Effect of corticosterone on adrenal 5-ene-3 beta-hydroxysteroid dehydrogenase in estrogen-treated rats.
Treatment of adult male rats with estradiol-17 beta for 7 days results in adrenal hyperplasia, increased level of serum ACTH along with reduction in serum level of alpha 2u-globulin and inhibition of adrenal 5-ene-3 beta-hydroxysteroid dehydrogenase (5-ene-3 beta-HSD) activity. Administration of corticosterone in estrogen-treated rats reverses the effects of estrogen while in normal rats corticosterone treatment reduces adrenal weight, serum ACTH and adrenal 5-ene-3 beta-HSD activity. In vitro experiments show that alpha 2u-globulin fails to change adrenal 5-ene-3 beta-HSD activity in corticosterone pretreated rats while in normal and estrogen pretreated rats alpha 2u-globulin increases 5-ene-3 beta-HSD activity.


Vaccine microarray patch self-administration: An innovative approach to improve pandemic and routine vaccination rates.
The high-density microprojection array patch (HD-MAP) is a novel vaccine delivery system with potential for self-administered vaccination. HD-MAPs provide an alternative to needle and syringe (N&S) vaccination. Additional advantages could include reduced cold-chain requirements, reduced vaccine dose, reduced vaccine wastage, an alternative for needle phobic patients and elimination of needlestick injuries. The drivers and potential benefits of vaccination by self-administering HD-MAPs are high patient acceptance and preference, higher vaccination rates, speed of roll-out, cost-savings, and reduced sharps and environmental waste. The HD-MAP presents a unique approach in pandemic preparedness and routine vaccination of adults. It could alleviate strain on the healthcare workforce and allows vaccine administration by minimally-trained workers, guardian or subjects themselves. Self-vaccination using HD-MAPs could occur in vaccination hubs with supervision, at home after purchasing at the pharmacy, or direct distribution to in-home settings. As a result, it has the potential to increase vaccine coverage and expand the reach of vaccines, while also reducing labor costs associated with vaccination. Key challenges remain around shifting the paradigm from medical professionals administrating vaccines using N&S to a future of self-administration using HD-MAPs. Greater awareness of HD-MAP technology and improving our understanding of the implementation processes required for adopting this technology, are critical factors underpinning HD-MAP uptake by the public.


Quercetin prevents necrotic cell death induced by co-exposure to benzo(a)pyrene and UVA radiation.
The phototoxicity of low-energy ultraviolet radiation, such as UVA, can be enhanced by the presence of photosensitizing agents. Hence, co-exposure of cells to benzo[a]pyrene (BaP), a widespread environmental carcinogen and photosensitizing agent, and UVA may synergistically induce DNA damage. In this study, exposure of cells to various concentrations of BaP for 1h followed by UVA irradiation (2J/cm(2)) increased DNA damage and decreased cell viability. Expression of apoptosis-related proteins (caspase-9, caspase-3, PARP, and Bax) and hypodiploid DNA content (sub-G(1)) were not changed. LDH release into the culture medium increased in a dose-dependent manner with BaP under UVA irradiation, suggesting that cell death due to BaP/UVA co-treatment occurred via necrosis. Intracellular reactive oxygen species (ROS) levels were increased significantly in the co-exposed cells, and treatment with the polyphenol quercetin, but not with sodium azide or N-acetylcysteine, decreased ROS levels and increased cell viability in BaP/UVA-treated cells. In conclusion, UVA irradiation combined with BaP synergistically promoted necrosis of A549 cells by increasing intracellular ROS levels, and quercetin prevented BaP-enhanced phototoxicity due to UVA irradiation.


Pregnancy-induced physiological hypertrophic preconditioning attenuates pathological myocardial hypertrophy by activation of FoxO3a.
Previous studies show a woman's pregnancy is correlated with post-reproductive longevity, and nulliparity is associated with higher risk of incident heart failure, suggesting pregnancy likely exerts a cardioprotection. We previously reported a cardioprotective phenomenon termed myocardial hypertrophic preconditioning, but it is unknown whether pregnancy-induced physiological hypertrophic preconditioning (PHP) can also protect the heart against subsequent pathological hypertrophic stress. We aimed to clarify the phenomenon of PHP and its mechanisms. The pluripara mice whose pregnancy-induced physiological hypertrophy regressed and the nulliparous mice underwent angiotensin II (Ang II) infusion or transverse aortic constriction (TAC). Echocardiography, invasive left ventricular hemodynamic measurement and histological analysis were used to evaluate cardiac remodeling and function. Silencing or overexpression of Foxo3 by adeno-associated virus was used to investigate the role of FoxO3a involved in the antihypertrophic effect. Compared with nulliparous mice, pathological cardiac hypertrophy induced by Ang II infusion, or TAC was significantly attenuated and heart failure induced by TAC was markedly improved in mice with PHP. Activation of FoxO3a was significantly enhanced in the hearts of postpartum mice. FoxO3a inhibited myocardial hypertrophy by suppressing signaling pathway of phosphorylated glycogen synthase kinase-3β (p-GSK3β)/β-catenin/Cyclin D1. Silencing or overexpression of Foxo3 attenuated or enhanced the anti-hypertrophic effect of PHP in mice with pathological stimulation. Our findings demonstrate that PHP confers resistance to subsequent hypertrophic stress and slows progression to heart failure through activation of FoxO3a/GSK3β pathway.


Serum osteocalcin concentrations in children with metabolic bone disease.
We surveyed both normal children and patient populations to identify the effects of metabolic bone disease and impaired renal function on serum levels of osteocalcin, a vitamin K-dependent protein synthesized in bone. Cord blood osteocalcin was nearly double that of maternal osteocalcin, but there was no correlation between the two. Infants with Apgar scores less than or equal to 7 had a lower mean serum osteocalcin value (8.7 ng/ml, n = 8) than did those with scores of 8 to 10 (16.6 ng/ml, n = 38). Serum osteocalcin elevation coincided with the pubertal growth spurt. In boys, levels decreased to adult values by 18 years of age, as do other indices of bone metabolism; in girls, the levels decreased earlier and had a less pronounced maximum. In children with renal failure, osteocalcin was substantially increased, presumably because of diminished renal clearance of the protein. Children receiving peritoneal dialysis, however, had mean serum concentrations less than half of those seen in children receiving hemodialysis (117 vs 328 ng/ml). The peritoneal dialysate contained significant amounts of osteocalcin, but none was detectable in hemodialysate. Correlation between bone disease and serum osteocalcin was evident in a longitudinal study of one patient with renal failure. Children with various forms of rickets had elevated osteocalcin levels; hypoparathyroidism and osteoporosis were accompanied by variable changes. Serum osteocalcin holds promise as a useful marker of subacute changes in bone metabolism.


Analysis of antioxidative factors related to AMD risk development in the polish patients.
Age-related macular degeneration (AMD) is a major cause of blindness in developed countries. Oxidative mechanisms may play a key role in the aetiology of AMD. The main aim of this study was to investigate antioxidative markers in the pathogenesis of AMD. A total of 510 subjects including 240 patients with AMD (mean age 77.9 ± 8.5 year) and 270 controls (mean age 74.0 ± 10.4 year) were allowed in this study. We measured activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) and examined their association with the SNPs of respective genes (SOD1 + 35A/C, CAT C-262T and GPx Pro197Leu). Restriction fragment length polymorphism (RFLP) technique was used to determine the selected gene polymorphisms. Sixty subjects including 30 patients with AMD (mean age 69.4 ± 9.3) and 30 controls (mean age 64.6 ± 8.2) were enrolled to determine the activity of antioxidant enzymes by spectrometry method. A significant decrease in enzymes, SOD (p = 0.011), CAT (p = 0.002) and GPx (p ≤ 0.001) in AMD patients compared to controls, was indicated. The risk of susceptibility to AMD was significantly higher in patients with AMD who had Pro197Leu C/T genotype of GPx (OR = 2.78; 95% CI = 1.78-4.35). The A/C genotype and the C allele frequencies of A/C polymorphism of SOD1 gene significantly reduce the risk of AMD (OR=0.48; 95% CI 0.27; 0.85). In conclusion, our data showed that insufficient antioxidant capacity may have an important role in age-related macular degeneration. The polymorphism of GPx Pro197Leu may reduce the ability to scavenge free radicals in retina and contribute to the development of AMD.


Progression of natural attenuation processes at a crude-oil spill site: I. Geochemical evolution of the plume.
A 16-year study of a hydrocarbon plume shows that the extent of contaminant migration and compound-specific behavior have changed as redox reactions, most notably iron reduction, have progressed over time. Concentration changes at a small scale, determined from analysis of pore-water samples drained from aquifer cores, are compared with concentration changes at the plume scale, determined from analysis of water samples from an observation well network. The small-scale data show clearly that the hydrocarbon plume is growing slowly as sediment iron oxides are depleted. Contaminants, such as ortho-xylene that appeared not to be moving downgradient from the oil on the basis of observation well data, are migrating in thin layers as the aquifer evolves to methanogenic conditions. However, the plume-scale observation well data show that the downgradient extent of the Fe2+ and BTEX plume did not change between 1992 and 1995. Instead, depletion of the unstable Fe (III) oxides near the subsurface crude-oil source has caused the maximum dissolved iron concentration zone within the plume to spread at a rate of approximately 3 m/year. The zone of maximum concentrations of benzene, toluene, ethylbenzene and xylene (BTEX) has also spread within the anoxic plume. In monitoring the remediation of hydrocarbon-contaminated ground water by natural attenuation, subtle concentration changes in observation well data from the anoxic zone may be diagnostic of depletion of the intrinsic electron-accepting capacity of the aquifer. Recognition of these subtle patterns may allow early prediction of growth of the hydrocarbon plume.


Treatment with a single vaginal suppository containing 15-methyl PGF2 alpha methyl ester at expected time of menstruation.
Termination of early pregnancy, by vaginal administration of prostaglandin analogues, one to three weeks after the first missed menstrual period, has advantages and disadvantages in comparison with vacuum aspiration. Some of these may be reduced if the patient is treated earlier. In the present study the effect and safety of one vaginal administration of 2.5 to 3 mg 15-methyl-PGF2 alpha methyl ester around the expected time of menstruation was evaluated in 16 women exposed to the risk of pregnancy. The overall number of treatment cycles was 35 and pregnancy was confirmed by plasma beta-HCG in eight. The treatment resulted in bleeding in all the pregnant cycles while in the nonpregnant ones it only provoked spotting and bleeding did not begin until the expected time of menstruation. Treatment with 2.5 mg 15-methyl-PGF2 alpha methyl ester resulted in complete abortion in one of three women. If the dose was increased to 3 mg all five treated women aborted. In nonpregnant patients no changes in the levels of estradiol-17 beta or progesterone at any time during the 24-hour observation period were found. Serum cortisol and prolactin but not TSH levels started to increase two hours after the start of treatment and reached a maximum after five hours. The increase coincided with the onset of uterine pain. Ovulatory cycles as judged from basal body temperature occurred in the first menstrual cycle following treatment in all nonpregnant patients. Although possible to use as a "once a month treatment" it seems preferable since the dose is the same, to postpone treatment until menstruation is delayed for a week or more.


Medication persistence for psoriatic arthritis in a Brazilian real-world setting.
To evaluate the persistence of biological (TNF inhibitor [anti-TNF]) and synthetic (conventional synthetic disease-modifying antirheumatic drugs [csDMARDs]) antirheumatic agents for psoriatic arthritis and their associated factors. A historical cohort was developed. Persistence and associated factors were evaluated at 6 and 12 months. A total of 161 patients were included. The anti-TNF treatment presented higher persistence as compared with csDMARDs at 6 (83.4 vs 50.8%; p < 0.05) and 12 months (66.4 vs 35.6%; p < 0.05). From anti-TNFs, adalimumab and etanercept presented similar persistence, along with leflunomide and methotrexate among the csDMARDs. The factors associated with non-persistence with regard to anti-TNF agents were female sex and use of infliximab. Anti-TNF agents are important therapeutic alternatives and present lower rates of discontinuation as compared with csDMARDs.


Postmenopausal hormone therapy and cognition.
This article is part of a Special Issue "Estradiol and cognition". Prior to the publication of findings from the Women's Health Initiative (WHI) in 2002, estrogen-containing hormone therapy (HT) was used to prevent age-related disease, especially cardiovascular disease, and to treat menopausal symptoms such as hot flushes and sleep disruptions. Some observational studies of HT in midlife and aging women suggested that HT might also benefit cognitive function, but randomized clinical trials have produced mixed findings in terms of health and cognitive outcomes. This review focuses on hormone effects on cognition and risk for dementia in naturally menopausal women as well as surgically induced menopause, and highlights findings from the large-scale WHI Memory Study (WHIMS) which, contrary to expectation, showed increased dementia risk and poorer cognitive outcomes in older postmenopausal women randomized to HT versus placebo. We consider the 'critical window hypothesis', which suggests that a window of opportunity may exist shortly after menopause during which estrogen treatments are most effective. In addition, we highlight emerging evidence that potential adverse effects of HT on cognition are most pronounced in women who have other health risks, such as lower global cognition or diabetes. Lastly, we point towards implications for future research and clinical treatments.


Effects of vehicles and enhancers on transdermal delivery of clebopride.
The effects of vehicles and penetration enhancers on the skin permeation of clebopride were evaluated using Franz type diffusion cells fitted with excised rat dorsal skins. The binary vehicle system, diethylene glycol monoethyl ether/isopropyl myristate (40/60, w/w), significantly enhanced the skin permeation rate of clebopride. The skin permeation enhancers, oleic acid and ethanol when used in the binary vehicle system, resulted in relatively high clebopride skin permeation rates. A gel formulation consisting of 1.5% (w/w) clebopride, 5% (w/w) oleic acid, and 7% (w/w) gelling agent with the binary vehicle system resulted in a permeation rate of 28.90 microg/cm2/h. Overall, these results highlight the potential of clebopride formulation for the transdermal route.


Interaction of melatonin with human lymphocytes: evidence for binding sites coupled to potentiation of cyclic AMP stimulated by vasoactive intestinal peptide and activation of cyclic GMP.
Melatonin binding sites were characterized in human blood lymphocytes. The specific binding 2-[125I]iodo-melatonin ([125I]MEL) to human lymphocytes was dependent on time and temperature, stability, saturation, and reversibility. Moreover, guanine nucleotides decreased the specific binding of [125I]MEL to crude membranes of human lymphocytes, suggesting the coupling of these binding sites to a guanosine nucleotide binding regulatory protein(s). In competition studies, the specific binding of [125I]MEL to lymphocytes was inhibited by increasing concentrations of native melatonin. Scatchard analysis showed that data were compatible with the existence of two classes of binding sites: a high-affinity site with a Kd of 5.20 +/- 0.79 nM and a binding capacity of 50.6 +/- 11.0 fmol/10(7) cells, and a low-affinity site with a Kd of 208.5 +/- 50.2 nM and a binding capacity of 2691 +/- 265 fmol/10(7) cells. However, concentration-dependent binding of [125I]MEL to lymphocytes was saturable and resulted in a linear Scatchard plot, suggesting binding to a single class of binding sites. The Kd for the single site was 1.02 +/- 0.34 nM with a binding capacity of 10.1 +/- 1.6 fmol/10(7) cells. Their affinities closely correlated with the production of cyclic nucleotides, suggesting a physiological role for the melatonin binding sites. Thus, melatonin potentiated the effect of vasoactive intestinal peptide (VIP) on cyclic AMP production (ED50 = 1.9 nM) and stimulated cyclic GMP accumulation (ED50 = 125 nM). Results demonstrate the existence of two binding sites for [125I]MEL in human blood lymphocytes, with a high-affinity binding site coupled to the potentiation of the effect of VIP on cyclic AMP production and a low-affinity binding site coupled to activation of cyclic GMP production.


Binding of Mg2+ to single-stranded polynucleotides: hydration and optical studies.
The binding of Mg(2+) to single-stranded ribo- and deoxy-polynucleotides, poly(rA), poly(rU), poly(dA) and poly(dT), has been investigated in dilute aqueous solutions at pH 7.5 and 20 degrees C. A combination of ultrasound velocimetry, density, UV and CD spectroscopy have been employed to study hydration and spectral effects of Mg(2+) binding to the polynucleotides. Volume and compressibility effects of Mg(2+) binding to random-coiled poly(rU) and poly(dT) correspond to two coordination bonds probably between the adjacent phosphate groups. The same parameters for poly(rA)+Mg(2+) correspond to an inner-sphere complex with three-four direct contacts. However, almost no hydration effects are arising in binding to its deoxy analog, poly(dA), indicating mostly a delocalized binding mode. In agreement with hydration studies, optical investigations revealed almost no influence of Mg(2+) on poly(dA) properties, while it stabilizes and aggregates poly(rA) single-helix. The evidence presented here indicates that Mg(2+) are able to bind specifically to single-stranded polynucleotides, and recognize their composition and backbone conformation.


Oxidants and the central nervous system: some fundamental questions. Is oxidant damage relevant to Parkinson's disease, Alzheimer's disease, traumatic injury or stroke?
Radicals are species containing one or more unpaired electrons. The oxygen radical superoxide (O2-) and the non-radical oxidant hydrogen peroxide (H2O2) are produced during normal metabolism and perform several useful functions. Excessive production of O2- and H2O2 can result in tissue damage, which often involves generation of highly-reactive hydroxyl radical (.OH) and other oxidants in the presence of "catalytic" iron ions. A major form of antioxidant defence is the storage and transport of iron ions in forms that will not catalyze formation of reactive radicals. Tissue injury, eg. by ischaemia or trauma, can cause increased iron availability and accelerate free radical reactions. This may be especially important in the brain, since areas of this organ are rich in iron and cerebrospinal fluid cannot bind released iron ions. Oxidant stress upon nervous tissue can produce damage by several interacting mechanisms, including rises in intracellular free Ca2+ and, possibly, release of excitatory amino acids. Recent suggestions that iron-dependent free radical reactions are involved in the neurotoxicity of aluminium and in damage to the substantia nigra in Parkinson's disease are reviewed. Finally, the nature of antioxidants is discussed, it being suggested that antioxidant enzymes and chelators of iron ions may be more generally-useful protective agents than chain-breaking antioxidants.


Multiple Testing and Pattern Recognition in 2-DE Proteomics.
After separation through two-dimensional gel electrophoresis (2-DE), several hundreds of individual protein abundances can be quantified in a cell population or sample tissue. However, gel-based proteomics has the reputation of being a slow and cumbersome art. But art is not dead! While 2-DE may no longer be the tool of choice in high-throughput differential proteomics, it is still very effective to identify and quantify protein species caused by genetic variations, alternative splicing, and/or PTMs. This chapter reviews some typical statistical exploratory and confirmatory tools available and suggests case-specific guidelines for (1) the discovery of potentially interesting protein spots, and (2) the further characterization of protein families and their possible PTMs.


Cortical Correlates of Low-Level Perception: From Neural Circuits to Percepts.
Low-level perception results from neural-based computations, which build a multimodal skeleton of unconscious or self-generated inferences on our environment. This review identifies bottleneck issues concerning the role of early primary sensory cortical areas, mostly in rodent and higher mammals (cats and non-human primates), where perception substrates can be searched at multiple scales of neural integration. We discuss the limitation of purely bottom-up approaches for providing realistic models of early sensory processing and the need for identification of fast adaptive processes, operating within the time of a percept. Future progresses will depend on the careful use of comparative neuroscience (guiding the choices of experimental models and species adapted to the questions under study), on the definition of agreed-upon benchmarks for sensory stimulation, on the simultaneous acquisition of neural data at multiple spatio-temporal scales, and on the in vivo identification of key generic integration and plasticity algorithms validated experimentally and in simulations.


Acquisition of MDR-GNB in hospital settings: a systematic review and meta-analysis focusing on ESBL-E.
Extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) and other multi-drug-resistant Gram-negative bacteria (MDR-GNB) have disseminated globally since their discovery in the late 20th century. Various infection prevention and control measures are in place to prevent nosocomial transmission of these organisms, but their efficacy remains disputed. New literature has emerged in recent years providing further evidence which can be used to formulate effective strategies to tackle this issue in the future. A systematic review was performed to characterize the prevalence of colonization of multi-drug-resistant organisms and subsequent acquisition of these organisms within hospital settings. A meta-analysis was performed to characterize the prevalence and acquisition of ESBL-E in Europe and North America. Twenty-eight studies fulfilled the inclusion criteria. Escherichia coli formed the main burden of MDR-GNB colonization worldwide. Patient-to-patient transmission of ESBL-E was found to be rare, but increased transmissibility of Klebsiella pneumoniae was described over E. coli. Within European and North American healthcare settings, a meta-analysis of eight studies identified a pooled prevalence of ESBL-E on admission to hospital of 7.91% and an acquisition rate of 3.73%. Low prevalence at the point of hospital admission and insufficient evidence of patient-to-patient transmission suggests that infection prevention and control measures such as universal surveillance screening and single-room isolation are unlikely to be practical or effective interventions in reducing the overall burden of ESBL-E in hospitals, in line with current European guidelines. Instead, it is argued that efforts should be placed on controlling the spread of these organisms and other MDR-GNB in the community, predominantly long-term care facilities.


Dissociation of immune capacity from nutritional status by triiodothyronine supplements in severe protein deficiency.
Weanling mice were fed ad libitum from age 23 to 37 days either an 18 or an 0.6% protein diet. Half the animals in each dietary group received supplemental triiodothyronine (T3, 0.2 mg/kg diet). T3 increased the primary in vivo antibody response of protein-deficient mice to sheep red blood cells, as measured by both splenic plaque-forming cells (PFC) per 10(6) nucleated spleen cells and serum hemagglutinin titers. T3 also increased PFC/spleen in well-nourished mice. The effect on protein-deficient animals was achieved although nutritional status in these animals, as estimated by weight loss and carcass composition, was further impaired by T3 supplementation. These results support the hypothesis that immune functions can be improved independently of nutritional status in severe (wasting) malnutrition. Insofar as T3 was effective in a model of malnutrition that does not reduce serum total or free T3 levels, the phenomenon appears to represent a pharmacological action of the hormone.


Predilection muscles and physical condition of raccoon dogs (Nyctereutes procyonoides) experimentally infected with Trichinella spiralis and Trichinella nativa.
The predilection muscles of Trichinella spiralis and T. nativa were studied in 2 experimental groups of 6 raccoon dogs (Nyctereutes procyonoides), the third group serving as a control for clinical signs. The infection dose for both parasites was 1 larva/g body weight. After 12 weeks, the animals were euthanized and 13 sampling sites were analysed by the digestion method. Larvae were found in all sampled skeleton muscles of the infected animals, but not in the specimens from the heart or intestinal musculature. Both parasite species reproduced equally well in the raccoon dog. The median density of infection in positive tissues was 353 larvae per gram (lpg) with T. spiralis and 343 lpg with T. nativa. All the infected animals had the highest larvae numbers in the carpal flexors (M. flexor carpi ulnaris). Also tongue and eye muscles had high infection levels. There were no significant differences in the predilection sites between these 2 parasite species. Trichinellosis increased the relative amount of fat, but not the body weight in the captive raccoon dogs. Thus, Trichinella as a muscle parasite might have catabolic effect on these animals.


Salmonella Pullorum effector SteE regulates Th1/Th2 cytokine expression by triggering the STAT3/SOCS3 pathway that suppresses NF-κB activation.
Salmonella enterica serovar Pullorum (S. Pullorum) can regulate host immunity via special effectors that promote persistent infection and its intracellular survival. SteE as an anti-inflammatory effector is involved in the systemic infection of Salmonella in host macrophages. Macrophage activation can indirectly reflect the immune regulatory function of T helper type 1 (Th1)/T helper type 2 (Th2) cytokines. However, information concerning the regulation of Th1/Th2 cytokine expression by steE in S. Pullorum infection is limited. This study evaluates the effects of steE on the Th1/Th2 balance, STAT3/SOCS3 pathway, and NF-κB P65 activation in S. Pullorum-infected HD-11 cells and in chicken models. We demonstrated that steE diminished the expression of Th1-related cytokines (IFN-γ and IL-12) and promoted the expression of Th2-related cytokines (IL-4 and IL-10) in HD-11 cells and chicken models of S. Pullorum infection. SOCS3 silencing suppressed the function of steE in HD-11 cells and led to the imbalance of Th1/Th2-related cytokines. SteE promoted SOCS3 expression by activating STAT3 in HD-11 cells. Moreover, steE inhibited NF-κB P65 expression and blocked its translocation to the nucleus by promoting SOCS3 expression. Our results illustrated that steE regulated the expression of Th1/Th2 cytokines via modulation of the STAT3/SOCS3 and NF-κB axis, which might be associated with Th1/Th2 cell differentiation and could, therefore, be a novel therapeutic strategy against salmonellosis.


Effect of a wildfire and of post-fire restoration actions in the organic matter structure in soil fractions.
The impact of wildfires and of restoration actions on soil organic matter (SOM) content and structure was studied in a soil under pine (Pinus pinea) from Doñana National Park (SW Spain). Samples were collected from burnt areas before (B) and after post-fire restoration (BR) and compared with an unburnt (UB) site. Analytical pyrolysis (Py-GC/MS) was used to investigate SOM molecular composition in whole soil samples and in coarse (CF) and fine (FF) fractions. The results were interpreted using a van Krevelen graphical-statistical method. Highest total organic carbon (TOC) was found in UB soil and no differences were found between B and BR soils. The CF had the highest TOC values and FF presented differences among the three scenarios. Respect to SOM structure, the B soil was depleted in lignin and enriched in unspecific aromatics and polycyclic aromatic hydrocarbons, and in all scenarios, CF SOM consisted mainly of lignocellulose derived compounds and fatty acids. In general, FF SOM was found more altered than CF. High contribution of unspecific aromatic compounds and polycyclic aromatic hydrocarbons was observed in B-FF whereas BR-FF samples comprised considerable proportions of compounds from labile biomass, possibly due to soil mixing during rehabilitation actions. The fire caused a defunctionalisation of lignin-derived phenolics and the formation of pyrogenic compounds. The van Krevelen diagram was found useful to-at first sight-differentiate between chemical processes caused by fire and of the rehabilitation actions. Fire exerted SOM demethoxylation, dealkylation and dehydration. Our results indicate that soil management actions after the fire lead to an increase in aromaticity corresponding to the accumulation of lignin and polycyclic aromatic compounds. This suggests additional inputs from charred lignocellulosic biomass, including black carbon, that was incorporated into the soil during rehabilitation practices.


Applications of and considerations for using CRISPR-Cas9-mediated gene conversion systems in rodents.
Genetic elements that are inherited at super-Mendelian frequencies could be used in a 'gene drive' to spread an allele to high prevalence in a population with the goal of eliminating invasive species or disease vectors. We recently demonstrated that the gene conversion mechanism underlying a CRISPR-Cas9-mediated gene drive is feasible in mice. Although substantial technical hurdles remain, overcoming these could lead to strategies that might decrease the spread of rodent-borne Lyme disease or eliminate invasive populations of mice and rats that devastate island ecology. Perhaps more immediately achievable at moderate gene conversion efficiency, applications in a laboratory setting could produce complex genotypes that reduce the time and cost in both dollars and animal lives compared with Mendelian inheritance strategies. Here, we discuss what we have learned from early efforts to achieve CRISPR-Cas9-mediated gene conversion, potential for broader applications in the laboratory, current limitations, and plans for optimizing this potentially powerful technology.


Hedgehog coordination of postnatal osteoclast and osteoblast activities.
The Hedgehog (Hh) pathway is important for skeletal patterning and morphogenesis during embryonic development. Papers by Ohba et al. and Mak et al. in this edition of Developmental Cell suggest that Hh signaling may exert delicate control over the activities of osteoclasts and osteoblasts, the cell types primarily responsible for bone resorption and formation.


Preparation of legionaminic acid analogs of sialo-glycoconjugates by means of mammalian sialyltransferases.
Legionaminic acids are analogs of sialic acid that occur in several bacteria. The most commonly occurring form is Leg5Ac7Ac, which differs from Neu5Ac only at the C7 (acetamido) and C9 (deoxy) positions. While these differences greatly reduce the susceptibility of Leg compounds to sialidases, several sialyltransferases have been identified that can use CMP-Leg5Ac7Ac as a donor (Watson et al. 2011). We report the successful modification with Leg5Ac7Ac of a glycolipid, GM1a, and two glycoproteins, interferon-α2b and α1-antitrypsin, by means of two mammalian sialyltransferases, namely porcine ST3Gal1 and human ST6Gal1. The Leg5Ac7Ac form of GD1a was not recognized by the myelin-associated glycoprotein (MAG, Siglec-4), confirming the importance of the glycerol moiety in the interaction of sialo-glycans with Siglecs.


Ductal breast carcinomas with whole chromosome gains as a particular subset of near-diploid tumors with different metastasis free survival.
We recently proposed the existence of a subtype of slightly hyperdiploid ductal breast cancers with cytogenetic alterations differing from those usually observed in the majority of these tumors. We aimed to establish whether these tumors, which represent about 50% of those with a DNA index (DI) comprised between 1.1 and 1.3, correspond to a particular clinicopathological entity. A retrospective study of 1771 patients operated for ductal carcinomas was performed. Three classes of tumors constituted according to DI were compared for the usual clinicopathological factors and clinical outcome. About 690 tumors (39%) were diploid/hypodiploid (DI < 1.1), 134 (7.6%) were hyperdiploid (1.1 < or = DI < 1.3) and 947 (53.4%) were polyploid (DI > or = 1.3). Median follow-up time was 106 months (range 1-177). Polyploid tumors were significantly associated with large tumor size, advanced clinical stage, high histological grade and S-phase fraction (SPF), positive lymph nodes and loss of steroid receptors. Hyperdiploid and diploid/hypodiploid tumors were similar for all the variables except SPF which was significantly higher in hyperdiploid tumors (p < 0.001). Overall survival was similar in hyperdiploid and diploid/hypodiploid tumors in univariate and multivariate analysis, while hyperdiploid tumors were significantly related to a poorer metastasis free survival, both in univariate (p = 0.023) and multivariate analysis (p = 0.031). Despite very close initial clinicopathological and biological characteristics, hyperdiploid tumors differed from diploid/hypodiploid tumors by a higher risk of metastasis, possibly related to their increased SPF.


Adalimumab for psoriasis in Greece: clinical experience in a tertiary referral centre.
Adalimumab, a fully human, anti-TNFα monoclonal antibody has been shown to be effective for moderate-to-severe psoriasis in clinical trial setting. However, only a limited number of studies reflect everyday clinical experience with this drug. To provide evidence on the efficacy, dose optimization and safety of adalimumab based on everyday clinical experience in a tertiary referral centre for psoriasis, in Greece. We retrospectively reviewed the records of all patients with moderate-to-severe psoriasis who received adalimumab, in our referral centre, between January 2008 and October 2010. In total, 52 patients were treated with adalimumab for a mean period of 14 months (range 4-30 months). Mean baseline Psoriasis Area and Severity Index (PASI) was 16.7 (range 9-40.3). At 4, 6, 12 and 18 months, PASI75 was attained by 68%, 82%, 89% and 88% of patients respectively. Nineteen of 52 patients (36%) reached a PASI100 at a mean time of 10 months (range 4-18 months). The dose interval between the injections of adalimumab was increased from 2 to 3 weeks for 14 patients (27%) who achieved and sustained a PASI100 after the first year of treatment, without any relapse. The overall rate of adverse events reached 38%, but treatment was discontinued only in two cases (4%). Our study demonstrates that adalimumab is effective and safe in patients with moderate-to-severe psoriasis in short- and long-term setting. At the same time, it points out novel and interesting issues for further investigation.


Ivabradine in combination with beta-blocker improves symptoms and quality of life in patients with stable angina pectoris: results from the ADDITIONS study.
Several clinical trials have demonstrated the antianginal and anti-ischemic efficacy of ivabradine in combination with beta-blocker in patients with stable angina pectoris. The ADDITIONS (PrActical Daily efficacy anD safety of Procoralan(®) In combinaTION with betablockerS) study evaluated the efficacy, safety, and tolerability of ivabradine added to beta-blocker, and its effect on angina symptoms and quality of life in routine clinical practice. This non-interventional, multicenter, prospective study included 2,330 patients with stable angina pectoris treated with a flexible dose of ivabradine twice daily in addition to beta-blocker for 4 months. The parameters recorded included heart rate, number of angina attacks, nitrate consumption, tolerance, and quality of life. After 4 months ivabradine (mean dose 12.37 ± 2.95 mg/day) reduced heart rate by 19.4 ± 11.4 to 65.6 ± 8.2 bpm (p < 0.0001). The number of angina attacks was reduced by 1.4 ± 1.9 per week (p < 0.0001), and nitrate consumption by 1.9 ± 2.9 U per week (p < 0.0001). At baseline (i.e., on beta-blocker), half of the patients (51%) were classified as Canadian Cardiovascular Society (CCS) grade II; 29% were CCS grade I. After 4 months' treatment with ivabradine, most of the patients were CCS grade I (68%). The EQ-5D index improved by 0.17 ± 0.23 (p < 0.0001). The overall efficacy of ivabradine was considered by the physicians as "very good" (61%) or "good" (36%) in most patients. Suspected adverse drug reactions were documented in 14 patients; none were severe. In daily clinical practice, combining ivabradine with beta-blocker not only reduces heart rate, number of angina attacks, and nitrate consumption, but also improves the quality of life in patients with stable angina pectoris.


Prognostic significance of pathogenic variants in BRCA1, BRCA2, ATM and PALB2 genes in men undergoing hormonal therapy for advanced prostate cancer.
The prognostic significance of germline variants in homologous recombination repair genes in advanced prostate cancer (PCa), especially with regard to hormonal therapy, remains controversial. Germline DNA from 549 Japanese men with metastatic and/or castration-resistant PCa was sequenced for 27 cancer-predisposing genes. The associations between pathogenic variants and clinical outcomes were examined. Further, for comparison, DNA from prostate biopsy tissue samples from 80 independent patients with metastatic PCa were analysed. Forty-four (8%) patients carried germline pathogenic variants in one of the analysed genes. BRCA2 was most frequently altered (n = 19), followed by HOXB13 (n = 9), PALB2 (n = 5) and ATM (n = 5). Further, the BRCA1, BRCA2, PALB2 and ATM variants showed significant association with a short time to castration resistance and overall survival (hazard ratio = 1.99 and 2.36; 95% CI, 1.15-3.44 and 1.23-4.51, respectively), independent of other clinical variables. Based on log-rank tests, the time to castration resistance was also significantly short in patients with BRCA1, BRCA2, PALB2 or ATM somatic mutations and TP53 mutations. Germline variants in BRCA1, BRCA2, PALB2 or ATM are independent prognostic factors of the short duration of response to hormonal therapy in advanced PCa.


Effects of microinjection of histamine into the anterior cingulate cortex on pain-related behaviors induced by formalin in rats.
The present study was aimed to investigate the effects of microinjection of histamine and its H1, H2 and H3 receptor antagonists, mepyramine, ranitidine and thioperamide, respectively, into the anterior cingulate cortex (ACC) on pain-related behaviors induced by formalin in rats. Two stainless steel guide canulas were bilaterally implanted into the ACC of anaesthetized rats. For induction of pain, intraplantar (ipl) injection of a 2.5% formalin solution was performed. The duration of paw licking/biting and the number of paw flinching were recorded in 5 min blocks for 60 min. Locomotor activity was assessed using an open-field test. Formalin produced a marked biphasic pattern of pain. Histamine reduced the second phases of paw licking/biting and flinching. Mepyramine (2 μg/side) prevented the suppressive effect of histamine (1 μg/side) on second phase of pain, but at a dose of 8 μg/side it did not inhibit the suppressive effects of 4 μg/side of histamine. Ranitidine at doses of 2 and 8 μg/side prevented histamine (1 and 4 μg/side)-induced antinociception. Thioperamide not only suppressed the second phases of pain, but also increased the suppressive effect of histamine. Naloxone prevented suppressive effects of histamine and thioperamide on pain. Mepyramine (8 μg/side) suppressed locomotor activity. The results of the present study showed pain suppressing effects for histamine. Histamine H2 and H3, and to a lesser extent, H1 receptors might be involved in histamine-induced antinociception. Opioid receptors might be involved in suppressive effects of histamine and thioperamide.


New thermodynamic/electrostatic models of adsorption and tension equilibria of aqueous ionic surfactant mixtures: application to sodium dodecyl sulfate/sodium dodecyl sulfonate systems.
The nonideal adsorbed solution (NAS) theory has been formally extended to adsorption at the air/water interface from aqueous mixtures of ionic surfactants, explicitly accounting for the surface potential of the adsorbed monolayer with the Gouy-Chapman theory. This new ionic NAS (iNAS) theory is thermodynamically consistent and, when coupled to a micellization model, is valid for concentrations below and above the mixed cmc. Counterion binding is incorporated into the model using two fractional binding parameters, beta(sigma) for the adsorbed monolayer and beta(m) for the micelles. The regular solution theory is used to model the nonideal interactions within the adsorbed monolayer and within the mixed micelles. New tension data for an equimolar mixture of sodium dodecyl sulfate (SDS) and sodium dodecyl sulfonate (SDSn) at two salinities fit this model well when mixing is ideal. The total surface densities, the surface compositions, and the surface potentials for the mixed monolayers are calculated. When there is no added salt, at total surfactant concentrations below the mixed cmc, the adsorbed monolayer is enriched in SDSn, but at total concentrations at and above the mixed cmc, the adsorbed monolayer is nearly an equimolar mixture. In the presence of 100 mM NaCl, the adsorbed monolayer is nearly an equimolar mixture, independent of the total surfactant concentration.


Efficient Mn(II) removal by biological granular activated carbon filtration.
Sufficient and sustainable manganese(II) removal is a challenging task to prevent Mn-related drinking water discoloration problems. This study investigated Mn(II) removal by granular activated carbon (GAC) filtration under various conditions. The results showed that biological GAC filter columns could reduce Mn(II) from 400 μg/L to 10 μg/L after a short ripening period, while sand filter columns did not show evident Mn(II) removal function. Water quality changes, pretreatment with NaClO and chemogenic MnOx coating on GAC media surface did not influence the Mn(II) removal capacity of GAC filter columns. 16S rRNA gene sequencing showed that the abundance of potential Mn(II)-oxidizing bacteria in the GAC media was similar to that in the sand media. However, qPCR results indicated that GAC media colonized dramatically more biomass than sand media, resulting in highly effective Mn(II) removal by GAC filter columns. Under chlorinated conditions, GAC filtration underperformed sand filtration in Mn(II) removal, although activated carbon has been reported to be capable of catalyzing Mn(II) oxidation by chlorine. Fast chlorine decay in GAC filter columns made it hard to sustain chemical Mn(II) oxidation and thus led to less Mn(II) removal. This study highlighted the advantage of biological GAC filtration over sand filtration in Mn(II) removal.


An in vitro study on joint fitting and cartilage thickness in the radiocarpal joint of foals.
The change in the degree of fitting of the opposing articular cartilage surfaces of the radiocarpal joint of foals was studied in vitro using a pneumatic loading device. The thickness of the articular cartilage of the distal radius was examined using radiographic and histological techniques. The thickest cartilage corresponded with the approximate centre of the contact area of the opposing articular surface. The variations in articular cartilage contact area and thickness are discussed.


Intraoperative pulsed Doppler assessment of carotid endarterectomy.
A 20 MHz pulsed Doppler velocimeter and fast Fourier transform spectrum analyzer were used at operation to assess the velocity patterns just prior to and immediately following carotid endarterectomy (TEA). In all 45 sides studied, the status of the endarterectomized segment was verified by operative arteriography. Corresponding Pre-TEA and Post-TEA internal carotid artery spectra were compared to each other and classified according to criteria developed using the ultrasonic Duplex scanner. Of 39 arteries with significant Pre-TEA flow disturbances, improvement in Post-TEA spectral characteristics was observed in 35, and 4 were not changed. Six arteries had only minimal flow disturbances both before and after endarterectomy. In one case the initial Post-TEA spectrum showed a worsening of the flow disturbance which was found on operative arteriography to be due to a stenosis secondary to a technical error. After vein patch angioplasty, the spectrum and repeat arteriogram were both improved. No other significant technical problems were encountered. Although the velocity patterns were improved by endarterectomy in most cases, some residual flow disturbance often remained. Technical factors were not a major cause of the Post-TEA flow disturbances. Lack of improvement or deterioration in the spectra after closure of the arteriotomy may be useful in selecting patients for operative arteriography. Intraoperative spectra also provide important baseline data for long term followup studies.


Three-dimensional reconstruction of the connector of bacteriophage phi 29 at 1.8 nm resolution.
The three-dimensional reconstruction of the connector of bacteriophage phi 29 has been obtained from tilt series of negatively stained tetragonal ordered aggregates under low-dose conditions and up to a resolution of (1/1.8) nm-1. These connectors are built up as dodecamers of only one structural polypeptide (p10). Two connectors form the crystal unit cell, each one facing in the opposite direction with respect to the plane of the crystal and partially overlapping. The main features of the two connectors that build the unit cell were essentially the same, although they were negatively stained in slightly different ways, probably due to their situations with respect to the carbon-coated support grid. The main features of the phi 29 connector structure revealed by this three-dimensional reconstruction are: the existence of two clearly defined domains, one with a diameter of around 14 nm and the other narrower (diameter approximately equal to 7.5 nm); an inner hole running all along the structure (around 7 to 8 nm in height) with a cylindrical profile and an average diameter of 4 nm; a general 6-fold symmetry along the whole structure and a 12-fold one in the wider domain; a clockwise twist of the more contrasted regions of both domains from the narrower towards the wider domain (the direction of DNA encapsidation). These features are compatible with an active role for the connector in the process of DNA packaging.


Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer.
The presence of circulating tumor cells (CTC) is common in prostate cancer patients, however until recently their clinical significance was unknown. The CTC stage is essential for the formation of distant metastases, and their continuing presence after radical prostatectomy has been shown to predict recurrent or latent disease. Despite their mechanistic and prognostic importance, due both to their scarcity and difficulties in their isolation, little is known about the characteristics that enable their production and survival. The aim of this study was to investigate the molecular mechanisms underlying the survival of CTC cells. A novel CTC cell line from the bloodstream of an orthotopic mouse model of castration-resistant prostate cancer was established and compared with the primary tumor using attachment assays, detachment culture, Western blot, flow cytometry and 2D gel electrophoresis. Decreased adhesiveness and expression of adhesion molecules E-cadherin, beta4-integrin and gamma-catenin, together with resistance to detachment and drug-induced apoptosis and upregulation of Bcl-2 were integral to the development of CTC and their survival. Using proteomic studies, we observed that the GRP94 glycoprotein was suppressed in CTC. GRP94 was also shown to be suppressed in a tissue microarray study of 79 prostate cancer patients, indicating its possible role in prostate cancer progression. Overall, this study suggests molecular alterations accounting for the release and survival of CTC, which may be used as drug targets for either anti-metastatic therapy or the suppression of latent disease. We also indicate the novel involvement of GRP94 suppression in prostate cancer metastasis.


[Reconstruction of partial defects at the end of the fingers].
To study the reconstruction of partial defects at the end of the thumbs and other fingers with microsurgical free toe flaps. 21 partial defects (19 cases) at the end of thumbs and other fingers were reconstructed with microsurgical free toe flaps taking from the corresponding toe part. All the free flaps survived. The patients were followed up for 3 - 6 months. The aesthetic and functional results were both satisfactory. The two-point-discrimination distance was 4 - 6 mm. The microsurgical free toe flaps have good therapeutic effect for the reconstruction of partial defects at the end of the fingers.


Effects of cranial electrotherapy stimulation with novel in-ear electrodes on anxiety and resting-state brain activity: A randomized double-blind placebo-controlled trial.
Cranial Electrotherapy Stimulation (CES) is a promising non-invasive brain stimulation technique with the potential to alleviate anxiety. We examined the effectiveness of home-based CES with novel, headphone-like, in-ear electrodes on anxiety-related symptoms and resting-state brain activity. This study spanned 3-weeks, with randomized, double blind, and active-controlled design. Nonclinical volunteers experiencing daily anxiety were randomly assigned to either the active or the sham groups. CES provides an alternating current (10 Hz frequency, 500 μA intensity), connected to smartphone recording treatment logs. Participants treated themselves with 20 trials of CES at home. We evaluated the effectiveness using State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), Wisconsin Card Sort Test (WCST), and resting-state electroencephalography (EEG). The active group showed a significant improvement in state-anxiety compared to sham, while there was a statistical trend in the WCST-Category Completed (p = .061) and no change in depression. In EEG analysis, the active group showed significantly increased relative power for theta in the left frontal region compared with the sham, and this significantly correlated with the changes in state-anxiety. The active group exhibited significantly increased high-beta source activity in cuneus and middle occipital gyrus after intervention compared with the baseline. This study had a relatively short treatment period and small sample size. Our findings provide the first electrophysiological evidence for CES for novel in-ear electrodes to improve anxiety. The modulatory effects of CES on resting-state oscillations of EEG imply that CES could beneficially affect functional brain activity.


Preferential homing of tumor-infiltrating lymphocytes in tumor-bearing mice.
In view of the current interest in the use of lymphoid cells in adoptive immunotherapy of patients with advanced cancer, we have studied the homing patterns of various lymphoid effector cells in mammary-tumor-bearing mice. Single-cell suspensions of total splenocytes, natural killer (NK) cells, and lymphokine-activated killer (LAK) cells were prepared from the spleens of C3H/OuJ mice. Tumor-infiltrating lymphocytes (TIL) were isolated from mammary adenocarcinomas excised from retired breeder females of the same substrain. Effector cells were labeled with indium-111 and injected via a tail vein into female C3H/OuJ mice bearing one or more mammary tumors. Twenty-four hours after administration, total splenocytes, NK cells, and LAK cells distributed themselves evenly between normal mammary tissue and mammary adenocarcinomas. Only TIL had a higher concentration in tumors than in corresponding normal mammary tissue. The ability of the different lymphocyte preparations to lyse YAC-1 cells was determined by means of a 4-h 51Cr-release cytotoxicity assay. Cells harvested from LAK cell cultures and further enriched by centrifugation through a discontinuous Percoll gradient and interleukin-2 (IL-2)-stimulated TIL demonstrated the highest levels of cytotoxicity, while total splenocytes and fresh TIL were characterized by the lowest levels. Since IL-2-stimulated TIL were highly cytotoxic and exhibited better tumor localization than both NK cells and LAK cells in this system, they may be the lymphoid effectors of choice for adoptive immunotherapy of advanced cancer.


Deep Learning in mHealth for Cardiovascular Disease, Diabetes, and Cancer: Systematic Review.
Major chronic diseases such as cardiovascular disease (CVD), diabetes, and cancer impose a significant burden on people and health care systems around the globe. Recently, deep learning (DL) has shown great potential for the development of intelligent mobile health (mHealth) interventions for chronic diseases that could revolutionize the delivery of health care anytime, anywhere. The aim of this study is to present a systematic review of studies that have used DL based on mHealth data for the diagnosis, prognosis, management, and treatment of major chronic diseases and advance our understanding of the progress made in this rapidly developing field. A search was conducted on the bibliographic databases Scopus and PubMed to identify papers with a focus on the deployment of DL algorithms that used data captured from mobile devices (eg, smartphones, smartwatches, and other wearable devices) targeting CVD, diabetes, or cancer. The identified studies were synthesized according to the target disease, the number of enrolled participants and their age, and the study period as well as the DL algorithm used, the main DL outcome, the data set used, the features selected, and the achieved performance. In total, 20 studies were included in the review. A total of 35% (7/20) of DL studies targeted CVD, 45% (9/20) of studies targeted diabetes, and 20% (4/20) of studies targeted cancer. The most common DL outcome was the diagnosis of the patient's condition for the CVD studies, prediction of blood glucose levels for the studies in diabetes, and early detection of cancer. Most of the DL algorithms used were convolutional neural networks in studies on CVD and cancer and recurrent neural networks in studies on diabetes. The performance of DL was found overall to be satisfactory, reaching >84% accuracy in most studies. In comparison with classic machine learning approaches, DL was found to achieve better performance in almost all studies that reported such comparison outcomes. Most of the studies did not provide details on the explainability of DL outcomes. The use of DL can facilitate the diagnosis, management, and treatment of major chronic diseases by harnessing mHealth data. Prospective studies are now required to demonstrate the value of applied DL in real-life mHealth tools and interventions.


Primary intrarenal neuroblastoma: a rare, aggressive tumour of childhood mimicking Wilms' tumour.
Primary intrarenal neuroblastoma is an extremely rare and aggressive tumour of the kidney. We report on a case that mimicked Wilms' tumour. Differentiating primary intrarenal neuroblastoma from Wilms' tumour is important both for management and prognosis.


Fabry disease during childhood: clinical manifestations and treatment with agalsidase alfa.
Fabry disease is a rare X-linked disorder that leads to widespread and progressive disease manifestations, with patients at risk of premature mortality as a result of renal, cardiovascular or cerebrovascular complications. In recent years there has been a growing awareness that the first signs and symptoms of Fabry disease may begin during childhood. Studies show that clinical manifestations such as pain, hypohidrosis, gastrointestinal disturbances, angiokeratomas, cornea verticillata and acroparaesthesiae may be common in childhood and that such manifestations may become apparent during the first few years of life. Despite the early onset of these signs and symptoms, however, diagnosis is often delayed. Interest is now focused on whether enzyme replacement therapy can slow or prevent the onset of these disease manifestations. Preliminary data from two studies suggest that treatment with agalsidase alfa is well tolerated in children and that it may have beneficial clinical effects; however, further research is needed to determine whether enzyme replacement therapy can prevent the development of disease manifestations. The manifestations of Fabry disease first become apparent during childhood. It is well known that disease-associated manifestations are progressive; however, it has yet to be determined whether specific treatment with enzyme replacement therapy can prevent the development of the associated severe and life-threatening complications.


Resolution of superior oblique myokymia with memantine.
We describe a novel treatment of superior oblique myokymia. A 40-year-old woman was treated with gabapentin for this disorder with partial success and reported significant side effects including loss of libido and weight gain. After a drug holiday, memantine therapy was initiated resulting in a substantial improvement in her symptoms with far fewer side effects and stability on long-term maintenance therapy.


Analysis of Density Changes of Selected Brain Receptors After a 14-Day Supply of Chromium(III) and Evaluation of Chromium(III) Affinity to Selected Receptors and Transporters.
Chromium(III) is one of the most controversial biometals. Although, it is no longer on the list of minerals necessary for the proper functioning of the human body, and its pharmacological effect is still under discussion. One of the purposes of Cr(III) administration is to use it in patients with mood disorders and it is strictly related to its pharmacological, not dietary effect. This is because its high doses are necessary to obtain the results and additionally, no deficiencies in human population have been noted. In this study, the affinity of chromium(III) to selected receptors and transporters in the rat brain was evaluated, and the effect of the 14-day administration of this metal was assessed on the density of selected receptors. All analyses were performed in vitro using radioligand binding assays, and the results indicated lack of affinity to β1 and α1 receptors and serotonin transporter (SERT), furthermore very weak affinity to the 5-HT1A receptor (30% inhibition at 10-4 and 10-5 M). Analysis of the α1 and β1 adrenergic receptor density indicated lack of any adaptive effects after 14 days of Cr(III) administration through intraperitoneal injections (doses 6 and 12 mg/kg). The antidepressant activity of chromium(III) indicated in clinical trials concerned patients with atypical, seasonal, or dystonic symptoms. This effect, as it seems based on the presented results, does not depend on direct affinity to serotonin receptors and transporter nor is the result of adaptive changes in the adrenoreceptor system.


Metabolic effects of anti-angiogenic therapy in tumors.
Anti-angiogenic therapy has recently been added to the panel of cancer therapeutics, but predictive biomarkers of response are still not available. In animal models, anti-angiogenic therapy causes tumor starvation by increasing hypoxia and impairing nutrients supply. It is thus conceivable that angiogenesis inhibition causes remarkable metabolic perturbations in tumors, although they remain largely uncharted. We review here recent acquisitions about metabolic effects of angiogenesis blockade in tumors and discuss the possibility that some metabolic features of tumor cells - i.e. their dependency from glucose as primary energy substrate - might affect tumor responses to anti-VEGF treatment.


Effects of chlorogenic acid on adenine nucleotides hydrolyzing enzyme activities and expression in platelets of rats experimentally demyelinated with ethidium bromide.
The effects of chlorogenic acid (one of the major phenolic acid found in human diets) were investigated on the adenine nucleotides hydrolyzing enzymes; ecto-nucleotide pyrophosphatase/phophodiesterase (E-NPP), ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase), E-5'- nucleotidase and ecto-adenosine deaminase (E-ADA) activities and expression in platelets of rats experimentally demyelinated with ethidium bromide. Rats were divided into four groups of eight animals each. Group I rats were control rats; injected with saline (CT), group II rats were injected with saline and treated with chlorogenic acid (AC), group III rats were injected with 0.1% ethidium bromide (EB) and group IV rats were injected with 0.1% EB and treated with chlorogenic acid (EB+AC). The activities of the enzymes were analyzed using colorimetric methods, and the gene expression of NTPDase 1, 2 and 3 were analyzed using the polymerase chain reaction (PCR). The results revealed that there was a significant (P<0.01) reduction in E-NPP activity in EB group (1.63±0.10nmol p-nitrophenol released/min/mg protein) when compared to CT group (2.33±0.14nmol p-nitrophenol released/min/mg protein). However, treatment with chlorogenic acid significantly (P<0.05) increased E-NPP activity in EB group. Furthermore, no significant (P>0.05) change was observed in the E-NPP activity of EB+AC group (2.19±0.08nmol p-nitrophenol released/min/mg protein) when compared to CT group (2.33±0.14nmol p-nitrophenol released/min/mg protein). In addition, there was a significant (P<0.05) increase in AMP hydrolysis in EB rat group when compared to CT group. No significant (P>0.05) difference was observed in AMP hydrolysis between AC, AC+EB and CT groups. Conversely, there were no significant (P>0.05) differences in ATP and ADP hydrolyses between all the groups (AC, EB, AC+EB and CT groups). Likewise, there were no significant (P>0.05) changes in E-ADA activity and percentage platelet aggregation among all groups studied. Similarly, no significant (P>0.05) change was observed in the expression of E-NTPDase 1, 2 and 3 in all the groups tested. Our study revealed that chlorogenic acid may modulate the hydrolysis of adenine nucleotides in platelets of rats demyelinated and treated with chlorogenic acid via alteration of E-NPP and ecto-5'-nucleotidase activities.


Both the phosphoinositide and receptor binding activities of Dab1 are required for Reelin-stimulated Dab1 tyrosine phosphorylation.
Reelin-stimulated tyrosine phosphorylation of the Dab1 adaptor protein is required during brain development for Reelin-dependent neuron positioning in the cerebral cortex and various other laminated regions. Dab1 contains an amino-terminal PTB/PI domain through which it can bind to Reelin receptors and membrane phosphoinositides. The relative contributions of these binding activities were unknown. Here, we identify a mutation in the PTB domain of Dab1 that inhibits membrane localization without inhibiting receptor binding. In neurons, this mutation reduces both basal and Reelin-stimulated Dab1 tyrosine phosphorylation. In contrast, a mutation that inhibits receptor binding reduces Reelin-stimulated but not basal tyrosine phosphorylation. These results support a model in which phospholipids recruit Dab1 to membranes but do not play a direct role in relaying the Reelin signal, while direct Dab1-receptor interaction is responsible for relaying the Reelin signal but not for membrane recruitment.


Predictors of Nonsentinel Lymph Node Metastasis in Cutaneous Melanoma: A Systematic Review and Meta-Analysis.
Although completion lymph node dissection (CLND) is not routinely performed for a positive sentinel lymph node (SLN) anymore, adjuvant therapy depends on the risk factors available from SLN biopsy, including the risk of nonsentinel node metastases (NSNM). A systematic review and meta-analysis was performed in an attempt to identify risk factors that could be used to predict the risk of NSNM. Medline, Web of Science, Embase, and Cochrane were searched for articles discussing predictive factors for NSNM. PRISMA guidelines were followed, and RevMan software was used to calculate pooled odds ratios (OR) using the Mantel-Haenszel test. Fifty publications were suitable for additional analysis. The clinical and primary tumor factors that were consistently identified as risk factors for NSNMs were: age >50, T stage 3 or 4, Clark level IV/V, ulceration, microsatellitosis, lymphovascular invasion, nodular histology, and extremity versus trunk primary tumor location. SLN factors that predicted NSNMs were >1 positive SLN, SLN micrometastatic tumor burden, diameter >2 mm, extracapsular extension, nonsubcapsular location (Dewar), and Rotterdam > 1 mm or ≥ 0.1 mm. The findings in this study support that many clinical and pathologic risk factors that can be assessed with SLN biopsy alone can be used to predict the risk of NSNMs. The factors identified in this review should be evaluated in clinical prediction models to predict the risk of NSNMS, a prediction that may be used to select patients for adjuvant therapy in high-risk melanoma.


Modulation of RNA expression by intracellular calcium. Existence of a threshold calcium concentration for induction of VL30 RNA by epidermal growth factor, endothelin, and protein kinase C.
We investigated the role of intracellular [Ca2+] in mediating the independent signal transduction pathways leading to induction of VL30 RNA expression by multiple agonists in the Rat-1-derived RVL-3 cell line. This cell line contains a single integrated VL30 element, and displays a rapid transcriptional activation of VL30 following stimulation by epidermal growth factor, endothelin, or the phorbol ester tumor promoter 12-O-tetradecanoylphorbol acetate (Rodland, K. D., Brown, A. M. C., and Magun, B. E. (1987) M. Cell. Biol. 7, 2296-2298). Neither epidermal growth factor nor endothelin is dependent upon protein kinase C for activation of VL30 expression, as both of these agonists induce normal levels of VL30 RNA expression, even in cells which have been severely depleted of protein kinase C following chronic 12-O-tetradecanoylphorbol acetate exposure. Induction of VL30 RNA expression by either endothelin or 12-O-tetradecanoylphorbol acetate was blocked by concomitant exposure of RVL-3 cells to the intracellular Ca2(+)-chelating agent 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid at a concentration sufficient to buffer intracellular [Ca2+] below 200 nM, and VL30 RNA was induced by the application of the Ca2+ ionophore A23187 in the absence of agonist. Normal levels of VL30 expression in response to epidermal growth factor were observed at 165 nM [Ca2+], but were significantly inhibited at 115 nM [Ca2+]. Both the protein kinase C-dependent and protein kinase C-independent pathways leading to VL30 transcription were dependent upon the presence of an intracellular [Ca2+] exceeding 115 nM. The dependence upon intracellular Ca2+ transients for transcriptional induction by endothelin appears to be a characteristic of VL30 expression, as 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid treatment did not prevent the endothelin-induced transcription of the protooncogenes c-jun and c-fos.


Biomedical Ethical Aspects Towards the Implementation of Artificial Intelligence in Medical Education.
The increasing use of artificial intelligence (AI) in medicine is associated with new ethical challenges and responsibilities. However, special considerations and concerns should be addressed when integrating AI applications into medical education, where healthcare, AI, and education ethics collide. This commentary explores the biomedical ethical responsibilities of medical institutions in incorporating AI applications into medical education by identifying potential concerns and limitations, with the goal of implementing applicable recommendations. The recommendations presented are intended to assist in developing institutional guidelines for the ethical use of AI for medical educators and students.


Correction to: Determining the effects of trastuzumab, cetuximab and afatinib by phosphoprotein, gene expression and phenotypic analysis in gastric cancer cell lines.
An amendment to this paper has been published and can be accessed via the original article.


Akt2 regulates Rac1 activity in the insulin-dependent signaling pathway leading to GLUT4 translocation to the plasma membrane in skeletal muscle cells.
The small GTPase Rac1 plays a pivotal role in insulin-stimulated glucose uptake in skeletal muscle, which is mediated by GLUT4 translocation to the plasma membrane. However, regulatory mechanisms for Rac1 and its role in the signaling pathway composed of phosphoinositide 3-kinase and the serine/threonine kinase Akt remain obscure. Here, we investigate the role of Akt in the regulation of Rac1 in myocytes. Insulin-induced, but not constitutively activated Rac1-induced, GLUT4 translocation was suppressed by Akt inhibitor IV. Insulin-induced Rac1 activation, on the other hand, was completely inhibited by this inhibitor. Constitutively activated phosphoinositide 3-kinase induced Rac1 activation and GLUT4 translocation. This GLUT4 translocation was almost completely suppressed by Rac1 knockdown. Furthermore, constitutively activated phosphoinositide 3-kinase-induced, but not constitutively activated Rac1-induced, GLUT4 translocation was suppressed by Akt2 knockdown. Finally, insulin-induced Rac1 activation was indeed inhibited by Akt2 knockdown. Together, these results reveal a novel regulatory mechanism involving Akt2 for insulin-dependent Rac1 activation.


Detection and quantification of Citrobacter freundii and C. braakii by 5'-nuclease polymerase chain reaction.
A new 5'-nuclease polymerase chain reaction (PCR) system for the detection and quantification of Citrobacter freundii and C. braakii was developed with primers and the probe oriented to a specific region of the cfa gene encoding a cyclopropane fatty acid synthase. The qualitative variant of the method consisted of a conventional PCR with end-point fluorimetry or agarose gel electrophoresis, and the quantitative variant used kinetic real-time PCR measurement. The PCR system was specific for C. freundii and C. braakii, detecting neither other Citrobacter spp. nor other enteric bacteria (Escherichia coli, Salmonella enterica, and others). The detection limit of the qualitative variant of the method was 10(3) cfu/mL when the amplification was followed by fluorimetry and 10(4) cfu/mL when the amplification was followed by gel electrophoresis. The real-time PCR variant of the method facilitated quantification over a range of concentrations from 10(2) to 10(8) cfu/mL, with Escherichia coli (10(6) cfu/mL) and Salmonella enterica (10(6) cfu/mL) having no effect on the quantification.


Role of alpha class glutathione transferases (GSTs) in chemoprevention: GSTA1 and A4 overexpressing human leukemia (HL60) cells resist sulforaphane and curcumin induced toxicity.
Alpha-class glutathione transferases (α-GSTs) have been shown to protect cells from the harmful effects of reactive oxygen species (ROS) induced lipid peroxidation (LPO) during oxidative stress caused by various physico-chemical agents. While GSTA1-1/A2-2 isozymes exhibit high activity towards lipid and fatty acid hydroperoxides through their selenium independent glutathione peroxidase (GPx) activity, the GSTA4-4 isozyme efficiently metabolizes the LPO product 4-hydroxynonenal (4-HNE) by conjugating it with glutathione (GSH). Because of the fact that ROS generated by the chemopreventive agents, sulforaphane (SFN) and curcumin (Cur), are implicated in the mechanisms of cancer cell killing, the present studies were designed to investigate the contribution of ROS induced LPO in the cytotoxic effects of these agents and the role of α-class GSTs in modulating their toxicity. Human erythroleukemic (HL60) cells were stably transfected with the cDNA encoding the hGSTA1-1 and mGsta4-4 isozymes. After analysing the expression and activities of the respective GST isozymes, the effects of SFN and Cur on the extent of LPO, cytotoxicity and apoptosis were compared in empty vector (VT), hGSTA1-1 and mGsta4-4 expressing HL60 cells. These studies demonstrate that when compared with SFN, Cur was relatively more cytotoxic to HL60 cells. The ectopic expression of hGSTA1-1 and mGsta4-4 isozymes provided resistance to SFN and Cur induced cytotoxicity and apoptosis through a significant suppression of LPO in these cells. Overall, the results suggest that the expression of α-class GSTs in cancer cells can modulate the therapeutic efficacy of chemopreventive agents.


The relationship between unmet cancer care needs and self-rated health among adolescents and young adults with cancer.
Adolescents and young adults (AYA) with cancer face unique psychosocial challenges that often impact their outcomes, including self-rated health. To date, few studies have focused on AYA cancer survivors' multidimensional unmet needs of cancer care in relation to their health status. This study surveyed 324 AYA cancer survivors in a cross-sectional design using the Cancer Needs Questionnaire - Young People (CNQ-YP). In addition to descriptive statistics and bivariate correlations, multinomial logistic regressions were used for analysis. AYA cancer survivors' daily life needs were found to be significantly and negatively associated with self-rated health, OR = 0.910, 95% CI 0.843, 0.983, p < 0.01, and OR = 0.888, 95% CI 0.818, 0.966, p < 0.01. In addition, the unmet work needs were significantly and positively associated with participants' self-rated health, OR = 1.207, 95% CI 1.003, 1.452, p < 0.05. Moving beyond simply describing the unique psychosocial needs confronting AYA cancer survivors, this study empirically identified two specific dimensions of unmet needs of AYA cancer survivors that were significantly correlated to their SRH, both of which should be considered in future service and intervention research to support AYAs with cancer.


Polyglobulia in patients with hemangioblastomas is related to tumor size but not to serum erythropoietin.
Hemangioblastomas are associated with elevated hemoglobin (Hb) levels (polyglobulia), which is associated with a higher risk for cerebral stroke, cardiac infarction and pulmonary embolism. The pathomechanism of polyglobulia remains unclear and different theories have been postulated. Among those are elevated serum erythropoietin (EPO) levels caused by secretion of the tumor or associated tumor cyst. To elucidate the pathomechanism, we systematically investigated the relation between polyglobulia, serum EPO level, size of the solid tumor and associated cyst in hemangioblastomas. We prospectively evaluated hemoglobin and EPO levels in a series of 33 consecutive patients operated on hemangioblastomas in our center. We measured the size of the solid tumor and associated cyst in magnetic resonance imaging. Statistical evaluations were performed using the Fisher's exact test and student's t-test. As a result five patients had elevated hemoglobin levels. Only one of these had an elevated serum EPO level. Of 26 patients with normal hemoglobin levels, 4 patients had elevated EPO levels.Patients with low or normal hemoglobin levels (84%) had an average tumor size of 0.8 cm3, which differed significantly from patients with elevated hemoglobin levels (16%), who had an average solid tumor size of 8.0 cm3 (p < 0.05). We did not observe a significant correlation between EPO levels or polyglobulia and associated cysts. We therefore conclude that in contrast to previous case reports and interpretations, our data show no correlation between polyglobulia and EPO levels or associated cysts in patients with hemangioblastomas. In fact, it is the size of the solid tumor that correlates with polyglobulia.The study was retrospectively registered in the German Clinical Trial Registry on 10 July 2014; Trial registration: DRKS00006310.


Assessment of atrial capture in committed atrioventricular sequential (DVI) pacing systems.
Two patients with committed dual unipolar AV sequential pacing systems are presented in whom atrial capture was unable to be demonstrated on the surface electrocardiogram. The bedside examination is proposed as a means of identifying the presence or absence of atrial capture with subsequent confirmation by M-mode echocardiographs and jugular venous pulse tracings. Mode, rate, and output programmability may aid in the evaluation of these pacing systems. Intentional reduction of the ventricular output to subthreshold levels in pacemakers capable of this degree of programmability will permit the rapid bedside confirmation of atrial capture without the need for expensive and time-consuming noninvasive tests.


Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial.
HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis. The AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed. The AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US$1369 (95% CI 1314-1424) in the AmBisome group and $1237 (1181-1293) in the control group. The incremental cost-effectiveness ratio was $128 (59-257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to $80 (15-275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from $71 in Botswana to $121 in Uganda. The AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays. European Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research. For the Chichewa, Isixhosa, Luganda, Setswana and Shona translations of the abstract see Supplementary Materials section.


Covalent attachment of the heme to Synechococcus hemoglobin alters its reactivity toward nitric oxide.
The cyanobacterium Synechococcus sp. PCC 7002 produces a monomeric hemoglobin (GlbN) implicated in the detoxification of reactive nitrogen and oxygen species. GlbN contains a b heme, which can be modified under certain reducing conditions. The modified protein (GlbN-A) has one heme-histidine C-N linkage similar to the C-S linkage of cytochrome c. No clear functional role has been assigned to this modification. Here, optical absorbance and NMR spectroscopies were used to compare the reactivity of GlbN and GlbN-A toward nitric oxide (NO). Both forms of the protein are capable of NO dioxygenase activity and both undergo heme bleaching after multiple NO challenges. GlbN and GlbN-A bind NO in the ferric state and form diamagnetic complexes (FeIII-NO) that resist reductive nitrosylation to the paramagnetic FeII-NO forms. Dithionite reduction of FeIII-NO GlbN and GlbN-A, however, resulted in distinct outcomes. Whereas GlbN-A rapidly formed the expected FeII-NO complex, NO binding to FeII GlbN caused immediate heme loss and, remarkably, was followed by slow heme rebinding and HNO (nitrosyl hydride) production. Additionally, combining FeIII GlbN, 15N-labeled nitrite, and excess dithionite resulted in the formation of FeII-H15NO GlbN. Dithionite-mediated HNO production was also observed for the related GlbN from Synechocystis sp. PCC 6803. Although ferrous GlbN-A appeared capable of trapping preformed HNO, the histidine-heme post-translational modification extinguished the NO reduction chemistry associated with GlbN. Overall, the results suggest a role for the covalent modification in FeII GlbNs: protection from NO-mediated heme loss and prevention of HNO formation.


Management of severe bilateral ureteropelvic junction obstruction in neonates with prenatally diagnosed bilateral hydronephrosis.
The management of prenatally detected bilateral ureteropelvic junction obstruction (UPJO) remains controversial. We attempted to develop a treatment plan for patients with severe bilateral UPJO. We evaluated the records of 13 patients with prenatally diagnosed grade 3 or more bilateral hydronephrosis that led to the postnatal diagnosis of severe bilateral UPJO. Ultrasonography and (99m)technetium mercaptoacetyltriglycine ((99m)Tc-MAG3) renal scans were performed within 1 month. Four renal units had grade 3 and 22 had grade 4 hydronephrosis. All 13 patients were managed by unilateral pyeloplasty, and the patients' mean age was 3 months. At 1 month postoperatively, we decided whether delayed surgery in the opposite renal unit was necessary according to the findings of ultrasonography and (99m)Tc-MAG3 scans. Of 13 patients, 11 underwent initial pyeloplasty on renal units with more severe hydronephrosis or lower relative renal function (RRF) on (99m)Tc-MAG3 scans. The remaining 2 patients simultaneously underwent percutaneous nephrostomy on renal units with a lower RRF and initial pyeloplasty on renal units with a higher RRF. In 5 patients, contralateral hydronephrosis had spontaneously improved at 1 month postoperatively, and 8 patients underwent delayed contralateral pyeloplasty at 2 months postoperatively. In children with severe bilateral UPJO, the non-operated renal units with grade 3 and some with grade 4 hydronephrosis improved spontaneously after unilateral pyeloplasty. Therefore, delayed pyeloplasty of the opposite side should be considered at 1 month following initial pyeloplasty.


Executive Summary of Joint Task Force Practice Parameters on Diagnosis and Management of Rhinitis.
Rhinitis is a significant cause of widespread morbidity, medical treatment costs, reduced work productivity and lost school days. Although sometimes mistakenly viewed as a trivial disease, symptoms of allergic and non-allergic rhinitis may significantly impact a patient's quality of life, by causing fatigue, headache, cognitive impairment and other systemic symptoms. In addition, many antihistamines commonly used for treatment can themselves cause performance impairment that may contribute to fatal automobile accidents, work place accidents, decreased work productivity and in children, impaired school performance. Appropriate management of rhinitis may be an important component in effective management of coexisting or complicating respiratory conditions, such as asthma, sinusitis, or chronic otitis media. Rhinitis may be caused by allergic, non-allergic, infectious, hormonal, occupational, and other factors. Defining the causes of rhinitis in an individual is important because different rhinitis syndromes may require different therapeutic approaches for optimal management, an important consideration as more treatment options become available. This Executive Summary reviews key points about diagnosis and management of rhinitis contained in the comprehensive document, Diagnosis and Management of Rhinitis: Complete Guidelines of Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology, and Joint Task Force Algorithm and Annotations for Diagnosis and Management of Rhinitis. These documents represent a consensus opinion of the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology, a national panel co-sponsored by the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council on Allergy, Asthma and Immunology.


Quality of life outcomes after pedicled TRAM flap delayed breast reconstruction.
To evaluate the impact of TRAM flap delayed breast reconstruction on health related quality of life in patients who had undergone mastectomy. Twenty-five patients following mastectomy were selected consecutively from the Plastic Surgery/Mastology Units of two university hospitals. All subjects underwent breast reconstruction with the use of pedicled TRAM flap. The patients' health related quality of life was assessed by a validated instrument, the SF-36 Health Survey Questionnaire. This was applied preoperatively and postoperatively at 3, 6 and 12-months follow-up. A group of 20 women with mastectomies who have not undergone breast reconstruction was used as a control. To assess patients' satisfaction with breast reconstruction we used Alderman's modified general satisfaction subscale. There was a progressive improvement in all dimensions of the SF-36, and this was statistically significant for seven of the eight dimensions. The scores were significantly higher on 'role emotional' and 'mental health' at 3 months postoperatively, on 'health perception' and 'role physical' at month 6 and on 'physical function', 'pain', health perception and 'social function' at postoperative month 12. Despite the increase in scores, no significant changes in 'vitality' were found. There was no significant preoperative difference between the control group and studied patients, and the control group's scores were significantly lower in all dimensions when compared to postoperative month 12, except on 'physical function'. The level of patients' satisfaction with the TRAM flap breast reconstruction was high. The data of this study suggest that delayed breast reconstruction with the use of the pedicled TRAM flap provides an improvement in health related quality of life of patients who have undergone mastectomy.


Predictors of Moderate or Severe Cognitive Impairment at Six Months of the Hip Fracture in the Surgical Patient over 65 Years of Age.
cognitive impairment is known to be very common in patients with hip fractures, but studies are needed to help understand the relationship between both events. Our goal was to determine the relationship between moderate or severe cognitive impairment and hip fractures during the six months following that episode. a retrospective longitudinal study was conducted on a sample of 665 people over 65 years of age. The main variable of the study was cognitive impairment at six months of fracture, assessed using the Pfeiffer scale (PS). Other data related to clinical features were also collected for further analysis. binary logistic regression analyses showed that the main factors related to moderate or severe cognitive impairment at the sixth month of the fracture were age (OR = 1.078), initial cognitive impairment (OR = 535.762), and discharge (OR = 547.91), cognitive worsening at the sixth month with respect to the time of admission (OR = 7.024), moderate dependence on admission (OR = 15.474) and at six months (OR = 8.088), poor ambulation at discharge (OR = 5.071) and institutionalization prior to admission (OR = 5.349) or during the first semester after fracture (OR = 6.317). this research provides evidence about the clinical factors that predict moderate or severe cognitive decline at the sixth month in patients undergoing surgery for a hip fracture.


Establishing order at the systems level in mammalian brain evolution.
The present paper presents a new view of mammalian brain evolution based upon the finding of a level of neural organization at which phylogenetic constraints appear to play a channeling role. It is proposed that the subdivisions of a neural system exhibit the same complement (i.e. the same number of homologous subdivisions) within all species of a particular mammalian order, irrespective of the brain size, phenotype or life history. Specific examples from monotremes, cetaceans, rodents, carnivores and primates are given to provide an empirical basis for the presented hypothesis. The conclusion reached is that the presented evolutionary pattern shows a far higher relative frequency of occurrence than do other potential evolutionary explanations of systems level evolution in the mammalian nervous system.


Amphiphilic chitosan-g-poly(trimethylene carbonate) - A new approach for biomaterials design.
The paper presents the synthesis and characterization of poly(trimethylene carbonate) grafted chitosan as a new water soluble biopolymer suitable for in vivo applications. The synthesis was performed via ring-opening polymerization of 1,3-dioxan-2-one (trimethylene carbonate) (TMC) monomer, initiated by the functional groups of chitosan in the presence of toluene as solvent/swelling agent. By varying the molar ratio between the glucosamine units of chitosan and TMC, a series of chitosan derivatives with different content of poly(trimethylene carbonate) chains was synthetized. The structural characterization of the polymers was realized by FTIR and 1H NMR spectroscopy and their solubility was assessed in water and in organic solvents as well. The biocompatibility was investigated by MTS assay on Normal Human Dermal Fibroblasts, and the biodegradability was evaluated in lysozyme buffer solution. Further, the surface properties of the polymer films were analyzed by polarized optical microscopy, atomic force microscopy and water-to-air contact angle measurements. It was established that, by 5% substitution of chitosan with poly(trimethylene carbonate) chains having an average polymerization degree of 7, a water soluble polymer can be attained. Compared to the pristine chitosan, it has improved biocompatibility in solution and moderate wettability and higher biodegradability rate in solid state, pointing its suitability for in vivo applications.


Primary pulmonary meningioma: an unusual cause of a nodule with strong and homogeneous enhancement.
We report a case of a 61-year-old female with atypical chest pain. The chest CT scan revealed a well-circumscribed large intrapulmonary nodule that showed vigorous and homogeneous contrast enhancement. The nodule was diagnosed as a meningioma after surgery. Metastatic meningioma was excluded by brain and spine MRI scans. Primary pulmonary meningioma usually appears as a solitary well-defined round or lobulated nodule with variable enhancement on CT; this case is unique because of the intense and homogeneous enhancement. Although rare, primary pulmonary meningioma should be considered in the differential diagnosis of a well-defined pulmonary nodule with dense and homogeneous enhancement.


Mitogenic activity and epidermal growth factor content in human milk.
The concentration of epidermal growth factor (EGF) was determined by radioimmunoassay in colostral and mature human milk. The content of EGF in colostral milk was 25-38 ng/ml compared to 5.2-11.5 ng/ml in samples of mature milk. The radioimmunoassayable EGF content in mature milk was not influenced by pasteurization and EGF was detected in a preparation of human milk protein at a concentration similar to that found in mature milk. The growth promoting activity in human milk measured by 3H-thymidine incorporation in human fibroblasts was higher in colostral milk (stimulated incorporation 8.7 fold) than in mature milk (stimulated incorporation about 7-fold).


Mixing of immiscible polymers using nanoporous coordination templates.
The establishment of methodologies for the mixing of immiscible substances is highly desirable to facilitate the development of fundamental science and materials technology. Herein we describe a new protocol for the compatibilization of immiscible polymers at the molecular level using porous coordination polymers (PCPs) as removable templates. In this process, the typical immiscible polymer pair of polystyrene (PSt) and poly(methyl methacrylate) (PMMA) was prepared via the successive homopolymerizations of their monomers in a PCP to distribute the polymers inside the PCP particles. Subsequent dissolution of the PCP frameworks in a chelator solution affords a PSt/PMMA blend that is homogeneous in the range of several nanometers. Due to the unusual compatibilization, the thermal properties of the polymer blend are remarkably improved compared with the conventional solvent-cast blend. This method is also applicable to the compatibilization of PSt and polyacrylonitrile, which have very different solubility parameters.


Oroxylin A analogs exhibited strong inhibitory activities against iNOS-mediated nitric oxide (NO) production.
A number of oroxylin A analogs were prepared and evaluated for their inhibitory activities against iNOS-mediated nitric oxide (NO) production from LPS-stimulated BV2 cells. The analogs were synthesized from purchased 2'-hydroxy-4,5,6-trimethoxyacetophenone and aldehydes in 3 steps. Among the tested compounds, several analogs (3b, 3c, 3d, 3f) exhibited strong inhibitory activities. Especially, the analog with 4-nitrophenyl group (3b) showed stronger inhibitory activity (IC(50)=4.73 μM) than that of wogonin (IC(50)=7.80 μM).


Plasma catecholamine levels in acute myocardial infarction: influence of beta-adrenergic blockade and relation to central hemodynamics.
In a prospective study, 20 patients with acute myocardial infarction were randomly assigned in a double-blind fashion to treatment with intravenous metoprolol followed by oral metoprolol or placebo. All patients underwent hemodynamic monitoring for 24 hours. Plasma adrenaline and noradrenalin levels were estimated at baseline (mean 6.0 +/- 0.9 hours from onset of symptoms) and at 1 and 24 hours after the start of therapy. Plasma adrenaline and noradrenalin levels were elevated in all but one patient, with a further increase at 1 hour after administration of metoprolol (p less than 0.05). At baseline pulmonary capillary wedge pressure was directly related to both plasma adrenaline (r = -0.44; p less than 0.05) and noradrenalin levels (r = -0.44; p less than 0.05). There was also an inverse relationship between stroke volume index and the plasma noradrenalin level (r = -0.44; p less than 0.05) but not the plasma adrenaline level. These relationships were lost after the baseline measurements. However, between baseline and 1 hour there was a close relationship between the change in systemic vascular resistance and the changes in both adrenaline (r = -0.48; p less than 0.05) and noradrenalin levels (r = -0.66; p less than 0.01). Thus, in the early stages of myocardial infarction high plasma catecholamine levels are associated with the hemodynamic markers of severe left ventricular damage. Beta-adrenergic blockade with metoprolol produced a further increase in catecholamine levels that was associated with an increase in systemic vascular resistance.


New spiro-piperidines as 5-HT2B receptor antagonists.
A functional screening highlighted a series of spiro-piperidines as 5-HT2B receptor antagonists. Preliminary structure-activity relationship has been explored driving to potent antagonists (IC50 = 1 nM) and indicating directions for further explorations.


Accurate measurement of the exciton diffusion length in a conjugated polymer using a heterostructure with a side-chain cross-linked fullerene layer.
Exciton diffusion and photoluminescence quenching in conjugated polymer/fullerene heterostructures are studied by time-resolved photoluminescence. It is observed that heterostructures consisting of a spin-coated poly(p-phenylene vinylene) (PPV)-based derivative and evaporated C60 are ill-defined because of diffusion of C60 into the polymer, leading to an overestimation of the exciton diffusion length. This artifact is resolved by the use of a novel, thermally side-chain polymerizing and cross-linking fullerene derivative (F2D) containing two diacetylene moieties, forming a completely immobilized electron acceptor layer. With this heterostructure test system, an exciton diffusion length of 5 +/- 1 nm is derived for this PPV derivative from time-integrated luminescence quenching data.