5-Azacytidine-treated human mesenchymal stem/progenitor cells derived from umbilical cord, cord blood and bone marrow do not generate cardiomyocytes in vitro at high frequencies.
Mesenchymal stem/progenitor cells (MSCs) are multipotent progenitors that differentiate into such lineages as bone, fat, cartilage and stromal cells that support haemopoiesis. Bone marrow MSCs can also contribute to cardiac repair, although the mechanism for this is unclear. Here, we examine the potential of MSCs from different sources to generate cardiomyocytes in vitro, as a means for predicting their therapeutic potential after myocardial infarction. Mesenchymal stem/progenitor cells were isolated from the perivascular tissue and Wharton's jelly of the umbilical cord and from cord blood. Their immunophenotype and differentiation potential to generate osteoblasts, chondrocytes, adipocytes and cardiomyoxcytes in vitro was compared with those of bone marrow MSCs. Mesenchymal stem/progenitor cells isolated from umbilical cord and cord blood were phenotypically similar to bone marrow MSCs, the exception being in the expression of CD106, which was absent on umbilical cord MSCs, and CD146 that was highly expressed in cord blood MSCs. They have variable abilities to give rise to osteoblasts, chondrocytes and adipocytes, with bone marrow MSCs being the most robust. While a small proportion (approximately 0.07%) of bone marrow MSCs could generate cardiomyocyte-like cells in vitro, those from umbilical cord and cord blood did not express cardiac markers either spontaneously or after treatment with 5-azacytidine. Although MSCs may be useful for such clinical applications as bone or cartilage repair, the results presented here indicate that such cells do not generate cardiomyocytes frequently enough for cardiac repair. Their efficacy in heart repair is likely to be due to paracrine mechanisms.


Expanding the early intervention offer: A new care pathway for children's wellbeing practitioners in a south London child and adolescent mental health service.
Child and Adolescent Mental Health Services (CAMHS) have been under recent increased demand, with increasingly limited resources, contributing to longer waiting lists, and a growing proportion of rejected referrals due to limited capacity and increasing thresholds. Child and Wellbeing Practitioners (CWPs) provide an opportunity to meet the needs of rejected referrals. We aimed to determine the feasibility of a new and direct referral route within a South London CAMHS. All referrals rejected to the local CAMHS in one year were assessed for inclusion to an embedded child and youth wellbeing in schools team (CYWS), and data collected on reasons for rejection, demographics and eligibility for the CYWS team. Of the 1,322 referrals made to CAMHS in this period, 317 were rejected. The most common reason for referral rejection was not meeting the severity threshold. One third of rejected referrals were judged to be eligible for inclusion to the CYWS team. Therefore, a significant number of children and young people (CYP) being rejected by CAMHS would be eligible for assessment and possible treatment under the CYWS team, making a new referral route potentially feasible, allowing more CYP to access mental health support and have a positive impact on waiting times.


Pituitary Ca2+ channels: blockade by conventional and novel Ca2+ antagonists.
We have identified several new agents that block Ca2+ channels in the rat pituitary GH4C1 cell line. These drugs, which include the diphenylbutylpiperidine antipsychotic pimozide, the calmodulin antagonist calmidazolium, and the steroidal Na+ channel toxin veratridine, were compared with several conventional Ca2+ antagonist in 45Ca2+ uptake, prolactin secretion, and whole cell patch voltage-clamp experiments. Pimozide, the most potent of these novel Ca2+ antagonists, inhibited depolarization-dependent 45Ca2+ uptake and prolactin secretion half maximally at a concentration of 100 nM, whereas calmidazolium and veratridine produced 50% inhibition at concentrations of 500 nM and 1 microM. In comparison, the three organic Ca2+ antagonists nitrendipine, verapamil, and diltiazem blocked 45Ca2+ uptake half maximally at concentrations of 2.5 nM, 1 microM, and 2.5 microM, respectively. All of the antagonists inhibited Ca2+ uptake and prolactin secretion stimulated by the dihydropyridine Ca2+ agonist BAY-K 8644 less potently than KCl-stimulated responses. In patch-clamp experiments, pimozide, veratridine, and nitrendipine blocked Ca2+ current through the slowly inactivating Ca2+ channels of GH4C1 cells. These results demonstrate that Ca2+ channels in an endocrine cell line can be blocked by a variety of molecules including sodium channel toxins and calmodulin antagonists. The data extend the pharmacological similarity between Ca2+ channels in pituitary and other excitable cells and suggest a structural similarity among several cellular proteins.


The effect of urbanization on carbon dioxide emissions efficiency in the Yangtze River Delta, China.
Cities have been one of the most important areas of CO2 emissions. It is increasingly important to research the effect of urbanization on CO2 emissions, especially in large emerging and developing economies, due to the indispensable need for understanding the effect of urbanization on CO2 emissions, evaluating carbon reduction tasks and providing the scientific basis for low-carbon urbanization. Utilizing a balanced panel dataset in the Yangtze River Delta (YRD), China, during the period of 2000-2010, this paper employed data envelopment analysis (DEA) window analysis and a spatial lag panel Tobit model to investigate the effect of urbanization on CO2 emissions efficiency (the ratio of the target CO2 emissions to the actual CO2 emissions). The results show that the average CO2 emissions efficiency was 0.959 in 2010, and CO2 emissions efficiency ranged from 0.816 to 1 and exhibited spatial clustering in the region. The larger potential of CO2 emissions reduction appeared in Zhenjiang and Yangzhou, indicating that more CO2 emissions reduction tasks should be allocated to these two cities. Urbanization has negative effects on improving CO2 emissions efficiency, and there is a U-curve relation between CO2 emissions efficiency and urbanization, indicating that CO2 emissions efficiency decreases at the early stage of urbanization, then increases when urbanization reach a high level. There is spatial spillover effect among the prefecture-level cities, suggesting that different prefecture-level governments should coordinate with each other to improve CO2 emissions efficiency in the whole area. Gross domestic product (GDP) per capita also plays a markedly positive role in improving CO2 emissions efficiency. This research highlights the effect of urbanization on CO2 emissions efficiency and the importance of improving CO2 emissions efficiency in developing countries.


Matrix-assisted laser desorption/ionization directed nano-electrospray ionization tandem mass spectrometric analysis for protein identification.
In those cases where the information obtained by peptide mass fingerprinting or matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS) is not sufficient for unambiguous protein identification, nano-electrospray ionization (nano-ESI) and/or electrospray ionization tandem mass spectrometry (ESI-MS/MS) analysis must be performed. The sensitivity of nano-ESI/MS, however, is lower than that of MALDI-MS, especially at very low analyte concentrations and/or in the presence of contaminants, such as salt and detergents. Moreover, to perform ESI-MS/MS, the peptide masses of the precursor ions must be known. The approach described in this paper, MALDI-directed nano-ESI-MS/MS, makes use of information obtained from the more sensitive MALDI-MS experiments in order to direct subsequent nano-ESI-MS/MS experiments. Peptide molecular ions found in the MALDI-MS analysis are then selected, as their (+2) precursor ions, for nano-ESI-MS/MS sequencing, even though these ions cannot be detected in the ESI-MS spectra. This method, originally proposed by Tempst et al. (Anal. Chem. 2000, 72: 777-790), has been extended to provide better sensitivity and shorter analysis times; also, a comparison with liquid chromatography/tandem mass spectrometry (LC/MS/MS) has been performed. These experiments, performed using quadrupole time-of-flight instruments equipped with commercially available nano-ESI sources, have allowed the unambiguous identification of in-gel digested proteins at levels below their ESI-MS detection limits, even in the presence of salts and detergents.


North American Neuromodulation Society Educational Curriculum for Intrathecal Drug Delivery Systems Implantation and Management.
Intrathecal drug delivery systems (IDDSs) are used for the treatment of pain and spasticity. A wide range of educational criteria exist for these devices. The North American Neuromodulation Society (NANS) Education Committee developed a comprehensive IDDS curriculum to function as a standard for physician graduate education and assessment through training and into practice. A multidisciplinary and diverse task force gathered by the NANS Education Committee met in person and virtually over several sessions and developed an IDDS curriculum modeling their previous work on spinal cord stimulation and following the Accreditation Council for Graduate Medical Education (ACGME) Milestones. There were iterative revisions and adaptations to the curriculum, and the final version was approved by the NANS Board of Directors. The curriculum was developed with distinction between implanting physicians and managing physician and physicians who perform both tasks. There is a lateral temporal progression from early learner to practitioner, with advanced learner in the middle. In addition, there is a modular vertical organization that divides the curriculum into the six educational competencies outlined by the ACGME. A comprehensive, modular, graduated, and segmented educational curriculum for IDDSs was developed by NANS. We propose the curriculum to be the standard for guidance and assessment of trainees and physicians pursuing training in implanting or managing IDDSs.


Effects of the newer nonsteroidal anti-inflammatory agents, ibuprofen, fenoprofen, and sulindac, on neutrophil adherence.
Administration of corticosteroids, aspirin, or indomethacin induces marked inhibition of adherence of polymorphonuclear leukocytes (PMNLs) in vitro. The effects of three newer nonsteroidal anti-inflammatory agents on PMNL adherence were defined. Adherence of PMNLs after passage through a nylon-wool column was measured in normal volunteers who had ingested a single tablet of 300 mg of ibuprofen, 300 mg of fenoprofen, or 200 mg of sulindac. Adherence was significantly decreased from baseline at 4 hr after ibuprofen or fenoprofen was taken, remained suppressed at 24 hr, and returned to normal at 48 hr. Sulindac mildly inhibited PMNL adherence 48 hr after drug ingestion. Inhibition of adherence with ibuprofen and fenoprofen also occurred after incubation of control PMNLs with plasma specimens from volunteers 4 and 24 hr after drug administration, a result suggesting a partially plasma-mediated factor. Zymosan-induced augmented adherence was also inhibited by pretreatment in vitro with ibuprofen at a concentration of 25 micrograms/ml and fenoprofen at 50 micrograms/ml.


Dynamic contrast-enhanced MR imaging in monitoring response to isolated limb perfusion in high-grade soft tissue sarcoma: initial results.
The objective of this study was to evaluate whether dynamic contrast-enhanced MR imaging can determine tumor response and localize residual viable tumor after isolated limb perfusion (ILP) chemotherapy in soft tissue tumors. Twelve consecutive patients, with histologically proven high-grade soft tissue sarcoma, prospectively underwent non-enhanced MR and dynamic contrast-enhanced MR imaging before and after ILP. Tumor volume was measured on non-enhanced MR images. The temporal change of signal intensity in a region of interest on dynamic contrast-enhanced MR images was plotted against time. Start, pattern, and progression of enhancement were recorded. Histopathologic response was defined as complete response if no residual viable tumor was present, partial remission if <50% viable tumor was present, and no change if > or =50% viable tumor was present in the resection specimen. Resected specimens for correlation with histopathology were available for 10 patients; 5 patients had partial remission and 5 had no change. Volume measurements correctly predicted tumor response in 6 of 10 patients. Dynamic contrast-enhanced MR correctly predicted tumor response in 8 of 10 patients. Early rapidly progressive enhancement correlated histologically with residual viable tumor. Late and gradual, or absence of enhancement, was associated with necrosis, predominantly centrally located, or granulation tissue. These preliminary results show that dynamic contrast-enhanced MR imaging offers potential for non-invasive monitoring of response to isolated limb perfusion in soft tissue sarcomas due to identification of residual areas of viable tumor and subsequently may provide clinically useful information with regards to timing and planning of additional surgery. Further prospective studies in a larger patient population is warranted.


Comparison of the effects of long-chain omega-3 fatty acid supplementation on plasma levels of free and esterified oxylipins.
It is believed that many of the beneficial effects of long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) are mediated by their oxidized metabolites, the oxylipins. The formation and biological role of many cytochrome P450 and lipoxygenase derived hydroxy, epoxy and dihydroxy FA, particularly of oxylipins esterified in polar lipids and triglycerides remain unclear. In this study, we compared the impact of twelve weeks of LC n-3 PUFA supplementation on the patterns of free and total (sum of esterified and free) hydroxy, epoxy and dihydroxy FAs. Subjects (5 male; 5 female) between 46 and 70 years were supplemented with 1.1g/d of eicosapentaenoic acid (EPA) and 0.74g/d docosahexaenoic acid (DHA) as ethyl esters. Blood samples were drawn before and after twelve weeks of treatment. Oxylipins in plasma were analyzed by LC-MS directly for free oxylipins and after saponification. Relative FA composition in erythrocyte membranes was analyzed by GC. LC n-3 PUFA treatment led to a significant increase in EPA (200%) and DHA (23%) in erythrocyte membranes. Of the oxylipins measured in plasma, total and free EPA-derived metabolites were highly increased (70-150%), while total AA-derived metabolites were decreased on average by 30%. There was no effect on DHA-metabolites. Concentrations of total hydroxy and epoxy FAs in plasma were considerably higher compared to free hydroxy and epoxy FAs (up to 350 times), while levels of most free dihydroxy FAs were in a similar range to total dihydroxy FAs. However, the individual ratios between total and free plasma oxylipins remained unchanged after LC n-3 PUFA treatment. LC n-3 PUFA supplementation causes a shift in the levels of circulating oxylipins, having the strongest impact on EPA-derived epoxy, dihydroxy and hydroxy FA. The unchanged ratio of free and esterified oxylipins in plasma indicates that both concentrations are valuable biomarkers for assessing the individual status of these lipid mediators.


The epizootiology of anatid herpesvirus 1 infection in free-flying waterfowl: a comparison of latent and active infections among native waterfowl, captive-reared released ducks, and peridomestic or feral ducks.
The epizootiology of anatid herpesvirus 1 (AHV-1) infection in waterfowl is poorly understood but apparently involves persistence of the virus in latently infected birds. Epornitics have often occurred in captive waterfowl or semiwild ducks in parklike settings, and many wildlife professionals conclude that such ducks may be the source of infection for wild waterfowl. We assessed the prevalence of latent infection and viral shedding from four groups of waterfowl: naturally occurring populations of native waterfowl, captive-reared waterfowl released for shooting, introduced nonmigratory waterfowl (e.g., resident, wild Mallards; Anas platyrhynchos), and semiwild peridomestic waterfowl (e.g., park ducks) in North Carolina and Florida, USA from 2004 to 2009. A nested PCR assay was used to detect viral DNA in trigeminal ganglia and cloacal swabs. Detection of viral DNA in trigeminal ganglia, but not cloacal swabs, was assumed to indicate latent infection, whereas PCR-positive cloacal swabs indicated active shedding of the virus. We collected 2,045 samples from 23 species of native, wild waterfowl, and detected latent infections in nine species. Wild Northern Pintails (Anas acuta), a species reportedly resistant to the virus, had the highest prevalence (8.1%). However, low prevalences were identified in other waterfowl from various families. Cloacal shedding was rarely detected (0.1% prevalence) among native waterfowl and was observed in one Blue-winged Teal (Anas discors) and one Mottled Duck (Anas fulvigula). All captive-reared, released waterfowl (n=13) collected were Mallards and one was latently infected, suggesting that these birds could also serve as a source of AHV-1 for naive waterfowl. All nonmigratory waterfowl sampled (n=90) were also Mallards. None of the resident Mallards were shedding virus, but one was latently infected. The peridomestic waterfowl sampled included breeds of domestic Mallard (n=6) and Muscovy Ducks (Cairina moschata; n=73). One peridomestic Mallard and four Muscovy Ducks were shedding virus at the time they were sampled, but no latently infected, asymptomatic carriers were identified.


Effect of direct angioplasty therapy on acute middle cerebral artery occlusion with good leptomeningeal collateral.
The objective of this study was to investigate and discuss the effect of direct angioplasty therapy on acute middle cerebral artery occlusion (MCAO) patients with good leptomeningeal collateral circulation in 4.5 h. We retrospectively reviewed our acute ischemic stroke database from January 2017 to January 2019, then selected consecutive patients with evidence of the proximal M1 segments of MCAO and good leptomeningeal collateral who have received angioplasty or mechanical thrombectomy (MT). The baseline characteristics and outcome of patients was statistical analysis, included age, gender and risk factors, baseline national institutes of health stroke scale (NIHSS) scores, preoperative alberta stroke programme early CT (ASPECT) score, time from door to needle, time of door to puncture, endovascular procedure time, 7d NIHSS score and the modified treatment in cerebral infarction (m-TICI) 2b or 3, symptomatic hemorrhage, average hospital stays, modified rankin scale (mRS) score 0-2 at 3-month and mortality. All the thrombi were analyzed by histopathology. All statistical analysis was done with t-test for continuous data and χ2 test for binary data. A total of 93 patients were included (direct angioplasty = 41 (44.1 %), MT = 52 (55.9 %)). There was no significant difference in baseline data between the two groups. The difference in the time of door to recanalization, the time of puncture to recanalization, symptomatic hemorrhage, and average hospital stays were significantly different between groups (P < 0.05). The other agents were not significantly different between groups (P > 0.05 each). Histopathological analysis showed all thrombi contained different amounts of platelets, fibrinogen, white blood cell, and red blood cell. Direct angioplasty therapy on acute MCAO with good leptomeningeal collateral may help to shorten the time of surgery, reduce symptomatic hemorrhage, and hospital stay.


CD4CD25 regulatory T lymphocytes in allergy and asthma.
Allergic asthma is characterized by airway hyper-responsiveness and chronic mucosal inflammation mediated by CD4(+) Th2 lymphocytes. Regulatory CD4(+)CD25(+) T cells are important components of the homeostasis of the immune system, as impaired CD4(+)CD25(+) T cell activity can cause autoimmune diseases and allergy. The mechanism of suppression by CD4(+)CD25(+) T cells remains controversial; different in vivo and in vitro studies raise possible roles for the immunosuppressive cytokines interleukin-10 and transforming growth factor-beta, forkhead transcription factor Foxp3, glucocorticoid-induced tumor necrosis factor receptor, cytotoxic lymphocyte associated antigen-4, 4-1BB costimulator receptor, a CD4-related molecule LAG-3, and neuropilin-1. Current data suggest that Th2 responses to allergens are normally suppressed by CD4(+)CD25(+) T cells. Suppression by CD4(+)CD25(+) T cells is decreased in allergic individuals. Furthermore, CD4(+)CD25(+) T cells play a key role in regulating airway eosinophilic inflammation. The immunomodulatory properties of CD4(+)CD25(+) T cells do extend to Th2 responses, most notably by limiting the development of a proinflammatory CD4(+) Th2 phenotype characterized by reduced cytokine production. An understanding of the roles of CD4(+)CD25(+) T cells in vivo could provide better insight into the design of novel approaches to modulate the chronic airway inflammatory reaction evident in bronchial asthma.


Surface fluctuation scattering using grating heterodyne spectroscopy.
Heterodyne photon spectroscopy is used for the study of the viscoelastic properties of the liquid interface by studying light scattered from thermally generated surface fluctuations. A theory of a heterodyne apparatus based on a grating is presented, and the heterodyne condition is given in terms of the parameters of the experimental setup. Particular attention is paid to those conditions of the experiment that can cause systematic errors. An instrument function for the apparatus relating the measured output to the experimental parameters of interest is derived. It is shown that the instrument function is generally not Gaussian but that its functional form can depend strongly on the parameters of the experimental setup. In particular, it is shown that significant systematic deviations are expected from previous published analysis of the problem. This is primarily due to the nonlinear relation of the surface wave number to the frequency. An algorithm is suggested to arrive at the frequency and width parameters of the spectrum from a typical noisy experimental data set and applied to data obtained from ethanol surfaces.


Obesity associated genetic variation in FTO is associated with diminished satiety.
Polymorphisms within the FTO gene have consistently been associated with obesity across multiple populations. However, to date, it is not known whether the association between genetic variation in FTO and obesity is mediated through effects on energy intake or energy expenditure. Our objective was to examine the association between alleles of FTO known to increase obesity risk and measures of habitual appetitive behavior. The intronic FTO single nucleotide polymorphism (rs9939609) was genotyped in 3337 United Kingdom children in whom measures of habitual appetitive behavior had been assessed using two scales (Satiety Responsiveness and Enjoyment of Food) from the Child Eating Behaviour Questionnaire, a psychometric tool that has been validated against objective measures of food intake. Associations of FTO genotype with indices of adiposity and appetite were assessed by ANOVA. As expected, the A allele was associated with increased adiposity in this cohort and in an independent case-control replication study of United Kingdom children of similar age. AA homozygotes had significantly reduced Satiety Responsiveness scores (P = 0.008, ANOVA). Mediation analysis indicated that the association of the AA genotype with increased adiposity was explained in part through effects on Satiety Responsiveness. We have used a unique dataset to examine the relationship between a validated measure of children's habitual appetitive behavior and FTO obesity risk genotype and conclude that the commonest known risk allele for obesity is likely to exert at least some of its effects by influencing appetite.


Poly(ADP-ribose) polymerase 1 modulates the lethality of CHK1 inhibitors in carcinoma cells.
Prior studies have demonstrated that inhibition of CHK1 can promote the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and phosphorylation of histone H2AX and that inhibition of poly(ADP-ribose) polymerase 1 (PARP1) can affect growth factor-induced ERK1/2 activation. The present studies were initiated to determine whether CHK1 inhibitors interacted with PARP1 inhibition to facilitate apoptosis. Transient expression of dominant-negative CHK1 raised basal ERK1/2 activity and prevented CHK1 inhibitors from activating ERK1/2. CHK1 inhibitors modestly increased the levels of PARP1 ADP ribosylation and molecular or small-molecule inhibition of PARP1 blocked CHK1 inhibitor-stimulated histone H2AX phosphorylation and activation of ERK1/2. Stimulated histone H2AX phosphorylation was ataxia telangiectasia-mutated protein-dependent. Multiple CHK1 inhibitors interacted in a greater than additive fashion with multiple PARP1 inhibitors to cause transformed cell-killing in short-term viability assays and synergistically killed tumor cells in colony-formation assays. Overexpression of BCL-xL or loss of BAX/BAK function, but not the function of BID, suppressed CHK1 inhibitor + PARP1 inhibitor lethality. Inhibition of BCL-2 family protein function enhanced CHK1 inhibitor + PARP1 inhibitor lethality and restored drug-induced cell-killing in cells overexpressing BCL-xL. Thus, PARP1 plays an important role in regulating the ability of CHK1 inhibitors to activate ERK1/2 and the DNA damage response. An inability of PARP1 to modulate this response results in transformed cell death mediated through the intrinsic apoptosis pathway.


Cell migration driven by substrate deformation gradients.
Identifying the cues followed by cells is key to understand processes as embryonic development, tissue homeostasis, or several pathological conditions. Based on a durotaxis model, it is shown that cells moving on predeformed thin elastic membrane follow the direction of increasing strain of the substrate. This mechanism, straintaxis, does not distinguish the origin of the strain, but the active stresses produce large strains on cells or tissues being used as substrates. Hence, straintaxis is the natural realization of duratoaxis in vivo. Considering a circular geometry for the substrate cells, it is shown that if the annular component of the active stress component increases with the radial distance, cells migrate toward the substrate cell borders. With appropriate estimation for the different parameters, the migration speeds are similar to those obtained in recent experiments (Reig et al 2017 Nat. Commun. 8 15431). In these, during the annual killifish epiboly, deep cells that move in contact with the epithelial enveloping cell layer (EVL), migrate toward the EVL cell borders with speeds of microns per minute.


Demographic inference from whole-genome and RAD sequencing data suggests alternating human impacts on goose populations since the last ice age.
We investigated how population changes and fluctuations in the pink-footed goose might have been affected by climatic and anthropogenic factors. First, genomic data confirmed the existence of two separate populations: western (Iceland) and eastern (Svalbard/Denmark). Second, demographic inference suggests that the species survived the last glacial period as a single ancestral population with a low population size (100-1,000 individuals) that split into the current populations at the end of the last glacial maximum with Iceland being the most plausible glacial refuge. While population changes during the last glaciation were clearly environmental, we hypothesize that more recent demographic changes are human-related: (1) the inferred population increase in the Neolithic is due to deforestation to establish new lands for agriculture, increasing available habitat for pink-footed geese, (2) the decline inferred during the Middle Ages is due to human persecution, and (3) improved protection explains the increasing demographic trends during the 20th century. Our results suggest both environmental (during glacial cycles) and anthropogenic effects (more recent) can be a threat to species survival.


Alpha-interferon in the treatment of nodular lymphomas.
Patients with nodular lymphoma initially respond to a number of therapies but relapse is common and inexorable with time, and despite further therapy, most patients will ultimately die of their lymphoma. The recent demonstration of their sensitivity to alpha-interferon is promising. The importance of this human antitumor effect is that it is presumably based on mechanisms different from conventional agents. Phase I trials of various doses and schedules of recombinant alpha-interferon have shown that effective serum levels can be obtained by intramuscular (IM), intravenous (IV), or subcutaneous (SC) routes. Virtually all patients experienced some degree of acute toxicity manifested by fever, chills, myalgia, and headache. Tolerance usually developed to acute adverse effects within the first few weeks of therapy, regardless of dose or schedule. Fatigue and anorexia were the most important adverse reactions, occurring during the first two weeks of treatment and generally persisting for the duration of therapy. Occasional adverse effects relating to the central nervous and cardiovascular systems have been reported. Primary laboratory abnormalities observed during treatment include decreases in hematologic parameters and elevations of liver function tests. The clinical efficacy of alpha-interferon, both natural and recombinant, has been demonstrated in both untreated and heavily pretreated patients with nodular lymphoma. The response rate has approached 50% in recent studies; however, less than half were complete responders. Future directions include combination of interferon with cytotoxic agents or other biological response modifiers and use as adjuvant therapy.


Discovery of a potent and orally bioavailable benzolactam-derived inhibitor of Polo-like kinase 1 (MLN0905).
This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.


The Myrtle rust pathogen, Puccinia psidii, discovered in Africa.
Puccinia psidii, the cause of a disease today commonly referred to as Myrtle rust, is considered a high priority quarantine threat globally. It has a wide host range in the Myrtaceae and it is feared that it may result in significant damage to native ecosystems where these plants occur. The fungus is also of considerable concern to plantation forestry industries that propagate Australian Eucalyptus species. In May 2013, symptoms of a rust disease resembling those of P. psidii were observed on an ornamental Myrtaceous shrub in a garden in South Africa. The fungus was identified based on DNA sequence data of the ITS and 5.8S nrRNA gene regions and here we report, for the first time, the presence of P. psidii in Africa.


Circumferential esophageal leiomyoma: Management by combined robotic surgery and intraoperative endoscopy.
Leiomyoma is the most common benign tumor of the esophagus. Open thoracotomy, the traditional approach adopted for the enucleation of the esophageal leiomyoma, over the years, has been gradually replaced by video-assisted thoracoscopic surgery. However, this minimally invasive approach has limitations, such as two-dimensional vision and reduced range of motion, which have recently been overcome by technical advantages of robot-assisted surgery. In the surgical management of circumferential esophageal leiomyoma, a combined use of robotic surgery and intraoperative endoscopy may be helpful to facilitate tumor enucleation and to prevent esophageal mucosal injury during the surgical procedure.


Stimulation of non-oxidative glucose utilization by L-carnitine in isolated myocytes.
The effects of L-carnitine on 14CO2 release from [1-14C]pyruvate oxidation (an index of pyruvate dehydrogenase activity, PDH), [2-14C]pyruvate, and [6-14C]glucose oxidation (indices of the acetyl-CoA flux through citric acid cycle), and [U-14C]glucose (an index of both PDH activity and the flux of acetyl-CoA through the citric acid cycle), were studied using isolated rat cardiac myocytes. L-carnitine increased the release of 14CO2 from [1-14C]pyruvate, and decreased that of [2-14C]pyruvate in a time and concentration-dependent manner. At a concentration of 2.5 mM, L-carnitine produced a 50% increase of CO2 release from [1-14C]pyruvate and a 50% decrease from [2-14C]pyruvate oxidation. L-carnitine also increased CO2 release from [1-14C]pyruvate oxidation by 35%, and decreased that of [2-14C]pyruvate oxidation 30%, in isolated rat heart mitochondria. The fatty acid oxidation inhibitor, etomoxir, stimulated the release of CO2 from both [1-14]pyruvate and [2-14C]pyruvate. These results were supported by the effects of L-carnitine on the CO2 release from [6-14C]- and [U-14C]glucose oxidation. L-carnitine (5 mM) decreased the CO2 release from [6-14C]glucose by 37%, while etomoxir (50 microM) increased its release by 24%. L-carnitine had no effect on the oxidation of [U-14C]glucose. L-carnitine increased palmitate oxidation in a time- and concentration-dependent manner in myocytes. Also, it increased the rate of efflux of acetylcarnitine generated from pyruvate in myocytes. These results suggest that L-carnitine stimulates pyruvate dehydrogenase complex activity and enhances non-oxidative glucose metabolism by increasing the mitochondrial acetylcarnitine efflux in the absence of exogenous fatty acids.


Randomized trial of an alternate human papillomavirus vaccine administration schedule in college-aged women.
Human papillomavirus (HPV) vaccine is effective against HPV types 16 and 18, which cause 70% of cervical cancers. The three-dose vaccination schedule at 0, 2, and 6 months may be inconvenient for college-aged women. This study assessed noninferiority of the immune response to an alternate vaccination schedule at 0, 2, and 12 months. Two hundred nonpregnant women, aged 18-23 years, with <5 sexual partners were randomized into standard and alternate schedules. Blood samples were drawn before dose 1 and 2-6 weeks after dose 3 and analyzed with the competitive Luminex immunoassay. Seropositives at baseline were eliminated from analyses by HPV type. Log-transformed titers were used to calculate HPV type-specific geometric mean titers (GMTs) and 95% confidence intervals (CI) for each group. Noninferiority was tested against a one-sided null hypothesis that the post-dose 3 GMT ratio of the alternate to standard schedule was < or =0.5 for each HPV type. One hundred eighty-eight women completed the study, with all 12 dropouts in the alternate schedule group (p < 0.001). Antibody responses in the alternate schedule were noninferior to the standard schedule for all vaccine types (p < 0.0001). Among the per-protocol population, GMTs (95% CI) for the alternate schedule were 4,440 (3,080-5,696), 5,688 (3,960-7,291), 12,443 (8,611-15,977), and 2,129 (1,183-3,063) for HPV types 6, 11, 16, and 18, respectively, vs. 2,153 (1,794-2,478), 1,966 (1,401-2,491), 6,218 (4,367-7,946), and 1,370 (1,167-1,553) for the standard schedule. Time between doses 2 and 3 significantly predicted final titer for all virus types (p < 0.005). For all HPV vaccine types, the GMT ratios indicated noninferiority of the alternate vaccine administration schedule at 0, 2, and 12 months. The alternate schedule may be used to expand options for the timing of the third dose in the HPV vaccine schedule.


Recruitment and retention of participants in a pragmatic randomized intervention trial at three community health clinics: results and lessons learned.
Obesity and hypertension and their associated health complications disproportionately affect communities of color and people of lower socioeconomic status. Recruitment and retention of these populations in research trials, and retention in weight loss trials has been an ongoing challenge. Be Fit, Be Well was a pragmatic randomized weight loss and hypertension management trial of patients attending one of three community health centers in Boston, Massachusetts. Participants were asked to complete follow-up assessments every 6-months for two years. We describe challenges encountered and strategies implemented to recruit and retain trial participants over the 24-month intervention. We also identify baseline participant characteristics associated with retention status. Retention strategies included financial incentives, contact between assessment visits, building relationships with health center primary care providers (PCPs) and staff, and putting participant convenience first. Active refusal rates were low with 130 of 2,631 patients refusing participation (4.9%). Of 474 eligible persons completing telephone screening, 365 (77.0%) completed their baseline visit and were randomized into the study. The study population was predominantly non-Hispanic Black (71.2%), female (68.5%) and reported annual household income of less than $35,000 (70.1%). Recruitment strategies included use of passive approval of potential participants by PCPs, use of part-time staff, and outsourcing calls to a call center. A total of 314 (86.0%) people completed the 24-month visit. Retention levels varied across study visits and intervention condition. Most participants completed three or more visits (69.6%), with 205 (56.2%) completing all four. At 24-months, lower retention was observed for males and the intervention condition. Retention strategies included building strong relationships with clinic staff, flexibility in overcoming participant barriers through use of taxi vouchers, night and weekend appointments, and keeping participants engaged via newsletters and social gatherings. We were able to retain 86.0% of participants at 24-months. Recruitment and retention of high percentages of racial/ethnic minorities and lower income samples is possible with planning, coordination with a trusted community setting and staff (e.g. community health centers and RAs), adaptability and building strong relationships. Clinicaltrials.gov Identifier: NCT00661817.


[Therapeutic hemapheresis].
This is the first survey of therapeutic hemapheresis in Norway. The purpose was to collect data from all Norwegian dialysis and blood units performing hemapheresis treatment and stem cell collection for comparison with Swedish data. Questionnaires were sent to all regional and central hospitals in Norway including two specialized centres for stem cell apheresis. The questions included the number of hemapheresis procedures, patients, and indications. All units responded to the questionnaire. There were 17 dialysis units; seven blood units and two special units who performed 2,141 procedures. 12 units did not carry out any hemapheresis treatment at all. There were five stem cell collections per 100,000 inhabitants and 42.5 therapeutic apheresis procedures per 100,000 inhabitants. Hemapheresis treatment is performed in all Norwegian health regions. The indications are quite similar to those reported from Sweden except for stem cell collections and erythrocytaphereses. The dominance of the dialysis units in the total number of procedures performed and the prominent use of filtration techniques are special features of the Norwegian practice of apheresis.


Evaluation of nonspecific immunity and plasma levels of interferon-gamma, interleukin-6 and tumor necrosis factor-alpha in preeclampsia.
In this study we evaluated the maternal cell-mediated immune aspects of preeclampsia in terms of phagocytosis and killing of monocytes and polymorphonuclear cells. To evaluate the contribution of cytokines (Cks) in the pathophysiology of preeclampsia, we investigated the plasma levels of interferon-gamma (IFN-gamma), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), respectively, by an enzyme-linked immunosorbent assay. Data showed that phagocytic and killing activities of monocytes were depressed in preeclamptic and normal pregnancies. At the same time, IFN-gamma plasma levels were undectable in both groups. Conversely, we detected significant levels of TNF-alpha in plasma from preeclamptic and normal pregnancies. Moreover, since in three preeclamptic patients the onset of severe preeclampsia was associated with a sharp increased of TNF-alpha plasma levels, we suggest that an increased production of this CK may be implicated in the pathophysiology of preeclampsia.


Adrenocortical function in acquired immunodeficiency syndrome.
Clinical features of adrenal steroid deficiency occur in patients with the acquired immunodeficiency syndrome (AIDS). To determine the frequency of aberrations in peripheral steroid levels in patients with AIDS and AIDS-related complex (ARC) we measured morning recumbent plasma cortisol, deoxycorticosterone, 18-hydroxydeoxycorticosterone (18-OHDOC), corticosterone, aldosterone, and 18-hydroxycorticosterone concentrations before and after administration of 0.25 mg ACTH (Cosyntropin) in 74 randomly selected hospitalized patients with AIDS and 19 patients with ARC. Basal (0800 h) cortisol levels in the AIDS patients were significantly higher (P less than 0.01) than those in normal subjects, while other ACTH-dependent steroids of the 17-deoxypathway, deoxycorticosterone, corticosterone, and 18-OHDOC, were normal. These latter steroids increased subnormally in response to ACTH in patients with either AIDS (P less than 0.001) or ARC (P less than 0.005), but in ARC patients plasma 18-OHDOC levels were significantly higher than in those with AIDS (P less than 0.001). Supraphysiological doses of ACTH were then administered for 3 consecutive days to 14 patients with AIDS and 9 with ARC, which confirmed and amplified the subnormal responses of these steroids in AIDS. The mean plasma cortisol response was reduced on the third day only in AIDS patients, whereas in the ARC patients the steroid responses were normal. Angiotensin III infusion and postural stimulation increased plasma aldosterone and 18-hydroxycorticosterone levels in AIDS and ARC patients. Defective stimulation of 18-OHDOC alone or in combination with defective stimulation of other 17-deoxysteroids can be a harbinger of subsequent impaired adrenal capacity in AIDS.


Transcranial magnetic stimulation on the modulation of gamma oscillations in schizophrenia.
Cognitive dysfunction is suggested to be the best predictor of functional outcome in schizophrenia. Therefore, new diagnostic and treatment strategies are needed to both ascertain the biological underpinning of cognitive deficits and to restore them. Modulation of gamma oscillations (30-50 Hz) has been associated with cognitive performance, particularly in the dorsolateral prefrontal cortex (DLPFC). In this manuscript, we review evidence for gamma modulation deficits during cognitive performance in schizophrenia. We demonstrate that transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) is a reliable method that permits systematic quantification of gamma modulation in the cortex. Using TMS-EEG, we show that patients with schizophrenia have selective gamma inhibition deficits in the DLPFC. Finally, we demonstrate that repetitive TMS therapy over the DLPFC can normalize excessive gamma oscillations and ultimately cognitive performance in patients. We suggest that restoring gamma impairments in the DLPFC may be a potential strategy for improving cognitive deficits in schizophrenia.


Mechanisms of carbon dioxide acquisition and CO2 sensing in marine diatoms: a gateway to carbon metabolism.
Diatoms are one of the most successful marine eukaryotic algal groups, responsible for up to 20% of the annual global CO2 fixation. The evolution of a CO2-concentrating mechanism (CCM) allowed diatoms to overcome a number of serious constraints on photosynthesis in the marine environment, particularly low [CO2]aq in seawater relative to concentrations required by the CO2 fixing enzyme, ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO), which is partly due to the slow diffusion rate of CO2 in water and a limited CO2 formation rate from [Formula: see text] in seawater. Diatoms use two alternative strategies to take up dissolved inorganic carbon (DIC) from the environment: one primarily relies on the direct uptake of [Formula: see text] through plasma-membrane type solute carrier (SLC) 4 family [Formula: see text] transporters and the other is more reliant on passive diffusion of CO2 formed by an external carbonic anhydrase (CA). Bicarbonate taken up into the cytoplasm is most likely then actively transported into the chloroplast stroma by SLC4-type transporters on the chloroplast membrane system. Bicarbonate in the stroma is converted into CO2 only in close proximity to RubisCO preventing unnecessary CO2 leakage. CAs play significant roles in mobilizing DIC as it is progressively moved towards the site of fixation. However, the evolutionary types and subcellular locations of CAs are not conserved between different diatoms, strongly suggesting that this DIC mobilization strategy likely evolved multiple times with different origins. By contrast, the recent discovery of the thylakoid luminal θ-CA indicates that the strategy to supply CO2 to RubisCO in the pyrenoid may be very similar to that of green algae, and strongly suggests convergent coevolution in CCM function of the thylakoid lumen not only among diatoms but among eukaryotic algae in general. In this review, both experimental and corresponding theoretical models of the diatom CCMs are discussed.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'.


Estrogen signaling and estrogen receptors as prognostic indicators in laryngeal cancer.
Laryngeal squamous cell carcinoma (LSCC) has been shown to respond to 17β-estradiol. However, the presence and characterization of estrogen receptors (ER) and other sex hormone receptors in LSCC are still being determined. Sex hormone receptors and the way sex hormones impact LSCC tumors are important for understanding which patients would benefit from hormone therapies, such as anti-estrogen therapies. This information also has prognostic value, as there may be a correlation between ER profiles and LSCC aggression. Recent work by our team and others has shown that the canonical ER, estrogen receptor α (ERα), and its splice variant ERα36, are important modulators of estrogen signaling in LSCC. This review describes some common 17β-estradiol signaling pathways, and explains how these signaling pathways might control LSCC tumor growth. We also show that loss of ERα, but not ERα36, imbues LSCC with enhanced aggression, a pattern which has previously only been observed in breast cancer. We make a case for using ERα as a tumorigenic modulator and pathogenic marker in LSCC on par with the use of ERα as a prognostic marker in breast cancer.


Therapeutic Plasticity of Neural Stem Cells.
Neural stem cells (NSCs) have garnered significant scientific and commercial interest in the last 15 years. Given their plasticity, defined as the ability to develop into different phenotypes inside and outside of the nervous system, with a capacity of almost unlimited self-renewal, of releasing trophic and immunomodulatory factors, and of exploiting temporal and spatial dynamics, NSCs have been proposed for (i) neurotoxicity testing; (ii) cellular therapies to treat CNS diseases; (iii) neural tissue engineering and repair; (iv) drug target validation and testing; (v) personalized medicine. Moreover, given the growing interest in developing cell-based therapies to target neurodegenerative diseases, recent progress in developing NSCs from human-induced pluripotent stem cells has produced an analog of endogenous NSCs. Herein, we will review the current understanding on emerging conceptual and technological topics in the neural stem cell field, such as deep characterization of the human compartment, single-cell spatial-temporal dynamics, reprogramming from somatic cells, and NSC manipulation and monitoring. Together, these aspects contribute to further disentangling NSC plasticity to better exploit the potential of those cells, which, in the future, might offer new strategies for brain therapies.


Sleep function.
A theory of sleep function and brain organization positing that sleep serves a neuronal connectivity function and is a fundamental property of highly interconnected groups of neurons (neuronal groups) is presented. Cellular electrical activity within neuronal groups leads to the production of sleep-promoting substances which are also cytokine growth factors. The somnogenic cytokine growth factors (SCGF) in turn, induce molecules necessary for synaptic connectivity. The SCGFs change the synaptic activation patterns within neuronal groups. SCGFs thus induce changes in the input-output relationships of neuronal groups and thereby, cause a neuronal group state shift. Altered input-output relations result in increased efficacy of some synapses. Sleep is thus, targeted to active neuronal groups and serves to incorporate novel stimulus patterns into a synaptic contextual network and also to preserve that network. Coordination of neuronal group state is brought about by sleep regulatory networks. Organism sleep is an emergent property of a population of neuronal groups in the sleep state. After the neuronal group state shift, environmental input is divorced from output. Sleep is thus, useful to keep the animal stationary at a time when its brain is most dysfunctional. Thus, not only is unconsciousness needed because output activity would be out of phase with environmental events, but it is the consequence of the process itself.


Determination of renal stone composition with dual-energy CT: in vivo analysis and comparison with x-ray diffraction.
To preoperatively assess the composition of urinary stones by using dual-energy computed tomography (CT), with postoperative in vitro x-ray diffraction analysis as the reference standard. Institutional review board approval was obtained, and all participants provided written informed consent. Twenty-seven patients aged 50-64 years with renal stones, who were scheduled for stone extraction with percutaneous nephrolithotomy (PCNL), preoperatively underwent nonenhanced single-source dual-energy multidetector CT with 2-mm section thickness, 1-mm increments, 140 kVp, and 250 mAs. Regions of interest were drawn on low- and high-energy images, and low- and high-energy attenuation ratios were calculated for each stone scanned in vivo. The attenuation ratios for the patients were compared with those for an in vitro stone library phantom model of 37 stones with known chemical compositions. After surgery, the extracted stones were analyzed by using x-ray diffraction. The results of in vivo multidetector CT and ex vivo chemical analysis were compared. Dual-energy low- and high-energy attenuation ratios measured with the phantom were less than 1.1 for uric acid, 1.1-1.24 for cystine, and greater than 1.24 for calcified stones. Struvite stones had attenuation ratios that overlapped with calcified stone ratios and thus could not be assessed reliably. Four patients had mixed stones (<75% of a single component), and one patient had a struvite stone. Of 27 patients, 22 (82%) (exact confidence interval [CI]: 68%, 92%) received a correct diagnosis with dual-energy CT: all six (100%; exact CI: 54%, 100%) patients with uric acid stones, 15 (79%; exact CI: 62%, 95%) of the 19 patients with calcium stones, and the one (100%) patient with a cystine stone. The patient with a struvite stone did not receive a correct dual-energy CT-based diagnosis. Dual-energy multidetector CT may enable accurate in vivo characterization of kidney stone composition.


Engineered bromodomains to explore the acetylproteome.
MS-based analysis of the acetylproteome has highlighted a role for acetylation in a wide array of biological processes including gene regulation, metabolism, and cellular signaling. To date, anti-acetyllysine antibodies have been used as the predominant affinity reagent for enrichment of acetyllysine-containing peptides and proteins; however, these reagents suffer from high nonspecific binding and lot-to-lot variability. Bromodomains represent potential affinity reagents for acetylated proteins and peptides, given their natural role in recognition of acetylated sequence motifs in vivo. To evaluate their efficacy, we generated recombinant proteins representing all known yeast bromodomains. Bromodomain specificity for acetylated peptides was determined using degenerate peptide arrays, leading to the observation that different bromodomains display a wide array of binding specificities. Despite their relatively weak affinity, we demonstrate the ability of selected bromodomains to enrich acetylated peptides from a complex biological mixture prior to mass spectrometric analysis. Finally, we demonstrate a method for improving the utility of bromodomain enrichment for MS through engineering novel affinity reagents using combinatorial tandem bromodomain pairs.


[Comparative analysis of the clinico-epidemiological and prognostic data in schizophrenic and epileptic psychoses].
Based on a material of a clinico-epidemiological study of 451 cases of schizophrenia and 329 cases of epilepsy with psychotic manifestations, the clinico-prognostic correlations were established in the two aspects: nosological and from the standpoint of the progress of the pathological process. The concept of isomorphism and the concept of varying prediction of the psychotic manifestations in schizophrenia and epilepsy are interpreted from the viewpoint of the primary localization of brain derangement.


Interferometers and decoherence matrices
It is shown that the Lorentz group is the natural language for two-beam interferometers if there are no decoherence effects. This aspect of the interferometer can be translated into six-parameter representations of the Lorentz group, as in the case of polarization optics where there are two orthogonal components of one light beam. It is shown that there are groups of transformations which leave the coherency or density matrix invariant, and this symmetry property is formulated within the framework of Wigner's little groups. An additional mathematical apparatus is needed for the transition from a pure state to an impure state. Decoherence matrices are constructed for this process, and their properties are studied in detail. Experimental tests of this symmetry property are possible.


Photoactive chitosan: a step toward a green strategy for pollutant degradation.
This article is a highlight of the paper by Ferrari et al. in this issue of Photochemistry and Photobiology. It describes the innovative use of rose bengal-conjugated chitosan as a reusable green catalyst that photo-degrades phenolic compounds in aqueous media, and thereby has decontamination potential of polluted waters. Whether a next-generation photoactive polymer that produces singlet oxygen is a solution to pollutant degradation can be argued. It is as yet unclear what polymeric sensitizer would be practical on a large scale. Nonetheless pursuing this goal is worthwhile.


Uterine extramedullary hematopoiesis: what is the clinical significance?
Extramedullary hematopoiesis (EMH) represents abnormal development and growth of hematopoietic tissue outside the bone marrow. Recent studies have shown its association with myelofibrosis and myeloid metaplasia, chronic myeloproliferative disorders, and other hematologic malignancies in up to two-thirds of the cases. Eleven cases of uterine EMH (UEMH) have been reported earlier; of these half had a concurrent, or subsequently developed a clinically significant hematologic disorder. We studied a larger group of patients with UEMH to understand the relationship with hematologic disorders. Cases diagnosed as UEMH between 1995 and 2007 were retrieved from our files (n=20). UEMH was confirmed in all 20 cases. Eighteen cases were located in the fundus including 5 in endometrial polyps and 5 in leiomyomas. Two foci were located within the cervix. The erythroid lineage was present in all foci; 35% also had myeloid precursors, and 2% had megakaryocytes. Twelve of 20 patients had underlying anemia (mean Hgb of 11 mg/dL, range: 5.5 to 15.7 mg/dL). No preexisting hematologic malignancy was identified in any of the patients. Follow-up information was available on 17 patients (mean: 2.88 yr; range: 0.2 to 9 yr). None of the patients developed a significant hematologic disorder other than anemia during follow-up. On the basis of our study, UEMH is frequently associated with chronic anemia. In comparison with existing literature suggesting a strong link between UEMH and hematopoietic disorders, our findings suggest that UEMH is rarely associated with serious underlying hematologic conditions and therefore does not warrant extensive hematologic workup.


Saving the limb in diabetic patients with ischemic foot lesions complicated by acute infection.
Ischemia and infection are the most important factors affecting the prognosis of foot ulcerations in diabetic patients. To improve the outcome of these patients, it is necessary to aggressively treat 2 important pathologies--namely, occlusive arterial disease affecting the tibial and femoral arteries and infection of the ischemic diabetic foot. Each of these 2 conditions may lead to major limb amputation, and the presence of both critical limb ischemia (CLI) and acute deep infection is a major risk factor for lower-extremity amputation. Thus, the management of diabetic foot ulcers requires specific therapeutic approaches that vary significantly depending on whether foot lesions are complicated by infection and/or ischemia. A multidisciplinary team approach is the key to successful treatment of a diabetic foot ulcer: ischemic diabetic foot ulcers complicated by acute deep infection pose serious treatment challenges because high levels of skill, organization, accuracy, and timing of intervention are required to maximize the chances of limb salvage: these complex issues are better managed by a multidisciplinary clinical group.


Spatial Patterns, Longitudinal Development, and Hemispheric Asymmetries of Cortical Thickness in Infants from Birth to 2 Years of Age.
Cortical thickness (CT) is related to normal development and neurodevelopmental disorders. It remains largely unclear how the characteristic patterns of CT evolve in the first 2 years. In this paper, we systematically characterized for the first time the detailed vertex-wise patterns of spatial distribution, longitudinal development, and hemispheric asymmetries of CT at 0, 1, and 2 years of age, via surface-based analysis of 219 longitudinal magnetic resonance images from 73 infants. Despite the dynamic increase of CT in the first year and the little change of CT in the second year, we found that the overall spatial distribution of thin and thick cortices was largely present at birth, and evolved only modestly during the first 2 years. Specifically, the precentral gyrus, postcentral gyrus, occipital cortex, and superior parietal region had thin cortices, whereas the prefrontal, lateral temporal, insula, and inferior parietal regions had thick cortices. We revealed that in the first year thin cortices exhibited low growth rates of CT, whereas thick cortices exhibited high growth rates. We also found that gyri were thicker than sulci, and that the anterior bank of the central sulcus was thicker than the posterior bank. Moreover, we showed rightward hemispheric asymmetries of CT in the lateral temporal and posterior insula regions at birth, which shrank gradually in the first 2 years, and also leftward asymmetries in the medial prefrontal, paracentral, and anterior cingulate cortices, which expanded substantially during this period. This study provides the first comprehensive picture of early patterns and evolution of CT during infancy.


[Current status of pancreas transplantation].
Today, combined kidney and pancreas transplantation is the best treatment for patients with type I diabetes and pre-end or end-stage renal disease due to the diabetic nephropathy. Twenty-nine patients underwent that procedure at our Institution. Recent technical modifications--with the use of a whole pancreas graft with urinary drainage of the exocrine secretion in the recipient by performing a pancreatico-duodeno-cystostomy--allow the monitoring of the exocrine secretion which is a pertinent immunological marker for pancreas rejection. In the next future, pancreas alone should be considered safely using the same procedure, in non uremic diabetic recipients in whom extra-renal secondary complications are more serious than the potential side effects of chronic immunosuppression. That type of pancreas transplantation should benefit of the forthcoming immunosuppressive drugs.


Circular RNA-0007059 protects cell viability and reduces inflammation in a nephritis cell model by inhibiting microRNA-1278/SHP-1/STAT3 signaling.
Increasing evidence has indicated that circular RNAs (circRNAs) play a role in various diseases. However, the influence of circRNAs in nephritis remains unknown. Microarray analysis and RT-qPCR were used to detect the expression of circRNA. Type I IFN were administrated to RMC and HEK293 cells to establish a nephritis cell model. CCK-8, MTT assay, and flow cytometry were used to assess cell proliferation, viability, and apoptosis of cells. Bioinformatics analysis and dual luciferase reporter assay detect the interaction of circ_0007059, miRNA-1278, and SHP-1. Glomerulonephritis was performed in a mouse model by administration of IFNα-expressing adenovirus. IHC staining showed the pathogenic changes. In the present study, the expression of circ_0007059 in type I interferon (IFN)-treated renal mesangial cells (RMCs), lupus nephritis (LN) specimens, and HEK293 cells was downregulated compared with that in normal healthy samples and untreated cells. Circ_0007059 overexpression resulted in increased cell proliferation, cell viability, apoptosis, and inflammation-associated factors (CXCL10, IFIT1, ISG15, and MX1) in RMCs and HEK293 cells. In addition, circ_0007059 overexpression significantly restored cell proliferation and viability and inhibited IFN-induced apoptosis. Further, the increased expression resulted in reduced inflammation and the downregulation of CXCL10, IFIT1, ISG15, and MX1 in RMCs and HEK293 cells. Circ_0007059 serves as a sponge for miR-1278 so that the latter can target the 3'-untranslated region of SHP-1. Overexpressed circ_0007059 inhibited miR-1278 expression and elevated SHP-1 expression, subsequently reducing STAT3 phosphorylation. Meanwhile, miR-1278 was upregulated and SHP-1 was downregulated in LN samples and IFN-treated cells. The restoration of miR-1278 counteracted the effect of circ_0007059 on viability, apoptosis, and inflammation as well as on SHP-1/STAT3 signaling in RMCs and HEK293 cells. We also investigated the role of SHP-1 overexpression in IFN-treated RMCs and HEK293 cells; SHP-1 overexpression resulted in a similar phenotype as that observed with circ_0007059 expression. The study indicates that circ_0007059 protects RMCs against apoptosis and inflammation during nephritis by attenuating miR-1278/SHP-1/STAT3 signaling.


Executive function in posttraumatic stress disorder (PTSD) and the influence of comorbid depression.
Posttraumatic stress disorder (PTSD) has been associated with neurocognitive deficits, such as impaired verbal memory and executive functioning. Less is known about executive function and the role of comorbid depression in PTSD. Recently, studies have shown that verbal memory impairments may be associated with comorbid depressive symptoms, but their role in executive function impairments is still unclear. To examine several domains of executive functioning in PTSD and the potentially mediating role of comorbid depressive symptoms in the relationship between executive function and PTSD. Executive functioning was assessed in 28 PTSD patients and 28 matched trauma-exposed controls. The Cambridge Neuropsychological Test Automated Battery (CANTAB) with subtests measuring response inhibition (SST), flexibility/set shifting (IED), planning/working memory (OTS) and spatial working memory (SWM) was administered in PTSD patients and trauma-exposed controls. Regression analyses were used to assess the predictive factor of PTSD symptoms (CAPS) and depressive symptoms (HADS-D) in relation to executive function when taking into account the type of trauma. Pearson's correlations were used to examine the association between PTSD symptom clusters (CAPS) and executive function. The mediating effects of depression and PTSD were assessed using regression coefficients and the Sobel's test for mediation. Our findings indicate that PTSD patients performed significantly worse on executive function than trauma-exposed controls in all domains assessed. PTSD symptoms contributed to executive functioning impairments (SST median correct, IED total errors, OTS latency to correct, SWM total errors and SWM strategy). Adding depressive symptoms to the model attenuated these effects. PTSD symptom clusters 'numbing' and to a lesser extent 'avoidance' were more frequently associated with worse executive function (i.e., IED total errors, OTS latency to correct and SWM total errors) than 'reexperiencing' and 'hyperarousal'. Depressive symptoms mediated the relation between PTSD and executive function on some executive function measures (IED total errors and OTS latency to correct), whereas PTSD did not mediate the relation between depression and executive function. PTSD patients perform worse on executive function. The impairments seem to be mostly associated with the less specific PTSD symptom cluster of 'numbing'. Depressive symptoms seem to mediate the relationship between PTSD and executive function. These findings may have clinical implications with regard to treatment indication and prognosis.


Untargeted Safety Pharmacology Screen of Blood-Activating and Stasis-Removing Patent Chinese Herbal Medicines Identified Nonherbal Ingredients as a Cause of Organ Damage in Experimental Models.
Blood activation and stasis removal from circulation is a central principle for treatment of syndromes related to cerebral and cardiovascular diseases in Chinese herbal medicine. However, blood-activating and stasis-removing patent Chinese herbal medicine (BASR-pCHM) widely used with or without prescription in China and elsewhere are highly variable in composition and manufacture standard, making their safety assessment a challenging task. We proposed that an integrated evaluation of multiple toxicity parameters of BASR-pCHM would provide critical reference and guidelines for their safe clinical application. Examination of standardized extracts from 58 compound BASR-pCHM in vivo in VEGFR2-luc mice and in vitro in cardiac, renal, and hepatic cells identified Naoluotong capsule (NLTC) as a potent organ/cell damage inducer. Composition analysis revealed that NLTC was the one that contained nonherbal ingredients among the BASR-pCHM collection. In vivo and in vitro experiments confirmed that NLTC, as well as its chemical supplement tolperisone hydrochloride, caused organ and cell damage by reducing cell viability, mitochondrial mass/activity, while the NLTC herbal components did not. Taken together, our study showed that safety evaluation of patent herbal medicines already on market is still necessary and urgently needed. In addition, chemical/herbal interactions should be considered as an important contributor of potential toxicity when evaluating the safety of herbal medicine.


Wheat and barley allergens associated with baker's asthma. Glycosylated subunits of the alpha-amylase-inhibitor family have enhanced IgE-binding capacity.
A 16 kDa protein, designated CM16*, which strongly binds IgE from baker's-asthma patients has been identified as a glycosylated form of the previously reported WTAI-CM16, which is a subunit of the wheat tetrameric alpha-amylase inhibitor. A glycosylated form (CMb*) of BTAI-CMb, the equivalent inhibitor subunit from barley, has been also found to have significantly enhanced IgE-binding capacity. In all, 14 purified members of the alpha-amylase/trypsin-inhibitor family showed very different IgE-binding capacities when tested by a dot-blot assay. The glycosylated components CM16*, CMb* and the previously described non-glycosylated 14.5 kDa allergen from barley (renamed BMAI-1) were found to be the strongest allergens.


Significance of the gel diffusion precipitin test for invasive amoebiasis.
The double diffusion precipitinin test for amoebiasis, has been evaluated in invasive amoebiasis. It gave positive percentages of 91-3 and 90-0 in cases of amoebic liver abscess and amoebic dysentery. False positive rates of 8-0 per cent and 0-0 per cent were obtained in miscellaneous non-amoebic disorders and in apparently healthy subjects, respectively. Its comparison with the indirect haemagglutination test revealed it to be slightly less sensitive but more specific. The agar gel precipitinin test became positive whenever the indirect haemagglutination titres were 1:256 or more. The adsorption studies revealed that both tests detected different types of antibodies. The use of the gel diffusion test is recommended as a routine method for amoebiasis as it is simple to perform in areas where sophisticated laboratory methods are not available.


Autosomal dominant retinitis pigmentosa with a rhodopsin mutation (Arg-135-Trp). Disease phenotype in a Swedish family.
We here present the clinical phenotype in 6 patients from a family with autosomal dominant retinitis pigmentosa found to carry a point mutation in the rhodopsin gene (arginine-135-tryptophan). The mutation is the second found by mutation screening of DNA from 20 Swedish families with dominant retinitis pigmentosa. With full-field electroretinography we could document a severe form of retinitis pigmentosa in patients belonging to the family, similar to the phenotype associated with the previously reported mutation (arginine-135-leucine). Our results indicate that different point mutations in the same region of the rhodopsin gene, resulting in amino acids with similar properties (both hydrophobic), may cause a similar clinical phenotype. Further, point mutations in this specific region seem to cause an agressive form of retinitis pigmentosa.


Convective Nozaki-Bekki holes in a long cavity OCT laser.
We show, both experimentally and theoretically, that the loss of coherence of a long cavity optical coherence tomography (OCT) laser can be described as a transition from laminar to turbulent flows. We demonstrate that in this strongly dissipative system, the transition happens either via an absolute or a convective instability depending on the laser parameters. In the latter case, the transition occurs via formation of localised structures in the laminar regime, which trigger the formation of growing and drifting puffs of turbulence. Experimentally, we demonstrate that these turbulent bursts are seeded by appearance of Nozaki-Bekki holes, characterised by the zero field amplitude and π phase jumps. Our experimental results are supported with numerical simulations based on the delay differential equations model.


A binary linear programming formulation of the graph edit distance.
A binary linear programming formulation of the graph edit distance for unweighted, undirected graphs with vertex attributes is derived and applied to a graph recognition problem. A general formulation for editing graphs is used to derive a graph edit distance that is proven to be a metric, provided the cost function for individual edit operations is a metric. Then, a binary linear program is developed for computing this graph edit distance, and polynomial time methods for determining upper and lower bounds on the solution of the binary program are derived by applying solution methods for standard linear programming and the assignment problem. A recognition problem of comparing a sample input graph to a database of known prototype graphs in the context of a chemical information system is presented as an application of the new method. The costs associated with various edit operations are chosen by using a minimum normalized variance criterion applied to pairwise distances between nearest neighbors in the database of prototypes. The new metric is shown to perform quite well in comparison to existing metrics when applied to a database of chemical graphs.


Evidence of extensive lymphocyte death in sheep Peyer's patches. I. A comparison of lymphocyte production and export.
The metaphase arrest technique was used to determine the rate at which cells divide in the Peyer's patches (PP) and the thymus of 5 to 8 wk old lambs. The metaphase indices of these tissues were determined by analyzing cell suspensions of tissues taken before and 1, 2, 3, and 4 hr after metaphase arrest was initiated with i.v. vincristine. The metaphase indices increased in both tissues at a linear rate, which provided an estimate of the rate at which cells entered mitosis and of the lymphocyte birth rate. The ileal PP had the highest lymphocyte birth rate, 2.8% of the lymphocytes entered mitosis each hour; the rate was lower in jejunal PP (1.0%/hr) and thymus (0.5%/hr). With these values and estimates of the lymphocyte content in all PP (1.45 X 10(11)) and in the thymus (1.71 X 10(11)), it was calculated that the hourly lymphocyte production by PP in a lamb was 3.61 X 10(9) cells, which is four to five times greater than for the thymus (0.82 X 10(9)). Lymphocyte production in PP could then be compared with the number of lymphocytes that emigrated from the small intestine. Newly produced cells leave PP via the intestinal lymph, which could be collected from the entire small intestine after removal of the mesenteric lymph nodes. Cells entered the lymph at a rate of 0.8 X 10(9)/hr, but the output fell rapidly during chronic lymphatic drainage, a procedure known to deplete long-lived recirculating cells. It was concluded that most of the cells in intestinal lymph were recirculating cells, and newly formed lymphocytes produced in PP probably account for less than 25% of the total or 0.2 X 10(9)/hr. It seems unlikely that emigration could occur at a rate comparable with the rate of production in the PP. At most, only 5% of the PP cells seemed destined to leave their site of production, and it is proposed that most die within the PP follicles. The high mortality rate associated with the production of large numbers of B lymphocytes in lamb PP seems likely to have a significant impact on the nature of the contribution that these tissues make to the immune system.


Investigating the Cardiovascular Benefits of Dapagliflozin: Vasodilatory Effect on Isolated Rat Coronary Arteries.
Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, is an antidiabetic medication that reduces blood glucose. Although it is well known that dapagliflozin has additional benefits beyond glycemic control, such as reducing blood pressure and lowering the risk of cardiovascular events, no sufficient research data are available on the direct effect of dapagliflozin on cardiovascular function. Thus, in this study, we investigated the direct vascular effect of dapagliflozin on isolated rat coronary arteries. The left descending coronary arteries of 13-week-old male Sprague Dawley rats were cut into segments 2-3 mm long and mounted in a multi-wire myography system to measure isometric tension. Dapagliflozin effectively reduced blood vessel constriction induced by U-46619 (500 nM) in coronary arteries regardless of the endothelium. Treatment with an eNOS inhibitor (L-NNA, 100 μM), sGC inhibitor (ODQ, 5 μM), or COX inhibitor (indomethacin, 3 μM) did not affect the vasodilation induced by dapagliflozin. The application of a Ca2+-activated K+ channel (KCa) blocker (TEA, 2 mM), voltage-dependent K+ channel (KV) blocker (4-AP, 2 mM), ATP-sensitive K+ channel blocker (KATP) glibenclamide (3 μM), and inward-rectifier K+ channel (KIR) blocker (BaCl2, 30 μM) did not affect the dapagliflozin-induced vasodilation either. The treatment with dapagliflozin decreased contractile responses induced by the addition of Ca2+, which suggested that the extracellular Ca2+ influx was inhibited by dapagliflozin. Treatment with dapagliflozin decreased the phosphorylation level of the 20 kDa myosin light chain (MLC20) in vascular smooth muscle cells. In the present study, we found that dapagliflozin has a significant vasodilatory effect on rat coronary arteries. Our findings suggest a novel pharmacologic approach for the treatment of cardiovascular diseases in diabetic patients through the modulation of Ca2+ homeostasis via dapagliflozin administration.


Hyperostosis frontalis interna: what does it tell us about our health?
To examine whether the prevalence and severity of hyperostosis frontalis interna (HFI) has significantly changed during the past 100 years. Two female populations, 100 years apart, were studied; 992 historic and 568 present day females. Detection of HFI was carried out via direct observation or CT images (Brilliance 64, Philips Medical Systems, Cleveland, Ohio). HFI was graded according to Hershkovitz et al.'s (1999) 4-scale definition and according May et al.'s (2010c) 3-scale definition. Following correction for age, present day females manifested a significantly higher HFI prevalence compared with historic females (P < 0.05). The risk of developing HFI was found to be approximately 2.5 times greater in present day females compared with females living 100 years ago (P < 0.05). In the young age cohort, present day females manifested a significantly higher prevalence of HFI type B (P < 0.05), whereas in the old age cohort, a significant difference in the prevalence of HFI types C and D was noted between the two groups (P < 0.05). HFI tended to appear at a younger age in the present population. The last two decades has witnessed an increase in HFI prevalence(from 55.6% to 75%). HFI prevalence has increased during the last century, especially among young individuals, possibly indicating a profound change in human fertility patterns, together with the introduction of various hormonal treatments) and new dietary habits.


Examining the Interaction Between Potentially Morally Injurious Events and Religiosity in Relation to Alcohol Misuse Among Military Veterans.
Given the disproportionate rate of alcohol misuse among veterans and related outcomes as compared to the general population, the examination of predictors of alcohol misuse in this population is imperative. Potentially morally injurious events (PMIEs), defined as severe transgressions of a moral code, have been positively associated with alcohol misuse. Exposure to PMIEs may challenge one's religious beliefs, which may, in turn, influence the strength of the association between PMIEs and alcohol misuse among military veterans. The goal of the current study was to examine the potential moderating role of religiosity in the association between PMIEs and alcohol misuse (i.e., alcohol consumption, drinking behaviors, adverse reactions to drinking, and alcohol-related problems). Participants were 496 military veterans in the community (Mage = 37.80 years, SD = 11.42; 70.5% male). The results of moderation analyses indicated that overall religiosity, organizational religiosity, and intrinsic religiosity significantly moderated the association between PMIEs and alcohol misuse such that the positive relation between PMIEs and alcohol misuse was stronger at high versus low levels of religiosity, R2 s = .01. Our findings highlight the importance of considering the role of religiosity in relation to alcohol misuse as a moral injury outcome and the potential utility of tailoring treatments for military veterans who have experienced moral injury.


Effect of menopausal status on carotid intima-media thickness and presence of carotid plaque in Chinese women generation population.
Menopause is an important physiological stage in women's life. The potential association of menopause with carotid intima-media thickness as well as with occurrence and stability of carotid plaque in Chinese female population is unclear. We conducted a population-based, cross-sectional study by recruiting 2,131 participants aged above 40 years from northeast of China. Carotid intima-media thickness (CIMT), presence of carotid plaque and its stability were evaluated by carotid duplex sonography. Among the participants, 1,133 (53.2%) were identified to be postmenopausal. After adjusting for potential confounding factors, presence of CIMT at 50(th-) 75(th) and ≥75(th) percentiles, carotid plaque and its unstable status were found to be significantly associated with the postmenopausal status (P < 0.001). When matched the participants by age, post-menopausal status was still associated with a higher risk of having unstable plaque. Moreover, our data show that postmenopausal status is a risk factor for intracranial arterial stenosis when compared with premenopausal status in the univariate analysis (OR = 1.314, P = 0.043), and such relationship is lost when the confounding factors are adjusted (OR = 0.828, P = 0.225). In conclusion, the vascular risk factors increase as the menopausal status changes. Compared with premenopausal status, postmenopausal status is associated with higher morbidity of CIMT, carotid plaque and its unstable status.


Combining direct viable count (DVC) and fluorescent in situ hybridisation (FISH) to enumerate viable E. coil in rivers and wastewaters.
In this study, a combination of the direct viable count procedure (DVC) and the FISH method was used to monitor by epifluorescence microscopy the abundance of viable E. coli in river water and wastewater samples. The DVC procedure consisted of exposing bacterial cells to a resuscitation medium containing antibiotics preventing cellular division and, thus, inducing an elongation of the viable cells. The FISH was performed using the "Colinsitu" probe specific for E. coil 16S r-RNA. Accuracy and detection limit of the epifluorescence microscopic DVC-FISH procedure were investigated. The method was then applied to river-water and wastewater samples. A good correlation was found in a log-log plot between the abundance of E. coil enumerated by a classical culture-based method (MPN method) and the DVC-FISH procedure. However, the DVC-FISH procedure gave consistently higher numbers. The ratio between both enumerations (DVC-FISH/MPN), which also indicated the ratio between viable and culturable E. coli, ranged between 2 and >30. It increased with decreasing abundance of culturable E. coli.


Expanding the scope of drug repurposing in pediatrics: the Children's Pharmacy Collaborative.
Drug repurposing is the use of 'old' drugs for new indications, avoiding the need for time- and cost-intensive toxicity studies. This approach should be particularly attractive for pediatrics, but its use in this population has been limited. One obstacle has been the lack of a comprehensive database of drugs for which there already is at least one indication in children. We describe the development of The Children's Pharmacy Collaborative, which should grow over time, serve as a resource for professionals and families, and stimulate drug-repurposing efforts for a range of pediatric disorders.


Revising PTEN in the Era of Immunotherapy: New Perspectives for an Old Story.
Immunotherapy has emerged as the new therapeutic frontier of cancer treatment, showing enormous survival benefits in multiple tumor diseases. Although undeniable success has been observed in clinical trials, not all patients respond to treatment. Different concurrent conditions can attenuate or completely abrogate the usefulness of immunotherapy due to the activation of several escape mechanisms. Indeed, the tumor microenvironment has an almost full immunosuppressive profile, creating an obstacle to therapeutic treatment. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) governs a plethora of cellular processes, including maintenance of genomic stability, cell survival/apoptosis, migration, and metabolism. The repertoire of PTEN functions has recently been expanded to include regulation of the tumor microenvironment and immune system, leading to a drastic reevaluation of the canonical paradigm of PTEN action with new potential implications for immunotherapy-based approaches. Understanding the implication of PTEN in cancer immunoediting and immune evasion is crucial to develop new cancer intervention strategies. Recent evidence has shown a double context-dependent role of PTEN in anticancer immunity. Here we summarize the current knowledge of PTEN's role at a crossroads between tumor and immune compartments, highlighting the most recent findings that are likely to change future clinical practice.


DNA methylation in former extremely low birth weight newborns: association with cardiovascular and endocrine function.
There is increased risk of cardiovascular, metabolic, and hypertensive disorders in later life in the preterm population. We studied school-age children who had been born extremely premature who had undergone endocrine, cardiovascular, and anthropometric evaluations. School age measurements of salivary cortisol, adrenal androgens, blood pressure, and anthropometric markers were correlated with DNA methylation of 11-betahydroxysteroid dehydrogenase type 2 (11BHSD2), leptin, and the LINE1 repetitive DNA element. We observed a modest correlation between log AUC for salivary cortisol and methylation of leptin in preterm infants and a negative correlation between methylation of region 1 of the glucocorticoid receptor (GR in term-born infants. There was an association between LINE1 methylation and cortisol response to awakening and a negative correlation between LINE1 and systolic blood pressure at 6-7 years. Methylation of the GR promoter region showed a positive association with systolic blood pressure at 6-7 years of age. These results show that extremely preterm birth, followed by complex patterns of endocrine, cardiovascular, and metabolic exposures during early postnatal life, is associated with lasting changes in DNA methylation patterns in genes involved in hypothalamic pituitary adrenal axis function, adrenal hormonal regulation, and cardiometabolic risk. Preterm infants have significant environmental and physiological exposures during early life that may have lasting impact on later function. Alterations in hypothalamic pituitary adrenal axis (HPA) function have been associated with these exposures. We examined the associated changes in DNA methylation of important genes involved in HPA function, metabolism, and global DNA methylation. The changes we saw in DNA methylation may help to explain associated cardiovascular, metabolic, and growth disturbance in these children in later life.


Emergence of macrolide-resistant strains during an outbreak of Mycoplasma pneumoniae infections in children.
Mycoplasma pneumoniae is a frequent cause of human lower respiratory tract infections (LRTIs) for which macrolides are the treatment of choice. The aim of this study was to determine the rate of macrolide resistance and to subtype M. pneumoniae strains in Italy. During an outbreak of M. pneumoniae infections in southern Italy in 2010, 48 clinical specimens from 43 paediatric patients hospitalized for LRTIs were analysed for macrolide resistance. The mutations associated with resistance (A2063G and A2064G) and M. pneumoniae subtypes were detected by sequencing the targeted domain V region of the 23S rRNA gene and a region in the MPN528a gene, respectively. Macrolide resistance genotypes were detected in 11 (26%) of the 43 M. pneumoniae-positive children. The A2063G mutation was identified in seven patients and the A2064G mutation was identified in the remaining four. Upon admission, the isolates from three patients showed a susceptible genotype but subsequently acquired the A2063G mutation. Genotyping revealed M. pneumoniae subtype 1 in 33 of 40 sequenced strains and subtype 2 in the remaining 7. There was no association between macrolide resistance or susceptibility and the M. pneumoniae subtypes. This is the first report of macrolide resistance among M. pneumoniae strains in Italy. Our findings indicate an unexpected high prevalence of macrolide resistance genotypes in children, and so macrolide resistance should be carefully considered in patients who do not respond appropriately to antibiotic treatment. The epidemiological monitoring of macrolide resistance has become necessary in Italy and in the rest of Europe.


Thermotropic liquid crystalline glycolipids.
Are the liquid crystalline properties of the materials of living systems important in biological structures, functions, diseases and treatments? There is a growing consciousness that the observed lyotropic, and often thermotropic liquid crystallinity, of many biological materials that possess key biological functionality might be more than curious coincidence. Rather, as the survival of living systems depends on the flexibility and reformability of structures, it seems more likely that it is the combination of softness and structure of the liquid-crystalline state that determines the functionality of biological materials. The richest sources of liquid crystals derived from living systems are found in cell membranes, of these glycolipids are a particularly important class of components. In this critical review, we will examine the relationship between chemical structure and the self-assembling and self-organising properties of glycolipids that ultimately lead to mesophase formation.


Quality attributes and harmful components of cured meats: Exploring the attitudes of Italian consumers towards healthier cooked ham.
In recent decades, processed meat consumers have drastically revised their consumption patterns and have gained an increasing awareness of related health concerns. Although several studies have examined the role of meat products in the human diet, we observed a certain scarcity in the multi-perspective approach to the health implications of cocked ham. Therefore, we decided to verify different sources of potentially unhealthy constituents by simultaneously analysing the role that saturated fats, salt and nitrites play in consumer perception. The purpose of this paper was to investigate consumer preferences for healthier processed meat, in particular the specific objective of this study was to evaluate the balance between intrinsic and extrinsic characteristics and the components or additives that could pose a risk to the health of consumers, by considering the sensory and marketing characteristics involved in the choice of cooked ham. With these aims, two different analyses on stated preferences were carried out: firstly, a principal component analysis was performed to identify the main consumer attitudes towards meat products; subsequently, a conjoint analysis was carried out in order to identify the descriptive attributes. The results show that the presence of high salt content and nitrites discourage the intention to purchase, as the presence of a high fat content also does, however at the same time, consumers attach importance to taste, colour and juiciness that are strongly influenced by the above mentioned potentially unhealthy compounds. The overall results are strongly consistent with previous studies but evidence a certain dichotomy between sensory properties and health attributes.


Remineralizing potential of CPP-ACP creams with and without fluoride in artificial enamel lesions.
This study evaluated the effect of pastes containing casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) with and without fluoride on enamel demineralization. Human enamel blocks were used and after incipient caries-like lesions were formed, they were assigned to four groups: G1 - saliva; G2 - MI Paste (RecaldentTM ); G3 - MI Paste Plus (RecaldentTM 900 ppm as NaF); and G4 - Crest™ (1.100 ppm as NaF). The specimens were soaked in demineralizing solution for 6 hours and remineralized in artificial saliva for 18 hours alternatively for 10 days. The dentifrice was prepared with deionized water in a 1:3 proportion (w/w) or applied undiluted in the case of the CPP-ACP formula. Demineralized enamel changes were analysed by surface microhardness (SMH), 3D-profilometry and SEM. Data were analysed by non-parametric Kruskal-Wallis and Mann-Whitney test comparisons and one-way ANOVA and Tukey's HSD post hoc test (α = 0.05). The SMH values observed in the G2 (47.8 ± 28.5) and G3 (53.6 ± 27.6) groups were different from that of G4 (90.2 ± 17.1), which were significantly higher than that found in G1 (39.4 ± 14.2). The %SMH was significantly lower in G4 when compared to G1 (p < 0.001) and G3 (p < 0.05). MI Paste Plus demonstrated a greater protective effect against demineralization than MI Paste and showed smoother surfaces.


The role of tides in bottom water export from the western Ross Sea.
Approximately 25% of Antarctic Bottom Water has its origin as dense water exiting the western Ross Sea, but little is known about what controls the release of dense water plumes from the Drygalski Trough. We deployed two moorings on the slope to investigate the water properties of the bottom water exiting the region at Cape Adare. Salinity of the bottom water has increased in 2018 from the previous measurements in 2008-2010, consistent with the observed salinity increase in the Ross Sea. We find High Salinity Shelf Water from the Drygalski Trough contributes to two pulses of dense water at Cape Adare. The timing and magnitude of the pulses is largely explained by an inverse relationship with the tidal velocity in the Ross Sea. We suggest that the diurnal and low frequency tides in the western Ross Sea may control the magnitude and timing of the dense water outflow.


Observation of the radiative decay D0-->phigamma.
We report the observation of the decay D0-->phigamma with a statistical significance of 5.4sigma in 78.1 fb(-1) of data collected by the Belle experiment at the KEKB e+e- collider. This is the first observation of a flavor-changing radiative decay of a charmed meson. The Cabibbo- and color-suppressed decays D0-->phipi(0), phieta are also observed for the first time. We measure branching fractions B(D0-->phigamma)=[2.60(+0.70)(-0.61)(stat)+0.15-0.17(syst)] x 10(-5), B(D0-->phipi(0))=[8.01+/-0.26(stat)+/-0.47(syst)] x 10(-4), and B(D0-->phieta)=[1.48+/-0.47(stat)+/-0.09(syst)] x 10(-4).


Anthelmintic Drugs: Their Efficacy and Cost-Effectiveness in Different Parity Cattle.
Gastrointestinal nematodes are responsible for economic losses in bovines and are characterized by reduced milk production, decreased working efficiency, and even death. In our study, the effect of different anthelmintic treatments on nematode control in different parity cattle (Friesian crossbreds) at calving and their effect on milk yield were evaluated. The economics of anthelmintics and farm benefits in terms of increased milk production after deworming was also calculated. We screened cattle of first and second parity for nematodes. Animals were randomly selected in each group. In first parity animals, there were 23 positive cattle found, which were divided into 3 different groups, while in second parity animals there were 20 positive cattle which were also divided into 3 groups. For treatment of gastrointestinal nematodes, we used albendazole (velbazine) at 10 mg/kg body weight and levamisole (Nilverm®) at 7.5 mg/kg. In this study, both drugs were found effective in controlling nematode infections in cattle. Percentage reduction of eggs per gram (EPG) by albendazole was 48.20, 85.34, and 93.90% and 51.54, 81.43, 91.74% on day 7, 14, and 21 in first and second parity animals, respectively. Percentage reduction of EPG by levamisole was 44.45, 76.92, and 88.03% and 46.60, 73.78, 85.43% on day 7, 14, and 21 in first and second parity animals, respectively. The average increase in milk production in albendazole-treated groups was 0.39 and 0.92 L per day while increases in levamisole treated groups were 0.27 and 0.55 L per day in first and second parity cattle, respectively. After treatment, albendazole increased the milk fat by 0.07 and 0.1% while levamisole decreased by 0.02 and 0.05% in first and second parity cattle, respectively. It is concluded that anthelmintic treatments of recently calved cattle have a significant effect on milk production due to the nematode control. Milk production increased significantly in second parity cattle following anthelmintic treatment as compared to first parity animals. Levamisole had a negative effect on fat concentration in cattle while albendazole-treated cattle showed a positive effect. Albendazole has been found more efficient in reducing EPG of helminths in both parity animals as compared to levamisole-treated animals while the cost-benefit ratio of levamisole was greater than albendazole.