The hydrodynamics of swimming at intermediate Reynolds numbers in the water boatman (Corixidae).
The fluid forces that govern propulsion determine the speed and energetic cost of swimming. These hydrodynamics are scale dependent and it is unclear what forces matter to the tremendous diversity of aquatic animals that are between a millimeter and a centimeter in length. Animals at this scale generally operate within the regime of intermediate Reynolds numbers, where both viscous and inertial fluid forces have the potential to play a role in propulsion. The present study aimed to resolve which forces create thrust and drag in the paddling of the water boatman (Corixidae), an animal that spans much of the intermediate regime (10<Re<200). By measuring the force generated by tethered water boatmen, we found that thrust is generated primarily by drag on the paddling appendages, with a negligible contribution from the acceleration reaction force. Based on these findings, we developed a forward-dynamic model of propulsion in free swimming that accurately predicted changes in the body's center of mass over time. For both tethered and free swimming, we used non-linear optimization algorithms to determine the force coefficients that best matched our measurements. With this approach, the drag coefficients on the body and paddle were found to be up to three times greater than on static structures in fully developed flow at the same Reynolds numbers. This is likely a partial consequence of unsteady interactions between the paddles or between the paddles and the body. In addition, the maximum values for these coefficients were inversely related to the Reynolds number, which suggests that viscous forces additionally play an important role in the hydrodynamics of small water boatmen. This understanding for the major forces that operate at intermediate Reynolds numbers offers a basis for interpreting the mechanics, energetics and functional morphology of swimming in many small aquatic animals.


Peristaltic pumps adapted for laminar flow experiments enhance in vitro modeling of vascular cell behavior.
Endothelial cells (ECs) are the primary cellular constituent of blood vessels that are in direct contact with hemodynamic forces over their lifetime. Throughout the body, vessels experience different blood flow patterns and rates that alter vascular architecture and cellular behavior. Because of the complexities of studying blood flow in an intact organism, particularly during development, the field has increasingly relied on in vitro modeling of blood flow as a powerful technique for studying hemodynamic-dependent signaling mechanisms in ECs. While commercial flow systems that recirculate fluids exist, many commercially available pumps are peristaltic and best model pulsatile flow conditions. However, there are many important situations in which ECs experience laminar flow conditions in vivo, such as along long straight stretches of the vasculature. To understand EC function under these contexts, it is important to be able to reproducibly model laminar flow conditions in vitro. Here, we outline a method to reliably adapt commercially available peristaltic pumps to study laminar flow conditions. Our proof-of-concept study focuses on 2D models but could be further adapted to 3D environments to better model in vivo scenarios, such as organ development. Our studies make significant inroads into solving technical challenges associated with flow modeling and allow us to conduct functional studies toward understanding the mechanistic role of shear forces on vascular architecture, cellular behavior, and remodeling in diverse physiological contexts.


Endothelial cells stimulate growth of normal and cancerous breast epithelial cells in 3D culture.
Epithelial-stromal interaction provides regulatory signals that maintain correct histoarchitecture and homeostasis in the normal breast and facilitates tumor progression in breast cancer. However, research on the regulatory role of the endothelial component in the normal and malignant breast gland has largely been neglected. The aim of the study was to investigate the effects of endothelial cells on growth and differentiation of human breast epithelial cells in a three-dimensional (3D) co-culture assay. Breast luminal and myoepithelial cells and endothelial cells were isolated from reduction mammoplasties. Primary cells and established normal and malignant breast cell lines were embedded in reconstituted basement membrane in direct co-culture with endothelial cells and by separation of Transwell filters. Morphogenic and phenotypic profiles of co-cultures was evaluated by phase contrast microscopy, immunostaining and confocal microscopy. In co-culture, endothelial cells stimulate proliferation of both luminal- and myoepithelial cells. Furthermore, endothelial cells induce a subpopulation of luminal epithelial cells to form large acini/ducts with a large and clear lumen. Endothelial cells also stimulate growth and cloning efficiency of normal and malignant breast epithelial cell lines. Transwell and gradient co-culture studies show that endothelial derived effects are mediated - at least partially - by soluble factors. Breast endothelial cells - beside their role in transporting nutrients and oxygen to tissues - are vital component of the epithelial microenvironment in the breast and provide proliferative signals to the normal and malignant breast epithelium. These growth promoting effects of endothelial cells should be taken into consideration in breast cancer biology.


New insights on glyphosate mode of action in nodular metabolism: Role of shikimate accumulation.
The short-term effects of the herbicide glyphosate (1.25-10 mM) on the growth, nitrogen fixation, carbohydrate metabolism, and shikimate pathway were investigated in leaves and nodules of nodulated lupine plants. All glyphosate treatments decreased nitrogenase activity rapidly (24 h) after application, even at the lowest and sublethal dose used (1.25 mM). This early effect on nitrogenase could not be related to either damage to nitrogenase components (I and II) or limitation of carbohydrates supplied by the host plant. In fact, further exposure to increasing glyphosate concentrations (5 mM) and greater time after exposure (5 days) decreased nodule starch content and sucrose synthase (SS; EC 188.8.131.52) activity but increased sucrose content within the nodule. These effects were accompanied by a great inhibition of the activity of phosphoenolpyruvate carboxylase (PEPC; EC 126.96.36.199). There were remarkable and rapid effects on the increase of shikimic and protocatechuic (PCA) acids in nodules and leaves after herbicide application. On the basis of the role of shikimic acid and PCA in the regulation of PEPC, as potent competitive inhibitors, this additional effect provoked by glyphosate on 5-enolpyruvylshikimic-3-phosphate synthase enzyme (EPSPS; EC 22.214.171.124) inhibition would divert most PEP into the shikimate pathway, depriving energy substrates to bacteroids to maintain nitrogen fixation. These findings provide a new explanation for the effectiveness of glyphosate as a herbicide in other plant tissues, for the observed differences in tolerance among species or cultivars, and for the transitory effects on glyphosate-resistant transgenic crops under several environmental conditions.


Observational study design.
Much can be learned about a process by observing changes over time or by comparing two different processes under different conditions. This chapter introduces the major types of observational study designs: the longitudinal or cohort study, the comparative or case-control study, and some of their variants. It also includes examples of the key measures of relationship between factor and outcome in observational studies, the relative risk and the odds ratio. The similarity of the two measures for low incidence outcomes is illustrated, as is the use of attributable risk to assess how much of a binary outcome is due to a single factor.


Hypothyroidism after thyroidectomy for Graves's disease: a search for an explanation.
Out of 38 patients who had undergone subtotal thyroidectomy for Graves's disease seven to 20 years previously 15 developed hypothyroidism. In these 15 patients autoantibodies against thyroid cytoplasm were significantly more frequent than in the 23 euthyroid patients, though there was no difference in the prevalence of autoantibodies against thyroglobulin. Histological examination of the thyroid tissue removed at operation showed that significantly more plasma cells and lymphoid follicles with germinal centres were present in patients who subsequently developed hypothyroidism than in those who remained euthyroid. No differences in the amount of lymphocytic infiltration were seen in hypothyroid and euthyroid patients.The results suggest that B lymphocytes play a part in the development of postoperative hypothyroidism in Graves's disease. It is proposed that Graves's disease and Hashimoto's disease are different aspects of the same basic autoimmune process.


Iterative, backscatter-analysis algorithms for increasing transmission and focusing light through highly scattering random media.
Scattering hinders the passage of light through random media and consequently limits the usefulness of optical techniques for sensing and imaging. Thus, methods for increasing the transmission of light through such random media are of interest. Against this backdrop, recent theoretical and experimental advances have suggested the existence of a few highly transmitting eigen-wavefronts with transmission coefficients close to 1 in strongly backscattering random media. Here, we numerically analyze this phenomenon in 2D with fully spectrally accurate simulators and provide rigorous numerical evidence confirming the existence of these highly transmitting eigen-wavefronts in random media with periodic boundary conditions that are composed of hundreds of thousands of nonabsorbing scatterers. Motivated by bio-imaging applications in which it is not possible to measure the transmitted fields, we develop physically realizable algorithms for increasing the transmission through such random media using backscatter analysis. We show via numerical simulations that the algorithms converge rapidly, yielding a near-optimum wavefront in just a few iterations. We also develop an algorithm that combines the knowledge of these highly transmitting eigen-wavefronts obtained from backscatter analysis with intensity measurements at a point to produce a near-optimal focus with significantly fewer measurements than a method that does not utilize this information.


Processing and characterization of stable, pH-sensitive layer-by-layer modified colloidal quantum dots.
Quantum Dots (QDs) stabilized with dihydrolipoic acid (DHLA) were used as a template for layer-by-layer (LbL) modification to study the effect on the QD optical properties. We studied several different polyelectrolytes to determine that large quantities of monodisperse DHLA-QDs could only be obtained with the weak polyelectrolyte pair of poly(allylamine hydrochloride) (PAH) and poly(acrylic acid) (PAA). The key to this success was the development of a two-step method to split the LbL process into adsorption and centrifugation phases, which require different pH solutions for optimum success. Solution pH is highlighted as an important factor to achieve sufficient QD surface coverage and QD recovery during wash cycles. We optimized the process to scale up synthesis by introducing a solvent precipitation step before ultracentrifugation that, when coupled with the correct pH conditions, results in a mean QD recovery of 86-90% after three wash cycles. We found that adsorption of PAH had a negligible effect on the quantum yield and lifetime but an additional layer of PAA resulted in a substantial decrease in both quantum yield and lifetime that could not be recovered by the addition of more layers. The PAH coating provides a protective coating that extends DHLA-QDs stability, prevents photo-oxidation mediated aggregation, alleviates concerns over batch variability, and results in pH-dependent emission.


Induction of intracellular ceramide by interleukin-1 beta in oligodendrocytes.
The sphingomyelin pathway has been implicated in mediating the effect of several extracellular agents leading to important biochemical and cellular changes. The aim of this investigation is to study interleukin-1 beta (IL-1 beta) signaling in oligodendrocytes. For this purpose, the CG4 oligodendrocyte cells were differentiated and incubated with IL-1 beta. This treatment induced a time- and dose-dependent increase of the endocellular ceramide. To mimic the effect of the elevation of endogenous ceramide, the CG4 cells were treated with the ceramide analogue C2-ceramide. Cell survival, measured with the MTT assay, showed that, by increasing the concentration of ceramide, up to 40% of CG4 cells were dying within 6 h, similar data were obtained with the primary differentiated oligodendrocytes. Condensation of chromatin, nuclear fragmentation, and formation of apoptotic bodies indicated that apoptosis was the cause of death. Surprisingly, long-term exposure (72 h) to increasing concentrations of IL-1 beta, which increases intracellular ceramide, did not induce oligodendroglial cell death. These results show that an increase of intracellular ceramide is not sufficient to induce apoptosis in oligodendrocytes and that IL-1 beta signaling through the ceramide pathway in these cells can mediate functions other than programmed cell death.


Long-term survival with primary glioblastoma multiforme: a clinical study in bulgarian patients.
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with an extremely poor prognosis in spite of multimodal treatment approaches. The estimated median survival in cases with GBM is about 12-16 months. Those patients who survive =3 years after the initial diagnosis are defined as long-term survivors. In this study, we retrospectively analyze 50 consecutive cases of Bulgarian patients with newly diagnosed GBM surgically treated at our institution for a period of 1 year. Four of them survived for more than 36 months after the initial intervention. The histological re-examination revealed features typical of primary GBM in 3 of these cases, which are described in detail in the present paper. A brief review of the relevant literature is also given.


Regenerative medicine and 3D bioprinting for human space exploration and planet colonisation.
3D printing also known as additive manufacturing (AM) is seen as one of the key enabling technologies for a large number of high-end industrial sectors including the automotive, aerospace and medical industry. Recent advances and breakthroughs in the last years have enabled 3D printing of biocompatible materials, cells and supporting components into complex 3D functional living tissues. 3D bioprinting is being applied to regenerative medicine, addressing the need for tissues and organs suitable for transplantation. Bioprinting implies additional complexities related to the sensitivities of living cells such as printing parameters and conditions, material selection, cell types etc. Despite these challenges, beating artificial heart cells, cartilage implants, skin repairs, functional kidney tissues have been printed successfully on Earth. The present paper addresses the possibility of performing regenerative medicine in space, which may guarantee sustainable life support on long term/long distance planetary exploration missions, opening to stable planet colonisation.


Mechanism of tissue Ca2+ gain during reoxygenation after hypoxia in rabbit myocardium.
The mechanism of increased tissue Ca2+ uptake during reoxygenation after hypoxia was studied in isolated, arterially perfused rabbit septum maintained at 27 degrees C or 37 degrees C. Tissue 47Ca2+, 85Sr2+, or 133Ba2+ uptake was measured by a juxtaposed gamma-probe and a counter. At 27 degrees C, Ba2+ flux across the sarcolemma is similar to that of Ca2+ and Sr2+, but Ba2+ is not taken up by sarcoplasmic reticulum or mitochondria. Therefore 133Ba2+ flux studies were used to delineate the effects of hypoxia and reoxygenation on sarcolemmal permeability to divalent cations. In muscles maintained at 27 degrees C, reoxygenation after 40 min of hypoxia caused significant increases in both 47Ca2+ and 85Sr2+ uptakes. In contrast, there was no change in tissue 133Ba2+ uptake, 133Ba2+ efflux, determined from 133Ba2+ washout studies, was also unchanged. When the sarcolemma was disrupted by perfusing the muscle with a solution containing phospholipase C, tissue 133Ba2+ uptake as well as 47Ca2+ and 85Sr2+ uptakes increased. Moreover an increase in 133Ba2+ efflux was observed after phospholipase infusion. Addition of an inhibitor or an uncoupler of mitochondrial respiration [sodium cyanide (5 X 10(-3) M) or dinitrophenol (5 X 10(-4) M), respectively] in the perfusate caused significant decreases in reoxygenation-induced tissue Ca2+ gain. In muscles perfused with a solution that did not contain permeant anions capable of proton donation (Tris buffer without HCO3(-) and H2PO4(-)), tissue CA2+ gain during reoxygenation was significantly reduced. Perfusion with Tris buffer also caused greater recovery of mechanical function and myocardial ATP concentration during reoxygenation. In muscles maintained at 37 degrees C, both tissue 47Ca2+ and 133Ba2+ uptakes increased during reoxygenation after 40 min of hypoxia. Isolated mitochondria accumulated both Ca2+ and Ba2+ at 37 degrees C. These data suggest that the reoxygenation-induced tissue Ca2+ uptake is primarily caused by an active uptake by mitochondria and that the increase in mitochondrial Ca2+ uptake can occur without any changes in sarcolemmal permeability to divalent cations (Ca2+, Sr2+, or Ba2+). The data also suggest that the increased mitochondrial Ca2+ uptake is responsible, at least in part, for the impaired recovery of myocardial mechanical and cellular function after hypoxia.


Choline metabolism in the cerebral cortex of guinea pigs. Stable-bound acetylcholine.
1. The turnover of synaptosomal (vesicular-cytoplasmic) and stable-bound (vesicular) acetylcholine isolated from cortical tissue was investigated after the administration, under local anaesthesia, of [N-Me-(3)H]choline into the lateral ventricles of guinea pigs. 2. Radioactive acetylcholine and choline present in acid extracts of subcellular fractions were separated by a combination of liquid and column ion-exchange and thin-layer chromatography. 3. The specific radioactivity and pattern of labelling of acetylcholine present in a fraction of monodisperse synaptic vesicles was found to be essentially the same as that of synaptosomal acetylcholine. 4. The specific radioactivity of stable-bound acetylcholine present in partially disrupted synaptosomes (fraction H) at short times (10-20min) after the injection of [N-Me-(3)H]choline was very variable and inversely related to the yield of acetylcholine in that fraction. 5. Evidence was found for the existence of two small, but highly labelled pools of acetylcholine, one which could be isolated in fraction H and the other which was lost when synaptosomes, after isolation by gradient centrifugation, were left at 0 degrees C or pelleted. 6. It is concluded that the results are best explained by metabolic differences among the nerve-ending compartments (thought to be vesicles) which contain stable-bound acetylcholine. Computer simulation of our experiments supports this possibility and suggests that the highly labelled pool in fraction H is present in vesicles close to the external membrane.


Assessment of the Glycan-Binding Profile of Pseudomonas aeruginosa PAO1.
Pseudomonas aeruginosa is an opportunistic pathogen that can establish acute and chronic infections in individuals who lack fully functional innate immunity. In particular, phagocytosis by neutrophils and macrophages is a key mechanism that modulates host control and clearance of P. aeruginosa. Individuals with neutropenia or cystic fibrosis are highly susceptible to P. aeruginosa infection, thus underscoring the importance of the host innate immune response. Cell-to-cell contact between host innate immune cells and the pathogen, a first step in phagocytic uptake, is facilitated by simple and complex glycan structures present at the host cell surface. We have previously shown that endogenous polyanionic N-linked glycans localized to the cell surface of phagocytes mediate the binding and subsequent phagocytosis of P. aeruginosa cells. However, the suite of glycans that P. aeruginosa cells bind to on host phagocytic cells remains poorly characterized. Here, we demonstrate, with the use of exogenous N-linked glycans and a glycan array, that P. aeruginosa PAO1 cells preferentially attach to a subset of glycans, including a bias toward monosaccharide versus more complex glycan structures. Consistent with these findings, we were able to competitively inhibit bacterial adherence and uptake by the addition of exogenous N-linked mono- and disaccharide glycans. We discuss our findings in the context of previous reports of P. aeruginosa glycan binding. IMPORTANCE P. aeruginosa cells bind to a variety of glycans as part of their interaction with host cells, and a number of P. aeruginosa-encoded receptors and target ligands have been described that allow this microbe to bind to such glycans. Here, we extend this work by studying the glycans used by P. aeruginosa PAO1 cells to bind to phagocytic cells and by using a glycan array to characterize the suite of such molecules that can facilitate host cell binding by this microbe. This study provides an increased understanding of the glycans bound by P. aeruginosa and furthermore provides a useful data set for future studies of P. aeruginosa-glycan interactions.


Silver-enhanced block copolymer membranes with biocidal activity.
Silver nanoparticles were deposited on the surface and pore walls of block copolymer membranes with highly ordered pore structure. Pyridine blocks constitute the pore surfaces, complexing silver ions and promoting a homogeneous distribution. Nanoparticles were then formed by reduction with sodium borohydride. The morphology varied with the preparation conditions (pH and silver ion concentration), as confirmed by field emission scanning and transmission electron microscopy. Silver has a strong biocide activity, which for membranes can bring the advantage of minimizing the growth of bacteria and formation of biofilm. The membranes with nanoparticles prepared under different pH values and ion concentrations were incubated with Pseudomonas aeruginosa and compared with the control. The strongest biocidal activity was achieved with membranes containing membranes prepared under pH 9. Under these conditions, the best distribution with small particle size was observed by microscopy.


Follow-up surgical excision is indicated when breast core needle biopsies show atypical lobular hyperplasia or lobular carcinoma in situ: a correlative study of 33 patients with review of the literature.
Atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS) diagnosed in core needle biopsy (CNB) are generally regarded as risk indicators for developing invasive ductal or lobular carcinoma in either breast. Currently, there are no well-established guidelines for management of these patients. The most common management options are careful observation and endocrine chemoprophylaxis for high-risk patients. Previous studies had contradicting recommendations regarding follow-up surgical excision (FSE) of CNB yielding ALH or LCIS. These studies, unfortunately, have been limited by their retrospective nature, small number of patients examined, and association with other high-risk lesions. Only CNB diagnosed as pure LCIS or ALH (not associated with other high-risk lesions such as ADH, radial scar, or papilloma) were included in the study. We reviewed 33 CNB (20 ALH and 13 LCIS) with subsequent FSE from 33 patients (age range, 30-83 years; mean, 58 years). Eighteen of these patients were prospectively analyzed, where FSE was performed in an unselected fashion. All CNBs were obtained by mammotome (11-gauge, 30 cases; and 14-gauge, 3 cases). Mammography identified calcifications in 29 cases (88%) and a mass in 4 cases (12%). FSE revealed infiltrating ductal and/or lobular carcinoma in 4 of 13 LCIS (31%). FSE of 20 ALH revealed cancer in 5 cases (25%), including 4 ductal carcinoma in situ (DCIS) and 1 invasive lobular carcinoma. Seven of these nine cancers were associated with calcifications, and two presented as masses. Sampling error and underestimation of cancer (DCIS or invasive carcinoma) was associated with CNB diagnosis of LCIS or ALH in 27% of all cases. Underestimation of cancer was seen in 28% of prospectively examined patients, including 20% of ALH and 38% of LCIS. CNB associated with mass lesions or that showed histologic features of pleomorphic LCIS or extensive classic LCIS had a higher rate of cancer underestimation. Despite removal of all abnormal mammographic calcifications by CNB in 6 patients, one cancer was detected on FSE. To the best of our knowledge, this is the largest study reported to date, and the only one to include prospectively examined patients with no pre-selection bias. Our data strongly suggests that subsequent FSE is warranted in all patients with CNB diagnoses of LCIS or ALH, to exclude the presence of cancer.


Characterization of products synthesized by galactosyltransferase purified from the ascites of ovarian cancer patients.
Galactosyltransferase purified from the ascites of ovarian cancer patients can use to an equal extent N-glycosidic glycoproteins, such as asialoagalactofetuin, and O-glycosidic mucin, such as asialo bovine submaxillary mucin (BSM), as acceptors. Thermal treatment and substrate competition experiments demonstrated that the same enzyme catalyzed the transfer of galactose to both types of acceptors. Alkaline borohydride treatment showed that, while the product with asialoagalactofetuin was totally resistant, about 90% of the product with asialo BSM was hydrolyzed by this treatment. Gel filtration of the released oligosaccharides on a calibrated Biogel P-2 column showed three peaks. One major oligosaccharide (O-2) of size 5.7 glucose U and two minor peaks (O-1 and O-3) of sizes 8.7 and 3.7 glucose U, respectively, were obtained. The oligosaccharides were doubly labeled, first by incubation with uridine-diphosphate [14C]galactose, followed by alkali treatment in the presence of [3H]borohydride. The doubly labeled oligosaccharides were separately purified by gel filtration and ion-exchange chromatography and digested with various exoglycosidases. The digested products were characterized by gel filtration and paper chromatography in three different systems. From these results, the structures of these oligosaccharides were computed as follows: O-1 = beta-galactosyl-beta-N-acetylglucosamine-galactosaminitol (sialic acid); O-2 = beta-galactose-beta-N-acetylglucosamine-galactosaminitol; O-3 = beta-galactose-galactosaminitol. These results suggest that the galactosyltransferase from the ascites of ovarian cancer patients catalyzes the transfer of galactose to N-acetylglucosamine, irrespective of whether it is a part of an N-glycan or an O-glycan.


The Proteus syndrome: CNS manifestations.
Proteus syndrome is a complex hamartomatous disorder characterized by multiple, diverse, somatic manifestations. We present a case in which severe, evolving CNS abnormalities were also exhibited. Imaging findings at presentation included hemimegalencephaly, subependymal calcified nodules, and periventricular cysts. Subsequently, dural sinus thrombosis developed. Eight previously reported patients may also have had hemimegalencephaly. When neuroimaging studies show hemimegalencephaly in a child with pigmented skin lesions, Proteus syndrome should be considered in the differential diagnosis.


Inhibition of L-type calcium channels by internal GTP [gamma S] in mouse pancreatic beta cells.
Pretreatment of pancreatic beta cells with pertussis toxin resulted in a 30% increase in peak whole-cell Ca2+ currents recorded in the absence of exogenous intracellular guanine nucleotides. Intracellular application of 90 microM GTP[gamma S], by liberation from a caged precursor, resulted in 40% reduction of the peak Ca2+ current irrespective of whether the current was carried by Ca2+ or Ba2+. Effects on the delayed outward K+ current were small and restricted to a transient Ca(2+)-dependent K+ current component. Inhibition by GTP[gamma S] of the Ca2+ current was not mimicked by standard GTP and could not be prevented either by pretreatment with pertussis toxin or by inclusion of GDP[beta S] or cyclic AMP in the intracellular medium. The inhibitory effect of GTP[gamma S] could be counteracted by a prepulse to a large depolarizing voltage. A similar effect of a depolarizing prepulse was observed in control cells with no exogenous guanine nucleotides. These observations indicate that inhibition of beta cell Ca2+ current by G protein activation results from direct interaction with the channel and does not involve second-messenger systems. Our findings also suggest that the beta cell Ca2+ current is subject to resting inhibition by G proteins.


Kinematic analysis of motor dysfunction in Niemann-Pick type C.
To provide the first descriptive analysis of upper limb motor physiology in Niemann-Pick Type C disease (NP-C). Fifteen patients with confirmed NP-C underwent motor physiology testing using accelerometry and surface EMG (sEMG). Tremor amplitude and frequency were quantified using accelerometry, and sEMG was examined for abnormal patterns consistent with various movement disorders. Forty-seven percent of patients had postural tremor in the upper limbs, generally bilateral, with frequencies ranging from 0.3 to 3 Hz, and an average amplitude of 1.20+/-0.98 mm. Eighty-seven percent of patients had bilateral action tremor with frequencies ranging from 2.0 to 3.7 Hz, and an average amplitude of 5.25+/-3.76 mm. sEMG revealed long but variable duration, variable amplitude muscle burst discharges during action in some patients, as well as short high frequency irregularly timed bursts in others. Accelerometric findings correlated with the clinical findings were most consistent with cerebellar outflow tremors. sEMG revealed a mix of dystonic, myoclonic and choreiform movements. These quantitative methods may serve as ancillary measures of disease pathophysiology, markers of change over time, and methods to evaluate efficacy, and side effects, of new treatments as they are developed.


Freud and Jung: an incomplete encounter.
The author discusses the bases of the close, personal and professional relationship between Freud and Jung, and conjectures that the eventual schism between them was the result of the different profound psychological needs that each had for the other. Because of his identification with the psychoanalytic enquiry, particularly as it was based in large measure on his own self analysis, Freud looked to Jung as a collaborator who would not deviate from the principles at the basis of psychoanalysis, seeking psychoanalysis' acceptance within the established scientific community. From Jung's point of view, Freud fulfilled the role of a respected father figure who, Jung hoped, would grant him the autonomy and freedom to pursue his own scientific enquiry, based on Freud's ideas, but which he would revise according to his own researches. These led Jung to certain revisions and additions, such as the nature and function of the libido, the broadening of the idea of the complex (as in the Oedipus complex) to include a number of universal, archetypal themes, and the elaboration of the concept of the self. During the years of their relationship, they shared a mutual psychological support which was deeply important to each, based on reciprocal love and respect but also on a fantasy that each would be able to supply to the other a key capacity that the other lacked. Jung was able to offer important scientific verifications of a number of psychoanalytic notions via the Word Association Test, such as the concept of repression, of the complex, including the Oedipus complex, and the proof of the existence of the unconscious. However, neither could supply to the other what each looked for in the other at the psychological level. The final breakdown and rupture in their relationship was caused by their theoretical differences and by the fact that they became bitter competitors in a race to publish treatises on the nature and origins of spirituality and religion. It has left in its wake the implicit traces of discord and misapprehension which have characterized much of subsequent professional relationships between the two traditions.


Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study.
To report radiological findings observed in computed tomography (CT) and magnetic resonance imaging (MRI) scans of the first cases of congenital infection and microcephaly presumably associated with the Zika virus in the current Brazilian epidemic. Retrospective study with a case series. Association for Assistance of Disabled Children (AACD), Pernambuco state, Brazil. 23 children with a diagnosis of congenital infection presumably associated with the Zika virus during the Brazilian microcephaly epidemic. Types of abnormalities and the radiological pattern of lesions identified on CT and MRI brain scans. Six of the 23 children tested positive for IgM antibodies to Zika virus in cerebrospinal fluid. The other 17 children met the protocol criteria for congenital infection presumably associated with the Zika virus, even without being tested for IgM antibodies to the virus--the test was not yet available on a routine basis. Of the 23 children, 15 underwent CT, seven underwent both CT and MRI, and one underwent MRI. Of the 22 children who underwent CT, all had calcifications in the junction between cortical and subcortical white matter, 21 (95%) had malformations of cortical development, 20 (91%) had a decreased brain volume, 19 (86%) had ventriculomegaly, and 11 (50%) had hypoplasia of the cerebellum or brainstem. Of the eight children who underwent MRI, all had calcifications in the junction between cortical and subcortical white matter, malformations of cortical development occurring predominantly in the frontal lobes, and ventriculomegaly. Seven of the eight (88%) children had enlarged cisterna magna, seven (88%) delayed myelination, and six each (75%) a moderate to severe decrease in brain volume, simplified gyral pattern, and abnormalities of the corpus callosum (38% hypogenesis and 38% hypoplasia). Malformations were symmetrical in 75% of the cases. Severe cerebral damage was found on imaging in most of the children in this case series with congenital infection presumably associated with the Zika virus. The features most commonly found were brain calcifications in the junction between cortical and subcortical white matter associated with malformations of cortical development, often with a simplified gyral pattern and predominance of pachygyria or polymicrogyria in the frontal lobes. Additional findings were enlarged cisterna magna, abnormalities of corpus callosum (hypoplasia or hypogenesis), ventriculomegaly, delayed myelination, and hypoplasia of the cerebellum and the brainstem.


Lysosomal alkalization to potentiate eradication of intra-osteoblastic Staphylococcus aureus in the bone and joint infection setting.
Beyond intracellular penetration, acidic lysosomal pH might affect the intracellular activity of some antimicrobials. This study evaluated the ability of lysosomotropic alkalizing agents to potentiate the antimicrobial eradication of an intra-osteoblastic Staphylococcus aureus reservoir in the setting of bone and joint infection (BJI). MICs of 16 anti-staphylococcal molecules active against methicillin-sensitive S. aureus (MSSA) were evaluated at pH 5 and pH 7. Additionally, the lysosomal alkalizing potential (spectrofluorometry) and cytotoxicity (MTT assay) of hydroxychloroquine, amantadine and ammonium chloride were assessed. The results led to further investigation of clindamycin, cotrimoxazole, daptomycin and levofloxacin-alone or in combination with hydroxychloroquine-in an in vitro model of osteoblast infection. The impact of hydroxychloroquine on autophagy was finally investigated using Western blot detection of two autophagic flux indicators, the LC3 membrane protein and the SQSTM1 cargo protein. Daptomycin, cotrimoxazole, clindamycin and levofloxacin alone significantly decreased the intracellular staphylococcal reservoir (5.12 log10 CFU/100 000 cells) by 0.14 (95%CI 0.01-0.34), 0.25 (95%CI 0.12-0.43), 0.16 (95%CI 0.004-0.39) and 1.18 (95%CI 1.04-1.38) log10 CFU/100 000 cells, respectively (p < 10-3). Adding hydroxychloroquine (20 mg/L) increased intralysosomal pH from 4.8 to 7, and concomitantly the inoculum of each antimicrobial was reduced by 0.50 (95%CI 0.30-0.84), 0.73 (95%CI 0.59-0.96), 0.59 (95%CI 0.46-0.78) and 1.8 (95%CI 1.66-2.1) log10 CFU/100 000 cells, respectively (p < 10-4). Cellular levels of LC3II and SQSTM1 showed that hydroxychloroquine has direct activity on the autophagic flux, fostering the eradication of intracellular S. aureus by antimicrobials. At high concentrations, hydroxychloroquine used as an adjuvant to antimicrobials improves eradication of an S. aureus intra-osteoblastic reservoir in our in vitro cell infection model. These findings advocate further in vivo evaluation of alkalization efficacy and tolerance in S. aureus BJI.


Regulation and aggregation of intrinsically disordered peptides.
Intrinsically disordered proteins (IDPs) are a unique class of proteins that have no stable native structure, a feature that allows them to adopt a wide variety of extended and compact conformations that facilitate a large number of vital physiological functions. One of the most well-known IDPs is the microtubule-associated tau protein, which regulates microtubule growth in the nervous system. However, dysfunctions in tau can lead to tau oligomerization, fibril formation, and neurodegenerative disease, including Alzheimer's disease. Using a combination of simulations and experiments, we explore the role of osmolytes in regulating the conformation and aggregation propensities of the R2/wt peptide, a fragment of tau containing the aggregating paired helical filament (PHF6*). We show that the osmolytes urea and trimethylamine N-oxide (TMAO) shift the population of IDP monomer structures, but that no new conformational ensembles emerge. Although urea halts aggregation, TMAO promotes the formation of compact oligomers (including helical oligomers) through a newly proposed mechanism of redistribution of water around the perimeter of the peptide. We put forth a "superposition of ensembles" hypothesis to rationalize the mechanism by which IDP structure and aggregation is regulated in the cell.


Cellular Sensing Governs the Stability of Chemotactic Fronts.
In contexts ranging from embryonic development to bacterial ecology, cell populations migrate chemotactically along self-generated chemical gradients, often forming a propagating front. Here, we theoretically show that the stability of such chemotactic fronts to morphological perturbations is determined by limitations in the ability of individual cells to sense and thereby respond to the chemical gradient. Specifically, cells at bulging parts of a front are exposed to a smaller gradient, which slows them down and promotes stability, but they also respond more strongly to the gradient, which speeds them up and promotes instability. We predict that this competition leads to chemotactic fingering when sensing is limited at too low chemical concentrations. Guided by this finding and by experimental data on E. coli chemotaxis, we suggest that the cells' sensory machinery might have evolved to avoid these limitations and ensure stable front propagation. Finally, as sensing of any stimuli is necessarily limited in living and active matter in general, the principle of sensing-induced stability may operate in other types of directed migration such as durotaxis, electrotaxis, and phototaxis.


PepSplice: cache-efficient search algorithms for comprehensive identification of tandem mass spectra.
Tandem mass spectrometry allows for high-throughput identification of complex protein samples. Searching tandem mass spectra against sequence databases is the main analysis method nowadays. Since many peptide variations are possible, including them in the search space seems only logical. However, the search space usually grows exponentially with the number of independent variations and may therefore overwhelm computational resources. We provide fast, cache-efficient search algorithms to screen large peptide search spaces including non-tryptic peptides, whole genomes, dozens of posttranslational modifications, unannotated point mutations and even unannotated splice sites. All these search spaces can be screened simultaneously. By optimizing the cache usage, we achieve a calculation speed that closely approaches the limits of the hardware. At the same time, we control the size of the overall search space by limiting the combinations of variations that can co-occur on the same peptide. Using a hypergeometric scoring scheme, we applied these algorithms to a dataset of 1 420 632 spectra. We were able to identify a considerable number of peptide variations within a modest amount of computing time on standard desktop computers.


Hemoglobin concentration and cognitive impairment in the renal REasons for Geographic And Racial Differences in Stroke (REGARDS) Study.
There is growing interest in determining the degree of anemia, which is clinically significant. The goal of this study was to determine the association between hemoglobin concentration and cognitive impairment in a large sample of U.S. adults. We used cross-sectional data from 19,701 adults participating in the REasons for Geographic And Racial Differences in Stroke study. Cognitive impairment was defined as a score of 4 or less on the six-item screener. Hemoglobin was analyzed in 1 g/dL increments relative to the World Health Organization (WHO) threshold (<13 g/dL for men and <12 g/dL for women). The mean hemoglobin concentration was 13.7 ± 1.5 g/dL. The prevalence of cognitive impairment increased from 4.3% among individuals with a hemoglobin >3 g/dL above the WHO threshold to 16.8% for those with a hemoglobin ≥2 g/dL below the WHO threshold. After adjustment for demographics, chronic health conditions, health status, and inflammation, the association between reduced hemoglobin and cognitive impairment was attenuated and no longer significant, including among those with hemoglobin ≥2 g/dL below the WHO threshold (odds ratio 1.39, 95% confidence interval = 0.94-2.04). A test for linear trend was of borderline significance (p value = .06). For 94% of the sample within 2 g/dL of the WHO threshold, there was no relationship between hemoglobin concentration and the odds of cognitive impairment. The associations did not differ by sex and race. Within a large sample of community-dwelling adults, there was no significant association between hemoglobin concentration and cognitive impairment after multivariable adjustment.


Habitual aerobic exercise increases plasma pentraxin 3 levels in middle-aged and elderly women.
Chronic inflammation that occurs with aging is one of the risk factors for cardiovascular disease. Regular exercise may prevent cardiovascular morbidity by decreasing chronic systematic inflammation. Additionally, excess inflammation can be reduced by the anti-inflammatory protein pentraxin 3 (PTX3). Thus, both habitual exercise and PTX3 have an anti-inflammatory effect. However, it is unclear whether regular exercise leads to increased plasma PTX3 concentration. In the present study, we investigated the effects of regular aerobic exercise on plasma PTX3 concentration in middle-aged and elderly women. Twenty-two postmenopausal women (60 ± 6 years) were randomly divided evenly into 2 groups (i.e., exercise intervention and control). Subjects in the exercise group completed 2 months of regular aerobic exercise training (walking and cycling, 30-45 min, 3-5 days·week⁻¹). Before and after the intervention, we evaluated plasma PTX3 concentration, peak oxygen uptake, blood chemistry, and arterial distensibility (carotid arterial compliance and β-stiffness) in all participants. There were no significant differences in baseline parameters between the 2 groups. Plasma PTX3 concentration was significantly increased in the exercise group after the intervention (p < 0.05). High-density lipoprotein cholesterol, peak oxygen uptake, and arterial compliance were also significantly increased (p < 0.05), while β-stiffness was markedly decreased (p < 0.01) after the intervention. On the other hand, there was no change in the parameters tested in the control group. This study demonstrates that regular aerobic exercise increases plasma PTX3 concentration with improvement of high-density lipoprotein cholesterol, peak oxygen uptake, and arterial distensibility in postmenopausal women.


Ryanodine and inositol trisphosphate receptors coexist in avian cerebellar Purkinje neurons.
Two intracellular calcium-release channel proteins, the inositol trisphosphate (InsP3), and ryanodine receptors, have been identified in mammalian and avian cerebellar Purkinje neurons. In the present study, biochemical and immunological techniques were used to demonstrate that these proteins coexist in the same avian Purkinje neurons, where they have different intracellular distributions. Western analyses demonstrate that antibodies produced against the InsP3 and the ryanodine receptors do not cross-react. Based on their relative rates of sedimentation in continuous sucrose gradients and SDS-PAGE, the avian cerebellar InsP3 receptor has apparent native and subunit molecular weights of approximately 1,000 and 260 kD, while those of the ryanodine receptors are approximately 2,000 and 500 kD. Specific [3H]InsP3- and [3H]ryanodine-binding activities were localized in the sucrose gradient fractions enriched in the 260-kD and the approximately 500-kD polypeptides, respectively. Under equilibrium conditions, cerebellar microsomes bound [3H]InsP3 with a Kd of 16.8 nM and Bmax of 3.8 pmol/mg protein; whereas, [3H]ryanodine was bound with a Kd of 1.5 nM and a capacity of 0.08 pmol/mg protein. Immunolocalization techniques, applied at both the light and electron microscopic levels, revealed that the InsP3 and ryanodine receptors have overlapping, yet distinctive intracellular distributions in avian Purkinje neurons. Most notably the InsP3 receptor is localized in endomembranes of the dendritic tree, in both the shafts and spines. In contrast, the ryanodine receptor is observed in dendritic shafts, but not in the spines. Both receptors appear to be more abundant at main branch points of the dendritic arbor. In Purkinje neuron cell bodies, both the InsP3 and ryanodine receptors are present in smooth and rough ER, subsurface membrane cisternae and to a lesser extent in the nuclear envelope. In some cases the receptors coexist in the same membranes. Neither protein is observed at the plasma membrane, Golgi complex or mitochondrial membranes. Both the InsP3 and ryanodine receptors are associated with intracellular membrane systems in axonal processes, although they are less abundant there than in dendrites. These data demonstrate that InsP3 and ryanodine receptors exist as unique proteins in the same Purkinje neuron. These calcium-release channels appear to coexist in ER membranes in most regions of the Purkinje neurons, but importantly they are differentially distributed in dendritic processes, with the dendritic spines containing only InsP3 receptors.


A wearable contact lens sensor for noninvasive in-situ monitoring of intraocular pressure.
Glaucoma is the second leading cause of blindness in the world. Intraocular pressure (IOP) is a primary indicator of glaucoma which can be measured for the treatment of the disease. This paper presents a piezo-resistive principle pressure sensor to monitor IOP continuously and non-invasively. The sensor is designed based on the Wheatstone bridge circuit and fabricated by the spray-coating method. The hybrid nanomaterials of graphene and carbon nanotubes are introduced as sensing layers which are embedded inside the soft contact lens substrate composed of flexible polydimethyl siloxane (PDMS) and parylene. The sensing performance is discussed followed by a brief description of our sensor design and fabrication. Tests on a PDMS eyeball model indicate that it has a high sensitivity of 36.01 μV mmHg-1. Also, the frequency response and the ability to track dynamic pressure change cycles are demonstrated in normal IOP variation range from 9 to 34 mmHg. It shows good repeatability and linearity, and can accurately track fluctuating IOP. Thus, this sensor, with its ease of fabrication and simple design, as well as allowance for continuous pressure measurement, offers a promising approach for IOP monitoring in clinical diagnosis of glaucoma.


Pathogenomics of Virulence Traits of Plesiomonas shigelloides That Were Deemed Inconclusive by Traditional Experimental Approaches.
One of the major challenges of modern medicine includes the failure of conventional protocols to characterize the pathogenicity of emerging pathogens. This is particularly apparent in the case of Plesiomonas shigelloides. Although a number of infections have been linked to this microorganism, experimental evidence of its virulence factors (VFs), obtained by traditional approaches, is somewhat inconclusive. Hence, it remains unclear whether P. shigelloides is a true or opportunistic one. In the current study, four publicly available whole-genome sequences of P. shigelloides (GN7, NCTC10360, 302-73, and LS1) were profiled using bioinformatics platforms to determine the putative candidate VFs to characterize the bacterial pathogenicity. Overall, 134 unique open reading frames (ORFs) were identified that were homologous or orthologous to virulence genes identified in other pathogens. Of these, 52.24% (70/134) were jointly shared by the strains. The numbers of strain-specific virulence traits were 4 in LS1; 7 in NCTC10360; 10 in 302-73; and 15 in GN7. The pathogenicity islands (PAIs) common to all the strains accounted for 24.07% ORFs. The numbers of PAIs exclusive to each strain were 8 in 302-73; 11 in NCTC10360; 14 in GN7; and 18 in LS1. A PAI encoding Vibrio cholerae ToxR-activated gene d protein was specific to 302-73, GN7, and NCTC10360 strains. Out of 33 antibiotic multi-resistance genes identified, 16 (48.48%) genes were intrinsic to all strains. Further, 17 (22.08%) of 77 antibiotic resistance islands were found in all the strains. Out of 23 identified distinct insertion sequences, 13 were only harbored by strain LS1. The number of intact prophages identified in the strains was 1 in GN7; 2 in 302-73; and 2 in NCTC10360. Further, 1 CRISPR element was identified in LS1; 2 in NCTC10360; and 8 in 302-73. Fifteen (78.95%) of 19 secretion systems and secretion effector variants were identified in all the strains. In conclusion, certain P. shigelloides strains might possess VFs associated with gastroenteritis and extraintestinal infections. However, the role of host factors in the onset of infections should not be undermined.


Regulation and function of signal transducer and activator of transcription 3.
Signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, is a key regulator of many physiological and pathological processes. Significant progress has been made in understanding the transcriptional control, posttranslational modification, cellular localization and functional regulation of STAT3. STAT3 can translocate into the nucleus and bind to specific promoter sequences, thereby exerting transcriptional regulation. Recent studies have shown that STAT3 can also translocate into mitochondria, participating in aerobic respiration and apoptosis. In addition, STAT3 plays an important role in inflammation and tumorigenesis by regulating cell proliferation, differentiation and metabolism. Conditional knockout mouse models make it possible to study the physiological function of STAT3 in specific tissues and organs. This review summarizes the latest advances in the understanding of the expression, regulation and function of STAT3 in physiological and tumorigenic processes.


Hydrogen peroxide spraying alleviates drought stress in soybean plants.
To ascertain the effect of exogenously applied hydrogen peroxide (H2O2) on drought stress, we examined whether the spraying of soybean leaves with H2O2 would alleviate the symptoms of drought stress. Pre-treatment by spraying leaves with H2O2 delayed foliar wilting caused by drought stress compared to leaves sprayed with distilled water (DW). Additionally, the relative water content of drought-stressed leaves pre-treated with H2O2 was higher than that of leaves pre-treated with DW. Therefore, we analyzed the effect of H2O2 spraying on photosynthetic parameters and on the biosynthesis of oligosaccharides related to water retention in leaves during drought stress. Under conditions of drought stress, the net photosynthetic rate and stomatal conductance of leaves pre-treated with H2O2 were higher than those of leaves pre-treated with DW. In contrast to DW spraying, H2O2 spraying immediately caused an increase in the mRNA levels of d-myo-inositol 3-phosphate synthase 2 (GmMIPS2) and galactinol synthase (GolS), which encode key enzymes for the biosynthesis of oligosaccharides known to help plants tolerate drought stress. In addition, the levels of myo-inositol and galactinol were higher in H2O2-treated leaves than in DW-treated leaves. These results indicated that H2O2 spraying enabled the soybean plant to avoid drought stress through the maintenance of leaf water content, and that this water retention was caused by the promotion of oligosaccharide biosynthesis rather than by rapid stomatal closure.


In eubacteria, unlike eukaryotes, there is no evidence for selection favouring fail-safe 3' additional stop codons.
Errors throughout gene expression are likely deleterious, hence genomes are under selection to ameliorate their consequences. Additional stop codons (ASCs) are in-frame nonsense 'codons' downstream of the primary stop which may be read by translational machinery should the primary stop have been accidentally read through. Prior evidence in several eukaryotes suggests that ASCs are selected to prevent potentially-deleterious consequences of read-through. We extend this evidence showing that enrichment of ASCs is common but not universal for single cell eukaryotes. By contrast, there is limited evidence as to whether the same is true in other taxa. Here, we provide the first systematic test of the hypothesis that ASCs act as a fail-safe mechanism in eubacteria, a group with high read-through rates. Contra to the predictions of the hypothesis we find: there is paucity, not enrichment, of ASCs downstream; substitutions that degrade stops are more frequent in-frame than out-of-frame in 3' sequence; highly expressed genes are no more likely to have ASCs than lowly expressed genes; usage of the leakiest primary stop (TGA) in highly expressed genes does not predict ASC enrichment even compared to usage of non-leaky stops (TAA) in lowly expressed genes, beyond downstream codon +1. Any effect at the codon immediately proximal to the primary stop can be accounted for by a preference for a T/U residue immediately following the stop, although if anything, TT- and TC- starting codons are preferred. We conclude that there is no compelling evidence for ASC selection in eubacteria. This presents an unusual case in which the same error could be solved by the same mechanism in eukaryotes and prokaryotes but is not. We discuss two possible explanations: that, owing to the absence of nonsense mediated decay, bacteria may solve read-through via gene truncation and in eukaryotes certain prion states cause raised read-through rates.


[Knowledge, strategies and ideologies of nursing: a reflection based on the Lopes' study].
This paper makes a reflection on the knowledge and ideologies present in the nursing practice within a hospital context, based on theoretical references used by the sociologist Noemia da Glória Mendes Lopes in her MS dissertation in Lisbon, Portugal, in 1994. In this dissertation she analyzes the work of nurses within hospital contexts. The author observed that within the professional context of nursing there are many social practices of work indicating different strategies of valuing and revaluating the profession. It was concluded from this reflection that there are better possibilities of performing such strategies in specialized services than in medical clinic services.


Healing: a model for an integrative health care system.
A previous article proposed that healing is the appropriate focus for nursing practice. Healing, the emergence of right relationship at or among the multiple levels of the human experience, was described as a process distinct from the curing of disease. The current article further explicates this theory as the foundation for an integral healing health care system in which advanced practice nurses have a key role to play. The concepts of healing and right relationship are explored in the context of the emerging sciences known collectively as the sciences of complexity.


[A new method for deep reflex muscular massage].
The idea of deep reflex muscular massage rests on the existence of a strong relationship between structural and functional changes in the skeletal muscles and visceral condition. The massage can be used for management of acute states in combination with herbs, food additives, reduced drug dosages, exercises, thermotherapy.


Fractional Curve in Adult Spinal Deformity: Is it a Driver of or a Compensation for Coronal Malalignment?
This was a retrospective review of the multicenter adult spine deformity database. The objective of this study was to investigate the role of the fractional curve (FC) on global coronal malalignment. Despite being very common, the role of the coronal FC as either a driver or compensation for global coronal malalignment is not well documented. Patients with the following characteristics were extracted from a prospective multicenter database: lumbar/thoracolumbar (TL) major coronal curve >15 degrees, apex at T11-L3, lower end vertebra at L3 or L4, above 45 years old, and FC >5 degrees. In addition to the classic radiographic parameters, baseline analysis included Cobb angle, pelvic obliquity (PO), fractional ratio (fractional Cobb/main Cobb), the sum of PO and FC, as well as the coronal Qiu classification. Curves distribution (TL vs. FC) were compared across the 3 Qui types, and the role of the FC was investigated. A total of 404 patients (63 y old, 83.3% female) were included: 43 patients were classified as type B, 120 as type C, and 241 were coronally balanced (type A). Compared with the balanced patients, type C patients had similar major TL Cobb angles but significantly larger fractional Cobb angles (17.5 vs. 22.3 degrees, P<0.001). By opposition, type B patients had significantly larger major TL Cobb angles (49 vs. 41 degrees, P=0.001) but smaller fractional Cobb angles (P<0.001). PO>5 degrees in the same direction as FC was more common in type B patients (20%) than in type C patients (7.5%), which suggests the preferential role of pelvic compensation. Our findings challenge the idea that FC is only a compensatory curve below a main lumbar or TL curve. In type B patients, FC acts as a compensation mechanism but fails to maintain coronal alignment despite the presence of PO. In type C patients, however, the lumbosacral FC acts as a primary driver of coronal malalignment. Level III.


A dual-functional benzobisthiadiazole derivative as an effective theranostic agent for near-infrared photoacoustic imaging and photothermal therapy.
Nanoparticles (NPs) with integrated functionalities of targeting, therapy, imaging contrast and biocompatibility have shown promise for application in improved disease diagnosis and therapy. Herein, we report a theranostic agent based on a narrow-bandgap small molecule, benzo[1,2-c;4,5-c']bis[1,2,5]thiadiazole-4,7-bis(9,9-dioctyl-9H-fluoren-2-yl)thiophene (denoted as BBT-2FT), with the strong absorption of near-infrared (NIR) light. Colloidal nanoparticles composed of BBT-2FT showed a photoacoustic signal intensity ten times higher than that of blood, and high photothermal conversion efficiency (η = 40%) under the irradiation of 808 nm laser light, which killed over 90% of HeLa cells in 10 min.


The use of surface electromyography in dysphagia evaluation.
Dysphagic patients usually have a variety of clinical problems such as malnutrition, significant weight loss, and aspiration pneumonia. Dysphagia is a complication commonly caused by strokes, and surface electromyography (sEMG) provides a simple, non-radioactive, and non-invasive method to measure the patterns of muscle activity during swallowing, allowing clinicians to describe the physiology of swallowing behavior. Most previous studies have described swallowing behavior in terms of amplitude and duration. However, there is no objective and precise approach available for the evaluation of swallowing coordination. In order to evaluate swallowing coordination more precisely, a wireless and wearable monitoring device for dysphagia evaluation was designed for the present study in order to measure four muscle groups simultaneously during swallowing. In this context, the variations of the cross-correlation coefficients were defined as the discoordination index, a metric which can effectively reflect the differences between the surface EMG patterns of the bilateral muscle groups. The experimental results of this study show that the discoordination indices for dysphagic patients are significantly larger than those for healthy subjects and that these discoordination indices can be used as an effective means of evaluating the coordination between bilateral swallowing muscles.


Reduced CFTR function and the pathobiology of idiopathic pancreatitis.
Idiopathic chronic pancreatitis (ICP) is the leading cause of chronic pancreatitis in children and nonalcoholic adults. The risk of developing ICP is increased in individuals who have mutations of the cystic fibrosis gene (CFTR) and of a trypsin inhibitor gene (PSTI). In studies from the United States and France, the risk of ICP is increased about 40-fold by having two abnormal copies of the CFTR gene, about 14-fold by having the N34S PSTI mutation, and about 500-fold by having both. When ICP patients have two abnormal copies of the CFTR gene, there is also evidence of reduced residual CFTR protein function in extrapancreatic tissues based on clinical findings and nasal ion transport responses. Thus, pancreatitis risk is highest in individuals who have abnormalities in both the pancreatic ducts (CFTR) and acini (PSTI). These findings indicate that PSTI is a modifier gene for CFTR-related ICP and have implications for the diagnosis and pathogenesis of pancreatitis.


New Developments in Understanding and Treating Adolescent Marijuana Dependence.
Marijuana is the most commonly used illicit substance in the United States and worldwide. Marijuana use is a problem of increasing magnitude among adolescents. Use typically begins in adolescence and is associated with a variety of adverse outcomes. This article will present an overview of trends in marijuana use, and will review the endocannabinoid system and marijuana. It will discuss recent policy developments in US and their implications, especially for adolescents. Existing treatments will be reviewed, including findings from a recent randomized double-blind trial of N-acetylcysteine, a compound that reverses the dysregulation of the glutamate system that occurs in substance dependence. The core treatment approaches include psychosocial interventions, sometimes in combination with each other. While a reduction in days of use is often achieved with most of these approaches, abstinence is a much more elusive goal. The evidence base for effective treatments remains inadequate especially with regard to adolescents, and there is an urgent need for more research in this area. Promising new treatments include N-acetylcysteine in conjunction with contingency management.


[Less neonatal morbidity with elective caesarean sections at term: local guideline for elective caesarean section is effective].
To assess the effect of a local guideline advising elective caesarean section without maternal comorbidity at a gestational age of >or= 39+0 weeks. Retrospective cohort study. Children born by elective caesarean section in the period 2003-2007 at the VUmc with a gestational age >or= 37+0 weeks and without maternal comorbidity were included. Respiratory complications, length of hospital stay, admission to the neonatal intensive care unit (NICU), respiratory support and medication were recorded from charts of admitted children. These data were compared with data collected in 1994-1998 before implementation of the local guideline. In 2003-2007, 501 children were born from 486 elective caesarean sections. In 1994-1998, 333 children were born from 324 elective caesarean sections. In 2003-2007, mean maternal age was younger, local anaesthesia more frequent, elective caesarean section was more often performed at >or= 39+0 weeks (p < 0.001) and the birth weight was higher. In 2003-2007, fewer infants were admitted to an NICU than in 1994-1998 (6/501 versus 17/333, p < 0.001), of whom fewer infants were born with gestational age <or= 39+0 weeks (50% versus 94%, p = 0.04). In 2003-2007, respiratory morbidity was lower in the group with gestational age 38+0/7-38+6 weeks than in 1994-1998. This is explained by the higher number of elective caesarean sections performed at gestational age of 38+4/7-38+6 weeks in 2003-2007 (63%) compared with 1994-1998 (28%; p < 0.001). After correction for confounders, the odds ratio for developing respiratory morbidity in 2003-2007 was 0.27 compared with 1994-1998 (95% CI: 0.10-0.70). Implementation of the guideline reduced elective caesarean sections before a gestational age of 39+0 weeks and consequently reduced neonatal respiratory morbidity.


Inhibition of nuclear factor-kappaB-mediated adhesion molecule expression in human endothelial cells.
The transcriptional regulatory protein nuclear factor-kappaB (NF-kappaB) participates in the control of gene expression of many modulators of the inflammatory and immune responses, including the adhesion molecules E-selectin and intercellular adhesion molecule-1 (ICAM-1). NF-kappaB is found in the cytoplasm complexed with its inhibitory protein IkappaB. On activation, IkappaB is phosphorylated and degraded, thereby freeing NF-kappaB for translocation to the nucleus. We have generated populations of endothelial cells expressing wild-type and a proteolysis-resistant mutation of IkappaB that is lacking the 36 N-terminal amino acids (IkappaBdeltaN) in order to examine the effects of expression of the mutated IkappaB on tumor necrosis factor-alpha (TNF-alpha)-induced E-selectin and ICAM-1 expression. Wild-type and IkappaBdeltaN were introduced into primary endothelial cells using retrovirus infection followed by selection with G418. The IkappaBdeltaN protein remained at untreated control levels in endothelial cells treated with TNF-alpha and also remained complexed with the NF-kappaB family member p65. Furthermore, TNF-alpha-induced NF-kappaB DNA binding activity was inhibited in the population of endothelial cells expressing IkappaBdeltaN. That population of cells was also refractory to upregulation of E-selectin and ICAM-1 after treatment with TNF-alpha. The use of a truncated IkappaBalpha protein to prevent NF-kappaB-mediated gene expression provides a novel and specific approach for investigating the role of NF-kappaB in processes associated with adhesion molecule expression during inflammation.


MR and iron magnetic nanoparticles. Imaging opportunities in preclinical and translational research.
Ultrasmall superparamagnetic iron oxide nanoparticles and magnetic resonance imaging provide a non-invasive method to detect and label tumor cells. These nanoparticles exhibit unique properties of superparamagnetism and can be utilized as excellent probes for magnetic resonance imaging. Most work has been performed using a magnetic resonance scanner with high field strength up to 7 T. Ultrasmall superparamagnetic iron oxide nanoparticles may represent a suitable tool for labeling molecular probes that target specific tumor-associated markers for in vitro and in vivo detection by magnetic resonance imaging. In our study, we demonstrated that magnetic resonance imaging at 1.5 T allows the detection of ultrasmall superparamagnetic iron oxide nanoparticle conjugated antibody specifically bound to human tumor cells in vitro and in vivo, and that the magnetic resonance signal intensity correlates with the concentration of ultrasmall superparamagnetic iron oxide nanoparticle antibody used and with the antigen density at the cell surface. The experiments were performed using two different means of targeting: direct and indirect magnetic tumor targeting. The imaging of tumor antigens using immunospecific contrast agents is a rapidly evolving field, which can potentially aid in early disease detection, monitoring of treatment efficacy, and drug development. Cell labeling by iron oxide nanoparticles has emerged as a potentially powerful tool to monitor trafficking of a large number of cells in the cell therapy field. We also studied the labeling of natural killer cells with iron nanoparticles to a level that would allow the detection of their signal intensity with a clinical magnetic resonance scanner at 1.5 T. Magnetic resonance imaging and iron magnetic nanoparticles are able to increase the accuracy and the specificity of imaging and represent new imaging opportunities in preclinical and translational research.


[Conservative procedures in 64 pregnant patients with myoma: the course of pregnancy, labor, and the puerperium].
During this period, the number of deliveries was 28235. Our results contradict the wide spread opinion concerning the high risk of a pregnancy in a myomatose uterus. In two thirds of the cases, the pregnancies showed a normal course, this applying also to myoma nodes of 8 cm or more dimater. Threat of premature delivery was ovserved in 11 cases; in two cases premature delivery did occur. More than nine out of ten pregnancies reached the 38th week of gestation. Spontaneous delivery was twice as frequent as Caesarean section. This, however, does not apply to myoma nodes with diameters of 8 cm or more, in which case the frequency of Caesarean section represented 50%. Puerperium was normal in 47 cases; complications were observed in 13 cases due to retarded uterine retraction. In 2 out of 4 cases with atonic post-partum haemorrhage, curettage was performed. Pregnancies in a myomatose uterus are high-risk pregnancies which require close observation. Sonography plays an important role in such cases. One of the authors (D.) proposes high-dose gestagen treatment as a useful therapy when threat of abortion is observed in myomatose uteri. In cases of menacing premature delivery, hospitalisation and tocolysis are highly recommended.


Establishment and characterization of cytopathogenic and noncytopathogenic pestivirus replicons.
Defective interfering particles (DIs) of bovine viral diarrhea virus (BVDV) have been identified and shown to be cytopathogenic (cp) in the presence of noncytopathogenic (noncp) helper virus. Moreover, a subgenomic (sg) RNA corresponding in its genome structure to one of those BVDV DIs (DI9) was replication competent in the absence of helper virus. We report here that an sg BVDV replicon which encodes from the viral proteins only the first three amino acids of the autoprotease N(pro) in addition to nonstructural (NS) proteins NS3 to NS5B replicates autonomously and also induces lysis of its host cells. This demonstrates that the presence of a helper virus is not required for the lysis of the host cell. On the basis of two infectious BVDV cDNA clones, namely, BVDV CP7 (cp) and CP7ins- (noncp), bicistronic replicons expressing proteins NS2-3 to NS5B were established. These replicons express, in addition to the viral proteins, the reporter gene encoding beta-glucuronidase; the release of this enzyme from transfected culture cells was used to monitor cell lysis. Applying these tools, we were able to show that the replicon derived from CP7ins- does not induce cell lysis. Accordingly, neither N(pro) nor any of the structural proteins are necessary to maintain the noncp phenotype. Furthermore, these sg RNAs represent the first pair of cp and noncp replicons which mimic complete BVDV CP7 and CP7ins- with respect to cytopathogenicity. These replicons will facilitate future studies aimed at the determination of the molecular basis for the cytopathogenicity of BVDV.


Late-life depressive symptoms, religiousness, and mood in the last week of life.
Aim of the current study is to examine whether previous depressive symptoms modify possible effects of religiousness on mood in the last week of life. After-death interviews with proxy respondents of deceased sample members of the Longitudinal Aging Study Amsterdam provided information on depressed mood in the last week of life, as well as on the presence of a sense of peace with the approaching end of life. Other characteristics were derived from interviews with the sample members when still alive. Significant interactions were identified between measures of religiousness and previous depressive symptoms (CES-D scores) in their associations with mood in the last week of life. Among those with previous depressive symptoms, church-membership, church-attendance and salience of religion were associated with a greater likelihood of depressed mood in the last week of life. Among those without previous depressive symptoms, church-attendance and salience of religion were associated with a higher likelihood of a sense of peace. For older adults in the last phase of life, supportive effects of religiousness were more or less expected. Fore those with recent depressive symptoms, however, religiousness might involve a component of existential doubt.


Real-time PCR detection and frequency of 16S rDNA mutations associated with resistance and reduced susceptibility to tetracycline in Helicobacter pylori from England and Wales.
To investigate the occurrence of 16S rDNA mutations associated with resistance or reduced susceptibility to tetracycline in Helicobacter pylori isolated in England and Wales, and to develop a real-time PCR assay to detect these DNA polymorphisms from culture and gastric biopsies. Tetracycline susceptibility was determined by disc diffusion. The MIC of isolates with reduced susceptibility was determined by Etest and agar dilution methods. The 16S rDNA of these isolates was sequenced and resistance-associated mutations identified. A LightCycler assay developed to detect these mutations was applied to DNA extracted from culture and gastric biopsies. From 1006 isolates of H. pylori examined, 18 showed reduced susceptibility to tetracycline. Of these, three were resistant (>or=4 mg/L). Mutations in 16S rDNA were detected in 10 of the reduced susceptibility isolates: one double base mutation of A926T/A928C, one A926C, one A928C; and seven A926G. The first two polymorphisms were novel and had not been reported from clinical isolates previously. The LightCycler assay identified each of the 10 isolates with 16S rDNA mutations, but did not detect polymorphisms in 100 tetracycline-susceptible H. pylori isolates. The assay correctly determined the tetracycline susceptibility of H. pylori in 20 gastric biopsy samples. Mutations in 16S rDNA were detected in H. pylori isolated in England and Wales with reduced susceptibility to tetracycline, but resistance to this antibiotic was uncommon. We show molecular-based susceptibility testing for tetracycline is possible direct from biopsy material.


Detection of Ganoderic Acid A in Ganoderma lingzhi by an Indirect Competitive Enzyme-Linked Immunosorbent Assay.
Ganoderma is a genus of medicinal mushroom traditionally used for treating various diseases. Ganoderic acid A is one of the major bioactive Ganoderma triterpenoids isolated from Ganoderma species. Herein, we produced a highly specific monoclonal antibody against ganoderic acid A (MAb 12 A) and developed an indirect competitive ELISA for the highly sensitive detection of ganoderic acid A in Ganoderma lingzhi, with a limit of detection of 6.10 ng/mL. Several validation analyses support the accuracy and reliability of the developed indirect competitive ELISA for use in the quality control of Ganoderma based on ganoderic acid A content. Furthermore, quantitative analysis of ganoderic acid A in G. lingzhi revealed that the pileus exhibits the highest ganoderic acid A content compared with the stipe and spore of the fruiting body; the best extraction efficiency was found when 50 % ethanol was used, which suggests the use of a strong liquor to completely harness the potential of Ganoderma triterpenoids in daily life.


Microbiological criteria: Principles for their establishment and application in food quality and safety.
Legislation on food safety has led towards the standardization of food productions which, together with the existing quality certifications, aim to increase the level of protection of public health. It is recognized the need for the agri-food industry to have tools to harmonize their productions and to adequately manage their quality systems in order to improve consumers' confidence. The implementation of microbiological criteria is focused on facilitating this harmonization by enabling the discrimination of defective lots and acting as control tools at industrial level. Therefore, knowledge of the principles, components and factors influencing the efficiency of microbiological criteria may be helpful to better understand the consequences of their application. In the present study the main principles, methodologies and applications of microbiological criteria in foods are addressed for their implementation as a part of the management quality systems of agrifood industries. In addition, potential limitations and impact of microbiological criteria on food safety are discussed. Finally, an assessment of the performance of microbiological criteria at EU level in berries is described for the compliance of the socalled risk-based metrics, namely Performance Objectives and Food Safety Objectives.


A transendocytosis model of CTLA-4 function predicts its suppressive behavior on regulatory T cells.
Manipulation of the CD28/CTLA-4 pathway is at the heart of a number of immunomodulatory approaches used in both autoimmunity and cancer. Although it is clear that CTLA-4 is a critical regulator of T cell responses, the immunological contexts in which CTLA-4 controls immune responses are not well defined. In this study, we show that whereas CD80/CD86-dependent activation of resting human T cells caused extensive T cell proliferation and robust CTLA-4 expression, in this context CTLA-4 blocking Abs had no impact on the response. In contrast, in settings where CTLA-4(+) cells were present as "regulators," inhibition of resting T cell responses was dependent on CTLA-4 expression and specifically related to the number of APC. At low numbers of APC or low levels of ligand, CTLA-4-dependent suppression was highly effective whereas at higher APC numbers or high levels of ligand, inhibition was lost. Accordingly, the degree of suppression correlated with the level of CD86 expression remaining on the APC. These data reveal clear rules for the inhibitory function of CTLA-4 on regulatory T cells, which are predicted by its ability to remove ligands from APC.


Frontal theta and alpha power and coherence changes are modulated by semantic complexity in Go/NoGo tasks.
To study the interactions between semantic processing and motor response inhibition, we recorded scalp EEG as subjects performed a series of Go/NoGo response inhibition tasks whose response criteria depended on different levels of semantic processing. Three different tasks were used. The first required the subject to make a Go/NoGo decision based on pictures of one particular car or one particular dog. The second used pictures of different types of cars and of dogs, and the final task used stimuli that ranged across multiple types of objects and animals. We found that the theta-band EEG power recorded during the NoGo response was attenuated as a function of semantic complexity while the peak latency was delayed in only the most complex category task. Further, frontal alpha-band desynchronization was strongest for the simplest task and remained close to baseline for the other tasks. Finally, there was significant theta-band coherence between the frontal pole and pre-SMA for the NoGo conditions across tasks, which was not found in the Go trials. These findings provide information about how more rostral frontal regions interact with the pre-SMA during response inhibition across different stimuli and task demands: specifically, level of processing affects latency, difficulty affects amplitude, and coherence is affected by whether the decision is Go or NoGo.


Stigma Reduction Among African American Women With HIV: UNITY Health Study.
African American women encounter disproportionately high rates of HIV-related morbidity and mortality, which is partially mediated through stigma and its effect on HIV treatment adherence. To assess the effect of the UNITY peer support workshop on HIV-related stigma among African American women living with HIV, compared with a time and attention control group. African American women living with HIV were randomized to the UNITY workshop or a breast cancer education control group. Interventions took place in HIV clinics in Chicago, IL and Birmingham, AL. Participants self-reported HIV-related stigma and social support at baseline, after workshop, and at 4 follow-up visits over 12 months. Two hundred thirty-nine participants (UNITY n = 124; breast cancer education n = 115) were assessed over 1 year. Both arms experienced decreases in mean stigma scores over time. Our model estimated that allocation to UNITY was not associated with a significant difference in stigma points over time. Post hoc analysis suggested that preceding increases in perceived social support are associated with decreased HIV-related stigma in this population. Although UNITY did not significantly reduce HIV-related stigma in this population, our findings suggest that social support may be key to HIV-related stigma reduction.


Pathotyping bla CTX-M Escherichia coli from Nigeria.
Escherichia coli have become the enterobacteriaceae species most affected by extended-spectrum β-lactamases (ESBLs) in view of the emergence of CTX-M-type ESBLs. These CTX-M-positive E. coli have been reported in numerous regions worldwide. Virulence determinants of already reported CTX-M-positive E. coli were investigated. To gain insights into the mechanism underlying this phenomenon, we assessed serogroup, susceptibility pattern and diversity of virulence profiles within a collection of nine bla CTX-M-positive E. coli strains and their virulent determinant using miniaturized DNA microarray techniques. The nine ESBL-positive E. coli isolates were from eight male and one female patient(s) selected for study based on previous work. Virulence potential was inferred by detection of 63 virulence factor (VF) genes. Four (44.4%) of the 9 E. coli isolates exhibited the same set of core characteristics: serotype O8:Hnt, while all were positive for OXA-1, ciprofloxacin resistance. Five of the isolates exhibited highly similar (91% to 100%) VF profiles. The findings describe a broadly disseminated, bla CTX-M-positive and virulent E. coli serogroup with highly homogeneous virulence genotypes, suggesting recent emergence in this zone. Understanding how this clone has emerged and successfully disseminated within the hospital and community, including across national boundaries, should be a public health priority.


Detecting individual sites subject to episodic diversifying selection.
The imprint of natural selection on protein coding genes is often difficult to identify because selection is frequently transient or episodic, i.e. it affects only a subset of lineages. Existing computational techniques, which are designed to identify sites subject to pervasive selection, may fail to recognize sites where selection is episodic: a large proportion of positively selected sites. We present a mixed effects model of evolution (MEME) that is capable of identifying instances of both episodic and pervasive positive selection at the level of an individual site. Using empirical and simulated data, we demonstrate the superior performance of MEME over older models under a broad range of scenarios. We find that episodic selection is widespread and conclude that the number of sites experiencing positive selection may have been vastly underestimated.


[Spontaneous coronary artery dissection: Report of two cases].
Spontaneous coronary artery dissection is a rare condition that usually causes a coronary syndrome, but may also cause sudden death. It is more common in women and is associated with factors such as the peripartum period and oral contraceptive use. We report two cases. A 45-year-old woman with hepatitis C, presenting in the emergency room with angina. An intravascular ultrasound showed a dissecting hematoma involving the left, anterior descending and circumflex coronary arteries. She was initially managed with nitroglycerin, anticoagulation and anti-platelet drugs but due to persistence of symptoms, she required surgical revascularization. A 32-year-old woman presenting in the emergency room with angina. A coronary angiogram revealed a dissection of the anterior descending coronary artery. Eight days later an intravenous ultrasound showed a retrograde progression of the dissection and she was subjected to a surgical revascularization.


Global emission inventories for C4-C14 perfluoroalkyl carboxylic acid (PFCA) homologues from 1951 to 2030, Part I: production and emissions from quantifiable sources.
We quantify global emissions of C4-C14 perfluoroalkyl carboxylic acid (PFCA) homologues during the life-cycle of products based on perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorooctane sulfonyl fluoride (POSF), and fluorotelomer compounds. We estimate emissions of 2610-21400 tonnes of C4-C14 PFCAs in the period from 1951 to 2015, and project 20-6420 tonnes to be emitted from 2016 to 2030. The global annual emissions steadily increased in the period 1951-2002, followed by a decrease and then another increase in the period 2002-2012. Releases from fluoropolymer production contributed most to historical PFCA emissions (e.g. 55-83% in 1951-2002). Since 2002, there has been a geographical shift of industrial sources (particularly fluoropolymer production sites) from North America, Europe and Japan to emerging Asian economies, especially China. Sources differ between PFCA homologues, sometimes considerably, and the relative contributions of each source change over time. For example, whereas 98-100% of historical (1951-2002) PFOA emissions are attributed to direct releases during the life-cycle of products containing PFOA as ingredients or impurities, a much higher historical contribution from PFCA precursor degradation is estimated for some other homologues (e.g. 9-78% for PFDA). We address the uncertainties of the PFCA emissions by defining a lower and a higher emission scenario, which differ by approximately a factor of eight.


DNA damage, somatic aneuploidy, and malignant sarcoma susceptibility in muscular dystrophies.
Albeit genetically highly heterogeneous, muscular dystrophies (MDs) share a convergent pathology leading to muscle wasting accompanied by proliferation of fibrous and fatty tissue, suggesting a common MD-pathomechanism. Here we show that mutations in muscular dystrophy genes (Dmd, Dysf, Capn3, Large) lead to the spontaneous formation of skeletal muscle-derived malignant tumors in mice, presenting as mixed rhabdomyo-, fibro-, and liposarcomas. Primary MD-gene defects and strain background strongly influence sarcoma incidence, latency, localization, and gender prevalence. Combined loss of dystrophin and dysferlin, as well as dystrophin and calpain-3, leads to accelerated tumor formation. Irrespective of the primary gene defects, all MD sarcomas share non-random genomic alterations including frequent losses of tumor suppressors (Cdkn2a, Nf1), amplification of oncogenes (Met, Jun), recurrent duplications of whole chromosomes 8 and 15, and DNA damage. Remarkably, these sarcoma-specific genetic lesions are already regularly present in skeletal muscles in aged MD mice even prior to sarcoma development. Accordingly, we show also that skeletal muscle from human muscular dystrophy patients is affected by gross genomic instability, represented by DNA double-strand breaks and age-related accumulation of aneusomies. These novel aspects of molecular pathologies common to muscular dystrophies and tumor biology will potentially influence the strategies to combat these diseases.


Amputation Rates in More Than 175,000 Open Tibia Fractures in the United States.
Open tibia fractures are often associated with considerable soft tissue injuries. Management of open tibia fractures can be challenging, and some patients require amputation. The patient and treatment factors have not been described on a population level in the United States. A retrospective analysis was completed using the 2000 to 2011 Nationwide Inpatient Sample. Amputation rates during the index hospitalization after open tibia fracture were computed based on injury, patient, and hospital characteristics in patients 18 years or older. The overall amputation rate in open tibia fractures during the index hospitalization was 2.2% (n=3769). Patients with midshaft tibia fractures comprised the largest portion of patients undergoing amputation (46.8% of total amputations) compared with distal tibia (34.0%) and proximal tibia (19.3%) fractures. Patients with no neurovascular injury comprised the largest portion of patients undergoing amputation (85.9%), followed by isolated arterial injury (11.1%), combined neurovascular injury (1.9%), and isolated nerve injury (1.1%). Amputation rates were significantly increased for midshaft tibia fractures with neurovascular injury (odds ratio, 12.39; 95% CI, 5.52-27.83) and distal tibia fractures with neurovascular injury (odds ratio, 5.45; 95% CI, 1.73-17.19) compared with tibia fractures with no neurovascular injury while controlling for confounders. On the basis of a review of the Nationwide In-patient Sample during the past decade, the authors have shown that the early amputation rate in open tibia fractures for all-comers is 2.2%. Rates of amputation varied based on fracture site, associated neurovascular injury, medical comorbidities, and hospital location. [Orthopedics. 2021;44(1):48-53.].


Anticarcinogenic effects of selenium.
Selenium (Se) exerts its anticarcinogenic effects by multiple mechanisms. In the physiological dosage range, Se appears to function as an antimutagenic agent, preventing the malignant transformation of normal cells and the activation of oncogenes. These protective effects of Se seem to be primarily associated with its presence in the glutathione peroxidases, which are known to protect DNA and other cellular components from damage by oxygen radicals. Selenoenzymes are also known to play roles in carcinogen metabolism, in the control of cell division, oxygen metabolism, detoxification processes, apoptosis induction and the functioning of the immune system. Other modes of action, either direct or indirect, may also be operative, such as the partial retransformation of tumor cells and the inactivation of oncogenes. However, the effects of Se in the physiological dosage range are not attributable to cytotoxicity, allowing Se to be defined as a genuine nutritional cancer-protecting agent. The anticarcinogenic effects of Se are counteracted by Se-antagonistic compounds and elements. For maximal utilization of its cancer-protective potential, Se supplementation should start early in life and be maintained over the entire lifespan. In addition, exposure to Se antagonists and carcinogenic risk factors should be minimized by appropriate dietary and lifestyle changes.


Emotional Value of Fear Memory and the Role of the Ventral Hippocampus in Systems Consolidation.
Recent studies have explored the circuitry involving the ventral hippocampus (vHPC), the amygdala, and the prefrontal cortex, a pathway mainly activated to store contextual information efficiently. Lesions in the vHPC impair remote memory, but not in the short term. However, how the vHPC is affected by distinct memory strength or its role in systems consolidation has not yet been elucidated. Here, we investigated how distinct training intensities, with strong or weak contextual fear conditioning, affect activation of the dorsal hippocampus (dHPC) and the vHPC. We found that the time course of memory consolidation differs in fear memories of different training intensities in both the dHPC and vHPC. Our results also indicate that memory generalization happens alongside greater activation of the vHPC, and these processes occur faster with stronger fear memories. The vHPC is required for the expression of remote fear memory and may control contextual fear generalization, a view corroborated by the fact that inactivation of the vHPC suppresses generalized fear expression, making memory more precise again. Systems consolidation occurs concomitantly with greater activation of the vHPC, which is accelerated in stronger fear memories. These findings lead us to propose that greater activation of the vHPC could be used as a marker for memory generalization.


Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy.
The success of antitumor immune responses depends on the infiltration of solid tumors by effector T cells, a process guided by chemokines. Here we show that in vivo post-translational processing of chemokines by dipeptidylpeptidase 4 (DPP4, also known as CD26) limits lymphocyte migration to sites of inflammation and tumors. Inhibition of DPP4 enzymatic activity enhanced tumor rejection by preserving biologically active CXCL10 and increasing trafficking into the tumor by lymphocytes expressing the counter-receptor CXCR3. Furthermore, DPP4 inhibition improved adjuvant-based immunotherapy, adoptive T cell transfer and checkpoint blockade. These findings provide direct in vivo evidence for control of lymphocyte trafficking via CXCL10 cleavage and support the use of DPP4 inhibitors for stabilizing biologically active forms of chemokines as a strategy to enhance tumor immunotherapy.


[Arterial diseases and their surgical treatment].
The paper is based on the analysis of 926 operations for atherosclerotic lesions of the abdominal aorta and arteries of the lower extremities, of 125 operations for abdominal aortic aneurysms, of 77 operations for chronic disorders in visceral circulation, of 405 operations for renovascular hypertension, of over 300 interventions for pathology of the aortic arch branches, of over 100 operations for non-specific aortitis, and of 506 operations for coarctation of the aorta. Emphasis is made on the diagnosis of these lesions in the course of a clinical examination of the patients. The successs of treatment largely depends on early referral of the patients to specialized surgical instituions for operative management, as well as on correct primary diagnosis of the vascular lesion by general practitioners.


[Social Determinants of Mental Health: Public Policies Based on the Biopsychosocial Model in Latin American CountriesDeterminantes sociais da saúde mental: políticas públicas a partir do modelo biopsicossocial em países latino-americanos].
This article presents evidence on the implementation of public policies on mental health, and describes the advances and challenges to implementing the biopsychosocial and community model, mainly in Latin America. A theoretical review was conducted of articles indexed in Web of Science, Scopus, PubMed and SciELO. Government reports and programs were included. Social determinants impact mental health. In particular, poverty significantly increases the risk of developing a mental disorder. Accordingly, the World Health Organization insists on the need to adopt a biopsychosocial paradigm to address mental health challenges. About a third of countries still do not have a national mental health policy and there are large disparities in funding and population coverage between high- and low-income countries. Particularly in Latin America, the results illustrate progress in low- and middle-income countries in terms of developing mental health programs with a community and biopsychosocial approach. However, there are challenges in their operationalization, financing, and adaptation to socio-cultural realities. The evidence indicates that in order to move from a biomedical paradigm to one that incorporates the social determinants of health, identical strategies should not be employed in all communities, since the needs of low- and middle-income countries differ from those of high-income countries. Therefore, it is essential to increase local research to generate evidence that reflects national needs with regard to public policies on mental health.