Hypertrophic scar fibroblasts accelerate collagen gel contraction.
Excessive contraction of hypertrophic scar and subsequent contracture formation are a formidable problem after thermal injury. A comparison between fibroblasts from hypertrophic scar and normal skin was made with the use of fibroblast-populated collagen lattices as a measure of cellular generated contractile forces. Hypertrophic scar and normal skin fibroblasts were mixed with soluble tendon collagen and Dulbecco's modified Eagle medium supplemented with 10% serum, and contraction was measured by serial area measurements. Parallel experiments in the presence of transforming growth factor-beta or anti-transforming growth factor-beta antibody examined the role of this cytokine on lattice contraction. Transforming growth factor-beta activity was measured in an additional set of 10 biopsy specimens. Hypertrophic scar fibroblasts contract lattices at a significantly faster rate than do normal skin fibroblasts. Exogenous transforming growth factor-beta increased lattice contraction by normal skin fibroblasts but had little effect on hypertrophic scar cell-populated lattices. The addition of anti-transforming growth factor-beta antibody decreased lattice contraction by both cell types. Transforming growth factor-beta activity was significantly increased in the hypertrophic scar biopsy specimens. Excessive scar contraction and post-burn scar contracture result from increased contraction forces generated by hypertrophic scar cells. This increased contractility appears to be mediated by increased endogenous presence of transforming growth factor-beta.


Novel function of E26 transformation-specific domain-containing protein ELK3 in lymphatic endothelial cells.
Lymphatic endothelial cells (LEC) are major components of the tumor microenvironment and, due to the relative leakiness of lymphatic vessels compared with blood vessels, are essential for tumor dissemination and metastasis. In the present study, small interfering RNA-mediated suppression of E26 transformation-specific domain-containing protein Elk-3 (ELK3) inhibited the proliferation, migration and tube-forming ability of LEC. Suppression of ELK3 decreased vascular endothelial-cadherin expression levels and increased the phosphorylation of β-catenin. Furthermore, vascular endothelial growth factor receptor-3 (VEGFR-3) mRNA and protein expression levels were suppressed by the transfection of LEC with siELK3. As VEGFR-3 serves a major role in lymphangiogenesis, ELK3 may be a novel therapeutic target to inhibit tumor dissemination through the lymphatic system.


[Analysis of correlative factors and prevalence on China's youth myopia].
To understand and address our vision changes in primary and secondary students, in order to explore the prevention of juvenile myopia to provide a response and suggestions. A random cluster sampling method, random sample of 90 rural and urban schools in Shandong, Qinghai, Yunnan, Shanghai and Wenzhou from May 2008 to September 2009, including 20 000 students (per province, 4000 x 5) from elementary school and junior high school of focus and non-focus, primary 11 246, junior high school students 3673, high school 4220, of which 11 177 were from the urban students, rural students in 7962, aged 6 to 19 years old, male to female ratio is basically the same. For myopia and related survey, a total of 19, 139 valid questionnaires were recovered. Using SPSS 13.0 software statistical analysis, different regions and different grades was used to compare the prevalence of myopia chi(2) test, using Logistic regression analysis on the major risk factors for myopia. The survey are as follows, the prevalence of myopia in primary was 13.7%; the prevalence of myopia in junior high was 42.9%, the prevalence of myopia in high school was 69.7%. The highest rate of myopia prevalence of primary school students in Shandong was 19.7%, the lowest was 11.9% in Qinghai, Shanghai, Wenzhou and Yunnan are similar; prevalence myopia of junior high in Wenzhou up to 50.6%, followed by Shanghai, and 47.2%, the lowest was 33.6% in Qinghai; the highest prevalence of myopia and high school students in Shandong, reaching 87.3%, followed by 72.0% in Wenzhou, and the lowest was 60.2% in Shanghai. This survey shows that the prevalence of myopia of China's primary and secondary schools in coastal was higher than areas of mainland, in developed regions was higher than in less developed regions, and the plateau region and the strong ultraviolet light similar to the plain areas. Provincial prevalence of myopia increased from primary to high school continued the same trend.


Unusual radiologic manifestations of bronchogenic cyst.
We have presented four cases of bronchogenic cyst, emphasizing the uncommon radiologic manifestations, including air trapping and/or lobulated contour. Two of the cysts were in the lung parenchyma, one in the left hilum adherent to the left lower lobe bronchus, and one in the posterior mediastinum. Recognition of the unusual radiologic features aids in establishing an appropriate differential diagnosis and directing subsequent evaluation.


Decaffeinated coffee and acute myocardial infarction. A case-control study in Italian women.
The relationship between consumption of decaffeinated coffee and acute myocardial infarction was analyzed in a case-control study conducted in Italy between 1983 and 1992. Case patients were 433 women with acute myocardial infarction, aged 24 to 69 years (median age, 52 years), and control subjects included 869 women in hospital for a wide spectrum of acute conditions, other than cardiovascular, neoplastic, digestive, and hormone-related diseases or conditions associated with long-term modification of diet. Regular use of decaffeinated coffee was reported by 11% of the case patients and 7% of the control subjects. Compared with women who did not drink decaffeinated coffee, the relative risk (RR) was 1.3 (95% confidence interval (CI), 0.8 to 2.2) for one cup/d and 2.1 (95% CI, 1.1 to 3.9) for 2 or more cups (chi 2(1) for trend = 5.62, P = 0.02). The estimates were somewhat higher after allowance for education, marital status, body mass index, and smoking status (RR for > or = 2 cups of decaffeinated coffee per day, 2.5; 95% CI, 1.2 to 4.9), and somewhat lower after further allowance for diabetes, hypertension, and hyperlipidemia (RR, 1.7; 95% CI, 0.8 to 3.6). There was no association between duration of use of decaffeinated coffee and infarction risk. The relationship between decaffeinated coffee and infarction was consistent across strata of age, education, smoking, and history of hyperlipidemia. Thus, a relationship of marginal significance was observed in this study between decaffeinated coffee and myocardial infarction, of similar magnitude to that described for caffeinated coffee. This indicates that (i) caffeine is unlikely to be a relevant factor in any potential coffee-myocardial infarction relationship, and (ii) shifting from caffeinated to decaffeinated coffee is unjustified in order to reduce any possible coffee-related infarction risk.


Measurement of magnetization transfer in different stages of neurocysticercosis.
The purpose of this study was to establish magnetization transfer ratio (MTR) in different stages of neurocysticercosis. A total 2,532 cysticerci were studied prospectively in 15 cases. MTR from different regions of the lesions (ie, the cyst, the protoscolex or mural nodule, the granuloma wall) were calculated in different stages of evolution/degeneration in all cases. Of a total 2,532 lesions studied, 2,261 (89.29%) were seen on routine spin-echo (SE) imaging. The rest of the lesions were only seen on magnetization transfer (MT) SE imaging. Maximum MTR was calculated from healing lesions (mean + SD = 31.0+/-2.8) and from the core of SE invisible lesions (30.0+/-5.1). Innocuous cystic lesions, which were hyperintense on T2-weighted images, did not show any MT (MTR = 5.10+/-1.2), whereas degenerating T2 hyperintense lesions showed MTR of 26.40+/-2.7. Nondegenerating and degenerating scolices showed an intermediate MTR of 21.7+/-3.3 and 15.0+/-4.5, respectively. MT varies between different parts of the lesion and also from the same part in different stages of evolution/degeneration of the lesion. The visibility of a lesion on MT-SE sequence was dependent on its MTR and its location at a particular site (cortical gray matter, white matter, or deep gray matter). The difference in MTR of the lesion and the surrounding brain parenchyma decides the resulting contrast and visibility of the lesion.


Artificial cells as bioreactive biomaterials.
Artificial cells can have the same dimensions as biological cells. They can enclose and retain a large variety of bioreactants. Artificial cell membranes can have the required permeability characteristics to allow the rapid equilibration of external molecules to be acted on by the enclosed bioreactants. Polymer, protein, protein-lipid, polymer-lipid, lipid or other materials can form artificial cell membranes. It is possible to vary the membrane thickness and permeability characteristics over a wide range. Many different forms of bioreactive artificial cells are available. This article contains only a few examples. This includes its applications in (1) red blood cell substitutes; (2) immobilisation of enzymes, multienzymes with cofactor recycling, cell cultures and other biotechnological applications; (3) hemoperfusion in kidney failure, poisoning, removal of aluminum and iron; (4) use in liver failure; (5) other applications in microencapsulation.


Congenital and environmental factors associated with adipocyte dysregulation as defects of insulin resistance.
The metabolic syndrome refers to insulin resistance and its associated cluster of related cardiovascular metabolic risk factors including type 2 diabetes, hypertension, dyslipidemia and central obesity. Although many hypotheses and facts have been proposed to explain the interaction between genetic and environmental causes of this syndrome, the primary etiology of the metabolic syndrome is adipose tissue dysregulation. Firstly, the thrifty genotype and phenotype hypothesis may explain the endemic increase in type 2 diabetes and cardiovascular disease in developing countries and elucidates the congenital susceptibility and environmental triggering of the metabolic syndrome. Secondly, over-nutrition leads to fatty acid (FA) accumulation in adipocytes and to an overflow to ectopic fat storage organs. This causes functional changes in adipocytes shifting the intra-cellular metabolic pathway toward insulin resistance. Thirdly, obese subjects exhibit increased fat cell size and over-secretion of biologic adipocytokines. Fourthly, failure to adequately develop adipose tissue mass, as seen in lipodystrophy cases, causes severe insulin resistance and diabetes. Lastly, similar to human type 2 diabetes, Psammonys obesus, a desert rat which feeds mainly on low-calorie vegetation, develops the metabolic syndrome when given a diet of calorie rich food. The above evidence indicates adipocyte dysregulation and secretion of FA as well as certain molecules from overloaded adipocytes/adipokines contribute to the pathogenesis of impaired insulin secretion and insulin resistance, endothelial dysfunction, a pro-inflammatory state and promote progression of atherosclerosis. The metabolic syndrome is a modern disease resulting adipocyte dysmetabolism resulting from the paradox of the slow human evolution combined with rapid environmental changes.


Chilli consumption and the incidence of overweight and obesity in a Chinese adult population.
The frequency of spicy food intake has recently been associated with a reduced risk of mortality in the Chinese population. This study aimed to prospectively examine the association between chilli intake and the incidence of overweight/obesity in a Chinese adult population. Adults aged 20-75 years in the China Health and Nutrition Survey were followed between 1991 and 2011. Dietary data were collected during home visits using a 3-day food record in 1991, 1993, 1997, 2000, 2004, 2006, 2009 and 2011. Cox regression was used in the analysis. Overweight/obesity was defined as body mass index ⩾25 kg m-2. A total 12 970 adults were followed for a median of 9 years. During 126 884 person-years of follow-up, 3203 subjects developed overweight/obesity. The absolute incidence rate of overweight/obesity was 26.4, 22.3, 24.4 and 20.5 per 1000 person-years among those who consumed no chilli or 1-20, 20.1-50, ⩾50.1 g per day, respectively. Chilli consumption was therefore inversely associated with the incidence of overweight/obesity. After adjusting for age, gender, energy and fat intake, smoking, alcohol drinking and physical activity, those whose cumulative average chilli intake was 0, 1-20, 20.1-50 and ⩾50.1 g per day had a hazard ratio for overweight/obesity of 1.00, 0.81 (95% confidence interval=0.73-0.89), 0.77 (0.69-0.86) and 0.73 (0.63-0.84); P for trend <0.001, respectively. There was no interaction between chilli intake and gender, income, education and residence (urban/rural) in relation to the risk of overweight/obesity. Chilli intake is inversely associated with the risk of becoming overweight/obese in Chinese adults.


Case report: Bitter vertigo.
There are many causes of episodes of vertigo and very few causes of episodes of changes in taste, and the combination of the two is very rare. Here, we describe a patient with recurrent short episodes of vertigo in combination with simultaneous episodes of recurrent paroxysmal dysgeusia and altered feeling on the left side of face. The symptoms were caused by compression of the vestibulocochlear nerve and the facial nerve due to dolichoectasia of the basilar artery. The patient was diagnosed in our routine clinical practice and underwent a complete neurological and neuro-otological examination, including video head impulse test, caloric irrigation, ocular and cervical vestibular evoked myogenic potentials, acoustic-evoked potentials, neuro-orthoptic examination, cranial MRI, and MR angiography. The patient was seen twice for follow-up. A 71-year-old patient primarily presented with a 2-year history of recurrent short episodes of spinning vertigo. Each of the episodes began with an altered feeling on the left side of the face, followed by a bitter taste on the left half of the tongue, and subsequently vertigo lasting for up to 15 s. The frequency of the attacks was high: up to 80 times per day. Laboratory tests revealed signs of a peripheral vestibular deficit on the left side. There were no signs of sensory or motor deficits or of altered taste between the episodes. An MRI of the brain showed an elongated basilar artery leading to an indentation of the facial and vestibulocochlear nerves on the left side. We propose a neurovascular compression in the proximal part of two cranial nerves because of pulsatile compression by the elongated basilar artery with ephatic discharges as the cause of the recurrent episodes. Consistent with the theory of ephatic discharges, treatment with the sodium channel blocker lacosamide for over six months with a final dosage of 200 mg per day p.o. led to a significant reduction of the attack frequency and intensity. This treatment option with a sodium channel blocker should therefore not only be considered in vestibular paroxysmia but also in cases of paroxysmal dysgeusia.


Association of the body mass index with outcomes in elderly patients (≥80 years) undergoing percutaneous coronary intervention.
The obesity paradox has been recognized in patients with cardiovascular disease. The association between obesity and outcomes in elderly patients undergoing percutaneous coronary intervention (PCI) has not been investigated, yet. A total of 990 elderly (≥80 years) patients undergoing PCI at our institution between January 2009 and December 2017 and with available data on body mass index (BMI) were divided according to BMI tertiles (lowest BMI tertile: ≪24.1 kg/m2, middle BMI tertile: 24.1-27.2 kg/m2, and highest BMI tertile: ≫27.2 kg/m2). The primary endpoint was all-cause mortality at a median follow-up of 233 [34-862] days. All-cause mortality was 11.2%, 7.6%, and 5.8% in the lowest, the middle, and the highest BMI tertiles (Log Rank p = 0.008). Belonging to the lowest BMI tertile was associated with an increased risk of all-cause mortality (HR 2.14, 95% CI 1.23-3.73, p = 0.007), and associations remained significant after multivariable adjustments (adjusted HR 1.92, 95% CI 1.05-3.52, p = 0.03). While belonging to the lowest BMI tertile was independently associated with an increased all-cause mortality in patients with acute coronary syndromes (HR 2.32, 95% CI 1.24-4.35, p = 0.009; adjusted HR 2.40, 95% CI 1.19-4.84, p = 0.01), relations were not significant in patients with stable coronary artery disease (HR 1.32, 95% CI 0.38-4.56, p = 0.67; adjusted HR 0.80, 95% CI 0.21-3.05, p = 0.75). In elderly (≥80 years) patients undergoing PCI, belonging to the lowest BMI tertile was associated with an increased mortality, mainly in acute coronary syndromes. Hence, the BMI should be incorporated into the risk stratification of elderly patients with coronary artery disease.


Gastrocnemius muscle fascicle behavior during stair negotiation in humans.
The aim of the present study was to establish the behavior of human medial gastrocnemius (GM) muscle fascicles during stair negotiation. Ten healthy male subjects performed normal stair ascent and descent at their own comfortable speed on a standard-dimension four-step staircase with embedded force platforms in each step. Kinematic, kinetic, and electromyographic data of the lower limbs were collected. Real-time ultrasound scanning was used to determine GM muscle fascicle length changes. Musculotendon complex (MTC) length changes were estimated from ankle and knee joint kinematics. The GM muscle was mainly active during the push-off phase in stair ascent, and the muscle fascicles contracted nearly isometrically. The GM muscle was mainly active during the touch-down phase of stair descent where the MTC was lengthened; however, the GM muscle fascicles shortened by approximately 7 mm. These findings show that the behavior and function of GM muscle fascicles in stair negotiation is different from that expected on the basis of length changes of the MTC as derived from joint kinematics.


Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management.
Intravenous iron is widely used for the treatment of iron deficiency anemia when oral iron is inappropriate, ineffective or poorly tolerated. Acute hypersensitivity reactions during iron infusions are very rare but can be life-threatening. This paper reviews their frequency, pathogenesis and risk factors, and provides recommendations about their management and prevention. Complement activation-related pseudo-allergy triggered by iron nanoparticles is probably a more frequent pathogenetic mechanism in acute reactions to current formulations of intravenous iron than is an immunological IgE-mediated response. Major risk factors for hypersensitivity reactions include a previous reaction to an iron infusion, a fast iron infusion rate, multiple drug allergies, severe atopy, and possibly systemic inflammatory diseases. Early pregnancy is a contraindication to iron infusions, while old age and serious co-morbidity may worsen the impact of acute reactions if they occur. Management of iron infusions requires meticulous observation, and, in the event of an adverse reaction, prompt recognition and severity-related interventions by well-trained medical and nursing staff.


A Randomized Phase II Study of Nivolumab Monotherapy or Nivolumab Combined with Ipilimumab in Patients with Advanced Gastrointestinal Stromal Tumors.
Most gastrointestinal stromal tumors (GIST) are driven by KIT/PDGFRa mutations. Tyrosine kinase inhibitor benefit is progressively less after imatinib failure. This phase II trial analyzed the efficacy of nivolumab (N) or nivolumab + ipilimumab (N + I) in patients with refractory GIST. Patients with advanced/metastatic GIST refractory to at least imatinib were randomized 1:1 in a noncomparative, parallel group, unblinded phase II trial of N (240 mg every 2 weeks) or N + I (240 mg every 2 weeks + 1 mg/kg every 6 weeks). The primary endpoint was the objective response rate of N alone or N+I by RECIST 1.1 in the intent-to-treat population. A total of 36 patients with a median of 3 (1-6) prior lines of therapies were enrolled. Ten of 19 (52.6%) patients had stable disease (SD) for a clinical benefit rate (CBR) of 52.6% in the N arm and the median progression-free survival (PFS) was 11.7 weeks [95% confidence interval (CI), 7.0-17.4]. In the N+I arm, 1 of 16 (6.7%) patients had a complete response (CR) and 4/16 (25.0%) had SD for a CBR of 31.3% and a median PFS of 8.3 weeks (95% CI, 5.6-22.2). The 4- and 6-month PFS were 42.1% and 26.3%, respectively for N, and 31.3% and 18.8%, respectively for N+I. The most common adverse events (AE) attributed to N and N+I were fatigue: 13.9% and 22.2%, respectively. There were nine total attributable grade 3-4 AEs. The primary endpoint of response rate > 15% was not observed for N or N + I. In a heavily pretreated GIST population, responses and long-term disease control with both N and N+I were observed. No new safety signals have been observed.


[2 cases of Waldenstrom's disease associated with a glioblastoma].
The association of Waldenström disease and glioblastoma was observed in two patients. Both diseases were diagnosed almost simultaneously. In the first patient the diagnosis of glioblastoma was made on cerebral biopsy. In the second case, the diagnosis was confirmed at autopsy. The association of Waldenström's disease and glioblastoma is rare but it does not seem to be coincidental. The physiopathological problems related to this coexistence are discussed.


Three-dimensional particle-in-cell simulations of energetic electron generation and transport with relativistic laser pulses in overdense plasmas.
The interaction of relativistic laser light with overdense plasmas is studied by three-dimensional particle-in-cell simulations. Generation of layered current sheets and quasistatic magnetic fields is observed near the target surface owing to anisotropic laser filamentation and Weibel instabilities. Later these current sheets tear into filaments that partially merge with each other to form isolated magnetic channels penetrating into the dense plasmas. It is found that fast electron energy flow is not only inside the magnetic channels but also it is widely distributed outside the channels. This is possible because of electron anomalous diffusion across self-generated magnetic fields. Consequently, the total hot electron current exceeds a few hundred kiloamperes and is much larger than the Alfvén current. Hence a considerable amount of energy flows towards the plasma core. Significant heating of the bulk plasma electrons is also observed.


Corticostriatal dynamics encode the refinement of specific behavioral variability during skill learning.
Learning to perform a complex motor task requires the optimization of specific behavioral features to cope with task constraints. We show that when mice learn a novel motor paradigm they differentially refine specific behavioral features. Animals trained to perform progressively faster sequences of lever presses to obtain reinforcement reduced variability in sequence frequency, but increased variability in an orthogonal feature (sequence duration). Trial-to-trial variability of the activity of motor cortex and striatal projection neurons was higher early in training and subsequently decreased with learning, without changes in average firing rate. As training progressed, variability in corticostriatal activity became progressively more correlated with behavioral variability, but specifically with variability in frequency. Corticostriatal plasticity was required for the reduction in frequency variability, but not for variability in sequence duration. These data suggest that during motor learning corticostriatal dynamics encode the refinement of specific behavioral features that change the probability of obtaining outcomes.


An investigation into the mechanisms of DNA strand breakage by direct ionization of variably hydrated plasmid DNA.
The mechanisms by which ionizing radiation directly causes strand breaks in DNA were investigated by comparing the chemical yield of DNA-trapped free radicals to the chemical yield of DNA single strand break (ssb) and double strand break (dsb), as a function of hydration (Gamma). Solid-state films of plasmid pUC18, hydrated to 2.5 < Gamma < 22.5 mol, were X-irradiated at 4 K, warmed to room temperature, and dissolved in water. Free radical yields were determined by EPR at 4 K. With use of the same samples, Gel electrophoresis was used to measure the chemical yield of total strand breaks, which includes prompt plus heat labile ssb; G'total(ssb) decreased from 0.092 +/- 0.016 micromol/J at Gamma= 2.5 to 0.066 +/- 0.008 micromol/J at Gamma= 22.5. Most provocative is that at Gamma= 2.5 the yield of total ssb exceeds the yield of trapped deoxyribose radicals: G'total(ssb) - G'sugar(fr) = 0.06 +/- 0.02 micromol/J. Nearly 2/3 of the strand breaks are derived from precursors other than radicals trapped on the deoxyribose moiety. To account for these nonradical precursors, we hypothesize that strand breaks are produced by two one-electron oxidations at a single deoxyribose residue within an ionization cluster.


Selecting appropriate postoperative dressings to support wound healing and reduce surgical site infection.
The appropriate choice of postoperative dressing supports effective wound healing by providing a moist wound environment and reducing the risk of surgical site infection and blistering. Wound management is complex and practitioners need to consider the location of the wound, method of wound closure, expected exudate level and length of time the dressing needs to remain in place when selecting a product. The correct dressing selection will have a positive impact wound healing and the patient's quality of life.


Multivariate analysis of relative growth in the limb bones of Arikara Indians.
The description of relative growth in the limb bones of Arikara Indians from a large archeological sample (N = 412 nonadults) is approached by (1) using a multivariate generalization of the bivariate scaling relationship, and (2) extracting the principal components of log shape. The two methods are shown to be complementary, and advantages accrue to both. Although most of the variability among individuals is related primarily to differences in size, significant age-related differences in shape are disclosed by both approaches. Negative forelimb growth allometry contrasts with positive hind limb allometry and results in decreasing intermembral indices with changing size and age. A within-limb, disto-proximal growth gradient is also evident, inasmuch as the proximal element within each limb grows faster than the distal. A functional link to the human specialization for bipedal locomotion and posture is apparent. A comparison between the ontogenetic results of this study and those from an analysis of static adult scaling from the same populations discloses no similarities between the two and suggests that one type of data cannot be substituted for the other.


Ultimate concerns in late modernity: Archer, Bourdieu and reflexivity.
Through a critique of Margaret Archer's theory of reflexivity, this paper explores the theoretical contribution of a Bourdieusian sociology of the subject for understanding social change. Archer's theory of reflexivity holds that conscious 'internal conversations' are the motor of society, central both to human subjectivity and to the 'reflexive imperative' of late modernity. This is established through critiques of Bourdieu, who is held to erase creativity and meaningful personal investments from subjectivity, and late modernity is depicted as a time when a 'situational logic of opportunity' renders embodied dispositions and the reproduction of symbolic advantages obsolete. Maintaining Archer's focus on 'ultimate concerns' in a context of social change, this paper argues that her theory of reflexivity is established through a narrow misreading and rejection of Bourdieu's work, which ultimately creates problems for her own approach. Archer's rejection of any pre-reflexive dimensions to subjectivity and social action leaves her unable to sociologically explain the genesis of 'ultimate concerns', and creates an empirically dubious narrative of the consequences of social change. Through a focus on Archer's concept of 'fractured reflexivity', the paper explores the theoretical necessity of habitus and illusio for understanding the social changes that Archer is grappling with. In late modernity, reflexivity is valorized just as the conditions for its successful operation are increasingly foreclosed, creating 'fractured reflexivity' emblematic of the complex contemporary interaction between habitus, illusio, and accelerating social change.


Mercury inhibits the non-photochemical reduction of plastoquinone by exogenous NADPH and NADH: evidence from measurements of the polyphasic chlorophyll a fluorescence rise in spinach chloroplasts.
Chlorophyll a fluorescence rise kinetics (from 50 mus to 1 s) were used to investigate the non-photochemical reduction of the plastoquinone (PQ) pool in osmotically broken spinach chloroplasts (Spinacia oleracea L.). Incubation of the chloroplasts in the presence of exogenous NADPH or NADH resulted in significant changes in the shape of the fluorescence transient reflecting an NAD(P)H-dependent accumulation of reduced PQ in the dark, with an extent depending on the concentration of NAD(P)H and the availability of oxygen; the dark reduction of the PQ pool was saturated at lower NAD(P)H concentrations and reached a higher level when the incubation took place under anaerobic conditions than when it occurred under aerobic conditions. Under both conditions NADPH was more effective than NADH in reducing PQ, however only at sub-saturating concentrations. Neither antimycin A nor rotenone were found to alter the effect of NAD(P)H. The addition of mercury chloride to the chloroplast suspension decreased the NAD(P)H-dependent dark reduction of the PQ pool, with the full inhibition requiring higher mercury concentrations under anaerobic than under aerobic conditions. This is the first time that this inhibitory role of mercury is reported for higher plants. The results demonstrate that in the dark the redox state of the PQ pool is regulated by the reduction of PQ via a mercury-sensitive NAD(P)H-PQ oxidoreductase and the reoxidation of reduced PQ by an O(2)-dependent pathway, thus providing additional evidence for the existence of a chlororespiratory electron transport chain in higher plant chloroplasts.


Markers, Reactions, and Interactions during the Aging of Pinus Resin Assessed by Raman Spectroscopy.
The resin extracted from the species of the Pinus genus (Pinaceae family) is a widely used material. Primarily, resins are made up of two types of diterpenoids: abietanes and pimaranes. Their composition changes with aging, affecting their chemical and physical properties; however, the chemical changes that occur during aging are not yet fully known. Understanding the evolution of pimaranes and abietanes and the chemical composition of the aged resins is essential to make the most of this substance and of its derivatives. A systematic study of the aging of Pinus resin with Raman complemented with infrared (IR) spectroscopy was carried out. This study provided new information about the interactions among the constituting molecules in resins aged over many years. In particular the formation of intermolecular hydrogen bonds in aged samples was detected for the first time, and the formation of acid anhydrides from the reaction between pimaranes was demonstrated. Furthermore, Raman and IR spectra band assignments are proposed, and the specific markers of the main compounds of the resin are tagged. This will facilitate the qualitative analysis of resin compounds.


Chlordecone-induced hepatic dysfunction.
Chlordecone (Kepone) is a decachloroketone analog of the dodecachlorohydrocarbon mirex and is used as a stomach poison insecticide. Despite the structural similarity to mirex, chlordecone is unlike mirex in general organ-specific toxic properties. Chlordecone is primarily accumulated in the liver, where it causes a variety of morphological and biochemical alterations. Although less effective than mirex as a hepatotoxin, it causes liver enlargement, focal necrosis, mitochondrial changes, fatty infiltration of hepatocytes, and proliferation of endoplasmic reticulum. Chlordecone accumulation and morphological alterations in the liver were also observed in occupationally exposed human patients. Induction of hepatic microsomal mixed-function oxidases (MFOs) and impaired production and utilization of hepatocellular energy are the principal biochemical aberrations produced by chlordecone. Chronic exposure causes carcinogenesis in mice and rats. Hyperplastic nodules, which progress to hepatocellular carcinomas, are the principal pathological lesions. Acute and chronic exposures to chlordecone result in hepatobiliary dysfunction manifested as impaired excretion of anionic compounds accompanied by choleresis. Exposure to chlordecone results of greatly potentiated haloalkane hepatotoxicity, representing a most potent toxic interaction at otherwise individually nontoxic levels. In view of the demonstrated carcinogenic effect of chlordecone, such interactions at very low levels assume extraordinary significance in terms of chronic toxicological and pathological manifestations induced by combinations of toxic chemicals.


N-Carboxyanhydride Polymerization of Glycopolypeptides That Activate Antigen-Presenting Cells through Dectin-1 and Dectin-2.
The C-type lectins dectin-1 and dectin-2 contribute to innate immunity against microbial pathogens by recognizing their foreign glycan structures. These receptors are promising targets for vaccine development and cancer immunotherapy. However, currently available agonists are heterogeneous glycoconjugates and polysaccharides from natural sources. Herein, we designed and synthesized the first chemically defined ligands for dectin-1 and dectin-2. They comprised glycopolypeptides bearing mono-, di-, and trisaccharides and were built through polymerization of glycosylated N-carboxyanhydrides. Through this approach, we achieved glycopolypeptides with high molecular weights and low dispersities. We identified structures that elicit a pro-inflammatory response through dectin-1 or dectin-2 in antigen-presenting cells. With their native proteinaceous backbones and natural glycosidic linkages, these agonists are attractive for translational applications.


Continuous shear wave measurements for dynamic cardiac stiffness evaluation in pigs.
Ultrasound-based shear wave elastography is a promising technique to non-invasively assess the dynamic stiffness variations of the heart. The technique is based on tracking the propagation of acoustically induced shear waves in the myocardium of which the propagation speed is linked to tissue stiffness. This measurement is repeated multiple times across the cardiac cycle to assess the natural variations in wave propagation speed. The interpretation of these measurements remains however complex, as factors such as loading and contractility affect wave propagation. We therefore applied transthoracic shear wave elastography in 13 pigs to investigate the dependencies of wave speed on pressure-volume derived indices of loading, myocardial stiffness, and contractility, while altering loading and inducing myocardial ischemia/reperfusion injury. Our results show that diastolic wave speed correlates to a pressure-volume derived index of operational myocardial stiffness (R = 0.75, p < 0.001), suggesting that both loading and intrinsic properties can affect diastolic wave speed. Additionally, the wave speed ratio, i.e. the ratio of systolic and diastolic speed, correlates to a pressure-volume derived index of contractility, i.e. preload-recruitable stroke work (R = 0.67, p < 0.001). Measuring wave speed ratio might thus provide a non-invasive index of contractility during ischemia/reperfusion injury.


Hands-on surgical training of congenital heart surgery using 3-dimensional print models.
Patient-based congenital heart surgery (CHS) training is opportunity-based and difficult. Three-dimensional (3D) print models of the heart were used for hands-on surgical training (HOST) at the 2015 AATS and subsequently in 2 local institutions. We aim to introduce the process of 3D printing for surgical simulation and to present the attendee's responses. Using CT or MR angiograms, the models of congenital heart disease were created and printed with flexible rubberlike material. Altogether, 81 established surgeons or trainees performed simulated surgical procedures with the expert surgeons' guidance and supervision. At the completion of the session, 50 of 81 attendees participated in the questionnaire assessment of the program. All responders found the course helpful in improving their surgical skills. All would consider including HOST sessions in the training programs. All found that the models showed the necessary pathologic findings. Most found that the consistency and elasticity of the model material were different from those of the human myocardium. However, the responders thought that the quality of the models was acceptable (88%) or manageable (12%) for surgical practice. The major weaknesses listed were related to the print material and poor representation of the cardiac valves. HOST using 3D print heart models is achievable and allows surgical practice on pathological hearts without patients' risk. HOST is a highly applicable surgical simulation format for CHS. Incorporation of HOST in training programs could change the traditional opportunity-based education to the requirement-based standardized education.


Normally and abnormally functioning left-sided porcine bioprosthetic valves after long-term implantation in patients: distinct spectra of histologic and histochemical changes.
This morphologic study (X-ray examination of gross specimens, histologic study and histochemical staining) compares two groups of explanted left-sided bioprosthetic valves: group I, 6 valves with normal cusp function and group II, 10 valves with significant dysfunction. Implantation periods ranged from 26 to 79 months. A computerized descriptive statistical method (principal component analysis) is used to analyze the qualitative results. Although qualitatively identical alterations are observed in both groups, the findings in the deep layers of the cusps of severe collagen breakdown, intensive fibrin penetration and various degrees of calcification are restricted to group II. Other findings of interest in both groups include amyloid deposits (four cases) and layering of fusiform host cells on the cusp surface (three cases). The computerized study shows that individuals of one clinical group are morphologically different from those of the other. Mechanical stress may contribute to surface alterations early after implantation, while further collagen breakdown and macrophagic activity result in deep penetration of plasma components and fibrin. Subsequent calcification is likely to be dystrophic rather than metabolic. Colonization of the cuspal surface by endothelial cells after long-term implantation of bioprosthetic valves expresses a new type of relation between host and bioprosthesis.


[Cultural hegemony of medicine in modern China].
The paper is to explore into how cultural hegemony had been established in modern China, focused on ideological debates and political conflicts between modernists and traditionalists. Relying upon historical, anthropological, and medico-historical researches respectively by Paul Cohen, Judith Farquhar and Paul Unschuld, I criticize free research paradigms that had prevailed in modern Chinese History: (i)the 'Chinese response to Western impact' perspective fails to explain how Chinese Western medical practitioners founded their own independent organization; (ii) a dichotomy of 'tradition versus modernity' is, from an epistemological viewpoint, incompatible with an ontological view of illness shared between traditional Chinese medicine and Western medicine; and (iii) while those Weberian social scientists tend to consider culture as the system of meanings and symbols, separated from their temporal and spatial matrix, they neglect political and historical spheres that are inevitably represented in cultural hegemony. My arguments are divided into two parts. The first part investigates that whereas Chinese modernists aggressively supported an immediate institutionalization of Western medicine for getting adapted to social Darwinian world, neo- traditionalists tried to maintain medical identity through national essence backed up by Chinese civilization. In the second part, the paper illuminates how having emerged as a conceptual idea for moving beyond 'tradition versus modernity', 'state medicine' became popularized to solve public health problems in 1930s' rural China. In conclusion, cultural hegemony-oriented debates that were seriously staged in the 1920s and 1930s between modernists and neo-traditionalists were transformed to "scientification of traditional Chinese medicine and popularization of Western medicine" a slogan proposed by Mao Ze-Dong.


The effect of cognitive testing and feedback on older adults' subjective age.
Subjective age, or how old a person feels, is an important measure of self-perception that is associated with consequential cognitive and health outcomes. Recent research suggests that subjective age is affected by certain situations, including cognitive testing contexts. The current study examined whether cognitive testing and positive performance feedback affect subjective age and subsequent cognitive performance. Older adults took a series of neuropsychological and cognitive tests and subjective age was measured at various time points. Participants also either received positive or no feedback on an initial cognitive task, an analogies task. Results showed that participants felt older over the course of the testing session, particularly after taking a working memory test, relative to baseline. Positive feedback did not significantly mitigate this subjective aging effect. Results suggest that subjective age is malleable and that it can be affected by standard cognitive and neuropsychological test conditions.


The Influence of Self-Concept on Clinical Decision-Making in Nurses and Nursing Students: A Cross-Sectional Study.
The aim of this study is to examine the influence of nurses' self-concept (NSC) on clinical decision-making (CDM) among nursing students and hospital nurses. A further aim is to examine whether there is a difference in CDM and NSC between hospital nurses with various levels of experience and nursing students. A cross-sectional study was conducted during 2018 in the Faculty of Dental Medicine and Health and the University Hospital Center, in Osijek, Croatia, EU. The respondents consisted of 568 hospital nurses, and 129 BSc nursing students. Data were collected with the clinical decision-making in nursing scale (CDMNS) and the nurses' self-concept questionnaire (NSCQ). There was no correlation between CDM and NSC in either students or hospital nurses. Hospital nurses generally had significantly higher scores in CDM than nursing students. On the other hand, students had a significantly higher total NSC level. The results of this study suggest that experience has a positive impact on nurses' CDM skills. The high NSC estimated by students enables them to easily take up their clinical roles and approach the patient in a holistic manner, which is an attitude that gradually develops during studies and with clinical experience.


Monoclonal antibodies raised against 167-180 aa sequence of human carbonic anhydrase XII inhibit its enzymatic activity.
Abstract Human carbonic anhydrase XII (CA XII) is a single-pass transmembrane protein with an extracellular catalytic domain. This enzyme is being recognized as a potential biomarker for different tumours. The current study was aimed to generate monoclonal antibodies (MAbs) neutralizing the enzymatic activity of CA XII. Bioinformatics analysis of CA XII structure revealed surface-exposed sequences located in a proximity of its catalytic centre. Two MAbs against the selected antigenic peptide spanning 167-180 aa sequence of CA XII were generated. The MAbs were reactive with recombinant catalytic domain of CA XII expressed either in E. coli or mammalian cells. Inhibitory activity of the MAbs was demonstrated by a stopped flow CO2 hydration assay. The study provides new data on the surface-exposed linear CA XII epitope that may serve as a target for inhibitory antibodies with a potential immunotherapeutic application.


More on parental living liver donation for children with fulminant hepatic failure: addressing concerns about competing interests, coercion, consent and balancing acts.
Parental living liver donation for children with fulminant hepatic failure raises complex ethical issues. According to a recent editorial in this journal, these include contradictory interests, the possibility of coercion and compromised consent and the need to balance the risks to the donor against the potential benefits for the recipient. Here I argue that in this setting, interests are often aligned rather than conflicted, that coercion of parental donors is rare, that consent may sometimes be valid even when it is not fully informed and that the correct balance to consider is the relative weights of risks and benefits for the donor. I conclude that living liver donation by parents of children with fulminant hepatic failure is consistent with societal norms of parental behavior, ethically acceptable and should be permitted regardless of the efficiency of the deceased donor organ recovery program.


Fabrication of novel nitrogen-doped graphene-hollow AuPd nanoparticle hybrid films for the highly efficient electrocatalytic reduction of H2O2.
Hollow AuPd (hAuPd) alloy nanoparticles (NPs) were prepared through simultaneous reduction of HAuCl4 and Na2PdCl4 using Co NPs as sacrificial template (i.e., reductant). Then, the hAuPd NPs were assembled on nitrogen-doped graphene (NG) to prepare an NG-hAuPd hybrid film. The obtained NG-hAuPd composite showed higher electrocatalytic activity toward the reduction of H2O2, compared with graphene-hAuPd hybrid, NG-solid AuPd hybrid, and hAuPd NPs. The enhanced performance was related to the hollow structure of hAuPd NPs and the synergistic effect between NG and hAuPd NPs. Under optimum conditions, the NG-hAuPd hybrid film showed a linear response to H2O2 in the range of 0.1-20 μM, with a sensitivity of 5095.5 μA mM(-1) cm(-2)and a comparable detection limit of 0.02 μM (S/N = 3). These results demonstrated that the NG-hAuPd composite was a promising electrocatalytic material for constructing sensors, etc.


The Internet and the menopause consultation: menopause management in the third millennium.
The Internet was born in 1969; it was originally developed so that computers could share information on research and development in the scientific and military fields. The original Internet consisted of four university computers networked in the United States. Email became available two years later. The infant Internet initially required complex computing knowledge to be used. However, this was all to change with the development of the World Wide Web in the early 1990s, which made the Internet much more widely accessible. The Internet has since grown at a phenomenal rate and has evolved into a global communications tool. It is by nature anarchic, in that it is an unrestricted broadcast medium. Although this lack of censorship is a strength, it is also a weakness. The quality of information available on the Web is variable and discernment is required. With the growth of e-health, medicine and its allied specialties are faced with the challenges of providing their services in a novel way while maintaining the first principle of medicine, primum non nocere (first, do no harm). This provision of e-health care is in its infancy and this review explores issues arising from the use of the Internet as a medium for organizing menopausal health care in the third millennium.


Role of autophagy in the control of body metabolism.
Autophagy plays a crucial role in the maintenance of cellular nutrient balance and the function of organelles such as mitochondria or the endoplasmic reticulum, which are important in intracellular metabolism, insulin release, and insulin sensitivity. In the insulin-producing pancreatic β-cells, autophagy is important in the maintenance of β-cell mass, structure, and function. Mice with deficiencies in β-cell-specific autophagy show reduced β-cell mass and defects in insulin secretion that lead to hypoinsulinemia and hyperglycemia but not diabetes. However, these mice developed diabetes when bred with ob/ob mice, suggesting that autophagy-deficient β-cells have defects in dealing with the increased metabolic stress imposed by obesity. These results also imply that autophagy deficiency in β-cells could be a factor in the progression from obesity to diabetes. Another important function of autophagy is in hypothalamic neurons for the central control of energy expenditure, appetite, and body weight. In addition, mice with autophagy deficiencies in the target tissues of insulin have yielded diverse phenotypes. Taken together, these results suggest that autophagy is important in the control of whole body energy and nutrient homeostasis, and its dysregulation could play a role in the development of metabolic disorders and diabetes.


Increase of plasma fibrinogen levels and variability with age in a sample of middle aged healthy men.
According to predictions from the current theoretical models for ageing the heterogeneity of the population is increasing with increasing age. Although the direct observation of such changes in humans is extremely difficult, supporting evidence should be identifiable in key biomarkers associated with health and mortality. Using data from the Northwick Park Heart Study II of 3052 healthy middle-aged men (mean 56 years of age, range 49-69 years), with 5 annual measures of CHD risk factors, ageing effects were tested for plasma fibrinogen, cholesterol and triglycerides. Fibrinogen levels increased with age (p < 0.0001), while cholesterol showed a decrease, and triglycerides did not show any change with age. There was a significant increase in the variance of fibrinogen with age (p < 0.0007) but not for cholesterol or triglycerides. The raising effect on fibrinogen levels associated with the A allele of the FIBB - 455G>A promoter variant also decreased with age (p = 0.005). The age-associated changes observed in the fibrinogen variability and the association of phenotype to genotype are discussed in light of the evolutionary theory, and their implications are considered.


Influence of growing phase feed efficiency classification on finishing phase growth performance and carcass characteristics of beef steers fed different diet types.
A 5-yr study was conducted using 985 crossbred steers (464 kg [SD 32]) fed in 6 separate, replicated groups to determine the influence of growing phase (GP) feed efficiency (FE) classification and diet type on finishing phase (FP) FE of steers. During the GP at the University of Missouri, steers were fed either a whole shell corn-based diet (G-Corn; 528 steers) or a roughage-based diet (G-Rough; 457 steers) using GrowSafe feed bunks to measure DMI for 69 to 89 d. At the end of the GP, steers were ranked by residual feed intake (RFI) within diet, shipped to Iowa State University, and blocked into FP pens (5 to 6 steers/pen) by GP diet and RFI rank (upper, middle, or lower one-third). Steers were transitioned to either FP cracked corn- or byproduct-based diets and fed until 1.27 cm backfat was reached. After completion of the sixth group, average GP G:F within GP diet was calculated for each FP pen (168 total pens) using GP initial BW as a covariate (G-Corn: 0.207 [SD 0.038]; G-Rough: 0.185 [SD 0.036]). Pens were classified as highly feed efficient (HFE; >0.5 SD from the G:F mean; 58 pens), mid feed efficient (MFE; ±0.5 SD from the G:F mean; 60 pens), or lowly feed efficient (LFE; <0.5 SD from the G:F mean; 50 pens). Data were analyzed using PROC MIXED of SAS. Experimental unit was FP pen and the model included the fixed effects of GP diet, FE classification, FP diet, and the interactions. Group (1 to 6) was included as a fixed effect. There were no 3-way interactions ( ≥ 0.2) for any measured traits. Finishing phase G:F was not affected by any interactions ( ≥ 0.5) but was greater ( ≤ 0.03) for HFE versus MFE and LFE and greater ( = 0.02) for MFE versus LFE. Growing phase diet × FE classification effects were detected ( ≤ 0.01) for FP final BW (FBW), ADG, and DMI. Among G-Rough steers, HFE and MFE had greater ( ≤ 0.04) FBW and ADG than LFE, but among G-Corn steers, LFE had heavier ( = 0.03) FBW than HFE whereas ADG was unaffected ( ≥ 0.2) by FE classification. Dry matter intake was unaffected ( ≥ 0.3) by FE classification among G-Rough steers, but among G-Corn steers, LFE had greater ( ≤ 0.003) DMI than MFE and HFE. Overall, differences in FP G:F between FE classifications were driven by different factors depending on diet; ADG differed among roughage-grown steers and DMI differed among corn-grown steers. Ultimately, steers classified as HFE during the GP still had superior FE during the FP.


Comparison of MSC-Neurogenin1 administration modality in MCAO rat model.
Intracerebral (IC) grafting of mesenchymal stem cells (MSCs) is not currently used in humans due to its potential complications. On the other hand, intra-arterial (IA) administration can be facilitated for engrafting of intensifed MSCs in the injured human brain. The study is designed to compare the two methods of MSC administration using IA and IC routes through the parameters of behavior, infarct volume, cell distribution, and MSC identification. An ischemic stroke model was generated in Sprague Dawley male rats. This experiment used MSCs/Ngn1 that express Neurogenin1 (Ngn1) to ensure grafted MSC maintenance. MSCs/Ngn1 or normal saline was administrated via the IC or IA route on day 3. All animals were randomly assigned into four groups (five rats in each group): IC-control, IA-control, IC-MSCs/Ngn1, or IA-MSCs/Ngn1. Motor behaviors, infarct volume, and distribution of superparamagnetic iron oxide (SPIO)-labeled cells on magnetic resonance imaging (MRI) were compared from each group. There were no baseline differencess in motor behaviors or infarct volume between IC-MSCs/Ngn1 and IA-MSCs/Ngn1. Hovever, the IA-MSCs/Ngn1 group showed the greatest recovery on Rotarod testing and adhesive removal tests (p = 0.003 and p = 0.009 vs. IC-MSCs/Ngn1, respectively). The IA-MSCs/Ngn1 group also had more evenly distributed SPIO-labeled cells on MRI. The results suggest that IA administration is likely to be benefcial for humans based on its ability to improve behavioral outcomes and ensure even MSC engrafting.


Inhaled nitric oxide for acute right-ventricular dysfunction after extrapleural pneumonectomy.
Increased pulmonary vascular pressure and decreased right-ventricular performance may occur following pneumonectomy. Inhaled nitric oxide decreases right-ventricular afterload and improves cardiac index by selectively decreasing pulmonary vascular resistance without causing systemic hypotension. We report the use of inhaled nitric oxide in a patient with acute right-ventricular dysfunction after extrapleural pneumonectomy.


Prevalence, multiple antibiotic resistance and virulence profile of methicillin-resistant Staphylococcus aureus (MRSA) in retail poultry meat from Edo, Nigeria.
Staphylococcus aureus causes staphylococcal food poisoning and several difficult-to-treat infections. The occurrence and dissemination of methicillin-resistance S. aureus (MRSA) in Nigeria is crucial and well documented in hospitals. However, findings on MRSA from meat in the country are yet to be adequately reported. The current study determined the prevalence, virulence profile and antibiogram characteristics of MRSA from a raw chicken product from retail outlets within Edo. A total of 368 poultry meat samples were assessed for MRSA using a standard culture-based approach and characterized further using a molecular method. The antimicrobial susceptibility profile of the isolates was determined using the disc diffusion method. The biofilm profile of the isolates was assayed via the crystal violet microtitre-plate method. Virulence and antimicrobial resistance genes were screened using polymerase chain reaction via specific primers. Of the samples tested, 110 (29.9%) were positive for MRSA. All the isolates were positive for deoxyribonuclease (DNase), coagulase and beta-hemolysis production. Biofilm profile revealed 27 (24.55%) weak biofilm formers, 18 (16.36%) moderate biofilm formers, and 39 (35.45%) strong biofilm formers. The isolates harboured 2 and ≤17 virulence genes. Enterotoxin gene profiling revealed that 100 (90.9%) isolates harboured one or more genes. Resistance against the tested antibiotics followed the order: tetracycline 64(58.2%), ciprofloxacin 71(64.6%), trimethoprim 71(64.6%) and rifampin 103(93.6%). A total of 89 isolates were multidrug-resistant, while 3 isolates were resistant to all 22 antibiotics tested. The isolates harboured antimicrobial-resistant determinants such as methicillin-resistant gene (mecA), tetracycline resistance genes (tetK, tetL), erythromycin resistance genes (ermA, ermC), trimethoprim resistance gene (dfrK). All the staphylococcal cassette chromosome mec (SCCmec) IVa and SCCmec V positive isolates harboured the Panton-Valentine Leukocidin Gene (PVL). In conclusion, S. aureus was resistant to commonly used antibiotics; a concern to public health concerning the transmission of these pathogens after consuming these highlight the significance of antimicrobial and enterotoxigenic monitoring of S. aureus in food chains.


Tryptase in rat mast cells: properties and inhibition by various inhibitors in comparison with chymase.
Previous studies with trans-4-(guanidinomethyl)cyclohexanecarboxylic acid 4-tert-butylphenyl ester (GMCHA-OPhBut), a trypsin inhibitor, strongly suggested the involvement of a trypsin-like protease in histamine release from mast cells induced by various secretagogues (Takei, M., Matumoto, T., Endo, K. & Muramatu, M. (1988) Agents and Actions, in press; Takei, M., Matumoto, T., Ito, T., Endo, K. & Muramatu, M.; Takei, M., Matumoto, T., Endo, K. & Muramatu, M. and Takei, M., Matumoto, T., Urashima, H., Endo, K. & Muramatu, M., unpublished results). Two serine proteases, chymase (Benditt, E.F. & Arase, M. (1959) J. Exp. Med. 110, 451-460) and tryptase Kido, H., Fukusen, N. & Katunuma, N. (1985) Arch. Biochem. Biophys. 239, 436-443) were demonstrated in rat peritoneal mast cells. Both enzymes were purified and the effects of inhibitors for trypsin and chymotrypsin on these proteases were examined. The trypsin-like protease was found in saline extract and purified by successive chromatographies on Sephadex G-100 and DEAE-cellulose columns. The molecular mass of this protease was apparently 120,000 Da. This protease showed maximal activity at pH 7.1 and was named pH 7 tryptase. Chymase was obtained from 1.5M NaCl extract. pH 7 Tryptase markedly hydrolysed Boc-Phe-Ser-Arg-NH-Mec and Boc-Val-Pro-Arg-NH-Mec among the various substrates containing arginyl and lysyl bonds but did not cleave Tos-Arg-OMe. Tos-Lys-CH2Cl and diisopropylfluorophosphate strongly inhibited this protease. Various inhibitors for trypsin inhibited pH 7 tryptase, and those for chymotrypsin inhibited chymase. Among the esters of GMCHA examined, GMCHA-OPhBut most strongly and competitively inhibited pH 7 tryptase but it had no effect on chymase.


Tubular up-regulation of clusterin mRNA in murine lupus-like nephritis.
Clusterin, a widely distributed glycoprotein, is detected in most tissues and in numerous physiological fluids. In the kidney, this protein is constitutively expressed in tubular epithelial cells, and its expression is enhanced following tubular injuries. In addition, clusterin has been detected in glomerular immune deposits of glomerulonephritis. The present study was designed to define the sites of clusterin mRNA accumulation in murine lupus-like nephritis in comparison with murine tubulopathies. In lupus-like nephritis, a significant increase of clusterin mRNA abundance was demonstrated. This up-regulation was localized exclusively in tubular epithelial cells exhibiting tubulointerstitial alterations, whereas no clusterin mRNA was detectable in diseased glomeruli, excluding an active synthesis of clusterin by glomerular cells. A similar tubular increase of clusterin mRNA abundance was observed in myeloma-like cast nephropathy induced by IgG3 monoclonal cryoglobulins and even in the absence of any detectable histological alterations in a model of septic shock induced by the injection of bacterial lipopolysaccharides. Our results suggest that tubular epithelial cells are the only sites of clusterin mRNA accumulation during the course of lupus-like nephritis and that the tubular up-regulation of clusterin gene expression may reflect the cellular response to various types of tubular injuries.


Dentatorubropallidoluysian atrophy with chronic renal failure in a Japanese family.
We describe a Japanese family with molecularly confirmed DRPLA associated with chronic renal failure of unclear etiology on hemodialysis. The clinical symptoms and laboratory data show that the renal failure in our DRPLA patients is not associated with known familial renal diseases. Thus, we suggest a possible unifying hypothesis that the coexistence of DRPLA and chronic renal failure may be caused by the same etiology.


Perceptions of utilization review nurses. "Nurses like us".
The purpose of this research was to describe the characteristics of nurses who perform telephonic care quality assessment, or utilization review, prior to, concurrent with, and after medical interventions and hospitalizations. It compares these nurses demographically to nurses employed in other settings, discusses the nurses' perceptions of the nature of their work, examines assertions that utilization review is a nursing activity, and documents the nurses' education and training for ethical decision-making. Implications for nursing care quality are discussed.


Palliation for nonpancreatic malignant obstruction of the biliary tract.
To determine the best palliation for nonpancreatic malignant obstruction of the biliary tract, we analyzed 36 patients with unresectable tumors who were treated from 1970 to 1986. Eleven men and 25 women were treated for 12 cholangiocarcinomas, ten carcinomas of the gallbladder, two advanced ampullary tumors and 12 metastatic tumors. Ten of the patients underwent biliary-enteric bypasses; 18 had stents placed, 11 operatively and nine percutaneously. The remaining eight patients received chemotherapy, radiation therapy or no treatment. Median survival time for patients was 209 days after discharge. Survival was not significantly prolonged for patients with bypass versus those with stents. Achieving and maintaining a bilirubin level of less than or equal to 4 were correlated with survival time (p less than 0.01, p less than 0.001). All ten patients with a bypass versus nine of 18 patients with a stent achieved a bilirubin level of less than or equal to 4 milligrams per deciliter (p less than or equal to 0.01). A multivariate analysis was done using 18 of 27 variables identified by univariate analysis. Albumin was found to be the primary predictor of over-all and hospital-free survival time and was a co-predictor of prolonged maintenance of low bilirubin levels along with biliary-enteric bypass. Placement of a stent was the only predictor of the number of episodes of sepsis and bypass was among the few predictors of length of hospitalization and of over-all morbidity (it was negatively correlated). We concluded that biliary-enteric bypass is the only effective means of palliation in that it improves the quality of life by maintaining low bilirubin levels and minimizing septic complications. Albumin is a strong predictor of survival and maintenance of low bilirubin values and should be a major factor in deciding which patient should undergo a bypass procedure.


Identification of an Immune-Related Gene Diagnostic Model and Potential Drugs in Sepsis Using Bioinformatics and Pharmacogenomics Approaches.
Sepsis is an organ dysfunction with high mortality. Early identification, diagnosis, and effective treatment of sepsis are beneficial to the survival of patients. This study aimed to find potential diagnosis and immune-related genes, and drug targets, which could provide novel diagnostic and therapeutic markers for sepsis. The GSE69063, GSE154918 and GSE28750 datasets were integrated to evaluate immune infiltration and identify differentially expressed genes (DEGs) and immune-related genes. Weighted gene co-expression network analysis (WGCNA) was applied to find the hub module related to immune score and sepsis. Immune-related key genes were screened out by taking interaction of DEGs, immune-related genes, and genes in hub module. Protein-protein interaction (PPI) analysis was used to further screen immune-related hub genes, followed by construction of a diagnostic model based on immune-related hub genes. Functional analysis and drug prediction of immune-related hub genes were, respectively, performed by David software and DGIdb database, followed by expression validation by reverse transcriptase polymerase chain reaction (RT-PCR). Totally, 93 immune-related key genes were identified between 561 DEGs, 1793 immune-related genes and 12,459 genes in the hub module of WGCNA. Through PPI analysis, a total of 5 diagnose and immune-related hub genes were further obtained, including IL7R, IL10, CD40LG, CD28 and LCN2. Relationship pairs between these 5 genes and immune cell were identified, including LCN2/IL7R/CD28-activated dendritic cell and IL10-immature B cell. Based on pharmacogenomics, 17 candidate drugs might interact with IL 10, including CYCLOSPORINE. Six candidate drugs might interact with CD28 and 11 with CD40LG, CD40LG and CD28 were drug targets of ALDESLEUKIN. Four significantly enriched signaling pathways were identified, such as T cell receptor signaling pathway, NF-kappa B signaling pathway and JAK-STAT signaling pathway. The 5-gene diagnostic model could be used to diagnose and guide clinical immunotherapy for sepsis.


Apparent deficiency of vitamin B6 in typical individuals who commonly serve as normal controls.
Individuals who typically serve as normal controls were found by the differential assay of the glutamic oxaloacetic transaminase in their erythrocytes to have a deficiency (P less than 0.001) of enzyme activity as well as a deficiency (P less than 0.001) of pyridoxal phosphate. Contrary to the understanding that the diet provides an adequate intake of vitamin B6, the dietary intake of vitamin B6 of these controls was inadequate.


Structure-activity relationships of a series of [D-Ala2]deltorphin I and II analogues; in vitro blood-brain barrier permeability and stability.
[D-Ala2]deltorphins are enzymatically stable, amphibian heptapeptides that have a higher affinity and selectivity for delta-opioid receptors than any endogenous mammalian compound known. This study investigated the in vitro blood-brain barrier permeability, using primary bovine brain microvessel endothelium culture, and the resistance to enzymatic degradation, in mouse 15% brain membrane homogenates and 100% plasma, of [D-Ala2]deltorphin I, [D-Ala2]deltorphin II and several analogues. Derivatives were designed with the addition of N-terminal neutral and basic amino acids or with alterations of the amino acids present within the deltorphin sequences. The results indicated that the N-terminal sequence and the amino acids in position 4 and 5 are critical to deltorphin analogue BBB permeability and biological stability, i.e., t 1/2 brain; 4.8 hr- [D-Ala2]deltorphin I; > 15 hr- [D-Ala2, Ser4, D-Ala5]deltorphin. Although, no analogue was found to increase the BBB permeability coefficient (PC; x10(-4) cm/min) of the parent compounds ([D-Ala2]deltorphin II, PC = 23.49 +/- 2.42) analogues were identified: [Arg0, D-Ala2]deltorphin II, PC = 19.06 +/- 3.73 and [Pro-1, Pro0, D-Ala2]deltorphin II, PC = 22.22 +/- 5.93; which had similar permeability coefficients, even though they had larger molecular weights and, in the case of the cationic prodrug, a significantly lower lipophilicity. These analogues provide directions in the development of future pro-drugs for the treatment of pain and this study further clarifies the structure-activity relationship of the deltorphins.


Comprehensive Analysis of Glycolysis-Related Genes for Prognosis, Immune Features, and Candidate Drug Development in Colon Cancer.
The dysregulated expression of glycolysis-related genes (GRGs) is closely related to the occurrence of diverse tumors and regarded as a novel target of tumor therapy. However, the role of GRGs in colon cancer is unclear. We obtained 226 differential GRGs (DE-GRGs) from The Cancer Genome Atlas (TCGA) database. Cox regression analysis was used to construct a DE-GRG prognostic model, including P4HA1, PMM2, PGM2, PPARGC1A, PPP2CB, STC2, ENO3, and CHPF2. The model could accurately predict the overall survival rate of TCGA and GSE17536 patient cohorts. The risk score of the model was closely related to a variety of clinical traits and was an independent risk factor for prognosis. Enrichment analysis revealed the activation of a variety of glycolysis metabolism and immune-related signaling pathways in the high-risk group. High-risk patients displayed low expression of CD4+ memory resting T cells and resting dendritic cells and high expression of macrophages M0 compared with the expression levels in the low-risk patients. Furthermore, patients in the high-risk group had a higher tumor mutation load and tumor stem cell index and were less sensitive to a variety of chemotherapeutic drugs. Quantitative reverse transcription polymerase chain reaction and immunohistochemistry analyses validated the expression of eight GRGs in 43 paired clinical samples. This is the first multi-omics study on the GRGs of colon cancer. The establishment of the risk model may benefit the prognosis and drug treatment of patients.


Inflammatory bowel disease and cholelithiasis: the association in patients with an ileostomy.
Sixty-nine patients were evaluated prospectively by sonography and history to determine the presence of cholelithiasis. Sixteen patients (23%) had a positive diagnosis. A control group was also prospectively evaluated. We have determined that patients above age 50 with a permanent ileostomy are at statistically significant risk of having cholelithiasis, and their risk is greater than that of a control group matched for age and sex. Radiologists should recognize this association and carefully evaluate the gallbladder of any patient with a permanent ileostomy who has abdominal pain.


First experience with MR-guided focused ultrasound in the treatment of Parkinson's disease.
Radiofrequency (RF) subthalamotomies have been proposed since the 1960s to treat patients suffering from Parkinson's disease (PD). Recently, the magnetic resonance (MR)-guided focused ultrasound technology (MRgFUS) offers the possibility to perform subthalamic thermocoagulations with reduced risks and optimized accuracy. We describe here the initial results of the MRgFUS pallidothalamic tractotomy (PTT), an anatomical and physiological update of the earlier subthalamotomies. Thirteen consecutive patients suffering from chronic (mean disease duration 9.7 years) and therapy-resistant PD were treated unilaterally with an MRgFUS PTT. Primary relief assessment indicators were the score reduction of the Unified Parkinson Disease Rating Scale (UPDRS) and the patient estimation of global symptom relief (GSR) taken at 3 months follow-up. Final temperatures at target were between 52°C and 59°C. The MR examinations were performed before the treatment, 2 days and 3 months after it. The accuracy of the targeting was calculated on 2 days post-treatment MR pictures for each PTT lesion. The first four patients received a PTT using the lesional parameters applied for thalamotomies. They experienced clear-cut recurrences at 3 months (mean UPDRS relief 7.6%, mean GSR 22.5%), and their MR showed no sign of thermal lesion in T2-weighted (T2w) images. As a consequence, the treatment protocol was adapted for the following nine patients by applying repetition of the final temperatures 4 to 5 times. That produced thermocoagulations of larger volumes (172 mm(3) against 83 mm(3) for the first four patients), which remained visible at 3 months on T2w images. These nine patients enjoyed a mean UPDRS reduction of 60.9% and a GSR of 56.7%, very close to the results obtained with radiofrequency lesioning. The targeting accuracy for the whole patient group was 0.5, 0.5, and 0.6 mm for the anteroposterior (AP), mediolateral (ML), and dorsoventral (DV) dimensions, respectively. This study demonstrated the feasibility, safety, and accuracy of the MRgFUS PTT. To obtain similar results as the ones of RF PTT, it was necessary to integrate the fact that white matter, in this case, the pallidothalamic tract, requires repeated thermal exposition to achieve full lesioning and thus full therapeutic effect.


Reactive oxygen species and tumor metastasis.
The migration and invasion of cancer cells are the first steps in metastasis. Through a series of cellular responses, including cytoskeletal reorganization and degradation of the extracellular matrix, cancer cells are able to separate from the primary tumor and metastasize to distant locations in the body. In cancer cells, reactive oxygen species (ROS) play important roles in the migration and invasion of cells. Stimulation of cell surface receptors with growth factors and integrin assembly generates ROS, which relay signals from the cell surface to important signaling proteins. ROS then act within cells to promote migration and invasion. In this review, we collect recent evidence pointing towards the involvement of ROS in tumor metastasis and discuss the roles of ROS at different stages during the process of cancer cell migration, invasion and epithelial-mesenchymal transition.


Effect of chronic treatment with spirapril on biochemical parameters in streptozotocin-diabetic and spontaneously hypertensive rats.
Present investigation was undertaken to study the effects of 6 week treatment with spirapril (2 mg/kg po) on insulin sensitivity, and serum lipid levels in streptozotocin (STZ)-diabetic and spontaneously hypertensive (SH) rats. Treatment of rats with spirapril in diabetic and diabetic with hypertensive animals significantly prevented STZ-induced loss of body weight, hypertension, and bradycardia. It also partially but significantly prevented STZ-induced hyperglycaemia in both diabetic Wistar and SH animals. Insulin level was not altered by spirapril treatment. There was significant reduction in cholesterol levels in the diabetic rats. In conclusion, the present investigation presents a number of beneficial effects of spirapril treatment in diabetic and/or hypertensive rats. Spirapril may be considered as one of the drugs of choice in treatment of hypertension when associated with diabetes


Evaluation of dry eye and Meibomian gland dysfunction in female androgenetic alopecia patients.
To evaluate dry eye tests and Meibomian gland functions in female androgenetic alopecia patients. Twenty left eyes of 20 female androgenetic alopecia patients (Group 1) and 20 left eyes of 20 healthy female volunteers (Group 2) were enrolled in the study. The presence of dry eye was evaluated with Schirmer 1 test, invasive tear film break-up time (T-BUT), Oxford scale scoring and Ocular Surface Disease Index (OSDI) score assessments. Evaluation of upper and lower eyelid Meibomian glands was performed using infrared filter of a slit-lamp biomicroscope, and the drop out ratio was scored for each eyelid. The mean ages of Group 1 and Group 2 were 48.3 ± 6.6 (range, 38-58) and 49.8 ± 5.4 (range, 38-59) years, respectively (P = 0.437). Mean T-BUT was statistically significantly lower in Group 1 (P = 0.013); mean OSDI score was significantly higher in Group 1 (P = 0.049). Mean Schirmer 1 score was lower and mean Oxford score was higher in Group 1, but the differences were not statistically significant (P = 0.291, P = 0.088, respectively). In addition, upper, lower and total meiboscores were significantly higher in Group 1 (P = 0.007, P = 0.003, P = 0.002, respectively). Alterations in sex hormones play a role in the pathogenesis of both female androgenetic alopecia and Meibomian gland dysfunction. Significant differences were detected in the results of dry eye tests and Meibomian gland dropout ratios between subjects with female androgenetic alopecia and healthy control subjects. For this reason, female androgenetic alopecia patients should be examined for dry eye and Meibomian gland dysfunction and should be treated to prevent serious consequences.


Reconstructability analysis as a tool for identifying gene-gene interactions in studies of human diseases.
There are a number of common human diseases for which the genetic component may include an epistatic interaction of multiple genes. Detecting these interactions with standard statistical tools is difficult because there may be an interaction effect, but minimal or no main effect. Reconstructability analysis (RA) uses Shannon's information theory to detect relationships between variables in categorical datasets. We applied RA to simulated data for five different models of gene-gene interaction, and find that even with heritability levels as low as 0.008, and with the inclusion of 50 non-associated genes in the dataset, we can identify the interacting gene pairs with an accuracy of > or =80%. We applied RA to a real dataset of type 2 non-insulin-dependent diabetes (NIDDM) cases and controls, and closely approximated the results of more conventional single SNP disease association studies. In addition, we replicated prior evidence for epistatic interactions between SNPs on chromosomes 2 and 15.


Combined Effects of Feedforward Inhibition and Excitation in Thalamocortical Circuit on the Transitions of Epileptic Seizures.
The mechanisms underlying electrophysiologically observed two-way transitions between absence and tonic-clonic epileptic seizures in cerebral cortex remain unknown. The interplay within thalamocortical network is believed to give rise to these epileptic multiple modes of activity and transitions between them. In particular, it is thought that in some areas of cortex there exists feedforward inhibition from specific relay nucleus of thalamus (TC) to inhibitory neuronal population (IN) which has even more stronger functions on cortical activities than the known feedforward excitation from TC to excitatory neuronal population (EX). Inspired by this, we proposed a modified computational model by introducing feedforward inhibitory connectivity within thalamocortical circuit, to systematically investigate the combined effects of feedforward inhibition and excitation on transitions of epileptic seizures. We first found that the feedforward excitation can induce the transition from tonic oscillation to spike and wave discharges (SWD) in cortex, i.e., the epileptic tonic-absence seizures, with the fixed weak feedforward inhibition. Thereinto, the phase of absence seizures corresponding to strong feedforward excitation can be further transformed into the clonic oscillations with the increasing of feedforward inhibition, representing the epileptic absence-clonic seizures. We also observed the other fascinating dynamical states, such as periodic 2/3/4-spike and wave discharges, reversed SWD and clonic oscillations, as well as saturated firings. More importantly, we can identify the stable parameter regions representing the tonic-clonic oscillations and SWD discharges of epileptic seizures on the 2-D plane composed of feedforward inhibition and excitation, where the physiologically plausible transition pathways between tonic-clonic and absence seizures can be figured out. These results indicate the functional role of feedforward pathways in controlling epileptic seizures and the modified thalamocortical model may provide a guide for future efforts to mechanistically link feedforward pathways in the pathogenesis of epileptic seizures.


Colcemid-induced apoptosis of cultured human glioma: electron microscopic and confocal laser microscopic observation of cells sorted in different phases of cell cycle.
The effect of the antitubulin agent colcemid on human glioma cells was investigated by sorting cells with different DNA content and subjecting them to confocal laser microscopy and transmission electron microscopy. The human glioma cell line U251MG was exposed to colcemid at a concentration of 0.05 microg for 16 h. Flow cytometric analysis revealed the accumulation of cells in S/G2M phase. Cells harvested from each of G0/G1 and S/G2M peaks were then analyzed by confocal laser microscopy and transmission electron microscopy. Confocal laser microscopy revealed that colcemid-treated cells harvested from the G0/G1 peak contained mitotic and apoptotic cells in addition to interphase cells. Electron microscopy confirmed that colcemid-treated cells in the G0/G1 peak had fragmented nuclei typical of apoptotic cells and mitotic cells with altered chromatin structure. Some mitotic cells obtained by mitotic shake-off after treatment with colcemid showed DNA strand breaks defined by in situ nick end labeling. The present study indicates that mitotic as well as interphase apoptosis occurs in U251MG cells following colcemid treatment.


Laboratory Risk Indicator for Necrotizing Fasciitis score for early diagnosis of necrotizing fasciitis in Darwin.
Soft tissue infections are a major health burden in the Top End of the Northern Territory of Australia. Necrotizing fasciitis (NF) is associated with mortality rates from 8 to 40%. Early recognition and aggressive surgical debridement are the cornerstones of successful treatment. The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score, developed by Wong et al., uses six routine biochemical variables to aid early diagnosis. We aim to assess the diagnostic efficacy of the LRINEC score in our population. A retrospective review of patients with NF between 2005 and 2013 was conducted. A time matched cohort of abscesses/cellulitis was selected. Admission bloods were used to calculate the LRINEC score. An intraoperative finding of NF was used as the gold standard definition for comparison. The diagnostic accuracy of the LRINEC score was assessed. Ninety-eight patients with NF and 205 control patients were identified. The area under the receiver operator curve for the LRINEC score in detecting NF was 0.925 (0.890-0.959, P < 0.001). The sensitivity of the LRINEC ≥5 for NF was 76.3%, with a specificity of 93.1%. The positive and negative predictive values were 95.5 and 88.1%, respectively. The positive and negative likelihood ratios were 11 and 0.25. The LRINEC score is a useful, robust, non-invasive and easily calculated scoring system that can be used as an adjunct to early diagnosis of NF. However, a high degree of clinical suspicion remains the most important factor in early diagnosis of NF.


Oromandibular dystonia, mental distress and oro-facial dysfunction-A follow-up 8-10 years after start of treatment with botulinum toxin.
Oromandibular dystonia (OMD) with involuntary jaw and tongue movements may be misdiagnosed as temporomandibular disorders (TMD) and because of the complex muscle activity and involvement of several small muscles, OMD is also considered difficult to treat. The aim was to evaluate OMD in patients 8-10 years after start of treatment with botulinum toxin (BoNT) by self-reported and standardised global scales and questionnaires. Of 21 previously reported patients with OMD, 14 responded to a mail health questionnaire to describe the disease course and treatment effect as well as the overall impact of OMD by a visual analogue scale (VAS), the Patient Health Questionnaire (PHQ) for depression and anxiety, and the Jaw Functional Limitation Scale (JFLS). The results were analysed with non-parametric statistical analysis (Wilcoxon matched-pairs test and Spearman's rank-order correlations). The OMD was still present in 13 patients. In nine patients, the BoNT treatment had continued as monotherapy or combined with oral medication. VAS for OMD was significantly reduced (P < 0.04) over the years, and most patients felt improvement from the treatment. However, the patients had still some functional limitations, typically regarding jaw mobility and communication, and both JFLS and mental distress (PHQ) were significantly correlated with the OMD VAS (rS 0.77 and 0.74). The results showed marked reduction of the experienced OMD with treatment and over time, and also stressed similarities between OMD and TMD. Both dentists and neurologists should be aware of this overlap and reduce misdiagnosis by applying an interdisciplinary approach.


Arrays of sealed silicon nanotubes as anodes for lithium ion batteries.
Silicon is a promising candidate for electrodes in lithium ion batteries due to its large theoretical energy density. Poor capacity retention, caused by pulverization of Si during cycling, frustrates its practical application. We have developed a nanostructured form of silicon, consisting of arrays of sealed, tubular geometries that is capable of accommodating large volume changes associated with lithiation in battery applications. Such electrodes exhibit high initial Coulombic efficiencies (i.e., >85%) and stable capacity-retention (>80% after 50 cycles), due to an unusual, underlying mechanics that is dominated by free surfaces. This physics is manifested by a strongly anisotropic expansion in which 400% volumetric increases are accomplished with only relatively small (<35%) changes in the axial dimension. These experimental results and associated theoretical mechanics models demonstrate the extent to which nanoscale engineering of electrode geometry can be used to advantage in the design of rechargeable batteries with highly reversible capacity and long-term cycle stability.


Physiological Effects of Dietary Amino Acids on Gut Health and Functions of Swine.
Gut health has significant implications for swine overall health status and nutrient utilization, due to its various functions including digestion and absorption of nutrients, secretion of mucins and immunoglobulins, and selective barrier protection against harmful antigens and pathogens. Both the basic anatomical structure of the gut (such as epithelial cells) and its luminal microbiota play important roles for maintaining gut health and functions. The interactions between epithelial cells and luminal microbiota have significant impact on host nutrition and health through the metabolism of dietary components. Amino acids, which are major nutrients for pigs, are not only obligatory for maintaining the intestinal mucosal mass and integrity, but also for supporting the growth of microorganisms in the gut. Dietary amino acids are the major fuel of the small intestinal mucosa. Particularly, glutamate, glutamine, and aspartate are the major oxidative fuel of the intestine. Emerging evidence shows that arginine activates the mTOR signaling pathway in the small intestine. Utilization of glycine by the small intestinal mucosa to synthesize glutathione is a very important physiological pathway, and the role of glycine as a powerful cytoprotectant has also been recognized. The major end products of methionine and cysteine metabolism are glutathione, homocysteine and taurine, which play important roles in the intestinal immune and anti-oxidative responses. Threonine is highly utilized by the gut and is particularly important for mucin synthesis and maintenance of gut barrier integrity. Moreover, either a deficiency or an excess of dietary threonine can reduce the synthesis of intestinal mucosal proteins and mucins in young pigs. Various new functions of amino acids on gut health and functions have been discovered in recent years. Thus, this review is to provide some up-to-date knowledge for industry application of dietary amino acids in order to enhance swine gut health and functions, and also it is to provide a comprehensive reference for further scientific research in this regard.


Screen-Based Behaviors of Children and Cardiovascular Risk Factors.
To determine whether the amount of time spent in screen-based behaviors (SBBs; television viewing, computer use, and playing electronic games) is independently associated with individual and clustered cardiovascular disease (CVD) risk factors among elementary school children. Baseline data were used from 264 children (age 7-10 years) participating in the Transform-Us! cluster-randomized controlled trial. Time (h/d) spent in SBBs was obtained using a parent proxy-report questionnaire. Anthropometrics, blood pressure (BP), and lipids were measured using standard techniques. A clustered CVD risk score was calculated as the average of the standardized values of the subcomponents (waist circumference [WC], systolic BP, diastolic BP, and lipids). After adjusting for sex, parent education, physical activity (accelerometry), diet, and WC (when adiposity was not the outcome), television viewing time was positively associated with body mass index z-score (P = .002), WC (P = .02), and systolic BP (P = .05). Electronic games was positively associated with low density lipoprotein levels (P = .05), and total screen-time was positively associated with body mass index (P = .02). Differential associations were observed between types of SBBs and CVD risk factors, indicating that not all SBBs are adversely associated with obesity and CVD risk. There is a need to differentiate between types of SBBs when evaluating the CVD risk associated with screen behaviors in children. International Standard Randomized Controlled Trial: ISRCTN83725066; Australian New Zealand Clinical Trials Registry: ACTRN12609000715279.


Health-Related Quality of Life Dynamics 2 Years Following Aneurysmal Subarachnoid Hemorrhage: A Prospective Cohort Study Using EQ-5D.
Previous studies have shown that aneurysmal subarachnoid hemorrhage (aSAH) affects health-related quality of life (HRQoL) to a large extent. However, longitudinal studies on HRQoL after aSAH are scarce, and there is limited knowledge whether different HRQoL dimension scores change over time, and if so, if the scoring differs from results from the general population. To evaluate HRQoL dynamics over time, 2 years following aSAH, and compare the results with general population. In a prospective cohort design, 88 consecutive aSAH patients (85% of eligible) were followed up with the generic HRQoL instrument EQ-5D at 3 time points: 6 months, 1 year, and 2 years after the onset. Data were collected in 2006 to 2009, and the results were compared with a general population sample from the Stockholm Public Health Survey 2006, matched by age and sex. Overall HRQoL in the aSAH sample was stationary over time. Improved function was only found in the usual activities dimension (P = .026). HRQoL was most affected in participants reporting comorbidity. Compared with the general population, women in the aSAH sample reported significantly more problems in 4 out of 5 dimensions (mobility, self-care, usual activities, and anxiety/depression). Men in the aSAH sample reported significantly more problems in the usual activities dimension in comparison to the general population. HRQoL is stationary during the first 2 years following aSAH, and is significantly worse when compared to the general population. Rehabilitation efforts should be initiated shortly after hospitalization.


The behavioral economics of drug dependence: towards the consilience of economics and behavioral neuroscience.
In this chapter, we review the research in this growing field by first discussing the concepts related to price and consumption (demand), its applications to the study of drug consumption and drug seeking, and the impact of other commodities on drug consumption. We then review the discounting of future commodities and events among the addicted, review the most recent research examining the neural correlates of discounting, and describe and review the new theory of addiction that results from that research. We conclude by addressing the next research steps that these advances engender.


Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab.
Dimerization is essential for activity of human epidermal growth factor receptors (HER1/EGFR, HER2/ErbB2, HER3/ErbB3, and ErbB4) and mediates intracellular signaling events leading to cancer cell proliferation, survival, and resistance to therapy. HER2 is the preferred dimerization partner. Activation of HER signaling pathways may be blocked by inhibition of dimer formation using a monoclonal antibody (MAb) directed against the dimerization domain of HER2. The murine MAb 2C4 that specifically binds the HER2 dimerization domain was cloned as a chimeric antibody, humanized using a computer-generated model to guide framework substitutions, and variants were tested as Fabs. Pharmacokinetics and toxicology were evaluated in rodents and cynomolgus monkeys. Cloning the variable domains of MAb 2C4 into a vector containing human kappa and CH1 domains allowed construction of a mouse-human chimeric Fab. DNA sequencing of the chimeric clone permitted identification of CDR residues. The full-length IgG1 of variant F-10 was equivalent in binding to chimeric IgG1 and was designated pertuzumab (rhuMAb 2C4; Omnitarg). Pertuzumab pharmacokinetics was best described by a two-compartment model with a distribution phase of <1 day, terminal half-life of approximately 10 days, and volume of distribution of approximately 40 mL/kg that approximates serum volume. With the exception of diarrhea, pertuzumab was generally well tolerated in cynomolgus monkeys. Pertuzumab, a recombinant humanized IgG1 MAb, is the first of a new class of agents known as HER dimerization inhibitors. Inhibition of HER dimerization may be an effective anticancer strategy in tumors with either normal or elevated expression of HER2.


Influence of porcine circovirus type 2 vaccination on the probability and severity of pneumonia detected postmortem.
To evaluate the influence of porcine circovirus type 2 vaccination (PCV-2) on the probability and severity of pneumonia, postmortem findings of 247,505 pigs slaughtered between 2008 and 2011 were analysed by applying a cumulative link mixed model. Three major effects could be observed: (1) PCV-2 vaccination significantly (P<0.01) reduced the odds (coefficient: -0.05) of postmortem findings of mild, moderate and severe pneumonia for vaccinated pigs. (2) Pigs from fattening farms were less likely (coefficient: -0.44; P<0.05) to exhibit signs of pneumonia at slaughter than pigs from farrow-to-finish farms. (3) When vaccinated, the odds of detecting postmortem signs showed an even more pronounced reduction (coefficient: -0.19; P<0.001) for pigs from fattening farms. Combining PCV-2 vaccination, farm type and interaction effects between these two factors, a pig vaccinated against PCV-2 from a fattening farm had only half the chance (OR 0.51) of pneumonia being detected at postmortem than a non-vaccinated pig from a farrow-to-finish farm. The study demonstrates the benefit of a vaccination programme against PCV-2 as an important tool to reduce the risk of postmortem pneumonia findings and the severity of pneumonia in pigs at slaughter.


NMR study on the binding of neuropeptide achatin-I to phospholipid bilayer: the equilibrium, location, and peptide conformation.
Molecular mechanism of the binding of neuropeptide achatin-I (Gly-D-Phe-Ala-Asp) to large unilamellar vesicles of zwitterionic egg-yolk phosphatidylcholine (EPC) was investigated by means of natural-abundance (13)C and high-resolution (of 0.01 Hz order) (1)H NMR spectroscopy. The binding equilibrium was found to be sensitive to the ionization state of the N-terminal NH(3)(+) group in achatin-I; the de-ionization of NH(3)(+) decreases the bound fraction of the peptide from approximately 15% to nearly none. The electrostatic attraction between the N-terminal positive NH(3)(+) group and the negative PO(4)(-) group in the EPC headgroup plays an important role in controlling the equilibrium. Analysis of the (13)C chemical shifts (delta) of EPC showed that the binding location of the peptide within the bilayer is the polar region between the glycerol and ester groups. The binding caused upfield changes Delta delta of the (13)C resonance for almost all the carbon sites in achatin-I. The changes Delta delta for the ionic Asp at the C-terminus are more than five times as large as those for the other residues. The drastic changes for Asp result from the dehydration of the ionic CO(2)(-) groups, which are strongly hydrated by electrostatic interactions in bulk water. The side-chain conformational equilibria of the aromatic d-Phe and ionic Asp residues were both affected by the binding, and the induced changes in the equilibria appear to reflect the peptide-lipid hydrophobic interactions.