Bradycardia during Transradial Cardiac Catheterization due to Catheter Manipulation: Resolved by Catheter Removal.
Purpose. To report the resolution of bradycardia encountered during transradial cardiac catheterization through the catheter pullback technique in two cases. Case Report. A 62-year-old male and an 81-year-old male underwent coronary angiogram to evaluate for coronary artery disease and as a result of positive stress test, respectively. Upon engagement of the FL 3.5 catheter into the ascending aorta through the transradial approach, the first case developed bradycardia with a heart rate of 39 beats per minute. The second case developed profound bradycardia with a heart rate of 25 beats per minute upon insertion of the 5 Fr FL 3.5 catheter near the right brachiocephalic trunk through the right radial access. Conclusion. Bradycardia can be subsided by removal of the catheter during catheter manipulation in patients undergoing transradial coronary angiogram if there is a suspicion of excessive stretching of aortic arch receptors and/or carotid sinus receptors.


Site- and cell-specific alteration of lung copper/zinc and manganese superoxide dismutases by chronic ozone exposure.
The antioxidant enzymes copper/zinc (Cu-Zn) and manganese (Mn) superoxide dismutase (SOD) have been implicated in protection of the lungs from oxidant damage. Mn SOD in particular may be related to acquired tolerance in cells following chronic ozone exposure. In order to study these protective and adaptive phenomena in oxidant injury, the cellular location and relative abundance of Mn SOD and Cu-Zn SOD were examined in the lungs of Fischer 344 rats following exposure to 0.0 and 1.0 ppm ozone for up to 3 mo using immunolabeling and morphometric techniques. Cu-Zn SOD labeling was found to be markedly reduced following ozone exposure in epithelial cells within airways and parenchyma. In contrast, a significant increase was noted in Mn SOD labeling in the centriacinar regions of exposed lungs for both alveolar macrophages and epithelial type II cells. Mn SOD labeling per epithelial type II cell was significantly increased in alveoli 0-400 microm beyond the bronchiole-alveolar duct junction (BADJ), while type II cell Mn SOD labeling was similar to control values with greater distance down the alveolar duct. No induction of Mn SOD was noted in type I epithelial cells, fibroblasts, or Clara cells. Thus, alterations in Cu-Zn and Mn SOD are both site and cell specific in the lungs. The differential increase in Mn SOD in type II cells of the proximal alveolar duct may reflect the ability of these cells to acquire tolerance and to resist further injury to repeated ozone exposure.


Choosing Disability, Visualizing Care.
This article explores how visual images of dependency and care reflect and reinforce perceptions of people who are ill, disabled, or otherwise dependent, those who sustain them, and the meaning of the work they do. Scenes of care are a valuable index for understanding cultural assumptions about who is deserving of care, how and where care should be given, and who is obligated to serve as a giver of care. It positions these images in the context of the emphasis, within the disability rights movement, on independence. I argue that the insistence on independence entails a form of what Lauren Berlant calls "cruel optimism"-desire for the very things that undermine happiness and well-being-because they rely on a willful disregard of the inevitable interdependency that is a fact of all human existence, as well as the particular forms of dependency that pertain to many disabled bodies. The end of the article considers works of visual art that challenge dominant modes for representing how care is given and received. If the invisibility of caregiving is one aspect of our willful forgetting that all bodies are dependent, I'll argue that visual images of care are an essential resource for recognizing and reimagining its status in our society. One desired outcome of such reconsideration would be to complicate the meaning of autonomy-as it relates to choosing disability-as well as how the work of caregiving is acknowledged and valued.


Selected contribution: chemoreflex responses to CO2 before and after an 8-h exposure to hypoxia in humans.
The ventilatory sensitivity to CO2, in hyperoxia, is increased after an 8-h exposure to hypoxia. The purpose of the present study was to determine whether this increase arises through an increase in peripheral or central chemosensitivity. Ten healthy volunteers each underwent 8-h exposures to 1) isocapnic hypoxia, with end-tidal PO2 (PET(O2)) = 55 Torr and end-tidal PCO2 (PET(CO2)) = eucapnia; 2) poikilocapnic hypoxia, with PET(O2) = 55 Torr and PET(CO2) = uncontrolled; and 3) air-breathing control. The ventilatory response to CO2 was measured before and after each exposure with the use of a multifrequency binary sequence with two levels of PET(CO2): 1.5 and 10 Torr above the normal resting value. PET(O2) was held at 250 Torr. The peripheral (Gp) and the central (Gc) sensitivities were calculated by fitting the ventilatory data to a two-compartment model. There were increases in combined Gp + Gc (26%, P < 0.05), Gp (33%, P < 0.01), and Gc (23%, P = not significant) after exposure to hypoxia. There were no significant differences between isocapnic and poikilocapnic hypoxia. We conclude that sustained hypoxia induces a significant increase in chemosensitivity to CO2 within the peripheral chemoreflex.


Negative regulation of prolactin receptor stability and signaling mediated by SCF(beta-TrCP) E3 ubiquitin ligase.
Ubiquitin-dependent degradation of hormone receptors is emerging as a key mechanism that regulates the magnitude and duration of hormonal effects on cells and tissues. The pituitary hormone prolactin (PRL) is involved in regulating cell differentiation, proliferation, and survival. PRL engages its receptor (PRLR) to initiate various signaling cascades, including the phosphorylation and activation of Stat5. We found that PRL promotes interaction between PRLR and the F-box protein beta-TrCP2, which functions as a substrate recognition subunit of the SCF(beta-TrCP) E3 ubiquitin ligase. This interaction requires PRLR phosphorylation and the integrity of serine 349 within a conserved motif, which is similar to conserved motifs present in other substrates of SCF(beta-TrCP). The PRLR(S349A) mutant is resistant to ubiquitination and is more stable than its wild-type counterpart. Phosphorylated PRLR undergoes ubiquitination by SCF(beta-TrCP) in vitro. Knockdown of beta-TrCP expression inhibits the ubiquitination and degradation of PRLR and promotes PRL-dependent phosphorylation of Stat5 as well as Stat5-dependent transcription in cells. Furthermore, the activation of Stat5 and the stimulation of cell growth by PRL are augmented in cells expressing the PRLR(S349A) mutant. These data indicate that PRLR is a novel SCF(beta-TrCP) substrate and implicate beta-TrCP as an important negative regulator of PRL signaling and cellular responses to this hormone.


Deposition of lignin droplets produced during dilute acid pretreatment of maize stems retards enzymatic hydrolysis of cellulose.
Electron microscopy of lignocellulosic biomass following high-temperature pretreatment revealed the presence of spherical formations on the surface of the residual biomass. The hypothesis that these droplet formations are composed of lignins and possible lignin carbohydrate complexes is being explored. Experiments were conducted to better understand the formation of these "lignin" droplets and the possible implications they might have on the enzymatic saccharification of pretreated biomass. It was demonstrated that these droplets are produced from corn stover during pretreatment under neutral and acidic pH at and above 130 degrees C, and that they can deposit back onto the surface of residual biomass. The deposition of droplets produced under certain pretreatment conditions (acidic pH; T > 150 degrees C) and captured onto pure cellulose was shown to have a negative effect (5-20%) on the enzymatic saccharification of this substrate. It was noted that droplet density (per unit area) was greater and droplet size more variable under conditions where the greatest impact on enzymatic cellulose conversion was observed. These results indicate that this phenomenon has the potential to adversely affect the efficiency of enzymatic conversion in a lignocellulosic biorefinery.


A possible coupling of postjunctional ATP release and transmitters' receptor stimulation in smooth muscles.
The nature of ATP release from mainly smooth muscles of guinea-pig was evaluated with KCl and agonists for different kinds of receptors. In ileal longitudinal muscles, amounts of net ATP release by ACh and bethanechol (1-10 microM) were much larger (about 10 fold) than that by other drugs, e.g., histamine, 5-hydroxytryptamine, prostaglandin-F2 alpha, substance P and bradykinin, including KC1, although differences between contractions of the tissue evoked by test drugs were approximately 1.5 times at most. The ATP release, as well as the contraction, evoked by ACh or bethanechol was markedly reduced by atropine (0.3 microM), thus, indicating primarily postjunctional release of ATP. The remarkable ATP release from vas deferens by norepinephrine (NE), but not by substance P, was abolished almost completely by prazosin (0.3 microM). Increases in intracellular Ca2+ and subsequent contraction in the ileal tissue were produced by ATP and these responses were fully antagonized by nifedipine (0.1 microM). These findings provide evidence that the drugs-stimulated ATP release from smooth muscles does not result from contractility of muscles, but is substantially elicited only by stimulation of neurotransmitter (NE or ACh) receptors, suggesting the existence of the receptor-stimulus-postjunctional ATP release coupling. The released ATP may contribute, in part, to the muscle contractility via increase of Ca2(+)-influx, presumably, in a manner related to the voltage-gated Ca2(+)-channels.


Interaction of aminoglycosides with the outer membranes and purified lipopolysaccharide and OmpF porin of Escherichia coli.
The mechanism of uptake of aminoglycosides across the outer membrane of Escherichia coli was reevaluated. Porin-deficient mutants showed no alteration in gentamicin or kanamycin susceptibility. Furthermore, the influence of kanamycin on intrinsic tryptophan fluorescence of porin OmpF (Y. Kobayashi, and T. Nakae, Eur. J. Biochem. 151:231-236, 1985) was shown to be strongly influenced by protein concentration and EDTA. This led to the hypothesis that aminoglycoside-mediated increases and decreases in intrinsic tryptophan fluorescence were due to aggregation-disaggregation of OmpF mediated by interaction at a divalent cation binding site on OmpF. Gentamicin, kanamycin, and polymyxin B increased E. coli outer membrane permeability to the hydrophobic fluorescent compound 1-N-phenyl-naphthylamine (NPN) and the peptidoglycan-degrading enzyme lysozyme. Addition of Mg2+ blocked these permeabilizing activities. Furthermore, gentamicin and polymyxin B bound to Mg(2+)-binding sites on E. coli lipopolysaccharide, as determined in dansyl polymyxin displacement experiments. A polymyxin-resistant, lipopolysaccharide-altered pmr mutant of E. coli had a fourfold-lower MIC of gentamicin and kanamycin and was more poorly permeabilized to 1-N-phenylnaphthylamine than was its parent strain. These data were consistent with uptake of aminoglycosides across the E. coli outer membrane by the self-promoted uptake mechanism.


Clinical utility of the Revised Cardiac Risk Index in non-cardiac surgery for elderly patients: a prospective cohort study.
We investigated the association between the Revised Cardiac Risk Index (RCRI) and postoperative outcomes in patients undergoing non-cardiac surgery. The predictive value of the RCRI for the risk of perioperative complications, length of hospital stay and hospital cost were evaluated from a prospective cohort of 119 patients aged ≥65 years undergoing elective major digestive, breast or vascular surgery. Comparing three groups RCRI 0, 1 and ≥2, the morbidity rates were 0, 30 and 68 %; the median length of hospitalization was 5, 14 and 28 days; and the median cost was 665,000, 1,480,000 and 2,160,000 yen, respectively. The mortality rate was 0 % in all groups. The RCRI 0 group included only non-high-risk (breast and peripheral vascular) surgeries. In addition, comparing the two groups by excluding non-high-risk surgeries (RCRI 1 and ≥2), the median morbidity rates were 31 and 67 %, the median length of hospitalization was 15 and 28 days, and the median cost was 1,550,000 and 2,130,000 yen, respectively. The RCRI score was the only independent predictor of the perioperative complications. In the case of non-cardiac surgery, the RCRI can identify patients at higher risk of perioperative complications, a prolonged hospital stay and higher hospital cost.


The epithelial barrier and beyond: Claudins as amplifiers of physiological organ functions.
Epithelial cell layers are interconnected by a meshwork of tight junction (TJ) protein strands, which are localized within apicolateral membranes. The proteins that form TJs are regarded to provide a static barrier, determining epithelial properties. However, recent findings in the field of barriology suggest that TJs contribute to more physiological aspects than indicated by the sum of the qualities of the single TJ proteins. Generally, TJs exhibit four major functions: (i) a "gate function," defining transepithelial permeability (i.e., barrier) properties, (ii) a "fence function" determining epithelial cell polarity, (iii) a "signaling function," affecting regulatory pathways, and (iv) a "stabilizing function," maintaining the integrity of the epithelium. This review presents a critical view on how the efficacy of physiological processes in epithelia and thus organ function might be improved by changes in the expression of claudins, the latter representing the largest and most variable family of TJ proteins. Major focus is set on (i) the coordinated regulation of transport and barrier in the intestine, (ii) the role of TJs in defining the route for antigen uptake and presentation in intestinal Peyer's patches, and (iii) the TJ function in mammary glands in response to milk accumulation, which represent impressive examples to highlight the amplification of epithelial functions by TJ proteins. © 2017 IUBMB Life, 69(5):290-296, 2017.


Effect of dietary supplementation with selenium-enriched yeast or sodium selenite on selenium tissue distribution and meat quality in commercial-line turkeys.
The objective of this study was to determine the concentration of total selenium (Se) and proportions of total Se comprised as selenomethionine (SeMet) and selenocysteine (SeCys) in the tissues of female turkeys offered diets containing graded additions of selenized-enriched yeast (SY), or sodium selenite (SS). Oxidative stability and tissue glutathione peroxidase (GSH-Px) activity of breast and thigh muscle were assessed at 0 and 10 days post mortem. A total of 216 female turkey poults were enrolled in the study. A total of 24 birds were euthanized at the start of the study and samples of blood, breast, thigh, heart, liver, kidney and gizzard were collected for determination of total Se. Remaining birds were blocked by live weight and randomly allocated to one of four dietary treatments (n = 48 birds/treatment) that differed either in Se source (SY v. SS) or dose (Con [0.2 mg/kg total Se], SY-L and SS-L [0.3 mg/kg total Se as SY and SS, respectively] and SY-H [0.45 mg total Se/kg]). Following 42 and 84 days of treatment 24 birds per treatment were euthanized and samples of blood, breast, thigh, heart, liver, kidney and gizzard were retained for determination of total Se and the proportion of total Se comprised as SeMet or SeCys. Whole blood GSH-Px activity was determined at each time point. Tissue GSH-Px activity and thiobarbituric acid reactive substances were determined in breast and thigh tissue at the end of the study. There were responses (P < 0.001) in all tissues to the graded addition of dietary Se, although rates of accumulation were highest in birds offered SY. There were notable differences between tissue types and treatments in the distribution of SeMet and SeCys, and the activity of tissue and erythrocyte GSH-Px (P < 0.05). SeCys was the predominant form of Se in visceral tissue and SeMet the predominant form in breast tissue. SeCys contents were greater in thigh when compared with breast tissue. Muscle tissue GSH-Px activities mirrored SeCys contents. Despite treatment differences in tissue GSH-Px activity, there were no effects of treatment on any meat quality parameter.


Tissue glutathione and cysteine levels in methionine-restricted rats.
Previously, we demonstrated that lifelong methionine (Met) restriction (MR) increases lifespan, decreases the incidence of aging-related diseases, increases blood glutathione (GSH) levels, and prevents loss of GSH during aging in rats. Our present objective was to elucidate the effects of MR on GSH metabolism and transport by determining the time course and nature of GSH and cysteine changes in blood and other tissues in young and mature rats. Male F-344 rats were placed on control (0.86% Met) or MR (0.17% Met) defined amino acid diets at age 7 wk and killed at different times thereafter. MR was also initiated in adult (12-mo-old) rats. Throughout the first 2 mo of MR, blood GSH levels increased 84% and liver GSH decreased 66% in relation to controls. After this period, liver GSH levels remained constant through at least 6 mo. GSH levels also decreased in the pancreas (80%) and kidney (22%) but remained unchanged in other tissues examined after 11 wk of MR. The increase in blood GSH was evident as soon as 1 wk after initiating MR and reached a plateau by 6 wk. A similar increase in erythrocyte GSH levels was observed when MR was administered to mature adult rats. Fasting decreased liver GSH in controls but had no further effect in MR animals. By 1 mo, cysteine levels had decreased in all tissues except brain. These results suggest that adaptive changes occur in the metabolism of Met, cysteine, and/or GSH as a result of MR in young and adult rats. These early metabolic changes lead to conservation of GSH levels in most extrahepatic tissues and increased GSH in erythrocytes by depleting liver GSH to a critical level.


The tobacco lectin, prototype of the family of Nictaba-related proteins.
In the last decade, a new class of low abundant plant l ectins was identified. These proteins are expressed after exposure of the plant to different stress factors and changing environmental conditions, and therefore are referred to as "inducible" lectins. Interestingly, these lectins accumulate in the nucleocytoplasmic compartment of plant cells. At present at least six carbohydrate recognition domains have been identified within the group of nucleocytoplasmic plant lectins. This review will focus on a group of proteins that show homology to the Nicotiana tabacum (tobacco) agglutinin or Nictaba. The tobacco lectin is a 38 kDa nucleocytoplasmic protein which is only expressed upon treatment with jasmonate-related compounds or after insect herbivory. The lectin exhibits specificity towards GlcNAc, but also reacts with N-glycan structures. Extensive searches revealed that Nictaba-related sequences are widespread in the plant kingdom. Analyses of the different transcriptome databases showed that the Nictaba domain is often part of chimeric proteins comprising one or more Nictaba domain(s) fused to unrelated N- and C-terminal domains with (un)known function. At present only few proteins of these Nictaba-related proteins have been studied and characterized for their biological properties and physiological role. Despite the sequence similarity and the conserved amino acids constituting the binding site, the Nictaba domain has a promiscuous carbohydrate binding site capable of interacting with different carbohydrate motifs, suggesting that subtle changes in the vicinity of the binding site can alter its sugar specificity.


Nanocapsule-delivered Sleeping Beauty mediates therapeutic Factor VIII expression in liver sinusoidal endothelial cells of hemophilia A mice.
Liver sinusoidal endothelial cells are a major endogenous source of Factor VIII (FVIII), lack of which causes the human congenital bleeding disorder hemophilia A. Despite extensive efforts, gene therapy using viral vectors has shown little success in clinical hemophilia trials. Here we achieved cell type-specific gene targeting using hyaluronan- and asialoorosomucoid-coated nanocapsules, generated using dispersion atomization, to direct genes to liver sinusoidal endothelial cells and hepatocytes, respectively. To highlight the therapeutic potential of this approach, we encapsulated Sleeping Beauty transposon expressing the B domain-deleted canine FVIII in cis with Sleeping Beauty transposase in hyaluronan nanocapsules and injected them intravenously into hemophilia A mice. The treated mice exhibited activated partial thromboplastin times that were comparable to those of wild-type mice at 5 and 50 weeks and substantially shorter than those of untreated controls at the same time points. Further, plasma FVIII activity in the treated hemophilia A mice was nearly identical to that in wild-type mice through 50 weeks, while untreated hemophilia A mice exhibited no detectable FVIII activity. Thus, Sleeping Beauty transposon targeted to liver sinusoidal endothelial cells provided long-term expression of FVIII, without apparent antibody formation, and improved the phenotype of hemophilia A mice.


Identification of dominant negative mutants of Rheb GTPase and their use to implicate the involvement of human Rheb in the activation of p70S6K.
Rheb GTPases represent a unique family of the Ras superfamily of G-proteins. Studies on Rheb in Schizosaccharomyces pombe and Drosophila have shown that this small GTPase is essential and is involved in cell growth and cell cycle progression. The Drosophila studies also raised the possibility that Rheb is involved in the TOR/S6K signaling pathway. In this paper, we first report identification of dominant negative mutants of S. pombe Rheb (SpRheb). Screens of a randomly mutagenized SpRheb library yielded a mutant, SpRhebD60V, whose expression in S. pombe results in growth inhibition, G1 arrest, and induction of fnx1+, a gene whose expression is induced by the disruption of Rheb. Alteration of the Asp-60 residue to all possible amino acids by site-directed mutagenesis led to the identification of two particularly strong dominant negative mutants, D60I and D60K. Characterization of these dominant negative mutant proteins revealed that D60V and D60I exhibit preferential binding of GDP, while D60K lost the ability to bind both GTP and GDP. A possible use of the dominant negative mutants in the study of mammalian Rheb was explored by introducing dominant negative mutations into human Rheb. We show that transient expression of the wild type Rheb1 or Rheb2 causes activation of p70S6K, while expression of Rheb1D60K mutant results in inhibition of basal level activity of p70S6K. In addition, Rheb1D60K and Rheb1D60V mutants blocked nutrient- or serum-induced activation of p70S6K. This provides critical evidence that Rheb plays a role in the mTOR/S6K pathway in mammalian cells.


High performance enzyme-linked immunosorbent assay for determination of miroestrol, a potent phytoestrogen from Pueraria candollei.
Pueraria candollei associated preparation is widely applied in folk Thai medicine for rejuvenating purpose in aged people, which correlated with its pharmacological activities reported by pre-clinical and clinical trials. Therefore, standardized products of this plant are needed by consumers and health care personnel. Miroestrol, a potent and stable phytoestrogen in P. candollei, exhibited potential to be biomarker for quality control of P. candollei samples in research or industrial levels. Indirect competitive enzyme-linked immunosorbant assay (ELISA) for miroestrol determination was developed and validated by using polyclonal antibody from rabbit immunization. The polyclonal antibody recognized specifically to miroestrol, which exhibited cross-reactivity to deoxymiroestrol and isomiroestrol with 6.68% and 1.05%, respectively. The linearity range of measurement was 0.73-3000 ng mL(-1), which coefficient of variation (CV) of both intra- and inter-plate determination was less than 5%. With spiked samples of known amount miroestrol, the percentages of recovery were 98.80-104.37% and 98.31-106.69% in P. candollei and its involved product samples, respectively. Validated ELISA was comparable with published HPLC method (R(2)=0.9996) (Yusakul et al.) in samples with various miroestrol contents. For application, the P. candollei involved preparations contained miroestrol 0.695±0.037-12.108±0.285 μg g(-1) dry wt. The developed ELISA was high performance for miroestrol determination, which could be applied for P. candollei quality control in research fields and industrial productions.


Microvilli appear to represent the first step in actin bundle formation in Drosophila bristles.
During bristle development the emerging bristle shaft, socket cell, and the apical surface of thoracic epithelial cells form tiny protuberances or pimples that contain electron-dense material located on the cytoplasmic surface of the pimple tip. In a few cases short actin filaments extend from this material into the cortical cytoplasm. When cultured in the presence of jasplakinolide, an agent that prevents filament disassembly, pimples elongate to form microvilli containing a core of crosslinked filaments. Emerging-bristle mutants delay cortical bundle formation and are aggregated by forked protein crossbridges. Using these mutants and enhancing core bundle formation with jasplakinolide we found that microvillar formation represents the first stage in the morphogenesis of much larger actin bundles in Drosophila bristle shaft cells. Evidence is presented showing that socket cells do not contain forked protein crossbridges, a fact that may explain why cortical bundles only appear in bristle shaft cells. Furthermore, as pimples and microvilli form in the absence of both forked and fascin crossbridges, we also conclude that neither of these crossbridges account for core bundle formation in microvilli, but there must exist a third, as yet unidentified crossbridge in this system. Immunocytochemisty suggested that this new crossbridge is not Drosophila villin. Finally, ultrastructural comparisons suggest that microspikes and microvilli form very differently.


A dissociation between engagement and learning: Enthusiastic instructions fail to reliably improve performance on a memory task.
Despite widespread assertions that enthusiasm is an important quality of effective teaching, empirical research on the effect of enthusiasm on learning and memory is mixed and largely inconclusive. To help resolve these inconsistencies, we conducted a carefully-controlled laboratory experiment, investigating whether enthusiastic instructions for a memory task would improve recall accuracy. Scripted videos, either enthusiastic or neutral, were used to manipulate the delivery of task instructions. We also manipulated the sequence of learning items, replicating the spacing effect, a known cognitive technique for memory improvement. Although spaced study reliably improved test performance, we found no reliable effect of enthusiasm on memory performance across two experiments. We did, however, find that enthusiastic instructions caused participants to respond to more item prompts, leaving fewer test questions blank, an outcome typically associated with increased task motivation. We find no support for the popular claim that enthusiastic instruction will improve learning, although it may still improve engagement. This dissociation between motivation and learning is discussed, as well as its implications for education and future research on student learning.


[Primary systemic therapy of carcinoma of the breast - update of the geparduo studies].
Primary systemic therapy represents today the standard of care in patients with locally advanced breast cancer and becomes more and more an alternative to adjuvant postoperative chemotherapy in patients with operable breast cancer. In a subset of large randomized trials it could be shown that sequential schedules with more than 4 cycles can reach the highest rates of clinical and histopathological complete remissions. In two randomized trials (NSABP B-27, Geparduo) using 4 cycles of Adriamycin/Cyclophosphamide followed by 4 cycles of Docetaxel significant better results could be obtained in comparison with the referring control arm. New approaches try to further individualize chemotherapy, either using molecular biological tumor factors or the early effect of some chemotherapy cycles. In the Gepartrio study clinical response evaluation after 2 cycles can identify patients with a high or low chance for a histopathological complete remission and further treatment strategies can be developed for these different subgroups.


A comparison of episodic memory deficits in neuropathologically-confirmed Dementia with Lewy bodies and Alzheimer's disease.
Little is known about possible differences in the memory deficits that occur in Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). We compared 24 autopsy-confirmed DLB and 24 age-, education-, and MMSE-matched autopsy-confirmed AD patients on the California Verbal Learning Test (CVLT) and the Wechsler Memory Scale-Revised Logical Memory subtest. The DLB and AD groups were similarly impaired on CVLT Total Learning (Trials 15) and Long Delayed Free Recall, but the DLB group demonstrated relative improvement in Savings scores and on recognition testing compared to the AD group. Likewise, the patient groups were equally impaired on Logical Memory immediate and delayed recall, but the DLB group's Saving scores were significantly better than those of the AD patients. These results indicate that while both DLB and AD patients exhibit significant memory impairment, the ability to consolidate information may be less severely impaired in DLB patients than in AD patients.


C60H2: Synthesis of the Simplest C60 Hydrocarbon Derivative.
The reaction of C(60) with BH(3): tetrahydrofuran in toluene followed by hydrolysis yielded C(60)H(2). This product was separated by high-performance liquid chromatography and characterized as the addition product of H(2) to a 6,6-ring fusion (1alb isomer). The (1)H nuclear magnetic resonance (NMR) spectrum of the product remained a sharp singlet between -80 degrees and +100 degrees C, which suggests a static structure on the NMR time scale. Hydrolysis of the proposed borane addition product with acetic acid-d(1) or D(2)O yielded C(60)HD, and its (3)J(HD) coupling constant is consistent with vicinal addition. The observation of a single C(60)H(2) isomer is in complete agreement with earlier calculations that indicated that at most 2 of the 23 possible isomers of C(60) would be observable at equilibrium at room temperature. These results suggest that organoborane chemistry may be applied to further functionalization of fullerenes.


Recombinant allergens Pru av 1 and Pru av 4 and a newly identified lipid transfer protein in the in vitro diagnosis of cherry allergy.
In central and northern Europe food allergy to fruits of the Rosaceae family is strongly associated with birch pollinosis because of the existence of IgE cross-reactive homologous allergens in birch pollen and food. By contrast, in the Mediterranean population allergic reactions to these fruits frequently are not related to birch pollen allergy and are predominantly elicited by lipid transfer proteins (LTPs). We sought to determine the prevalence of IgE sensitization to the recombinant cherry allergens Pru av 1 and Pru av 4 in comparison with cherry extract within a representative group of patients who were allergic to cherries recruited in Germany and to compare the relevance of IgE to cherry LTPs in Italian patients. Recombinant Pru av 1 and rPru av 4 were available from earlier studies. The cDNA of the cherry LTPs was obtained by using a PCR-cloning strategy. The protein was expressed in Escherichia coli and purified by means of metal chelate affinity chromatography. Sera from 101 German patients with birch pollinosis and oral allergy syndrome to cherry and sera from 7 Italian patients with cherry allergy were investigated by using enzyme allergosorbent tests for IgE reactivity with cherry extract, rPru av 1, rPru av 4, and the recombinant cherry LTP. Inhibition experiments were performed to compare the IgE reactivity of natural and recombinant cherry LTPs and to investigate potential cross-reactivity with birch pollen allergens. The LTP from cherry comprises 91 amino acids and a 26 amino acid signal peptide. The mature cherry LTP shows high amino acid sequence identity with allergenic LTPs from peach (Pru p 3, 88%), apricot (Pru ar 3, 86%), and maize (Zea m 14, 59%) and displays no IgE cross-reactivity with birch pollen. The IgE prevalences in the German patients were as follows: LTP, 3 of 101 (3%); rPru av 1, 97 of 101 (96.0%); rPru av 4, 16 of 101 (16.2%); and cherry extract, 98 of 101 (97%). All 7 Italian patients had IgE against the cherry LTP. Recombinant allergens are useful tools for a more accurate in vitro IgE-based diagnosis of cherry allergy. Taken together, they mimic the allergenic activity of cherry extract, having slightly higher biologic activity. Sensitization to the cherry LTP is relevant for a minority of patients recruited in Germany, but our data indicate that it may be a major allergen in Italy.


Validation of quality indicators for end-of-life communication: results of a multicentre survey.
The lack of validated quality indicators is a major barrier to improving end-of-life communication and decision-making. We sought to show the feasibility of and provide initial validation for a set of quality indicators related to end-of-life communication and decision-making. We administered a questionnaire to patients and their family members in 12 hospitals and asked them about advance care planning and goals-of-care discussions. Responses were used to calculate a quality indicator score. To validate this score, we determined its correlation with the concordance between the patients' expressed wishes and the medical order for life-sustaining treatments recorded in the hospital chart. We compared the correlation with concordance for the advance care planning component score with that for the goal-of-care discussion scores. We enrolled 297 patients and 209 family members. At all sites, both overall quality indicators and individual domain scores were low and there was wide variability around the point estimates. The highest-ranking institution had an overall quality indicator score (95% confidence interval) of 40% (36%-44%) and the lowest had a score of 18% (11%-25%). There was a strong correlation between the overall quality indicator score and the concordance measure (r = 0.72, p = 0.008); the estimated correlation between the advance care planning score and the concordance measure (r = 0.35) was weaker than that between the goal-of-care discussion scores and the concordance measure (r = 0.53). Quality of end-of-life communication and decision-making appears low overall, with considerable variability across hospitals. The proposed quality indicator measure shows feasibility and partial validity. Study registration: ClinicalTrials.gov, no. NCT01362855.


Derivation of human skin fibroblast lines for feeder cells of human embryonic stem cells.
After the first derivations of human embryonic stem cell (hESC) lines on fetal mouse feeder cell layers, the idea of using human cells instead of mouse cells as feeder cells soon arouse. Mouse cells bear a risk of microbial contamination, and nonhuman immunogenic proteins are absorbed from the feeders to hESCs. Human skin fibroblasts can be effectively used as feeder cells for hESCs. The same primary cell line, which can be safely used for up to 15 passages after stock preparations, can be expanded and used for large numbers of hESC derivations and cultures. These cells are relatively easy to handle and maintain. No animal facilities or animal work is needed. Here, we describe the derivation, culture, and cryopreservation procedures of research grade human skin fibroblast lines. We also describe how to make feeder layers for hESC using these fibroblasts.


Managing violent patients.
There are many steps a health care facility can take in dealing with violent patients. This can be accomplished through a recognition of the causes of violent behavior. Unfortunately, each situation is different. While we can learn from previous experience, it is difficult to predict violent patient behavior. The steps that a hospital can take to deal with violence include intervention, restraint and seclusion, and proper training. This will increase quality of care and reduce liability. According to Steve Wilder, director of risk management at St. Mary's Hospital in Kankakee, IL, "The issue is not to fight, but to control and modify aggressive behavior and defuse the situation" (Hospital Risk Management, 1993).


Detailed deletion mapping in squamous cell carcinomas of the esophagus narrows a region containing a putative tumor suppressor gene to about 200 kilobases on distal chromosome 9q.
We previously reported definition of a region containing a putative tumor suppressor gene for esophageal squamous cell carcinoma within an approximately 4-cM genomic segment at 9q31-q32. We have investigated this region further using six new microsatellite markers isolated from yeast artificial chromosome clones covering the deleted region and have narrowly defined the commonly deleted region to a segment between two loci, KM9.1 and D9S177. On the basis of the contig map of cosmid and yeast artificial chromosome clones, we estimate the physical size of the region of interest to be about 200 kb. Because the distal 9q region also has been implicated as the site of a tumor suppressor gene(s) related to squamous cell carcinomas of other tissues, our map provides useful information for attempts to identify a common gene for carcinomas of this cell type.


Purification and characterization of the prothoracicotropic hormone of Drosophila melanogaster.
The prothoracicotropic hormone (PTTH) of Drosophila melanogaster is a modulator of ecdysteroid (molting hormone) synthesis and was isolated and characterized from extracts of whole larvae (approximately 4 x 10(5) larvae). The purification protocol included delipidation, salt-extraction, heat treatment, conventional column chromatography, and HPLC, and yielded about 50 microg of pure hormone. Biological activity was followed using a ring gland in vitro assay in which ecdysteroidogenesis by control ring glands as measured by radioimmunoassay was compared with ring gland incubations containing active fractions. The molecular weight of the purified PTTH was 45 kDa and N-terminal amino acid sequence analysis indicated that those analyzed sequences displayed no significant homology with known peptides or peptide hormones, including PTTH from the silkmoth, Bombyx mori. Western blot analysis indicated that the native form of Drosophila PTTH was a single 66-kDa polypeptide with N-linked carbohydrate chains and intrachain disulfide bonds. The purified 45-kDa peptide is the deglycosylated form, a result of glycosidase activity present during preparation of the PTTH extract. The deglycosylated form shows heterogeneity, presumably as a result of varying degrees of deglycosylation at the N terminus.


Ligand affinity for amino-terminal and juxtamembrane domains of the corticotropin releasing factor type I receptor: regulation by G-protein and nonpeptide antagonists.
Peptide ligands bind the CRF(1) receptor by a two-domain mechanism: the ligand's carboxyl-terminal portion binds the receptor's extracellular N-terminal domain (N-domain) and the ligand's amino-terminal portion binds the receptor's juxtamembrane domain (J-domain). Little quantitative information is available regarding this mechanism. Specifically, the microaffinity of the two interactions and their contribution to overall ligand affinity are largely undetermined. Here we measured ligand interaction with N- and J-domains expressed independently, the former (residues 1-118) fused to the activin IIB receptor's membrane-spanning alpha-helix (CRF(1)-N) and the latter comprising residues 110-415 (CRF(1)-J). We also investigated the effect of nonpeptide antagonist and G-protein on ligand affinity for N- and J-domains. Peptide agonist affinity for CRF(1)-N was only 1.1-3.5-fold lower than affinity for the whole receptor (CRF(1)-R), suggesting the N-domain predominantly contributes to peptide agonist affinity. Agonist interaction with CRF(1)-J (potency for stimulating cAMP accumulation) was 12000-1500000-fold weaker than with CRF(1)-R, indicating very weak direct agonist interaction with the J-domain. Nonpeptide antagonist affinity for CRF(1)-J and CRF(1)-R was indistinguishable, indicating the compounds bind predominantly the J-domain. Agonist activation of CRF(1)-J was fully blocked by nonpeptide antagonist, suggesting antagonism results from inhibition of agonist-J-domain interaction. G-protein coupling with CRF(1)-R (forming RG) increased peptide agonist affinity 92-1300-fold, likely resulting from enhanced agonist interaction with the J-domain rather than the N-domain. Nonpeptide antagonists, which bind the J-domain, blocked peptide agonist binding to RG, and binding of peptide antagonists, predominantly to the N-domain, was unaffected by R-G coupling. These findings extend the two-domain model quantitatively and are consistent with a simple equilibrium model of the two-domain mechanism: (1) The N-domain binds peptide agonist with moderate-to-high microaffinity, substantially increasing the local concentration of agonist and so allowing weak agonist-J-domain interaction. (2) Agonist-J-domain interaction is allosterically enhanced by receptor-G-protein interaction and inhibited by nonpeptide antagonist.


Porcine sclera as a model of human sclera for in vitro transport experiments: histology, SEM, and comparative permeability.
To evaluate porcine sclera as a model of human sclera for in vitro studies of transscleral drug delivery of both low and high molecular weight compounds. Human and porcine scleras were characterized for thickness and water content. The tissue surface was examined by scanning electron microscopy (SEM), and the histology was studied with hematoxylin-eosin staining. Comparative permeation experiments were performed using three model molecules, acetaminophen as the model compound for small molecules; a linear dextran with a molecular weight of 120 kDa as the model compound for high molecular weight drugs; and insulin, which was chosen as the model protein. Permeation parameters such as flux, lag time, and permeability coefficient were determined and compared. Human and porcine scleras have a similar histology and collagen bundle organization. The water content is approx 70% for both tissues while a statistically significant difference was found for the thickness, porcine sclera being approximately twofold thicker than human sclera. Differences in thickness produced differences in the permeability coefficient. In fact, human sclera was found to be two to threefold more permeable toward the three molecules studied than porcine sclera. The results obtained in the present paper prove that porcine sclera can be considered a good model for human sclera for in vitro permeation experiments of both low and high molecular weight compounds. In fact, if the different tissue thickness is taken into account, comparable permeability was demonstrated. This suggests a possible use of this model in the evaluation of the transscleral permeation of new biotech compounds, which currently represent the most innovative and efficient therapeutic options for the treatment of ocular diseases.


Subliminal attention bias modification training in socially anxious individuals.
Anxious individuals demonstrate threat-related attention biases both when threat stimuli are presented within conscious awareness and when presented below awareness threshold. Nevertheless, attention bias modification (ABM) research has rarely utilized sub-awareness protocols in an attempt to modify attention patterns and reduce anxiety. Exploring the potential of subliminal ABM is of interest, as it may target attention processes related to anxiety that are distinct from those engaged by supraliminal ABM. Here we examined the effect of a subliminal ABM training protocol on levels of social anxiety and stress vulnerability. Fifty-one socially anxious students were randomly assigned to either ABM or placebo condition, and completed a pre-training assessment, four training sessions, a social stressor task, and a post-training assessment. Results indicate that the subliminal ABM used here did not induce detectable changes in threat-related attention from pre- to post-training as measured by two independent attention tasks. Furthermore, the ABM and placebo groups did not differ on either self-reported social anxiety post-training or state anxiety following stress induction. Post-hoc auxiliary analyses suggest that ABM may be associated with smaller elevations in state anxiety during the stressor task only for participants who demonstrate attention bias toward threat at baseline. Implications and future research directions are discussed.


Characterizing the Mechanisms of Ca and Mg Carbonate Ion-Pair Formation with Multi-Level Molecular Dynamics/Quantum Mechanics Simulations.
The carbonate minerals of Ca and Mg are abundant throughout the lithosphere and have recently garnered significant research interest as possible long-term carbon sinks in the sequestration of atmospheric carbon dioxide. Nonetheless, an understanding of the atomic-level processes comprising their mineralization remains limited. Here, we characterize and contrast the mechanisms of contact ion-pair formation in aqueous Ca and Mg carbonate systems, which represents the most fundamental step leading to the formation of their mineral solids. Utilizing multilevel embedded correlated wavefunction-based ab initio molecular dynamics/quantum mechanics simulations, we characterize not only the dynamics of these processes but also factors arising from the electronic structure of the involved species, revealing further details of the fundamentally different mechanisms for the interconversion between the contact ion-pairs and solvent-shared ion-pairs of Ca versus Mg carbonate.


Form follows function: occlusion based rationale for esthetic dentistry.
Esthetic dentistry is one of the prime essential areas in dentistry today. The purpose of this article is to address the dependent relationship between excellent esthetics and optimum occlusion. Occlusal objectives must be addressed and achieved. If one is to expect to recreate ideal esthetics, one must first thoroughly investigate, diagnose, and establish an ideal occlusal scheme. The case study within this article revisits the most imperative principle with regards to esthetics and that is: form always follows function.


[Endosurgery of subretinal strands in proliferative vitreoretinopathy].
Subretinal strands were removed in 9 patients with retinal detachment complicated by proliferative vitreoretinopathy (Stages C 2 to D 1). A small retinotomy was made in the area of the strand. The subretinal proliferative tissue was then drawn to the surface with forceps. In this way it was possible to remove all of the strands completely. One strand snapped while being drawn, thus necessitating a further incision. Two additional small retinectomies had to be performed because of firm attachments to the retina. In all cases retinal reattachment was achieved by silicone oil injection. No postoperative recurrences of the proliferations were observed. The follow-up period ranged from 2 to 9 months.


Biodynamic simulations of the effect of a neck-mounted air bag on the head/neck response during high G acceleration.
New helmet-mounted devices (such as night-vision goggles, laser eye protection, etc.) have created new safety hazards for pilots during ejection or high G maneuvering. In order to prevent the resulting head/neck injuries, this study extends the air-bag protection system developed for ground vehicles to a neck mounted system for aircrew personnel. Results, carried out by computer biodynamic simulations using the Articulated Total Body Model (ATB), showed that: 1) helmet weight had little effect on head/neck torque, contact force and flexion angle; 2) initial head/neck position and center of gravity offsets of the helmet-mounted devices had significant effects on head-neck torques, contact forces, and neck flexion angles; and 3) the neck mounted air bag significantly reduced neck torques, contact forces, and neck flexion angles. We conclude that the neck-mounted air bag system could significantly reduce the severity of head/neck injuries to pilots during ejection or high G maneuvering.


DNA barcoding for bio-surveillance of emerging pests and species identification in Afrotropical Prioninae (Coleoptera, Cerambycidae).
DNA barcoding has been succesfully used for bio-surveillance of forest and agricultural pests in temperate areas, but has few applications in the tropics and particulary in Africa. Cacosceles newmannii (Coleoptera: Cerambycidae) is a Prioninae species that is locally causing extensive damage in commercially-grown sugarcane in the KwaZulu-Natal Province in South Africa. Due to the risk of spread of this species to the rest of southern Africa and to other sugarcane growing regions, clear and easy identification of this pest is critical for monitoring and for phytosanitary services. The genus Cacosceles Newman, 1838 includes four species, most being very similar in morphology. The damaging stage of the species is the larva, which is inherently difficult to distinguish morphologically from other Cerambycidae species. A tool for rapid and reliable identification of this species was needed by plant protection and quarantine agencies to monitor its potential abundance and spread. Here, we provide newly-generated barcodes for C. newmannii that can be used to reliably identify any life stage, even by non-trained taxonomists. In addition, we compiled a curated DNA barcoding reference library for 70 specimens of 20 named species of Afrotropical Prioninae to evaluate DNA barcoding as a valid tool to identify them. We also assessed the level of deeply conspecific mitochondrial lineages. Sequences were assigned to 42 different Barcode Index Numbers (BINs), 28 of which were new to BOLD. Out of the 20 named species barcoded, 11 (52.4%) had their own unique Barcode Index Number (BIN). Eight species (38.1%) showed multiple BINs with no morphological differentiation. Amongst them, C. newmannii showed two highly divergent genetic clusters which co-occur sympatrically, but further investigation is required to test whether they could represent new cryptic species.


Prevalence and correlates of Attention Deficit Hyperactive Disorder (ADHD) risk factors among school children in a rural area of North India.
Attention-deficit hyperactive disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood and has the potential for continuity into adolescence and adulthood. Its presence increases difficulties in academic performance and social interactions besides leading to low self-esteem. The present study aimed to determine the prevalence of ADHD among children of age 6-12 years in Government schools of a rural area in Jammu district of J and K. The present study was conducted in R.S. Pura block of Jammu district. Miran Sahib zone of R.S Pura block was chosen randomly and all the government primary schools in this zone were included in the survey. The presence of ADHD was assessed using Vanderbilt ADHD diagnostic teacher rating scale. The children positive for ADHD were visited at their residential places and a personal information questionnaire (PIQ) was administered to their parents-preferably the mother. The data thus collected was presented as proportions. ADHD prevalence was found to be 6.34% (13/205). Majority (69.3%) of the ADHD-positive children were living in a joint family and belonged to lower/lower middle class. Family history of ADHD was absent in all the ADHD-positive children. The current study conducted in a rural area among 6- to 12-year-old children of Government schools has shown a reasonably high ADHD prevalence of 6.34%.


Viscoelasticity as a biomarker for high-throughput flow cytometry.
The mechanical properties of living cells are a label-free biophysical marker of cell viability and health; however, their use has been greatly limited by low measurement throughput. Although examining individual cells at high rates is now commonplace with fluorescence activated cell sorters, development of comparable techniques that nondestructively probe cell mechanics remains challenging. A fundamental hurdle is the signal response time. Where light scattering and fluorescence signatures are virtually instantaneous, the cell stress relaxation, typically occurring on the order of seconds, limits the potential speed of elastic property measurement. To overcome this intrinsic barrier to rapid analysis, we show here that cell viscoelastic properties measured at frequencies far higher than those associated with cell relaxation can be used as a means of identifying significant differences in cell phenotype. In these studies, we explore changes in erythrocyte mechanical properties caused by infection with Plasmodium falciparum and find that the elastic response alone fails to detect malaria at high frequencies. At timescales associated with rapid assays, however, we observe that the inelastic response shows significant changes and can be used as a reliable indicator of infection, establishing the dynamic viscoelasticity as a basis for nondestructive mechanical analogs of current high-throughput cell classification methods.


Prokaryotic Chaperonins as Experimental Models for Elucidating Structure-Function Abnormalities of Human Pathogenic Mutant Counterparts.
All archaea have a chaperonin of Group II (thermosome) in their cytoplasm and some have also a chaperonin of Group I (GroEL; Cpn60; Hsp60). Conversely, all bacteria have GroEL, some in various copies, but only a few have, in addition, a chaperonin (tentatively designated Group III chaperonin) very similar to that occurring in all archaea, i.e., the thermosome subunit, and in the cytosol of eukaryotic cells, named CCT. Thus, nature offers a range of prokaryotic organisms that are potentially useful as experimental models to study the human CCT and its abnormalities. This is important because many diseases, the chaperonopathies, have been identified in which abnormal chaperones, including mutant CCT, are determinant etiologic-pathogenic factors and, therefore, research is needed to elucidate their pathologic features at the molecular level. Such research should lead to the clarification of the molecular mechanisms underlying the pathologic lesions observed in the tissues and organs of patients with chaperonopathies. Information on these key issues is necessary to make progress in diagnosis and treatment. Some of the archaeal organisms as well as some of the bacterial models suitable for studying molecular aspects pertinent to human mutant chaperones are discussed here, focusing on CCT. Results obtained with the archaeon Pyrococcus furiosus model to investigate the impact of a pathogenic CCT5 mutation on molecular properties and chaperoning functions are reviewed. The pathogenic mutation examined weakens the ability of the chaperonin subunit to form stable hexadecamers and as a consequence, the chaperoning functions of the complex are impaired. The future prospect is to find means for stabilizing the hexadecamer, which should lead to a recovering of chaperone function and the improving of lesions and clinical condition.


Unique signalling connectivity of FGFR3-TACC3 oncoprotein revealed by quantitative phosphoproteomics and differential network analysis.
The FGFR3-TACC3 fusion is an oncogenic driver in diverse malignancies, including bladder cancer, characterized by upregulated tyrosine kinase activity. To gain insights into distinct properties of FGFR3-TACC3 down-stream signalling, we utilised telomerase-immortalised normal human urothelial cell lines expressing either the fusion or wild-type FGFR3 (isoform IIIb) for subsequent quantitative proteomics and network analysis. Cellular lysates were chemically labelled with isobaric tandem mass tag reagents and, after phosphopeptide enrichment, liquid chromatography-high mass accuracy tandem mass spectrometry (LC-MS/MS) was used for peptide identification and quantification. Comparison of data from the two cell lines under non-stimulated and FGF1 stimulated conditions and of data representing physiological stimulation of FGFR3 identified about 200 regulated phosphosites. The identified phosphoproteins and quantified phosphosites were further analysed in the context of functional biological networks by inferring kinase-substrate interactions, mapping these to a comprehensive human signalling interaction network, filtering based on tissue-expression profiles and applying disease module detection and pathway enrichment methods. Analysis of our phosphoproteomics data using these bioinformatics methods combined into a new protocol-Disease Relevant Analysis of Genes On Networks (DRAGON)-allowed us to tease apart pathways differentially involved in FGFR3-TACC3 signalling in comparison to wild-type FGFR3 and to investigate their local phospho-signalling context. We highlight 9 pathways significantly regulated only in the cell line expressing FGFR3-TACC3 fusion and 5 pathways regulated only by stimulation of the wild-type FGFR3. Pathways differentially linked to FGFR3-TACC3 fusion include those related to chaperone activation and stress response and to regulation of TP53 expression and degradation that could contribute to development and maintenance of the cancer phenotype.


The influence of split doses of gamma-radiation on human erythrocytes.
Human erythrocyte suspensions in an isotonic Na-phosphate buffer, pH 7.4, of hematocrit of 2% were exposed under air to gamma radiation at a dose rate of 2.2 kGy. Erythrocytes were irradiated with single doses, and identical doses split into two fractions with an interval time of 3.5 h between following exposures. The obtained results indicated that the irradiation of enucleated human erythrocytes with split doses caused a reduction of hemolysis (2.4 times), a decrease in the level of damage to membrane lipids and the contents of MetHb, compared with identical single doses. However, the splitting of radiation doses did not change the level of damage to the membrane proteins, as was estimated with a maleimide spin label. The obtained results suggest that a decrease in the level of damage to lipids was related to a decrease in hemolysis.


A prospective comparison of surgical approach for anterior L4-L5 fusion: laparoscopic versus mini anterior lumbar interbody fusion.
A prospective comparison of 50 consecutive patients who underwent L4-L5 anterior lumbar interbody fusion (ALIF). To compare surgical time, blood loss, time in hospital, complications and adequacy of exposure between laparoscopic and mini-ALIF surgical approaches for L4-L5 anterior spinal fusion. Advances in minimally invasive laparoscopic techniques have resulted in many centers adopting the endoscopic approach to L5-S1 as routine. However, the endoscopic approach to L4-L5 can be much more difficult. A direct comparison of open and laparoscopic techniques of exposure has not been reported. From 1995 through 1998, data were prospectively collected on a series of 50 consecutive patients who underwent L4-L5 anterior interbody fusion with a threaded device, by either a laparoscopic or an open mini-ALIF approach. Twenty-five patients underwent a laparoscopic procedure and 25 an open mini-ALIF approach. For single-level L4-L5 fusions, there was no statistical difference in operating time, blood loss, or length of hospital stay between laparoscopic or mini-ALIF groups. For two-level procedures, only the operative time differed, with laparoscopic procedures taking 25 minutes longer (P = 0.035). The rate of complications was significantly higher in the laparoscopic group (20% vs. 4%). In the laparoscopic group, 16% of patients had inadequate exposure, with the result that only a single cage was placed. In the open mini-ALIF group, two cages were placed in all cases. There does not appear to be a significant advantage at the L4-L5 level of the transperitoneal laparoscopic surgical approach when compared with an open mini-ALIF retroperitoneal technique.


Activity and mechanism of action of insect oostatic peptides in flesh fly.
The relationship between structure and activity of insect oostatic decapeptide (Aed-TMOF) analogues in flesh fly was analyzed. The highest oostatic activity was exhibited by the pentapetide and tetrapeptide analogues, H-Tyr-Asp-Pro-Ala-Pro-OH and H-Tyr-Asp-Pro-Ala-OH, respectively. The tetrapeptide, either native or tritiated, was used to study its metabolism in the ovaries and hemolymph and to detect putative binding sites in the flesh fly ovaries and head. A high metabolism of the tetrapeptide with a half-life in the hemolymph and ovaries less than 1h was determined. The initial limiting step in the degradation is tyrosine(1) cleavage. Other degradation products were detected only transiently in low quantities. Using tritiated tetrapeptide, we found that only very low specific binding was detected in the homogenates of ovaries and in the rough membrane preparation in the presence and absence of protease inhibitors.


Terminating a long-term clinical trial.
Long-term clinical trials often include more than one active treatment group. These may be discontinued independently if found to be ineffective or possibly harmful. Certain subgroups of patients may be discovered, in the course of a clinical trial, who do not respond satisfactorily and are, therefore, excluded during the course of a trial. Yet another kind of termination comes when we have a therapeutic breakthrough or when hope has to be abandoned for demonstrating beneficial effects for one, several, or all treatments included in a trial. Examples from the authors' experience are presented, as are successful and unsuccessful techniques in managing terminations of various types.


7-Chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide: a partial modulator of AMPA receptor desensitization devoid of neurotoxicity.
In cerebellar granule neurons of neonatal rats micromolar concentrations of 7-chloro-3-methyl-3,4-dihydro-2H-1,2, 4-benzothiadiazine S,S-dioxide (IDRA-21) and cyclothiazide, two negative modulators of the spontaneous agonist-dependent rapid desensitization of alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA)-gated ion channels, facilitate AMPA receptor function by increasing the content of free cytosolic Ca2+ as measured by single-cell fura-2 acetoxymethyl ester (Fura-2) Ca2+-dependent fluorescence and intracellular Na+ measured with the sodium-binding bezofuran isophthalate acetoxymethyl ester fluorescence indicator. IDRA-21 increases intracellular Na+ transient with a threshold (5 microM) that is approximately 10 times higher and has an intrinsic activity significantly lower than that of cyclothiazide. By virtue of its low intrinsic activity, IDRA-21 elicits a free cytosolic Ca2+ transient increase that is shorter lasting than that elicited by cyclothiazide even when the drug is left in contact with cultured granule cells for several minutes. Additionally, while dose dependently, 5-25 microM cyclothiazide in the presence of AMPA is highly neurotoxic, IDRA-21 (up to 100 microM) is devoid of neurotoxicity. The neurotoxicity elicited by cyclothiazide persists in the presence of dizocilpine (an antagonist of N-methyl-D-aspartate-selective glutamate receptors) but is blocked by 2,3-dihydroxy-6-nitrosulfamoylbenzo[f]quinoxaline (a competitive AMPA receptor antagonist) and the 1-(aminophenyl)-4-methyl-7, 8-methylendioxy-5H-2,3-benzodiazepine (GYKI 52466; a noncompetitive AMPA receptor antagonist). Since the doses of IDRA-21 that enhance cognitive processes in rats and monkeys are several orders of magnitude lower than those required to elicit marginal neurotoxicity in cultured neurons, it can be surmised that IDRA-21 is a potent cognition-enhancing drug virtually devoid of neurotoxic liability because it acts as a partial negative allosteric modulator of AMPA receptor desensitization.


Modification of the equine gastrointestinal microbiota by Jerusalem artichoke meal supplementation.
The objective of this study was to investigate the impact of natural prebiotic active compounds on the microbial composition in different regions of the equine gastrointestinal tract. Twelve adult horses (body weight [bwt] 534 ± 64.5 kg; age 14 ± 7.5 years) were randomly divided into two feeding groups. Six horses received a basal diet consisting of 1.5 kg hay/100 kg bwt x d-1 and oat grains equal to 1.19 g starch/kg bwt x d-1, supplemented with Jerusalem artichoke meal providing prebiotic fructooligosaccharides + inulin in a quantity of 0.15 g/kg bwt x d-1. The remaining horses received a placebo added to the basal diet. The horses were fed for 21 d and euthanized at the end of the feeding period. Digesta samples from different parts of the gastrointestinal tract were taken, DNA extracted and the V1-V2 region of the 16S rRNA gene amplified. Supplementation with the prebiotic increased the relative abundance of Lactobacillus (P < 0.05), with a concurrent reduction of the relative abundance of Streptococcus mainly in the stomach (P < 0.05). In the hindgut, the supplemental prebiotic also increased the relative abundance of Lactobacillus but further reduced the relative abundance of fibrolytic bacteria, specifically the unclassified members of the families Lachnospiraceae (P < 0.05) and Ruminococcaceae. The relative abundance of the genus Ruminococcus increased solely in the caecum and colon transversum. Overall, the addition of the prebiotic significantly increased the diversity in nearly all parts of the gastrointestinal tract (P < 0.05). The feeding of this natural prebiotic compound to horses had an impact on the microbial community in the entire gastrointestinal tract. Furthermore, the effect on the bacterial community in the foregut (especially the stomach) was more pronounced in comparison to the effect in the hindgut. Therefore, the impact on stomach health should be carefully considered.


Red cell shape changes in the blood of people 60 years of age and older imply a role for blood rheology in the aging process.
Five-drop samples of venous blood, which was fixed immediately, were obtained from 76 males and 91 females who were 60 years of age and older, and did not take part in competitive sport, and from 73 males and 50 females participating in the Golden Oldies Soccer tournament or in the Dunedin Masters' Games. Most participants were nonsmokers. Those in the competitive group indicated a higher level of activity than those in the noncompetitive group, and the majority of participants indicated high levels of well-being. 30 different medical diagnoses were recorded including hypertension (36 cases), arthritis (17 cases), diabetes (6 cases), angina (6 cases) and coronary heart disease (7 cases). Most samples had high values for flat cells. Increased values for cells with altered margins were found in 7 males and 7 females, while 6 males and 1 female sample had increased values for cells with surface changes. It is concluded that some factor or factors in the aging process are responsible for red cell shape transformation. As high values for flat cells occur in people with chronic disorders, the lack of symptoms or evidence of dysfunction in people over 60 implies that survival is a consequence of having larger than usual capillaries.


[Comparative aspects of the course of periodic disease without and with amyloidosis (analysis of 437 case studies)].
The paper is concerned with an analysis of a course of periodic disease (PD) without and with amyloidosis using also a method of the determination of survival rates in 437 patients followed up for 20 yrs. A course of PD without amyloidosis was benign and did not affect the patients' survival. In the development of amyloidosis the prognosis was unfavorable and determined by a degree of generalization of amyloidosis.


Convergent potency of internalized gelonin immunotoxins across varied cell lines, antigens, and targeting moieties.
Gelonin-based immunotoxins vary widely in their cytotoxic potency as a function of antigen density, target cell internalization and trafficking kinetics, and conjugate properties. We have synthesized novel gelonin immunotoxins using two different binding scaffold types (single-chain antibody variable fragments and fibronectin domains) targeting two different tumor antigens (carcinoembryonic antigen and EGF receptor). Constructs were characterized using an antigen-negative cell line (HT-1080), cell lines positive for each antigen (HT-1080(CEA) for carcinoembryonic antigen and A431 for EGF receptor), and a cell line positive for both antigens (HT-29). Immunotoxins exhibited K(d) values between 8 and 15 nm and showed 20-2000-fold enhanced cytotoxicity compared with gelonin (IC(50) ∼ 0.25-30 nM versus 500 nM). Using quantitative fluorescence flow cytometry, we measured internalization of gelonin (via pinocytosis) and gelonin-based immunotoxins (via antigen-dependent, receptor-mediated endocytosis). Results were matched with cytotoxicity measurements made at equivalent concentration and exposures. Unexpectedly, when matched internalization and cytotoxicity data were combined, a conserved internalized cytotoxicity curve was generated that was common across experimental conditions. Considerable variations in antigen expression, trafficking kinetics, extracellular immunotoxin concentration, and exposure time were all found to collapse to a single potency curve on the basis of internalized immunotoxin. Fifty percent cytotoxicity occurred when ∼ 5 × 10(6) toxin molecules were internalized regardless of the mechanism of uptake. Cytotoxicity observed at a threshold internalization was consistent with the hypothesis that endosomal escape is a common, highly inefficient, rate-limiting step following internalization by any means tested. Methods designed to enhance endosomal escape might be utilized to improve the potency of gelonin-based immunotoxins.


It's Not Just Physical: Exercise Physiologist-Led Exercise Program Promotes Functional and Psychosocial Health Outcomes in Aged Care.
Regular physical activity has multiple benefits for older adults, including improved physical, cognitive, and psychosocial health. This exploratory study investigated the benefits of a 12-week exercise program for older adults (n = 11 control and n = 13 intervention) living in a residential aged care facility in Perth, Western Australia. The program, prescribed and delivered by an accredited exercise physiologist, aimed to maintain or improve participants' physical capacity. It comprised one-on-one exercise sessions (1 hr × 2 days/week × 12 weeks), involving a components-approach intervention. Physical performance measures (balance, strength, flexibility, and mobility) were assessed preintervention and postintervention. Qualitative interviews postintervention with residents participating in the exercise intervention, and with family members, staff, and research team members, explored barriers and enablers to participation and perceived psychosocial outcomes. Findings indicate the program provided physical benefits and enhanced social engagement for participants, illustrating the value of providing exercise physiology services in the aged care sector.


MR-Spectroscopy of GABA and Glutamate/Glutamine Concentrations in Auditory Cortex in Clinical High-Risk for Psychosis Individuals.
Psychosis involves changes in GABAergic and glutamatergic neurotransmission in auditory cortex that could be important for understanding sensory deficits and symptoms of psychosis. However, it is currently unclear whether such deficits are present in participants at clinical high-risk for psychosis (CHR-P) and whether they are associated with clinical outcomes. Magnetic Resonance Spectroscopy (MEGAPRESS, 1H-MRS at 3 Tesla) was used to estimate GABA, glutamate, and glutamate-plus-glutamine (Glx) levels in auditory cortex in a large sample of CHR-P (n = 99), CHR-N (clinical high-risk negative, n = 32), and 45 healthy controls. Examined were group differences in metabolite concentrations as well as relationships with clinical symptoms, general cognition, and 1-year follow-up clinical and general functioning in the CHR-P group. Results showed a marginal (p = 0.039) main group effect only for Glx, but not for GABA and glutamate concentrations, and only in left, not right, auditory cortex. This effect did not survive multiple comparison correction, however. Exploratory post-hoc tests revealed that there were significantly lower Glx levels (p = 0.029, uncorrected) in the CHR-P compared to the CHR-N group, but not relative to healthy controls (p = 0.058, uncorrected). Glx levels correlated with the severity of perceptual abnormalities and disorganized speech scores. However, in the CHR-P group, Glx levels did not predict clinical or functional outcomes. Accordingly, the findings from the present study suggest that MRS-measured GABA, glutamate and Glx levels in auditory cortex of CHR-P individuals are largely intact.


Herbarium specimens reveal a historical shift in phylogeographic structure of common ragweed during native range disturbance.
Invasive plants provide ample opportunity to study evolutionary shifts that occur after introduction to novel environments. However, although genetic characters pre-dating introduction can be important determinants of later success, large-scale investigations of historical genetic structure have not been feasible. Common ragweed (Ambrosia artemisiifolia L.) is an invasive weed native to North America that is known for its allergenic pollen. Palynological records from sediment cores indicate that this species was uncommon before European colonization of North America, and ragweed populations expanded rapidly as settlers deforested the landscape on a massive scale, later becoming an aggressive invasive with populations established globally. Towards a direct comparison of genetic structure now and during intense anthropogenic disturbance of the late 19th century, we sampled 45 natural populations of common ragweed across its native range as well as historical herbarium specimens collected up to 140 years ago. Bayesian clustering analyses of 453 modern and 473 historical samples genotyped at three chloroplast spacer regions and six nuclear microsatellite loci reveal that historical ragweed's spatial genetic structure mirrors both the palaeo-record of Ambrosia pollen deposition and the historical pattern of agricultural density across the landscape. Furthermore, for unknown reasons, this spatial genetic pattern has changed substantially in the intervening years. Following on previous work relating morphology and genetic expression between plants collected from eastern North America and Western Europe, we speculate that the cluster associated with humans' rapid transformation of the landscape is a likely source of these aggressive invasive populations.


Immunoblot for the Diagnosis of Cutaneous Leishmaniasis in French Guiana.
Cutaneous leishmaniasis (CL) is firmly established in South America. We aimed to assess the detection of IgG antibodies against 14 and/or 16 kDa antigens by immunoblot (IB) for CL serological diagnosis in French Guiana, an area where many endemic pathogens could interfere with it. This study was performed retrospectively on sera from 141 patients at the Cayenne tertiary hospital: 30 were patients with confirmed CL, 71 were diagnosed with various other endemic pathogens, 11 were diagnosed with an autoimmune disease, and 29 controls had no history of CL. Antibodies bound to the 14 and/or 16 kDa antigens in 27 of the 30 CL patients' sera and in 39 of the 111 non-CL patients' sera (26 from the infectious diseases group, four from the autoimmune diseases group, and nine from the dermatology department). The method tested showed a high sensitivity (90%) and a low specificity (66%), and a diagnosis odds ratio of 17.5 (95% CI [4.6-78.0]). This IB may be helpful to exclude the diagnosis of CL, prompting physicians to look for another diagnosis in the case of a negative IB.


Increased mammalian target of rapamycin complex 2 signaling promotes age-related decline in CD4 T cell signaling and function.
CD4 T cell function declines significantly during aging. Although the mammalian target of rapamycin (TOR) has been implicated in aging, the roles of the TOR complexes (TORC1, TORC2) in the functional declines of CD4 T cells remain unknown. In this study, we demonstrate that aging increases TORC2 signaling in murine CD4 T cells, a change blocked by long-term exposure to rapamycin, suggesting that functional defects may be the result of enhanced TORC2 function. Using overexpression of Rheb to activate TORC1 and Rictor plus Sin1 to augment TORC2 in naive CD4 T cells from young mice, we demonstrated that increased TORC2, but not TORC1, signaling results in aging-associated biochemical changes. Furthermore, elevated TORC2 signaling in naive CD4 T cells from young mice leads to in vivo functional declines. The data presented in this article suggest a novel model in which aging increases TORC2 signaling and leads to CD4 T cell defects in old mice.


Does cholesterol discriminate between sphingomyelin and phosphatidylcholine in mixed monolayers containing both phospholipids?
The objective of this work was to examine the interaction of cholesterol with both phosphatidylcholines, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and sphingomyelins, N-oleoyl-D-sphingomyelin (O-SPM) or N-palmitoyl-D-sphingomyelin (P-SPM), in monolayers at an air/water interface. We used cholesterol oxidase to probe for the relative strength of sterol-phospholipid interaction, and fluorescence microscopy to visualize lateral domain formation in the mixed monolayers. The ternary mixed monolayers, which contained cholesterol, POPC, and O-SPM had a twofold higher average oxidation rate than the corresponding system containing DPPC and P-SPM. This difference in oxidation rate between saturated and unsaturated systems was observed irrespective of the ratio between phosphatidylcholine and sphingomyelin in the monolayer. With either the saturated or the unsaturated systems, however, the rate of oxidation was influenced by the ratio of phosphatidylcholine to sphingomyelin. As the monolayer content of phosphatidylcholine increased and the sphingomyelin content decreased correspondingly (to maintain a constant cholesterol-to-phospholipid molar ratio), an increase in the average oxidation rate was seen in both saturated and mono-unsaturated monolayer systems. The relationship between the rate of cholesterol oxidation and the phosphatidylcholine/sphingomyelin ratio was not linear, suggesting a preferential interaction of cholesterol with sphingomyelin even when phosphatidylcholine was present in the monolayer. The formation and stability of cholesterol-rich lateral (liquid-condensed) domains in the monolayers, as determined by monolayer fluorescence microscopy, was found to be highly influenced by the phospholipid class, the degree of acyl chain saturation, and by the ratio of phosphatidylcholine to sphingomyelin in the monolayer. The differences in cholesterol oxidation rates and lateral domain formation, as a function of the ratio of two phospholipids in the monolayers, apparently derived from differences in the hydrophobic interactions between the lipids.


p21(WAF1) is required for butyrate-mediated growth inhibition of human colon cancer cells.
A diet high in fiber is associated with a decreased incidence and growth of colon cancers. Butyrate, a four-carbon short-chain fatty acid product of fiber fermentation within the colon, appears to mediate these salutary effects. We sought to determine the molecular mechanism by which butyrate mediates growth inhibition of colonic cancer cells and thereby to elucidate the molecular link between a high-fiber diet and the arrest of colon carcinogenesis. We show that concomitant with growth arrest, butyrate induces p21 mRNA expression in an immediate-early fashion, through transactivation of a promoter cis-element(s) located within 1.4 kb of the transcriptional start site, independent of p53 binding. Studies using the specific histone hyperacetylating agent, trichostatin A, and histone deacetylase 1 indicate that growth arrest and p21 induction occur through a mechanism involving histone hyperacetylation. We show the critical importance of p21 in butyrate-mediated growth arrest by first confirming that stable overexpression of the p21 gene is able to cause growth arrest in the human colon carcinoma cell line, HT-29. Furthermore, using p21-deleted HCT116 human colon carcinoma cells, we provide convincing evidence that p21 is required for growth arrest to occur in response to histone hyperacetylation, but not for serum starvation nor postconfluent growth. Thus, p21 appears to be a critical effector of butyrate-induced growth arrest in colonic cancer cells, and may be an important molecular link between a high-fiber diet and the prevention of colon carcinogenesis.


Frequency-dependent force between ac-voltage-biased plates in electrolyte solutions.
We analyze the frequency dependence of the force between ac-voltage-biased plates in electrolyte solutions. To this end we solve analytically the Poisson-Nernst-Planck transport model in the dilute concentration and low voltage regime for a 1:1 symmetric electrolyte with blocking electrodes under a dc+ac applied voltage. The total force, which is the resultant of the electric and osmotic forces, shows a complex dependence on plate separation, frequency, ion concentration, and compact layer properties, different from that predicted from electrostatic current models or equivalent circuit models, due to the relevance of the osmotic force contribution in almost the whole range of frequencies. For the total dc force, we show that it decays at fixed ion concentration, linearly with plate separation for separations larger than a few times the Debye screening length. This linear dependence is due to the assumption about the conservation of the number of ions in the system. Moreover, the 1ω and 2ω ac harmonics of the total force show a broad peak at intermediate frequencies; it is centered at about the inverse of the charging time of the double layer capacitance, and covers the frequency range between the inverse of the diffusion time and the inverse of the electrolyte dielectric relaxation time. Finally, the 1ω ac harmonic component attains its high frequency asymptotic value at frequencies much higher than the inverse of the electrolyte dielectric relaxation time due to the very slow relaxation of the osmotic 1ω harmonic component at high frequencies. The derived analytical expressions for the total force remain valid up to voltages of the order of the thermal voltage, as has been assessed by means of numerical calculations. The numerical calculations are also used to explore the onset of higher force harmonics for larger applied voltages. Understanding the frequency dependence of the force acting on voltage-biased plates in electrolyte solutions can be of relevance for electrical actuation strategies in microelectromechanical systems and for the interpretation of some emerging electric scanning probe force microscopy techniques operating in electrolyte solutions.


Understanding the spread of infectious diseases in edge areas of hotspots: dengue epidemics in tropical metropolitan regions.
Identifying clusters or hotspots from disease maps is critical in research and practice. Hotspots have been shown to have a higher potential for transmission risk and may be the source of infections, making them a priority for controlling epidemics. However, the role of edge areas of hotspots in disease transmission remains unclear. This study aims to investigate the role of edge areas in disease transmission by examining whether disease incidence rate growth is higher in the edges of disease hotspots during outbreaks. Our data is based on the three most severe dengue epidemic years in Kaohsiung city, Taiwan, from 1998 to 2020. We employed conditional autoregressive (CAR) models and Bayesian areal Wombling methods to identify significant edge areas of hotspots based on the extent of risk difference between adjacent areas. The difference-in-difference (DID) estimator in spatial panel models measures the growth rate of risk by comparing the incidence rate between two groups (hotspots and edge areas) over two time periods. Our results show that in years characterized by exceptionally large-scale outbreaks, the edge areas of hotspots have a more significant increase in disease risk than hotspots, leading to a higher risk of disease transmission and potential disease foci. This finding explains the geographic diffusion mechanism of epidemics, a pattern mixed with expansion and relocation, indicating that the edge areas play an essential role. The study highlights the importance of considering edge areas of hotspots in disease transmission. Furthermore, it provides valuable insights for policymakers and health authorities in designing effective interventions to control large-scale disease outbreaks.


Survival rates and productive herd life of dairy cattle in the United States.
Survival rates and productive herd life were examined for 13.8 million US dairy cows that calved from January 1, 1980, through March 2, 2005. Cows that left the herd for dairy purposes or were from herds that discontinued Dairy Herd Improvement testing were excluded from any calculations to prevent underestimation of population longevity. Mean lactation length for cows without subsequently recorded lactations ranged from 205 to 235 d across breed-parity subsets and were 4 to 29 d longer for parities 2 through 7 than for parity 1. Mean survival rates were 73% to parity 2; 50% to parity 3; 32% to parity 4; and 19, 10, 5, and 2% to parities 5 through 8, respectively. The mean number of parities for Holsteins declined from 3.2 for those first calving in 1980 to 2.8 for those first calving in 1994. Mean numbers of parities for other breeds first calving in 1994 were 2.9 for Ayrshires and Brown Swiss, 2.4 for Guernseys, and 3.2 for Jerseys. Breed means for productive herd life (through parity 8) ranged from 28 to 36 mo. All regressions of mean number of parities or mean productive herd life on year were negative. The trend for decline of many of those indicators of longevity slowed or ended after the early 1990s. Between 31 (Jersey) and 39% (Guernsey) of herds were made up of first-calf heifers.


Nutritional status and cardiac mass and function in children infected with the human immunodeficiency virus.
Malnutrition, skeletal muscle wasting, and changes in cardiac muscle mass and function have been described in children infected with the human immunodeficiency virus (HIV). This report analyzes the relation of nutritional status to cardiac muscle mass and function in HIV-infected children. Thirty-six children with symptomatic HIV infection underwent simultaneous anthropometric and echocardiographic evaluations before antiretroviral therapy or supplemental feedings. Nutritional measurements included weight, height, triceps skinfold thickness, and arm muscle circumference. Cardiac measurements included left ventricular mass, contractility, end-diastolic dimension, fractional shortening, blood pressure, and heart rate. In a cross-sectional analysis, children infected with HIV were significantly below age-adjusted standards for height (P = 0.0001), weight (P = 0.0001), triceps skinfold thickness (P = 0.001), and arm muscle circumference (P = 0.04). Left ventricular mass normalized to body surface area was below standard, but contractility was normal. Correlation analyses found an inverse relation between left ventricular mass and weight z score (r = -0.45, P = 0.01), height z score (r = -0.47, P = 0.006), and arm muscle circumference percentile (r = -0.51, P = 0.003). An inverse relation was also found between heart rate and weight z score (r = -0.47, P = 0.007) and arm muscle circumference percentile (r = -0.46, P = 0.007). In malnourished children with HIV infection, a paradoxical relation exists between nutritional status and cardiac muscle mass. The inverse relation between heart rate and nutritional status may suggest altered metabolic rates with possible increased sympathetic tone.


Local size segregation in polydisperse hard sphere fluids
The structure of polydisperse hard sphere fluids, in the presence of a wall, is studied by the Rosenfeld density functional theory. Within this approach, the local excess free energy depends on only four combinations of the full set of density fields. The case of continuous polydispersity thereby becomes tractable. We predict, generically, an oscillatory size segregation close to the wall, and connect this, by a perturbation theory for narrow distributions, with the reversible work for changing the size of one particle in a monodisperse reference fluid.


Preventive strategies for acute kidney injury in cancer patients.
Acute kidney injury (AKI) is a common complication of cancer that occurs in up to 50% of neoplastic patients during the natural history of their disease; furthermore, it has a huge impact on key outcomes such as overall prognosis, length of hospitalization and costs. AKI in cancer patients has different causes, either patient-, tumour- or treatment-related. Patient-related risk factors for AKI are the same as in the general population, whereas tumour-related risk factors are represented by compression, obstruction, direct kidney infiltration from the tumour as well by precipitation, aggregation, crystallization or misfolding of paraprotein (as in the case of multiple myeloma). Finally, treatment-related risk factors are the most common observed in clinical practice and may present also with the feature of tumour lysis syndrome or thrombotic microangiopathies. In the absence of validated biomarkers, a multidisciplinary clinical approach that incorporates adequate assessment, use of appropriate preventive measures and early intervention is essential to reduce the incidence of this life-threatening condition in cancer patients.


New strategies for dealing with Staphylococcus aureus colonization and the emerging methicillin-resistant Staphylococcus aureus epidemic in atopic dermatitis.
Atopic dermatitis is a common inflammatory skin disease and a global health problem. Patients are often colonized or infected by Staphylococcus aureus, usually by toxin-producing strains. Methicillin-resistant S. aureus (MRSA) has emerged as an important pathogen. Community-acquired MRSA, a frequent cause of skin and soft tissue infections has become epidemic. Basic skin care measures emphasizing repair and protection of the skin barrier reduce microbial colonization and decrease the need for specific antimicrobial therapy even in patients colonized by MRSA. Novel approaches directed at S. aureus colonization and prevention of infection include compounds mimicking antimicrobial peptides, vaccines targeting unique antigens and toxin-neutralizing agents.


Cultured lymphocytes' mitochondrial genome integrity is not altered by cladribine.
Cladribine tablets are a treatment for multiple sclerosis with effects on lymphocytes, yet its mode of action has not been fully established. Here, we analyzed the effects of cladribine on mitochondrial DNA integrity in lymphocytes. We treated cultured human T-cell lines (CCRF-CEM and Jurkat) with varying concentrations of cladribine to mimic the slow cell depletion observed in treated patients. The CCRF-CEM was more susceptible to cladribine than Jurkat cells. In both cells, mitochondrial protein synthesis, mitochondrial DNA copy number, and mitochondrial cytochrome-c oxidase-I mRNA mutagenesis was not affected by cladribine, while caspase-3 cleavage was detected in Jurkat cells at 100 nM concentration. Cladribine treatment at concentrations up to 10 nM in CCRF-CEM and 100 nM in Jurkat cells did not induce significant increase in mitochondrial DNA mutations. Peripheral blood mononuclear cells from eight multiple sclerosis patients and four controls were cultured with or without an effective dose of cladribine (5 nM). However, we did not find any differences in mitochondrial DNA somatic mutations in lymphocyte subpopulations (CD4+, CD8+, and CD19+) between treated versus nontreated cells. The overall mutation rate was similar in patients and controls. When different lymphocyte subpopulations were compared, greater mitochondrial DNA mutation levels were detected in CD8+ (P = 0.014) and CD4+ (P = 0.038) as compared to CD19+ cells, these differences were independent of cladribine treatment. We conclude that T cells have more detectable mitochondrial DNA mutations than B cells, and cladribine has no detectable mutagenic effect on lymphocyte mitochondrial genome nor does it impair mitochondrial function in human T-cell lines.


Protective Effects of Physical Exercise in Alzheimer's Disease and Parkinson's Disease: A Narrative Review.
Alzheimer's disease (AD) and Parkinson's disease (PD) are devastating, frequent, and still incurable neurodegenerative diseases that manifest as cognitive and motor disorders. Epidemiological data support an inverse relationship between the amount of physical activity (PA) undertaken and the risk of developing these two diseases. Beyond this preventive role, exercise may also slow down their progression. Several mechanisms have been suggested for explaining the benefits of PA in the prevention of AD. Aerobic physical exercise (PE) activates the release of neurotrophic factors and promotes angiogenesis, thereby facilitating neurogenesis and synaptogenesis, which in turn improve memory and cognitive functions. Research has shown that the neuroprotective mechanisms induced by PE are linked to an increased production of superoxide dismutase, endothelial nitric oxide synthase, brain-derived neurotrophic factor, nerve growth factor, insulin-like growth factor, and vascular endothelial growth factor, and a reduction in the production of free radicals in brain areas such as the hippocampus, which is particularly involved in memory. Other mechanisms have also been reported in the prevention of PD. Exercise limits the alteration in dopaminergic neurons in the substantia nigra and contributes to optimal functioning of the basal ganglia involved in motor commands and control by adaptive mechanisms involving dopamine and glutamate neurotransmission. AD and PD are expansive throughout our ageing society, and so even a small impact of nonpharmacological interventions, such as PA and exercise, may have a major impact on public health.


Comparison of sagittal plane realignment and reduction with posterior instrumentation in developmental low or high dysplastic spondylolisthesis.
In situ fusion is the gold standard method of treatment of spondylolisthesis. There is no study in the literature evaluating the effect of sagittal contour realignment on clinical outcomes in comparison with the addition of anterior slippage reduction. The correction of sagittal plane vs. reduction with instrumentation in the patients with low or high dysplastic spondylolisthesis. A prospective randomized study in patients treated with the same surgical team at the same center. 40 patients, 20 with low and 20 with high dysplastic spondylolisthesis (mean age: 33.1+/-10.6; average follow-up: 37.9+/-11.9 Mo.). The extent of displacement, lumbosacral angle values, lumbar sagittal contours, correction rates, JOA scores, SRS-22 questionnaire were evaluated preoperatively, postoperatively, and at the final visit. Fusion rates, complications and quality of fusion were recorded. 4 groups of patients were generated. Only posterolateral fusion, neural decompression, and sagittal plane correction with posterior instrumentation using 3rd generation instrumentation system transpedicular screws was accomplished in 20 patients (low dysplastic: 10 patients, high dysplastic: 10 patients). Additional reduction of anterior slippage was done in the remaining 20 patients (low dysplastic: 10 patients, high dysplastic: 10 patients). No statistically significant difference was found between low vs. high dysplastic patients and between patients with sagittal contour realignment vs. patients with additional anterior slippage reduction (p>0.05). The correction rates for displacement were statistically similar at the final visit. Postoperative and final JOA and SRS scores were similar between in situ fusion and reduction groups (p>0.05). A solid fusion mass of 77.5 % was achieved in both groups. A high percentage of fusion was achieved with posterolateral in situ fusion with or without reduction; and an additional reduction procedure did not have a statistically detectable impact on clinical outcomes. Successful fusion and neural decompression were the most important parameters that have an impact on clinical outcomes in patients with developmental spondylolisthesis, irrespective of the extent of preoperative displacement and the type of listhesis.