill-health. Psychiatric, somatic and lifestyle factors significantly and independently increase the risk of insomnia in older general practice patients. In predicting incident sleep disturbance, these factors exceed in importance the age and sex of patients.


Coping with heat stress during match-play tennis: does an individualised hydration regimen enhance performance and recovery?
To determine whether an individualised hydration regimen reduces thermal, physiological and perceptual strain during match-play tennis in the heat, and minimises alterations in neuromuscular function and physical performance postmatch and into recovery. 10 men undertook two matches for an effective playing time (ball in play) of 20 min (∼113 min) in ∼37°C and ∼33% RH conditions. Participants consumed fluids ad libitum during the first match (HOT) and followed a hydration regimen (HYD) in the second match based on undertaking play euhydrated, standardising sodium intake and minimising body mass losses. HYD improved prematch urine specific gravity (1.013±0.006 vs 1.021±0.009 g/mL; p<0.05). Body mass losses (∼0.3%), fluid intake (∼2 L/h) and sweat rates (∼1.6 L/h) were similar between conditions. Core temperature was higher during the first 10 min of effective play in HOT (p<0.05), but increased similarly (∼39.3°C) on match completion. Heart rate was higher (∼11 bpm) throughout HOT (p<0.001). Thermal sensation was higher during the first 7.5 min of effective play in HOT (p<0.05). Postmatch knee extensor and plantar flexor strength losses, along with reductions in 15 m sprint time and repeated-sprint ability (p<0.05), were similar in both conditions, and were restored within 24 h. Both the hydration regimen and ad libitum fluid consumption allowed for minimal body mass losses (<1%). However, undertaking match-play in a euhydrated state attenuated thermal, physiological and perceptual strain. Maximal voluntary strength in the lower limbs and repeated-sprint ability deteriorated similarly in both conditions, but were restored within 24 h.


Developmentally regulated volatiles geosmin and 2-methylisoborneol attract a soil arthropod to Streptomyces bacteria promoting spore dispersal.
Volatile compounds emitted by bacteria are often sensed by other organisms as odours, but their ecological roles are poorly understood1,2. Well-known examples are the soil-smelling terpenoids geosmin and 2-methylisoborneol (2-MIB)3,4, which humans and various animals sense at extremely low concentrations5,6. The conservation of geosmin biosynthesis genes among virtually all species of Streptomyces bacteria (and genes for the biosynthesis of 2-MIB in about 50%)7,8, suggests that the volatiles provide a selective advantage for these soil microbes. We show, in the present study, that these volatiles mediate interactions of apparent mutual benefit between streptomycetes and springtails (Collembola). In field experiments, springtails were attracted to odours emitted by Streptomyces colonies. Geosmin and 2-MIB in these odours induce electrophysiological responses in the antennae of the model springtail Folsomia candida, which is also attracted to both compounds. Moreover, the genes for geosmin and 2-MIB synthases are under the direct control of sporulation-specific transcription factors, constraining emission of the odorants to sporulating colonies. F. candida feeds on the Streptomyces colonies and disseminates spores both via faecal pellets and through adherence to its hydrophobic cuticle. The results indicate that geosmin and 2-MIB production is an integral part of the sporulation process, completing the Streptomyces life cycle by facilitating dispersal of spores by soil arthropods.


Ratio of waist-to-calf circumference and carotid atherosclerosis in Korean patients with type 2 diabetes.
To investigate whether waist circumference (WC), calf circumference (CC), and waist-to-calf ratio (WCR) are associated with carotid atherosclerosis in patients with type 2 diabetes. This was an observational study performed in 3,694 Korean patients with type 2 diabetes. Anthropometric measures and carotid ultrasound were performed on each subject. Carotid atherosclerosis was defined as having a clearly isolated focal plaque or mean carotid intima-media thickness (CIMT) ≥1.1 mm. CIMT and the frequency of carotid atherosclerosis were higher with increasing WC quartiles and decreasing CC quartiles. There was an augmentative effect of CC and WC on the frequency of carotid atherosclerosis, which was dramatically higher in both the highest WC quartile and lowest CC quartile. However, except for the relationship between the quartile of CC with the frequency of carotid atherosclerosis in men, those associations disappeared after adjusting for potential confounders. In contrast, WCR was significantly related to CIMT (only in women) and carotid atherosclerosis, even after adjustment (adjusted odds ratio for carotid atherosclerosis for the highest quartile of WCR compared with the lowest quartile being 1.178 [95% CI 1.026-1.353] and 1.276 [1.053-1.545] in men and women, respectively). A low CC and high WC seems to be associated with a carotid atherosclerotic burden in Korean diabetic patients. In particular, compared with each circumference, WCR is independently associated with carotid atherosclerosis. However, the cross-sectional nature of the study limits conclusions regarding the direction or causality. Further longitudinal study is warranted in this and other ethnic groups.


The Structure of Mycobacterium tuberculosis CYP125: molecular basis for cholesterol binding in a P450 needed for host infection.
We report characterization and the crystal structure of the Mycobacterium tuberculosis cytochrome P450 CYP125, a P450 implicated in metabolism of host cholesterol and essential for establishing infection in mice. CYP125 is purified in a high spin form and undergoes both type I and II spectral shifts with various azole drugs. The 1.4-A structure of ligand-free CYP125 reveals a "letterbox" active site cavity of dimensions appropriate for entry of a polycyclic sterol. A mixture of hexa-coordinate and penta-coordinate states could be discerned, with water binding as the 6th heme-ligand linked to conformation of the I-helix Val(267) residue. Structures in complex with androstenedione and the antitubercular drug econazole reveal that binding of hydrophobic ligands occurs within the active site cavity. Due to the funnel shape of the active site near the heme, neither approaches the heme iron. A model of the cholesterol CYP125 complex shows that the alkyl side chain extends toward the heme iron, predicting hydroxylation of cholesterol C27. The alkyl chain is in close contact to Val(267), suggesting a substrate binding-induced low- to high-spin transition coupled to reorientation of the latter residue. Reconstitution of CYP125 activity with a redox partner system revealed exclusively cholesterol 27-hydroxylation, consistent with structure and modeling. This activity may enable catabolism of host cholesterol or generation of immunomodulatory compounds that enable persistence in the host. This study reveals structural and catalytic properties of a potential M. tuberculosis drug target enzyme, and the likely mode by which the host-derived substrate is bound and hydroxylated.


Restoration of Glucose-Stimulated Cdc42-Pak1 Activation and Insulin Secretion by a Selective Epac Activator in Type 2 Diabetic Human Islets.
Glucose metabolism stimulates cell division control protein 42 homolog (Cdc42)-p21-activated kinase (Pak1) activity and initiates filamentous actin (F-actin) cytoskeleton remodeling in pancreatic β-cells so that cytoplasmic secretory granules can translocate to the plasma membrane where insulin exocytosis occurs. Since glucose metabolism also generates cAMP in β-cells, the cross talk of cAMP signaling with Cdc42-Pak1 activation might be of fundamental importance to glucose-stimulated insulin secretion (GSIS). Previously, the type-2 isoform of cAMP-regulated guanine nucleotide exchange factor 2 (Epac2) was established to mediate a potentiation of GSIS by cAMP-elevating agents. Here we report that nondiabetic human islets and INS-1 832/13 β-cells treated with the selective Epac activator 8-pCPT-2'-O-Me-cAMP-AM exhibited Cdc42-Pak1 activation at 1 mmol/L glucose and that the magnitude of this effect was equivalent to that which was measured during stimulation with 20 mmol/L glucose in the absence of 8-pCPT-2'-O-Me-cAMP-AM. Conversely, the cAMP antagonist Rp-8-Br-cAMPS-pAB prevented glucose-stimulated Cdc42-Pak1 activation, thereby blocking GSIS while also increasing cellular F-actin content. Although islets from donors with type 2 diabetes had profound defects in glucose-stimulated Cdc42-Pak1 activation and insulin secretion, these defects were rescued by the Epac activator so that GSIS was restored. Collectively, these findings indicate an unexpected role for cAMP as a permissive or direct metabolic coupling factor in support of GSIS that is Epac2 and Cdc42-Pak1 regulated.


Extracellular matrix of the central nervous system: from neglect to challenge.
The basic concept, that specialized extracellular matrices rich in hyaluronan, chondroitin sulfate proteoglycans (aggrecan, versican, neurocan, brevican, phosphacan), link proteins and tenascins (Tn-R, Tn-C) can regulate cellular migration and axonal growth and thus, actively participate in the development and maturation of the nervous system, has in recent years gained rapidly expanding experimental support. The swift assembly and remodeling of these matrices have been associated with axonal guidance functions in the periphery and with the structural stabilization of myelinated fiber tracts and synaptic contacts in the maturating central nervous system. Particular interest has been focused on the putative role of chondroitin sulfate proteoglycans in suppressing central nervous system regeneration after lesions. The axon growth inhibitory properties of several of these chondroitin sulfate proteoglycans in vitro, and the partial recovery of structural plasticity in lesioned animals treated with chondroitin sulfate degrading enzymes in vivo have significantly contributed to the increased awareness of this long time neglected structure.


Local Melting of Gold Thin Films by Femtosecond Laser-Interference Processing to Generate Nanoparticles on a Source Target.
Shape- and size-controlled metallic nanoparticles are very important due to their wide applicability. Such particles have been fabricated by chemosynthesis, chemical-vapor deposition, and laser processing. Pulsed-laser deposition and laser-induced dot transfer use ejections of molten layers and solid-liquid-solid processes to fabricate nanoparticles with a radius of some tens to hundreds of nm. In these processes, the nanoparticles are collected on an acceptor substrate. In the present experiment, we used laser-interference processing of gold thin films, which deposited nanoparticles directly on the source thin film with a yield ratio. A typical nanoparticle had roundness fr=0.99 and circularity fcirc=0.869, and the radius was controllable between 69 and 188 nm. The smallest radius was 82 nm on average, and the smallest standard deviation was 3 nm. The simplicity, high yield, and ideal features of the nanoparticles produced by this method will broaden the range of applications of nanoparticles in fields such as plasmonics.


Evaluation of the provision of helicopter emergency medical services in Europe.
Helicopter emergency medical services (HEMS) are a useful means of reducing inequity of access to specialist emergency care. The aim of this study was to evaluate the variations in HEMS provision across Europe, in order to inform the further development of emergency care systems. This is a survey of primary HEMS in the 32 countries of the European Economic Area and Switzerland. Information was gathered through internet searches (May to September 2016), and by emailing service providers, requesting verification and completion of data (September 2016 to July 2017). HEMS provision was calculated as helicopters per million population and per 1000 km2 land area, by day and by night, and per US$10 billion of gross domestic product (GDP), for each country. In 2016, the smallest and least prosperous countries had no dedicated HEMS provision. Luxembourg had the highest number of helicopters by area and population, day and night. Alpine countries had high daytime HEMS coverage and Scandinavia had good night-time coverage. Most helicopters carried a doctor. Funding of services varied from public to charitable and private. Most services performed both primary (from the scene) and secondary (interfacility) missions. Within Europe, there is a large variation in the number of helicopters available for emergency care, regardless of whether assessed with reference to population, land area or GDP. Funding of services varied, and did not seem to be clearly related to the availability of HEMS.


Evidence for a major gene underlying bone size variation in the Chinese.
Osteoporosis is a major public health problem defined as a loss of bone strength, of which bone size is an important determinant. In the present study, familial correlation and segregation analyses for the spine and hip bone sizes were performed for the first time in a Chinese sample composed of 393 nuclear families with a total of 1,193 individuals. The results indicate a major gene of codominant inheritance for spine bone size; however, there is no evidence of a major gene influencing hip bone size. Significant familial residual effects are found for both traits, suggesting their polygenic inheritance. Heritability estimates (+/-SE) for spine and hip bone size were 0.62 (0.13) and 0.59 (0.12), respectively. Sex and age differences in genotype-specific average bone size were observed. Compared with our previous study on bone mineral density (BMD) in the same population, this study suggests that genetic determination of bone size may be different from that of BMD, and thus studying bone size as one surrogate phenotype for osteoporotic fractures may be necessary.


Systemic inflammatory response does not correlate with acute lung injury associated with mechanical ventilation strategies in normal lungs.
Mechanical ventilation (MV) can lead to ventilator-induced lung injury secondary to trauma and associated increases in pulmonary inflammatory cytokines. There is controversy regarding the associated systemic inflammatory response. In this report, we demonstrate the effects of MV on systemic inflammation. This report is part of a previously published study (Hong et al. Anesth Analg 2010;110:1652-60). Female pigs were randomized into 3 groups. Group H-Vt/3 was ventilated with a tidal volume (Vt) of 15 mL/kg predicted body weight (PBW)/positive end-expiratory pressure (PEEP) of 3 cm H(2)O; group L-Vt/3 with a Vt of 6 mL/kg PBW/PEEP of 3 cm H2O; and group L-Vt/10 with a Vt of 6 mL/kg PBW/PEEP of 10 cm H(2)O, for 8 hours. Each group had 6 subjects (n = 6). Prelung and postlung sera were analyzed for inflammatory markers. Hemodynamics, airway mechanics, and arterial blood gases were monitored. There were no significant differences in systemic cytokines among groups. There were similar trends of serum inflammatory markers in all subjects. This is in contrast to findings previously published demonstrating increases in inflammatory mediators in bronchoalveolar lavage. Systemic inflammatory markers did not correlate with lung injury associated with MV.


Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe Mendelian disease gene.
Determination of variant pathogenicity represents a major challenge in the era of high-throughput sequencing. Erroneous categorization may result if variants affect genes that are in fact dispensable. We demonstrate that this also applies to rare, apparently unambiguous truncating mutations of an established disease gene. By whole-exome sequencing (WES) in a consanguineous family with congenital non-syndromic deafness, we unexpectedly identified a homozygous nonsense variant, p.Arg1066*, in AHI1, a gene associated with Joubert syndrome (JBTS), a severe recessive ciliopathy. None of four homozygotes expressed any signs of JBTS, and one of them had normal hearing, which also ruled out p.Arg1066* as the cause of deafness. Homozygosity mapping and WES in the only other reported JBTS family with a homozygous C-terminal truncation (p.Trp1088Leufs*16) confirmed AHI1 as disease gene, but based on a more N-terminal missense mutation impairing WD40-repeat formation. Morpholinos against N-terminal zebrafish Ahi1, orthologous to where human mutations cluster, produced a ciliopathy, but targeting near human p.Arg1066 and p.Trp1088 did not. Most AHI1 mutations in JBTS patients result in truncated protein lacking WD40-repeats and the SH3 domain; disease was hitherto attributed to loss of these protein interaction modules. Our findings indicate that normal development does not require the C-terminal SH3 domain. This has far-reaching implications, considering that variants like p.Glu984* identified by preconception screening ('Kingsmore panel') do not necessarily indicate JBTS carriership. Genomes of individuals with consanguineous background are enriched for homozygous variants that may unmask dispensable regions of disease genes and unrecognized false positives in diagnostic large-scale sequencing and preconception carrier screening.


Influence of computer-aided detection on performance of screening mammography.
Computer-aided detection identifies suspicious findings on mammograms to assist radiologists. Since the Food and Drug Administration approved the technology in 1998, it has been disseminated into practice, but its effect on the accuracy of interpretation is unclear. We determined the association between the use of computer-aided detection at mammography facilities and the performance of screening mammography from 1998 through 2002 at 43 facilities in three states. We had complete data for 222,135 women (a total of 429,345 mammograms), including 2351 women who received a diagnosis of breast cancer within 1 year after screening. We calculated the specificity, sensitivity, and positive predictive value of screening mammography with and without computer-aided detection, as well as the rates of biopsy and breast-cancer detection and the overall accuracy, measured as the area under the receiver-operating-characteristic (ROC) curve. Seven facilities (16%) implemented computer-aided detection during the study period. Diagnostic specificity decreased from 90.2% before implementation to 87.2% after implementation (P<0.001), the positive predictive value decreased from 4.1% to 3.2% (P=0.01), and the rate of biopsy increased by 19.7% (P<0.001). The increase in sensitivity from 80.4% before implementation of computer-aided detection to 84.0% after implementation was not significant (P=0.32). The change in the cancer-detection rate (including invasive breast cancers and ductal carcinomas in situ) was not significant (4.15 cases per 1000 screening mammograms before implementation and 4.20 cases after implementation, P=0.90). Analyses of data from all 43 facilities showed that the use of computer-aided detection was associated with significantly lower overall accuracy than was nonuse (area under the ROC curve, 0.871 vs. 0.919; P=0.005). The use of computer-aided detection is associated with reduced accuracy of interpretation of screening mammograms. The increased rate of biopsy with the use of computer-aided detection is not clearly associated with improved detection of invasive breast cancer.


Optimal compression plane for efficient video coding.
All existing video coding standards developed so far deem video as a sequence of natural frames (formed in the XY plane), and treat spatial redundancy (redundancy along X and Y directions) and temporal redundancy (redundancy along T direction) differently and separately. In this paper, we investigate into a new compression (redundancy reduction) method for video in which the frames are allowed to be formed in a non-XY plane. We are to exploit fuller extent of video redundancy, and propose an adaptive optimal compression plane determination process to be used as a preprocessing step prior to any standard video coding scheme. The essence of the scheme is to form the frames in the plane formed by two axes (among X, Y, and T) corresponding to signal correlation evaluation, which enables better prediction (therefore better compression). In spite of the simplicity of the proposed method, it can be used for both lossless and lossy compression, and with and without interframe prediction. Extensive experimental results show that the new coding method improves the performance of the video coding for a number of coding methods (inclusive of lossless and near-lossless Motion JPEG-LS, Motion JPEG, Motion JPG2K, H.264 intraonly profile, and H.264) and videos with different visual content.


Comparative study of exome copy number variation estimation tools using array comparative genomic hybridization as control.
Exome sequencing using next-generation sequencing technologies is a cost-efficient approach to selectively sequencing coding regions of the human genome for detection of disease variants. One of the lesser known yet important applications of exome sequencing data is to identify copy number variation (CNV). There have been many exome CNV tools developed over the last few years, but the performance and accuracy of these programs have not been thoroughly evaluated. In this study, we systematically compared four popular exome CNV tools (CoNIFER, cn.MOPS, exomeCopy, and ExomeDepth) and evaluated their effectiveness against array comparative genome hybridization (array CGH) platforms. We found that exome CNV tools are capable of identifying CNVs, but they can have problems such as high false positives, low sensitivity, and duplication bias when compared to array CGH platforms. While exome CNV tools do serve their purpose for data mining, careful evaluation and additional validation is highly recommended. Based on all these results, we recommend CoNIFER and cn.MOPs for nonpaired exome CNV detection over the other two tools due to a low false-positive rate, although none of the four exome CNV tools performed at an outstanding level when compared to array CGH.


Influence of perfusate pH on the postischemic recovery of cardiac contractile function: involvement of sodium-hydrogen exchange.
During reperfusion with pH 7.2 media after 55 min of ischemia, the recovery of developed tension (DT) and the maximal resting tension (RT) of the isolated right ventricular wall of rats were 58.8 +/- 6.5 and 201 +/- 20%, respectively, of the preischemic values. DT and RT in the ventricular wall perfused with pH 7.9 media for 6 min during reperfusion were 40 +/- 5.9 and 285 +/- 13%, respectively, of the preischemic values (P less than .05 vs. pH 7.2 group). The Na(+)-H+ exchange inhibitor, 5-(N,N-dimethyl)amiloride (DMA), effectively antagonized the detrimental effect of pH 7.9 media. A pH 6.5 media inhibited DT recovery and the rise in RT in the first 6 min of reperfusion. Subsequent reperfusion with pH 7.2 media resulted in cardiac dysfunction similar to that observed when reperfused at pH 7.2 only. Cellular Na+ and Ca++ were significantly elevated after 6 min of reperfusion at pH 7.2. Na+ and Ca++ levels were increased further if reperfusion was carried out at pH 7.9. Inclusion of 20 microM DMA during reperfusion at 7.9 significantly reduced cellular Na+ and Ca++. Creatine phosphokinase activity in the coronary effluent rose significantly during reperfusion at pH 7.2 and this was exacerbated if the reperfusion pH was 7.9. DMA treatment during reperfusion could significantly inhibit this elevation. The data lend further support for an important role of Na(+)-H+ exchange in the development of ischemia-reperfusion injury.


Whitmore's disease: an uncommon urological presentation.
The incidence of prostatic abscesses has much decreased in the antibiotic era. We present an uncommon cause of prostatic abscess secondary to melioidosis, also known as Whitmore's disease or pseudoglanders. The disease is endemic in South East Asia and Australia. Although India is considered endemic for Burkholderia pseudomallei, the causative organism of melioidosis, not many cases have been reported. Most of the reported cases from India are from the South-West coastal regions of Kerala and Karnataka, Vellore, West Bengal and Bihar. Our index patient was successfully treated with parenteral antibiotics and endoscopic deroofing of the abscess.


A human tumor necrosis factor p75 receptor agonist stimulates in vitro T cell proliferation but does not produce inflammation or shock in the baboon.
Tumor necrosis factor (TNF) is a potentially useful adjunct to anticancer therapies. However, the clinical utility of TNF has been limited by generalized toxicity and hypotension. Recently, studies have begun to dissect the individual proinflammatory and immunologic responses that result from TNF binding to its two cellular receptors, p55 and p75, in an attempt to develop TNF receptor agonists with reduced systemic toxicity. To evaluate a p75 receptor selective TNF mutant (p75TNF), TNF and p75TNF were administered to healthy anesthetized baboons. Intravenous infusion of the p75TNF produced none of the hemodynamic changes seen after the infusion of TNF. Infusion of p75TNF also failed to induce the plasma appearance of interleukins 6 and 8. However, p75TNF enhanced in vitro baboon thymocyte proliferation to concanavalin A, and infusion of p75TNF resulted in increased soluble p55 and p75 receptor plasma concentrations. Local skin necrosis and tissue neutrophil infiltration were seen after subcutaneous injections of TNF and p55TNF. Subcutaneous injection of p75TNF did not result in skin necrosis but did result in a modest dermal infiltration of lymphocytes and macrophages. The findings suggest that p75TNF may stimulate T cell proliferation without the systemic and local toxicity seen with TNF.


Advances in the treatment of mild asthma: recent evidence.
Asthma affects about 300 million individuals worldwide. Although most patients have mild disease, the majority of them do not have good control and are at risk of exacerbations. Poor compliance with regular maintenance treatment is a considerable problem and is believed to be the main reason for poor control in asthma. In patients with moderate to severe asthma, maintenance and as-needed treatment with one inhaler containing an inhaled corticosteroid (ICS) and the long-acting inhaled β2-agonist formoterol has been proved effective in reducing the risk of severe exacerbations. Recently, the results of 2 large double-blind randomized trials assessing the use of as-needed budesonide/formoterol in patients with mild asthma, who had indications for a regular controller treatment, were published. In comparison with as-needed terbutaline treatment, as-needed budesonide/formoterol treatment improved symptom control and reduced the risk of exacerbations. In comparison with regular ICS treatment, exacerbation rates were similar, but regular treatment schedule was associated with better asthma control (despite a higher cumulative ICS dose). The results of these trials have shown that as-needed budesonide/formoterol therapy has acceptable efficacy in mild asthma and may be viewed as a therapeutic option for these patients. As-needed treatment may be preferred by patients who fear the side effects of ICS treatment or by those who experience difficulty in following a fixed-dose regimen. Patients with mild asthma wishing to achieve optimal asthma control may prefer regular maintenance treatment with an ICS.


Concentration measurements in ionic liquid-water mixtures by mid-infrared spectroscopy and indirect hard modeling.
An analytical method for the quantitative characterization of binary mixtures of water and ionic liquids (ILs) is presented. Mid-infrared (mid-IR) spectroscopy in combination with indirect hard modeling (IHM) is employed to quantify the water content in 1-butyl-3-methylimidazolium chloride (BMIMCl), 1,3-dimethylimidazolium dimethylphosphate (DMIMDMP), and 1-ethyl-3-methylimidazolium acetate (EMIMAc). Despite significant nonlinear shifts of the spectral bands, a good spectral fit with calibration errors of less than 2.3 wt % can be achieved almost over the whole concentration range. A profound analysis of the spectral models including peak assignment substantiates the physico-chemical foundation of the spectral models. Furthermore, the shift of peak functions in the spectral models is shown to provide a measure of molecular interaction in IL-water mixtures, which can also be utilized quantitatively. The vibrational bands of the water dipole reveal differences in the strength of hydrogen bonding with water in the IL studied. These properties of the spectral hard models demonstrate their quantitative analytical potential and set the stage for multiway calibration in comprehensive reaction monitoring in these highly interacting mixtures of IL and water.


SMG7 is a 14-3-3-like adaptor in the nonsense-mediated mRNA decay pathway.
In metazoa, regulation of the phosphorylation state of UPF1 is crucial for nonsense-mediated mRNA decay (NMD), a process by which aberrant mRNAs containing nonsense mutations are degraded. UPF1 is targeted for dephosphorylation by three related proteins, SMG5, SMG6, and SMG7. We report here the crystal structure of the N-terminal domain of SMG7. The structure reveals that SMG7 contains a 14-3-3-like domain. Residues that bind phosphoserine-containing peptides in 14-3-3 are conserved at the equivalent positions in SMG7. Mutation of these residues impairs UPF1 binding to SMG7 in vitro and UPF1 recruitment to cytoplasmic mRNA decay foci in vivo, suggesting that SMG7 acts as an adaptor in targeting mRNAs associated with phosphorylated UPF1 for degradation. The 14-3-3 site of SMG7 is conserved in SMG5 and SMG6. These data also imply that the homologous human Est1 might have a 14-3-3 function at telomeres, and that phosphorylation events may be important for telomerase regulation.


Development of a molecularly imprinted solid-phase extraction sorbent for the selective extraction of telmisartan from human urine.
A novel molecularly imprinted solid-phase extraction with spectrofluorimetry method has been developed for the selective extraction of telmisartan from human urine. Molecularly imprinted polymers were prepared by a noncovalent imprinting approach through UV-radical polymerization using telmisartan as a template molecule, 2-dimethylamino ethyl methacrylate as a functional monomer, ethylene glycol dimethacrylate as a cross-linker, N,N-azobisisobutyronitrile as an initiator, chloroform as a porogen. Molecularly imprinted polymers and nonimprinted control polymer sorbents were dry-packed into solid-phase extraction cartridges, and eluates from cartridges were analyzed using a spectrofluorimeter. Limit of detection and limit of quantitation values were 11.0 and 36.0 ng/mL, respectively. A very high imprinting factor (16.1) was achieved and recovery values for the telmisartan spiked in human urine were in the range of 76.1-79.1%. In addition, relatively low within-day (0.14-1.6%) and between-day (0.11-1.31%) precision values were obtained. Valsartan was used to evaluate the selectivity of sorbent as well. As a result, a sensitive, selective, and simple molecularly imprinted solid-phase extraction with spectrofluorimetry method has been developed and successfully applied to the direct determination telmisartan in human urine.


Ribavirin revisited in the era of direct-acting antiviral therapy for hepatitis C virus infection.
Over the past two decades, ribavirin has been an integral component of treatment for hepatitis C virus (HCV) infection, where it has been shown to improve the efficacy of (pegylated) interferon. However, because of treatment-limiting side effects and its additive toxicity with interferon, the search for interferon- and ribavirin-free regimens has been underway. The recent approvals of all-oral direct acting antivirals (DAAs) have revolutionized the HCV therapeutic landscape, and initially it was expected that the role of ribavirin with DAA regimens would be eliminated. On the contrary, what we have witnessed is that ribavirin retains an important role in the optimal treatment of some subgroups of patients, particularly those that historically have been considered the most difficult to cure. Fortunately, it has also been recognized that the safety profile of ribavirin is improved when co-administered with all-oral DAA combinations in the absence of interferon. Despite the antiviral mechanism of action of ribavirin being poorly understood, we now have a range of novel insights into the potential role of ribavirin in all-oral DAA HCV treatment and greater insight into the antiviral mechanism by which it continues to provide clinical benefit for defined patient groups.


Risk models for recurrence and survival after kidney cancer: a systematic review.
To systematically identify and compare the performance of prognostic models providing estimates of survival or recurrence of localized renal cell cancer (RCC) in patients treated with surgery with curative intent. We performed a systematic review (PROSPERO CRD42019162349). We searched Medline, EMBASE and the Cochrane Library from 1 January 2000 to 12 December 2019 to identify studies reporting the performance of one or more prognostic model(s) that predict recurrence-free survival (RFS), cancer-specific survival (CSS) or overall survival (OS) in patients who have undergone surgical resection for localized RCC. For each outcome we summarized the discrimination of each model using the C-statistic and performed multivariate random-effects meta-analysis of the logit transformed C-statistic to rank the models. Of a total of 13 549 articles, 57 included data on the performance of 22 models in external populations. C-statistics ranged from 0.59 to 0.90. Several risk models were assessed in two or more external populations and had similarly high discriminative performance. For RFS, these were the Sorbellini, Karakiewicz, Leibovich and Kattan models, with the UCLA Integrated Staging System model also having similar performance in European/US populations. All had C-statistics ≥0.75 in at least half of the validations. For CSS, they the models with the highest discriminative performance in two or more external validation studies were the Zisman, Stage, Size, Grade and Necrosis (SSIGN), Karakiewicz, Leibovich and Sorbellini models (C-statistic ≥0.80 in at least half of the validations), and for OS they were the Leibovich, Karakiewicz, Sorbellini and SSIGN models. For all outcomes, the models based on clinical features at presentation alone (Cindolo and Yaycioglu) had consistently lower discrimination. Estimates of model calibration were only infrequently included but most underestimated survival. Several models had good discriminative ability, with there being no single 'best' model. The choice from these models for each setting should be informed by both the comparative performance and availability of factors included in the models. All would need recalibration if used to provide absolute survival estimates.


Tyrosine supplementation for phenylketonuria.
Phenylketonuria is an inherited disease for which the main treatment is the dietary restriction of the amino acid phenylalanine. The diet has to be initiated in the neonatal period to prevent or reduce mental handicap. However, the diet is very restrictive and unpalatable and can be difficult to follow. A deficiency of the amino acid tyrosine has been suggested as a cause of some of the neuropsychological problems exhibited in phenylketonuria. Therefore, this review aims to assess the efficacy of tyrosine supplementation for phenylketonuria. To assess the effects of tyrosine supplementation alongside or instead of a phenylalanine-restricted diet for people with phenylketonuria, who commenced on diet at diagnosis and either continued on the diet or relaxed the diet later in life. To assess the evidence that tyrosine supplementation alongside, or instead of a phenylalanine-restricted diet improves intelligence, neuropsychological performance, growth and nutritional status, mortality rate and quality of life. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register which is comprised of references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Additional studies were identified from handsearches of the Journal of Inherited Metabolic Disease (from inception in 1978 to 1998). The manufacturers of prescribable dietary products used in the treatment of phenylketonuria were also contacted for further references.Date of the most recent search of the Group's Inborn Errors of Metabolism Trials Register: 09 June 2010. All randomised or quasi-randomised trials investigating the use of tyrosine supplementation versus placebo in people with phenylketonuria in addition to, or instead of, a phenylalanine-restricted diet. People treated for maternal phenylketonuria were excluded. Two authors independently assessed the trial eligibility, methodological quality and extracted the data. Six trials were found, of which three trials reporting the results of a total of 56 participants, were suitable for inclusion in the review. The blood tyrosine concentrations were significantly higher in the participants receiving tyrosine supplements than those in the placebo group, mean difference 23.46 (95% confidence interval 12.87 to 34.05). No significant differences were found between any of the other outcomes measured. From the available evidence no recommendations can be made about whether tyrosine supplementation should be introduced into routine clinical practice. Further randomised controlled studies are required to provide more evidence.


Reduced fertility in female mice exposed transplacentally to diethylstilbestrol (DES).
Prenatal exposure to diethylstilbestrol (DES), a synthetic estrogen, has been associated with a low incidence of vaginal adenocarcinoma as well as a variety of more numerous benign abnormalities in the reproductive tract of human beings and experimental animals. For the purpose of assessing the effects of prenatal exposure to DES on postnatal reproduction tract function, timed pregnant CD-1 mice were treated subcutaneously with doses of DES ranging from 0.01 to 100 microgram/kg/day on days 9 through 16 gestation. The fertility of the female offspring was determined postnatally by a repetitive forced breeding technique. The most striking effect observed was a dose-related decrease in reproductive capacity ranging from minimal subfertility at the lower DES doses to a high frequency of total sterility at the highest DES doses. Reduced reproductive capacity appeared to be a reflection of both a decrease in the total number of litters and smaller litter sizes. A major component of the sterility seen in those females given higher doses of DES was oviductal/ovarian, since the number of ova recovered from the oviductal ampullae after induced ovulation was less than 30% that of controls. In addition, structural abnormalities of the oviduct, uterus, cervix, and vagina were observed, and contributed to infertility. These data suggest that in utero exposure to DES results in permanent impairment of female mouse reproductive capacity. Recent reports of altered pregnancy outcomes in young women who were exposed in utero to DES demonstrate the clinical importance of the findings obtained in mice.


The social, physical and economic impact of lymphedema and hydrocele: a matched cross-sectional study in rural Nigeria.
Lymphatic filariasis (LF) is a mosquito-borne parasitic disease and a major cause of disability worldwide. To effectively plan morbidity management programmes, it is important to estimate disease burden and evaluate the needs of patients. This study aimed to estimate patient numbers and characterise the physical, social and economic impact of LF in in rural Nigeria. This is a matched cross-sectional study which identified lymphedema and hydrocele patients with the help of district health officers and community-directed distributors of mass drug administration programmes. A total of 52 cases were identified and matched to 52 apparently disease-free controls, selected from the same communities and matched by age and sex. Questionnaires and narrative interviews were used to characterise the physical, social and economic impact of lymphedema and hydrocele. Forty-eight cases with various stages of lower limb lymphedema, and 4 with hydrocele were identified. 40% of all cases reported feeling stigma and were 36 times (95% CI: 5.18-1564.69) more likely to avoid forms of social participation. Although most cases engaged in some form of income-generating activity, these were low paid employment, and on average cases spent significantly less time than controls working. The economic effects of lower income were exacerbated by increased healthcare spending, as cases were 86 times (95% CI: 17.48-874.90) more likely to spend over US $125 on their last healthcare payment. This study highlights the importance of patient-search as a means of estimating the burden of LF morbidity in rural settings. Findings from this work also confirm that LF causes considerable psychosocial and economic suffering, all of which adversely affect the mental health of patients. It is therefore important to incorporate mental health care as a major component of morbidity management programmes.


Are managed care plans organizing for quality?
This article examines the degree to which managed care organizations (MCOs) are reorganizing to take responsibility for the quality of care and service they provide. Specifically, factors prompting plans to focus on quality improvement (QI) and how they may be building the capacity to improve quality are considered. The authors' analysis is based on executive interviews with the plan medical directors, QI directors, and chief executive officers (CEOs) in a sample of 24 health plans. The overall response rate was 58.3 percent (medical director = 62.5 percent, QI director = 79.2 percent, CEO = 33.3 percent). The authors queried respondents about (1) perceived drivers and obstacles to the development of an effective QI program, (2) plan organizational structure for QI, and (3) technical capacities for data collection, management, and performance measurement. The results suggest that MCOs are responding to outside pressures to engage in QI. They are reorganizing their management structures and more slowly and tentatively are building technical capacity for QI.


An ensemble of specifically targeted proteins stabilizes cortical microtubules in the human parasite Toxoplasma gondii.
Although all microtubules within a single cell are polymerized from virtually identical subunits, different microtubule populations carry out specialized and diverse functions, including directional transport, force generation, and cellular morphogenesis. Functional differentiation requires specific targeting of associated proteins to subsets or even subregions of these polymers. The cytoskeleton of Toxoplasma gondii, an important human parasite, contains at least five distinct tubulin-based structures. In this work, we define the differential localization of proteins along the cortical microtubules of T. gondii, established during daughter biogenesis and regulated by protein expression and exchange. These proteins distinguish cortical from mitotic spindle microtubules, even though the assembly of these subsets is contemporaneous during cell division. Finally, proteins associated with cortical microtubules collectively protect the stability of the polymers with a remarkable degree of functional redundancy.


Characterization of the purified hyaluronan synthase from Streptococcus equisimilis.
Hyaluronan synthase (HAS) utilizes UDP-GlcUA and UDP-GlcNAc in the presence of Mg(2+) to form the GAG hyaluronan (HA). The purified HAS from Streptococcus equisimilis (seHAS) shows high fidelity in that it only polymerizes the native substrates, UDP-GlcNAc and UDP-GlcUA. However, other uridinyl nucleotides and UDP-sugars inhibited enzyme activity, including UDP-GalNAc, UDP-Glc, UDP-Gal, UDP-GalUA, UMP, UDP, and UTP. Purified seHAS was approximately 40% more active in 25 mM, compared to 50 mM, PO(4) in the presence of either 50 mM NaCl or KCl, and displayed a slight preference for KCl over NaCl. The pH profile was surprisingly broad, with an effective range of pH 6.5-11.5 and the optimum between pH 9 and 10. SeHAS displayed two apparent pK(a) values at pH 6.6 and 11.8. As the pH was increased from approximately 6.5, both K(m) and V(max) increased until pH approximately 10.5, above which the kinetic constants gradually declined. Nonetheless, the overall catalytic constant (120/s) was essentially unchanged from pH 6.5 to 10.5. The enzyme is temperature labile, but more stable in the presence of substrate and cardiolipin. Purified seHAS requires exogenous cardiolipin for activity and is very sensitive to the fatty acyl composition of the phospholipid. The enzyme was inactive or highly activated by synthetic cardiolipins containing, respectively, C14:0 or C18:1(Delta9) fatty acids. The apparent E(act) for HA synthesis is 40 kJ (9.5 kcal/mol) disaccharide. Increasing the viscosity by increasing concentrations of PEG, ethylene glycol, glycerol, or sucrose inhibited seHAS activity. For PEGs, the extent of inhibition was proportional to their molecular mass. PEGs with average masses of 2.7, 11.7, and 20 kg/mol caused 50% inhibition of V(max) at 21, 6.5, and 3.5 mM, respectively. The apparent K(i) values for ethylene glycol, glycerol, and sucrose were, respectively, 4.5, 3.3, and 1.2 mM.


Extraction of force-chain network architecture in granular materials using community detection.
Force chains form heterogeneous physical structures that can constrain the mechanical stability and acoustic transmission of granular media. However, despite their relevance for predicting bulk properties of materials, there is no agreement on a quantitative description of force chains. Consequently, it is difficult to compare the force-chain structures in different materials or experimental conditions. To address this challenge, we treat granular materials as spatially-embedded networks in which the nodes (particles) are connected by weighted edges that represent contact forces. We use techniques from community detection, which is a type of clustering, to find sets of closely connected particles. By using a geographical null model that is constrained by the particles' contact network, we extract chain-like structures that are reminiscent of force chains. We propose three diagnostics to measure these chain-like structures, and we demonstrate the utility of these diagnostics for identifying and characterizing classes of force-chain network architectures in various materials. To illustrate our methods, we describe how force-chain architecture depends on pressure for two very different types of packings: (1) ones derived from laboratory experiments and (2) ones derived from idealized, numerically-generated frictionless packings. By resolving individual force chains, we quantify statistical properties of force-chain shape and strength, which are potentially crucial diagnostics of bulk properties (including material stability). These methods facilitate quantitative comparisons between different particulate systems, regardless of whether they are measured experimentally or numerically.


A prospective study of 708 form-stable silicone gel breast implants.
Form-stable silicone gel breast implants represent the fifth generation of silicone gel augmentation devices. Additional crosslinking between the silicone molecules allows these implants to retain their shape, especially in the vertical position. The authors evaluate the efficacy of Silimed form-stable silicone gel breast implants. A total of 355 patients (708 implants) were enrolled prospectively over a 60-month period. Data were collected on patient demographics, implant factors, complications, and revisions. Chi-square analysis and Fisher's exact test were implemented to compare groups with respect to differences in complication and revision rates. The overall tissue-related complication rate was 8.2% per patient, or 4.1% per breast. The overall implant-related cosmetic complication rate was 2.5% per patient, or 1.3% per implant. The overall implant-related complication rate, which was represented by the capsular contracture (CC) rate, was 1.4% per patient and 0.7% per implant. There were no complications in any of the reconstruction patients. There were no deep vein thromboses, pulmonary emboli, myocardial infarctions, or deaths among the patients in this study. In addition, there were no instances of flap necrosis, hematoma, or loss of implant integrity. The overall complication rate was 9.6% per patient, or 4.8% per implant. The overall tissue-related revision rate was 5.4% per patient, with the most common tissue-related reason for revision being unacceptable scarring. The overall implant-related cosmetic revision rate was 7.6% per patient, with the most common reason for revision in this category being size change. The overall implant-related revision rate was 1.1% per patient and was solely due to CC. This study demonstrates that form-stable silicone gel breast implants are safe and have a complication profile similar to other models of silicone breast implants, with a lower CC rate and a decreased incidence of wrinkling compared to fourth-generation silicone gel implants (as well as other published studies of fifth-generation implants).


Racial and ethnic disparity in low birth weight in Syracuse, New York.
This case-racial and ethnic disparity in low birth weight-is one of a series of teaching cases in the Case-Based Series in Population-Oriented Prevention (C-POP). It has been developed for use in medical school and residency prevention curricula. The complete set of cases is presented in this supplement to the American Journal of Preventive Medicine. Low birth weight is a leading cause of infant mortality. Unfortunately, despite declining rates of infant mortality, racial and ethnic disparities in both low birth weight and infant mortality rates persist. In this teaching case, a clinical vignette is used to draw attention to this public health priority in Syracuse, New York. Students learn essential epidemiology skills such as identifying limitations of sources of data and calculating relative risks, using the example of low birth weight. In performing these skills, students also identify etiologies for such disparity. Finally, students discuss interventions that, when implemented, may decrease infant mortality rates.


Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors.
Chronic stress impairs learning and memory in humans and rodents and disrupts long-term potentiation (LTP) in animal models. These effects are associated with structural changes in hippocampal neurons, including reduced dendritic arborization. Unlike the generally reversible effects of chronic stress on adult rat hippocampus, we have previously found that the effects of early-life stress endure and worsen during adulthood, yet the mechanisms for these clinically important sequelae are poorly understood. Stress promotes secretion of the neuropeptide corticotropin-releasing hormone (CRH) from hippocampal interneurons, activating receptors (CRF(1)) located on pyramidal cell dendrites. Additionally, chronic CRF(1) occupancy negatively affects dendritic arborization in mouse organotypic slice cultures, similar to the pattern observed in middle-aged, early-stressed (CES) rats. Here we found that CRH expression is augmented in hippocampus of middle-aged CES rats, and then tested whether the morphological defects and poor memory performance in these animals involve excessive activation of CRF(1) receptors. Central or peripheral administration of a CRF(1) blocker following the stress period improved memory performance of CES rats in novel-object recognition tests and in the Morris water maze. Consonant with these effects, the antagonist also prevented dendritic atrophy and LTP attenuation in CA1 Schaffer collateral synapses. Together, these data suggest that persistently elevated hippocampal CRH-CRF(1) interaction contributes importantly to the structural and cognitive impairments associated with early-life stress. Reducing CRF(1) occupancy post hoc normalized hippocampal function during middle age, thus offering potential mechanism-based therapeutic interventions for children affected by chronic stress.


Growth differentiation factor-5 promotes brown adipogenesis in systemic energy expenditure.
Although growth differentiation factor-5 (GDF5) has been implicated in skeletal development and joint morphogenesis in mammals, little is known about its functionality in adipogenesis and energy homeostasis. Here, we show a critical role of GDF5 in regulating brown adipogenesis for systemic energy expenditure in mice. GDF5 expression was preferentially upregulated in brown adipose tissues from inborn and acquired obesity mice. Transgenic overexpression of GDF5 in adipose tissues led to a lean phenotype and reduced susceptibility to diet-induced obesity through increased systemic energy expenditure. Overexpression of GDF5 facilitated the development of brown fat-like cells, called brite or beige cells, along with the expression of uncoupling protein-1 in inguinal subcutaneous white adipose tissue. In mutant mice harboring the dominant-negative GDF5, marked impairment in energy expenditure and thermogenesis was seen under obesogenic conditions. Recombinant GDF5 promoted brown adipogenesis through the mothers against decapentaplegic homolog (Smad) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) pathways after activation of bone morphogenetic protein receptor (BMPR). These results suggest that brown adipogenesis and energy homeostasis are both positively regulated by the GDF5/BMPR/Smad/PGC-1α signaling pathway in adipose tissues. Modulation of these pathways might be an effective therapeutic strategy for obesity and type 2 diabetes.


Occupational Exposure to Benzene and Non-Hodgkin Lymphoma in a Population-Based Cohort: The Shanghai Women's Health Study.
The association between benzene exposure and non-Hodgkin lymphoma (NHL) has been the subject of debate as a result of inconsistent epidemiologic evidence. An International Agency for Research on Cancer (IARC) working group evaluated benzene in 2009 and noted evidence for a positive association between benzene exposure and NHL risk. We evaluated the association between occupational benzene exposure and NHL among 73,087 women enrolled in the prospective population-based Shanghai Women's Health Study. Benzene exposure estimates were derived using a previously developed exposure assessment framework that combined ordinal job-exposure matrix intensity ratings with quantitative benzene exposure measurements from an inspection database of Shanghai factories collected between 1954 and 2000. Associations between benzene exposure metrics and NHL (n = 102 cases) were assessed using Cox proportional hazard models, with study follow-up occurring from December 1996 through December 2009. Women ever exposed to benzene had a significantly higher risk of NHL [hazard ratio (HR) = 1.87, 95% CI: 1.19, 2.96]. Compared with unexposed women, significant trends in NHL risk were observed for increasing years of benzene exposure (p(trend) = 0.006) and increasing cumulative exposure levels (p(trend) = 0.005), with the highest duration and cumulative exposure tertiles having a significantly higher association with NHL (HR = 2.07, 95% CI: 1.07, 4.01 and HR = 2.16, 95% CI: 1.17, 3.98, respectively). Our findings, using a population-based prospective cohort of women with diverse occupational histories, provide additional evidence that occupational exposure to benzene is associated with NHL risk.


Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression.
The increase in oral availability of felodipine and other commonly used medications when taken with grapefruit juice has been assumed to be due to inhibition of CYP3A4, a cytochrome P450 that is present in liver and intestine. To evaluate the effect of repeated grapefruit juice ingestion on CYP3A4 expression, 10 healthy men were given 8 oz of grapefruit juice three times a day for 6 d. Before and after receiving grapefruit juice, small bowel and colon mucosal biopsies were obtained endoscopically, oral felodipine kinetics were determined, and liver CYP3A4 activity was measured with the [14C N-methyl] erythromycin breath test in each subject. Grapefruit juice did not alter liver CYP3A4 activity, colon levels of CYP3A5, or small bowel concentrations of P-glycoprotein, villin, CYP1A1, and CYP2D6. In contrast, the concentration of CYP3A4 in small bowel epithelia (enterocytes) fell 62% (P = 0.0006) with no corresponding change in CYP3A4 mRNA levels. In addition, enterocyte concentrations of CYP3A4 measured before grapefruit juice consumption correlated with the increase in Cmax when felodipine was taken with either the 1st or the 16th glass of grapefruit juice relative to water (r = 0. 67, P = 0.043, and r = 0.71, P = 0.022, respectively). We conclude that a mechanism for the effect of grapefruit juice on oral felodipine kinetics is its selective downregulation of CYP3A4 in the small intestine.


Working memory: activation limitations on retrieval.
Two experiments which require subjects to hold a digit span while solving an equation and then recall the digit span are performed. The size of the memory span and the complexity of the equation are manipulated as well as whether the subject is required to substitute items from the digit span for constants in the equation. As either task (digit span recall or equation solving) gets more complex there are performance decrements (accuracy or latency) not only in that task but also in the other task. It is also shown that the majority of the errors are misretrievals. These results are consistent with the proposal that working memory load has its impact on retrieval from memory. These results are fit by the ACT-R theory (Anderson, 1993) which assumes that there is a limit on source activation and that this activation has to be divided between the two tasks. As either task increases in complexity there is less activation for retrieval of information from declarative memory. Subjects' misretrievals of associatively related information could be predicted by assuming a partial matching process in ACT-R.


Health resource use after robot-assisted surgery vs open and conventional laparoscopic techniques in oncology: analysis of English secondary care data for radical prostatectomy and partial nephrectomy.
To evaluate postoperative health resource utilisation and secondary care costs for radical prostatectomy and partial nephrectomy in National Health Service (NHS) hospitals in England, via a comparison of robot-assisted, conventional laparoscopic and open surgical approaches. We retrospectively analysed the secondary care records of 23 735 patients who underwent robot-assisted (RARP, n = 8 016), laparoscopic (LRP, n = 6 776) or open radical prostatectomy (ORP, n = 8 943). We further analysed 2 173 patients who underwent robot-assisted (RAPN, n = 365), laparoscopic (LPN, n = 792) or open partial nephrectomy (OPN, n = 1 016). Postoperative inpatient admissions, hospital bed-days, excess bed-days and outpatient appointments at 360 and 1 080 days after surgery were reviewed. Patients in the RARP group required significantly fewer inpatient admissions, hospital bed-days and excess bed-days at 360 and 1 080 days than patients undergoing ORP. Patients undergoing ORP had a significantly higher number of outpatient appointments at 1 080 days. The corresponding total costs were significantly lower for patients in the RARP group at 360 days (£1679 vs £2031 for ORP; P < 0.001) and at 1 080 days (£3461 vs £4208 for ORP; P < 0.001). In partial nephrectomy, Patients in the RAPN group required significantly fewer inpatient admissions and hospital bed-days at 360 days compared with those in the OPN group; no significant differences were observed in outcomes at 1 080 days. The corresponding total costs were lower for patients in the RAPN group at 360 days (£779 vs £1242 for OPN, P = 0.843) and at 1 080 days (£2122 vs £2889 for ORP; P = 0.570). For both procedure types, resource utilisation and costs for laparoscopic surgeries lay at the approximate midpoint of those for robot-assisted and open surgeries. Our analysis provides compelling evidence to suggest that RARP leads to reduced long-term health resource utilisation and downstream cost savings compared with traditional open and laparoscopic approaches. Furthermore, despite the limitations that arise from the inclusion of a small sample, these results also suggest that robot-assisted surgery may represent a cost-saving alternative to existing surgical options in partial nephrectomy. Further exploration of clinical cost drivers, as well as an extension of the analysis into subsequent years, could lend support to the wider commissioning of robot-assisted surgery within the NHS.


Body Condition Indices Predict Reproductive Success but Not Survival in a Sedentary, Tropical Bird.
Body condition may predict individual fitness because those in better condition have more resources to allocate towards improving their fitness. However, the hypothesis that condition indices are meaningful proxies for fitness has been questioned. Here, we ask if intraspecific variation in condition indices predicts annual reproductive success and survival. We monitored a population of Neochmia phaeton (crimson finch), a sedentary, tropical passerine, for reproductive success and survival over four breeding seasons, and sampled them for commonly used condition indices: mass adjusted for body size, muscle and fat scores, packed cell volume, hemoglobin concentration, total plasma protein, and heterophil to lymphocyte ratio. Our study population is well suited for this research because individuals forage in common areas and do not hold territories such that variation in condition between individuals is not confounded by differences in habitat quality. Furthermore, we controlled for factors that are known to impact condition indices in our study population (e.g., breeding stage) such that we assessed individual condition relative to others in the same context. Condition indices that reflect energy reserves predicted both the probability of an individual fledging young and the number of young produced that survived to independence, but only during some years. Those that were relatively heavy for their body size produced about three times more independent young compared to light individuals. That energy reserves are a meaningful predictor of reproductive success in a sedentary passerine supports the idea that energy reserves are at least sometimes predictors of fitness. However, hematological indices failed to predict reproductive success and none of the indices predicted survival. Therefore, some but not all condition indices may be informative, but because we found that most indices did not predict any component of fitness, we question the ubiquitous interpretation of condition indices as surrogates for individual quality and fitness.


Hypothalamic integration of immune function and metabolism.
The immune and neuroendocrine systems are closely involved in the regulation of metabolism at peripheral and central hypothalamic levels. In both physiological (meals) and pathological (infections, traumas and tumors) conditions immune cells are activated responding with the release of cytokines and other immune mediators (afferent signals). In the hypothalamus (central integration), cytokines influence metabolism by acting on nucleus involved in feeding and homeostasis regulation leading to the acute phase response (efferent signals) aimed to maintain the body integrity. Peripheral administration of cytokines, inoculation of tumor and induction of infection alter, by means of cytokine action, the normal pattern of food intake affecting meal size and meal number suggesting that cytokines acted differentially on specific hypothalamic neurons. The effect of cytokines-related cancer anorexia is also exerted peripherally. Increase plasma concentrations of insulin and free tryptophan and decrease gastric emptying and d-xylose absorption. In addition, in obesity an increase in interleukin (IL)-1 and IL-6 occurs in mesenteric fat tissue, which together with an increase in corticosterone, is associated with hyperglycemia, dyslipidemias and insulin resistance of obesity-related metabolic syndrome. These changes in circulating nutrients and hormones are sensed by hypothalamic neurons that influence food intake and metabolism. In anorectic tumor-bearing rats, we detected upregulation of IL-1beta and IL-1 receptor mRNA levels in the hypothalamus, a negative correlation between IL-1 concentration in cerebro-spinal fluid and food intake and high levels of hypothalamic serotonin, and these differences disappeared after tumor removal. Moreover, there is an interaction between serotonin and IL-1 in the development of cancer anorexia as well as an increase in hypothalamic dopamine and serotonin production. Immunohistochemical studies have shown a decrease in neuropeptide Y (NPY) and dopamine (DA) and an increase in serotonin concentration in tumor-bearing rats, in first- and second-order hypothalamic nuclei, while tumor resection reverted these changes and normalized food intake, suggesting negative regulation of NPY and DA systems by cytokines during anorexia, probably mediated by serotonin that appears to play a pivotal role in the regulation of food intake in cancer. Among the different forms of therapy, nutritional manipulation of diet in tumor-bearing state has been investigated. Supplementation of tumor bearing rats with omega-3 fatty acid vs. control diet delayed the appearance of tumor, reduced tumor-growth rate and volume, negated onset of anorexia, increased body weight, decreased cytokines production and increased expression of NPY and decreased alpha-melanocyte-stimulating hormone (alpha-MSH) in hypothalamic nuclei. These data suggest that omega-3 fatty acid suppressed pro-inflammatory cytokines production and improved food intake by normalizing hypothalamic food intake-related peptides and point to the possibility of a therapeutic use of these fatty acids. The sum of these data support the concept that immune cell-derived cytokines are closely related with the regulation of metabolism and have both central and peripheral actions, inducing anorexia via hypothalamic anorectic factors, including serotonin and dopamine, and inhibiting NPY leading to a reduction in food intake and body weight, emphasizing the interconnection of the immune and neuroendocrine systems in regulating metabolism during infectious process, cachexia and obesity.


Psychosocial adjustment in siblings of children with chronic life-threatening illness: a research note.
The psychosocial functioning of 10 siblings of children with chronic life-threatening illness and their parents was compared with 10 healthy matched controls. The main differences found were in family relationships, with the index siblings expressing more negative emotion in relation to their fathers than controls, index mothers being less involved in social activities and index fathers being less involved with the extended family. No significant differences were found in any of the measures of depression, anxiety and self concept. Index siblings expressed a number of other concerns such as a fear of the break up of their family after the sick child died. The need for increased awareness of the welfare of healthy siblings as well as closer involvement of the fathers is discussed.


Patient participation in patients with heart failure receiving structured home care--a prospective longitudinal study.
Patient participation is important for improving outcomes, respect for self-determination and legal aspects in care. However, how patients with heart failure view participation and which factors may be associated with participation is not known. The aim of this study was therefore to describe the influence of structured home care on patient participation over time in patients diagnosed with heart failure, and to explore factors associated with participation in care. The study had a prospective pre-post longitudinal design evaluating the influence of structured home care on participation in patients at four different home care units. Patient participation was measured using 3 scales and 1 single item. Self-care behavior, knowledge, symptoms of depression, socio- demographic and clinical characteristics were measured to explore factors associated with patient participation. Repeated measure ANOVA was used to describe change over time, and stepwise regression analyses were used to explore factors associated with patient participation. One hundred patients receiving structured heart failure home care were included. Mean age was 82 years, 38 were women and 80 were in New York Heart Association functional class III. One aspect of participation, received information, showed a significant change over time and had increased at both six and twelve months. Better self-care behavior was associated with all four scales measuring different aspects of participation. Experiencing lower degree of symptoms of depression, having better knowledge, being of male sex, being of lower age, cohabiting and having home help services were associated with one or two of the four scales measuring different aspects of participation. Patients experienced a fairly high level of satisfaction with participation in care at baseline, and there was a significant improvement over time for participation with regard to received information after being admitted to structured home care. Higher level of patient participation was consistently associated with better self-care behavior. This study shows that patient participation may need to be further focused upon, and that the association with self-care may be interesting to target in future interventions.