Identification of lesion components that influence visual function in age related macular degeneration.
To explore the relation between lesion composition as assessed by fundus photography and fluorescein angiography with clinical measures of vision in eyes of patients with age related macular degeneration (AMD). A standardised visual function assessment along with colour stereo pair fundus photography was carried out in both eyes of 58 subjects with a confirmed clinical diagnosis of AMD. The size, location, and composition of the macular lesion (blood, exudate, subretinal fluid, pigment, membrane, atrophy, and fibrosis) were measured on the colour photographs using computer assisted image analysis. Of the 58 subjects, 44 also had concurrent fluorescein angiography. Classic and occult choroidal neovascularisation (CNV), blood, blocked fluorescence, fibrosis, geographic atrophy, and the total area of abnormal fluorescence were measured. Multiple linear regression was used to examine the relation between clinical measures of vision and the location and extent of lesion components identified by both colour and fluorescein image capture. The composition of the macular lesion strongly influenced visual function, with atrophy (p=0.001) and fibrosis (p=0.002) accounting for most of the variation. When the location of the lesion with respect to the fovea was examined, fibrosis within the fovea significantly influenced all clinical measures of vision (p=0.008). The regression model selected the total area of abnormal fluorescence and a composite parameter (a semiquantitative measure of the following characteristics: atrophy, exudates, blood, and fibrosis ) from colour photography (r(2) =0.52) as the variables that explained most of the variation in clinical measures of vision. The composition and extent of the macular lesion strongly influences visual function in eyes with AMD. Both colour photography and angiography yielded information, which together explained considerably more of the variation in the clinical measures of vision than either on its own.


Quantification of the infectious dose of Leishmania major transmitted to the skin by single sand flies.
Leishmaniasis is transmitted between mammalian hosts by the bites of bloodsucking vector sand flies. The dose of parasites transmitted to the mammalian host has never been directly determined. We developed a real-time PCR-based method to determine the number of Leishmania major parasites inoculated into the ears of living mice during feeding by individual infected flies (Phlebotomus duboscqi). The number of parasites transmitted varied over a wide range in the 58 ears in which Leishmania were detected and demonstrated a clear bimodal distribution. Most of the infected mice were inoculated with a low dose of <600 parasites. One in four received a higher dose of >1,000 and up to 100,000 cells. High-dose transmission was associated with a heavy midgut infection of >30,000 parasites, incomplete blood feeding, and transmission of a high percentage of the parasite load in the fly. To test the impact of inoculum size on infection outcome, we compared representative high- (5,000) and low- (100) dose intradermal needle infections in the ears of C57BL/6 mice. To mimic natural transmission, we used sand fly-derived metacyclic forms of L. major and preexposed the injection site to the bites of uninfected flies. Large lesions developed rapidly in the ears of mice receiving the high-dose inoculum. The low dose resulted in only minor pathology but a higher parasite titer in the chronic phase, and it established the host as an efficient long-term reservoir of infection back to vector sand flies.


Strength or Nausea? Children's Reasoning About the Health Consequences of Food Consumption.
Children's reasoning on food properties and health relationships can contribute to healthier food choices. Food properties can either be positive ("gives strength") or negative ("gives nausea"). One of the main challenges in public health is to foster children's dietary variety, which contributes to a normal and healthy development. To face this challenge, it is essential to investigate how children generalize these positive and negative properties to other foods, including familiar and unfamiliar ones. In the present experiment, we hypothesized that children might rely on cues of food processing (e.g., signs of human intervention such as slicing) to convey information about item edibility. Furthermore, capitalizing on previous results showing that food rejections (i.e., food neophobia and picky eating) are a significant source of inter-individual variability to children's inferences in the food domain, we followed an individual approach. We expected that children would generalize the positive properties to familiar foods and, in contrast, that they would generalize more often the negative properties to unfamiliar foods. However, we expected that children would generalize more positive and less negative properties to unfamiliar sliced foods than to whole unfamiliar foods. Finally, we expected that children displaying higher levels of food rejections would generalize more negative properties than children displaying lower levels of food rejections. One-hundred and twenty-six children, aged 3-6 years, performed an induction task in which they had to generalize positive or negative health-related properties to familiar or unfamiliar foods, whole or sliced. We measured children's probability of generalization for positive and negative properties. The children's food rejection score was assessed on a standardized scale. Results indicated that children evaluated positively familiar foods (regardless of processing), whereas they tend to view unfamiliar food negatively. In contrast, children were at chance for processed unfamiliar foods. Furthermore, children displaying higher levels of food rejections were more likely to generalize the negative properties to all kinds of foods than children displaying lower levels of food rejections. These findings entitle us to hypothesize that knowledge-based food education programs should take into account the valence of the properties taught to children, as well as the state of processing of the food presented. Furthermore, one should take children's interindividual differences into account because they influence how the knowledge gained through these programs may be generalized.


Wingless/Wnt signaling in Drosophila: the pattern and the pathway.
Wnt signaling generates pattern in all animal embryos, from flies and worms to humans, and promotes the undifferentiated, proliferative state critical for stem cells in adult tissues. Inappropriate Wnt pathway activation is the major cause of colorectal cancers, a leading cause of cancer death in humans. Although this pathway has been studied extensively for years, large gaps remain in our understanding of how it switches on and off, and how its activation changes cellular behaviors. Much of what is known about the pathway comes from genetic studies in Drosophila, where a single Wnt molecule, encoded by wingless (wg), directs an array of cell-fate decisions similar to those made by the combined activities of all 19 Wnt family members in vertebrates. Although Wg specifies fate in many tissues, including the brain, limbs, and major organs, the fly embryonic epidermis has proven to be a very powerful system for dissecting pathway activity. It is a simple, accessible tissue, with a pattern that is highly sensitive to small changes in Wg pathway activity. This review discusses what we have learned about Wnt signaling from studying mutations that disrupt epidermal pattern in the fly embryo, highlights recent advances and controversies in the field, and sets these issues in the context of questions that remain about how this essential signaling pathway functions.


Naturally stressed? Glucocorticoid profiles in blubber of blue and gray whales in response to life history parameters.
The goal of the present study was to carry out a thorough methodological validation and describe baseline profiles for glucocorticoid hormones (cortisol and corticosterone) in blubber from blue (n = 77) and gray (n = 103) whales from the eastern North Pacific Ocean. For each species, we modelled cortisol and corticosterone concentrations in response to life history parameters (age, sex, reproductive status) and season or geographic location. In blue whales, cortisol concentrations did not vary significantly by age class, sex, or reproductive status, whereas corticosterone was significantly lower in immature than in adult females (p < .001). In gray whales, cortisol concentrations were significantly higher in lactating whales (p < .05), while corticosterone was significantly different between females and males (p = .001) and elevated in calves (p = .003). In gray whales, corticosterone concentrations were significantly lower in males sampled later in the year (August to November) compared to both sexes sampled between March and August (p = .05), but no seasonal trend occurred in blue whales. Our results indicate that glucocorticoid actions vary between species and sex in large whales. Analysis of multiple hormones improves our understanding of the physiology of maintaining metabolic homeostasis or coping with chronic stressors.


Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis.
Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007. Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.


Assessing the incidence trend and characteristics of eosinophilic esophagitis in children in Olmsted County, Minnesota.
Previous studies reported increased eosinophilic esophagitis (EoE) incidence in children. It is unclear whether this reported increased EoE incidence is true or due to increased recognition and diagnostic endoscopy among children. A population-based study that evaluated EoE incidence in OC, Minnesota, from 1976 to 2005 concluded that EoE incidence increased significantly over the past three 5-year intervals (from 0.35 [range: 0-0.87] per 100,000 person-years for 1991-1995 to 9.45 [range: 7.13-11.77] per 100,000 person-years for 2001-2005). The aim of this study is to assess the change of incidence and characteristics of EoE in children in the same population between 2005 and 2015 and compare the findings to those reported in the previous study. We retrospectively reviewed the electronic medical records from Olmsted Medical Center and Mayo Clinic between 2005 and 2015, using Rochester Epidemiology Project (REP) resources. All children with EoE diagnosis based on the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) guidelines were included. The incidence and characteristics of children with EoE during the study period were compared to those diagnosed between 1995 and 2005. The incidence of EoE in children adjusted for age and sex was 5.31 per 100,000 population person-years in 1995, 15.2 in 2005, and 19.2 in 2015. Change in annual incidence and seasonal variation were not significant, (P = .48) and (P = .32), respectively. Between 2005 and 2015, 73 children received an EoE diagnosis (boys 49; 67%) compared to 16 children (boys 10; 62.5) between 1995 and 2005. Mean (SD) age at diagnosis was 7.5 (5.2) and 12.8 (4.3) years, respectively. Symptoms differed by age of presentation, with vomiting the most common in children younger than 5 years (41.1% and 43.5%) and dysphagia in those older than 5 years (35.6% and 60.9%). The incidence of EoE was not increased for any specific age-group during the study period (P = .49). This study showed increased incidence of EoE in children in Olmsted County between 2005 and 2015 compared to the incidence between 1995 and 2005 (5.31 per 100,000 population person-years in 1995, 15.2 in 2005, and 19.2 in 2015). However, between 2005 and 2015, the change of incidence was not statically significant, (P = .48) despite the steady increase of EGD performed during the same time frame (64 in 2005 to 144 in 2015). By comparing children diagnosed between 2005 and 2015 to those diagnosed between 1995 and 2005, the mean age at diagnosis was younger in the former group, 7.5 versus 12.8 years. Vomiting replaced dysphagia as the most common clinical presentation. Otherwise, the presenting symptom of EoE in children remained consistent across specific age groups.


Ets2 and protein kinase C epsilon are important regulators of parathyroid hormone-related protein expression in MCF-7 breast cancer cells.
Parathyroid hormone-related protein (PTHrP) promotes the metastatic potential and proliferation of breast cancer cells, and acts anti-apoptotically. In invasive MDA-MB-231 breast cancer cells, transforming growth factor beta-regulated PTHrP synthesis is mediated by an Ets1/Smad3-dependent activation of the PTHrP P3 promoter. In the present study, we studied the regulation of PTHrP expression in non-invasive, Ets1-deficient and transforming growth factor beta-resistant MCF-7 cells. We found PMA to be a strong stimulator of P3-dependent PTHrP expression in MCF-7 cells. Mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) kinase 1 (MEK-1)/ERK1/2 inhibitor PD98059 interfered with this activity. Promoter studies revealed that the PMA effect depended on the Ets and stimulating protein-1 (Sp1)-binding sites. Of several Ets factors tested, Ets2, but not Ese-1, Elf-1 or Ets1, supported the PMA-dependent increase in promoter activity. PD98059 and a threonine to alanine mutation of the ERK1/2-responsive Ets2 phosphorylation site at position 72 inhibited the Ets2/PMA effect. Activated protein kinase C (PKC) epsilon could mimic PMA by stimulating the P3 promoter alone or in co-operation with Ets2 in an MEK-1/ERK1/2-dependent manner. Activated PKC alpha, although capable of co-operating with Ets2, failed to induce transcription from the P3 promoter on its own. The Ets2/PKalpha synergistic effect was neither sensitive to PD98059 nor to Thr(72)/Ala(72) mutation. PMA neither increased the expression of Sp1 nor modulated the transcriptional activity of Sp1. However, it induced the displacement of a yet unknown factor from the Sp1-binding site, which may result in Sp1 recruitment to the promoter. Our results suggest an ERK1/2-dependent Ets2/PKC epsilon synergism to be involved in PTHrP expression in MCF-7 breast cancer cells.


Extracorporeal membrane oxygenation experiences during COVID-19 pandemic, third wave with younger patients: A retrospective observational study.
In this article, the results of severe coronavirus disease 2019 (COVID-19) cases followed with extracorporeal membrane oxygenation (ECMO) support in a 3-month period in the third wave when there were an increased number of cases of young patients in our intensive care unit (ICU) were presented. The study was carried out with all COVID-19 patients who were given ECMO support in our tertiary referral hospital ICU after obtaining the consent of the Ministry of Health Scientific Research Platform and after the approval of the local ethics committee. Patient data were obtained retrospectively from intensive care bedside follow-up charts and computer records. The demographic and clinical characteristics of the patients were presented in average, median, and percentages. The data of the patients were evaluated and compared with the current literature. ECMO treatment was applied in seven patients who were followed up with severe COVID-19 pneumonia in the last 3 months. Venovenous extracorporeal membrane oxygenation (VV-ECMO) was applied to all patients. Five (71.5%) of seven patients were weaned from ECMO. Four (57.2%) of seven patients were discharged from the ICU and hospital in good health. While two of the patients had a cesarean section (C/S) before ECMO, one patient underwent C/S under ECMO. All three newborns were delivered via C/S and all were premature (C/S dates were 35 weeks, 32 weeks, and 27 weeks), and all were discharged from the hospital in good health. Our experience shows that ECMO in COVID-19 patients is a lifesaving treatment option that can be successfully applied in severe acute respiratory distress syndrome cases who do not respond to conventional treatments.


Mitochondrial topoisomerase I (top1mt) is a novel limiting factor of doxorubicin cardiotoxicity.
Doxorubicin is one of the most effective chemotherapeutic agents. However, up to 30% of the patients treated with doxorubicin suffer from congestive heart failure. The mechanism of doxorubicin cardiotoxicity is likely multifactorial and most importantly, the genetic factors predisposing to doxorubicin cardiotoxicity are unknown. On the basis of the fact that mtDNA lesions and mitochondrial dysfunctions have been found in human hearts exposed to doxorubicin and that mitochondrial topoisomerase 1 (Top1mt) specifically controls mtDNA homeostasis, we hypothesized that Top1mt knockout (KO) mice might exhibit hypersensitivity to doxorubicin. Wild-type (WT) and KO Top1mt mice were treated once a week with 4 mg/kg doxorubicin for 8 weeks. Heart tissues were analyzed one week after the last treatment. Genetic inactivation of Top1mt in mice accentuates mtDNA copy number loss and mtDNA damage in heart tissue following doxorubicin treatment. Top1mt KO mice also fail to maintain respiratory chain protein production and mitochondrial cristae ultrastructure organization. These mitochondrial defects result in decreased O2 consumption, increased reactive oxygen species production, and enhanced heart muscle damage in animals treated with doxorubicin. Accordingly, Top1mt KO mice die within 45 days after the last doxorubicin injection, whereas the WT mice survive. Our results provide evidence that Top1mt, which is conserved across vertebrates, is critical for cardiac tolerance to doxorubicin and adaptive response to doxorubicin cardiotoxicity. They also suggest the potential of Top1mt single-nucleotide polymorphisms testing to investigate patient susceptibility to doxorubicin-induced cardiotoxicity.


Membrane bioreactors for final treatment of wastewater.
The full-scale existing treatment plant in a paper mill in Hedera, Israel, includes equalization, solids separation by either straining or by dissolved air flotation and biological treatment by activated sludge. The operation of the existing biological process is often characterized by disturbances, mainly bad settling, voluminous bioflocs, followed by wash-out of the biosolids. This paper summarizes the results obtained in a study based on a pilot plant including a membrane biological reactor (MBR) compared to the "conventional" activated sludge process in the aerobic treatment of the effluent obtained from an anaerobic reactor. During the pilot operation period (about 90 days after achieving steady state) the MBR system provided steady operation performance, while the activated sludge produced effluent characterized by oscillatory values. The results are based on average values and indicate much lower levels of suspended solids in the MBR effluent, 2.5 mg/L, as compared to 37 mg/L in the activated sludge. As a result, the total organic mater content was also substantially lower in the MBR effluent, 129 vs 204 mg/L as COD, and 7.1 vs 83 mg/L as BOD. The MBR enabled better nitrification. The ability to develop and maintain a concentration of over 11,000 mg/L of mixed liquor volatile suspended solids in the MBR bioreactor enabled an intensive bioprocess at relatively high cell residence time. As a result the biosolids which had to be removed as excess sludge were characterized by relatively low volatile/total suspended solids ratio, around 0.78. This could facilitate and lower the cost of biosolids treatment and handling. The results of this comparative study indicate that in the case of MBR there will be no need for further treatment, while after activated sludge additional filtration will be required. The study leads to the conclusion that MBR will be the best technology for aerobic treatment of the anaerobic effluent of the paper mill.


Triglyceride lipases and atherosclerosis.
Lipoprotein lipase is at the center of lipoprotein metabolism, unloading triglycerides for metabolic use in extrahepatic tissues, regulated in concert with energy metabolism by insulin and other factors, and converting the input of large triglyceride-rich lipoproteins to smaller, potentially atherogenic remnants that are either remodeled into LDL and HDL, or quickly cleared. In addition, lipoprotein lipase has turned out to be a multifunctional protein that also acts as a ligand for binding of lipoproteins to proteoglycans and receptors. Hepatic lipase has evolved more recently, and its main role appears to be in the remodeling processes.


Epidermal growth factor induces tumour marker AKR1B10 expression through activator protein-1 signalling in hepatocellular carcinoma cells.
AKR1B10 (aldo-keto reductase 1B10) is overexpressed in liver and lung cancer, and plays a critical role in tumour development and progression through promoting lipogenesis and eliminating cytotoxic carbonyls. AKR1B10 is a secretory protein and potential tumour marker; however, little is known about the regulatory mechanism of AKR1B10 expression. The present study showed that AKR1B10 is induced by mitogen EGF (epidermal growth factor) and insulin through the AP-1 (activator protein-1) signalling pathway. In human HCC (hepatocellular carcinoma) cells (HepG2 and Hep3B), EGF (50 ng/ml) and insulin (10 nM) stimulated endogenous AKR1B10 expression and promoter activity. In the AKR1B10 promoter, a putative AP-1 element was found at bp -222 to -212. Deletion or mutation of this AP-1 element abrogated the basal promoter activity and response to EGF and AP-1 proteins. This AP-1 element bound to nuclear proteins extracted from HepG2 cells, and this binding was stimulated by EGF and insulin in a dose-dependent manner. Chromatin immunoprecipitation showed that the AP-1 proteins c-Fos and c-Jun were the predominant factors bound to the AP-1 consensus sequence, followed by JunD and then JunB. The same order was followed in the stimulation of endogenous AKR1B10 expression by AP-1 proteins. Furthermore, c-Fos shRNA (short hairpin RNA) and AP-1 inhibitors/antagonists (U0126 and Tanshinone IIA) inhibited endogenous AKR1B10 expression and promoter activity in HepG2 cells cultured in vitro or inoculated subcutaneously in nude mice. U0126 also inhibited AKR1B10 expression induced by EGF. Taken together, these results suggest that AKR1B10 is up-regulated by EGF and insulin through AP-1 mitogenic signalling and may be implicated in hepatocarcinogenesis.


Expression of trk in MAH cells lacking the p75 low-affinity nerve growth factor receptor is sufficient to permit nerve growth factor-induced differentiation to postmitotic neurons.
We have transfected MAH cells, an immortalized sympathoadrenal progenitor cell line, with a plasmid encoding the 140-kDa Trk protein, a nerve growth factor (NGF) receptor with protein-tyrosine kinase activity. NGF promotes neurite outgrowth and proliferation from such cells, indicating that Trk is sufficient to mediate such responses in the absence of significant levels of the endogenous 75-kDa low-affinity NGF receptor (p75). These initial NGF responses are indistinguishable from those evoked by basic fibroblast growth factor (bFGF). However, NGF is sufficient to promote terminal differentiation of a approximately 8% of trk-transfected MAH cells to postmitotic, NGF-dependent neurons, whereas all cells eventually die in medium with bFGF. Other environmental signals (such as depolarization or ciliary neurotrophic factor) can cooperate with NGF to enhance production of postmitotic NGF-dependent neurons in trk-transfected MAH cells. The terminal differentiation of sympathetic neurons thus involves sequential and cooperative actions of different growth and neurotrophic factors, as well as cell-intrinsic changes in the response to these factors.


Well-defined cationic alkyl- and alkoxide-aluminum complexes and their reactivity with epsilon-caprolactone and lactides.
We describe the synthesis, structure, and reactivity of low-coordinate Al-alkyl and -alkoxide cationic complexes incorporating the sterically bulky aminophenolate bidentate ligand 6-(CH(2)NMe(2))-2-CPh(3)-4-Me-C(6)H(2)O- (N,O). These complexes are derived from the ionization of neutral dialkyl Al complexes (N,O)Al2) (1 a, R=Me; 1 b, R=iBu), readily obtained by alkane elimination between AlR3 and the corresponding aminophenol ligand, with the alkyl abstracting reagents B(C(6)F(5))3 and [Ph(3)C][B(C(6)F(5))4]. The reactions of 1 a,b with B(C(6)F(5))3 yield complicated mixtures or decomposition products, however the ionization of the Al-diisobutyl derivative 1 b with [Ph(3)C][B(C(6)F(5))4] affords a stable four-coordinate Al-PhBr cationic adduct [(N,O)Al(iBu)(PhBr)]+ (3+), as deduced from elemental analysis data. Complex 3+ readily coordinates Lewis bases such as THF to form the corresponding adduct [(N,O)Al(iBu)(thf)]+ (4+), and also rapidly chain-transfers with 1-hexene to yield the three-coordinate Al-hexyl cation [(N,O)Al-hexyl]+ (5+). Both cations 3+ and 5+ slowly dimerize to form unprecedented organoaluminum dications [(N,O)AlR+]2 (3'++, R=iBu; 5'++, R=hexyl) as deduced from X-ray crystallographic analysis. Cation 3+ reacts quickly with iPrOH to form a stable Lewis acid/base adduct [(N,O)Al(iBu)(HOiPr)]+ (6+), which constitutes the first X-ray characterized adduct between an Al-alkyl complex and a simple ROH. The Al-ROH proton in 6+ is readily abstracted by NMe(2)Ph to form the neutral isopropoxide Al complex [(N,O)Al(iBu)(OiPr)] (7). Upon reaction with THF, cation 6+ undergoes an intramolecular proton transfer to yield the ammonium Al-THF complex [(eta1-HN,O)Al(iBu)(OiPr)(thf)] (8 b+), in which the aminophenolate is eta1-coordinated to the Al center. Cation 8 b+ can then be converted to the desired Al-alkoxide derivative [(N,O)Al(OiPr)(thf)](+) (10+), by an intramolecular protonolysis reaction, as confirmed by X-ray crystallography. The synthesized Al-alkyl cations form robust four-coordinate adducts in the presence of cyclic esters such as epsilon-caprolactone and (D,L)-lactide, but no insertion chemistry occurs, illustrating the poor ability of the Al-R+ moiety to ring-open. In contrast, the Al-alkoxide cation 10+ polymerizes epsilon-caprolactone in a controlled manner with excellent activity, but is inactive in the polymerization of (D,L)-lactide and L-lactide. Control experiments with L-lactide show that cation 10+ ring-opens L-lactide to yield a robust five-coordinated Al--lactate cation [(N,O)Al(eta2-L-lactate-OiPr)(thf)]+ (13+), derived from a monoinsertion of L-lactide into the Al--OiPr bond of 10+, that does not further react. Cation 13+ may be regarded as a structurally characterized close mimic of the initial intermediate in the ring opening polymerization (ROP), of lactides by [{LX}M(OR)(L)] (where LX-=bidentate monoanionic ligand and L=labile ligand) metal complex initiators.


Leaching properties of electric arc furnace dust prior/following alkaline extraction.
This study was carried out to determine the appropriate treatment of electric arc furnace (EAF) dust prior to permanent disposal. The total heavy metal content as well as heavy metal leaching from EAF dust was investigated in five composite samples obtained from three Croatian and Slovenian steelworks. In order to recover zinc and reduce its leaching from the dust, all five samples were submitted to alkaline extraction with 10 M NaOH. Reduction of Cr (VI) to Cr(III) was conducted using FeSO4 x 7H2O solution. The elements Mn, Fe, Cu, Ni, and notably Zn and Pb, exhibited highest mobility during toxicity characteristic leaching procedure (TCLP). Comparing to TCLP extracts of initial EAF dust, zinc was found to be over 15 times lower and lead over 200 times lower in TCLP extracts of EAF dust processed by the alkaline leaching method. Since Cr (VI) exceeded its permissible level in the DIN 38414-S4 extracts of both initial and alkaline digested dust, its reduction to Cr (III) prior to permanent disposal is necessary. The recovery of zinc from EAF dust treated with alkaline agent ranged from 50.3% to 73.2%. According to phase analysis, recovery yield showed dependence on zincite/franklinite ratio. The results of the study indicate that permanent disposal of EAF dust require the following procedure: alkaline digestion (followed by leachate purification and alkaline zinc electrolyses), chromate reduction (if necessary), solidification of leaching residue and its testing using the leaching analyses.


ARAF suppresses ERBB3 expression and metastasis in a subset of lung cancers.
RAF kinases are highly conserved serine/threonine kinases, and among the three RAF isoforms (ARAF, BRAF, and CRAF), the pathophysiological relevance of ARAF is not well defined. Here, we show that patients with lung cancer exhibit low expression of ARAF, which is associated with lymph node metastasis and poor patient survival. We uncover that depletion of ARAF promotes anchorage-independent growth and metastasis through activation of AKT signaling in a subset of lung cancer cells. We identified that loss of ARAF was associated with an increase in ERBB3 expression in a kinase-independent manner. ARAF suppressed the promoter activity of ERBB3, and reconstitution of ARAF in ARAF-depleted cells led to the reversal of enhanced ERBB3-AKT signaling. Furthermore, ARAF inhibited neuregulin 1 (hNRG1)-mediated AKT activation through controlling ERBB3 expression via the transcription factor KLF5. Our results disclose a critical dual role for ARAF kinase in the negative regulation of ERBB3-AKT signaling, thereby suppressing tumor metastasis.


Identification and partial purification of ABGP205, an integral membrane glycoprotein from brain that binds ankyrin.
1. A procedure was devised that allows the membrane-skeletal proteins brain spectrin and ankyrin to be extracted selectively from a membrane-skeletal preparation, together with some actin, an Mr-103,000 protein and a population of glycoproteins. 2. Ankyrin-binding activities of the glycoproteins were investigated by affinity chromatography. We detected only one, Mr 205,000, that binds ankyrin and is prevented from binding by the cytoplasmic domain of Band 3, the established erythrocyte-membrane-binding site for ankyrin. The Mr-205,000 glycoprotein, designated ABGP205, may be a candidate for a membrane-binding site for ankyrin.


[The gallery forests of the São Francisco river as corridors for Euglossine bees (Hymenoptera: Apidae) from tropical rainforests].
Euglossini are typical bees of Neotropical rainforests and only a few species occur in the Caatinga. The São Francisco river, which is the only permanent river in the semi-arid NE-Brazil, is bordered by a gallery forest with evergreen leaves. This environment offers flooral rewards along the year. Surveys of euglossine bees by attracting males to scent baits showed that species of the Atlantic Rainforest like Euglossa imperialis Cockerel, E. truncata Moure and Eulaema cingulata Fabricius occur in the gallery forest of the São Francisco river under the semi-arid climate of the caatinga region. These bees are restricted to the gallery forests which function as bio-corridors, and are absent at places where the forests were cut down. This emphasizes the need to protect the threatened gallery forests to maintain biodiversity.


Comparison of Outcomes Associated with Tibial Plateau Levelling Osteotomy and a Modified Technique for Tibial Tuberosity Advancement for the Treatment of Cranial Cruciate Ligament Disease in Dogs: A Randomized Clinical Study.
This study aimed to compare outcomes between the tibial plateau levelling osteotomy (TPLO) procedure and a modified tibial tuberosity advancement (TTA Rapid) in dogs with cranial cruciate ligament rupture. Twenty-six dogs were prospectively randomized into two groups: a TPLO group (n = 13) and a TTA Rapid group (n = 13). A lameness score evaluation, gait analysis and radiographical examination were performed before surgery, the 3 days after surgery, and then at 1, 3 and 6 months postoperatively. Finally, owners were asked to subjectively rate their level of satisfaction. The duration of surgery was significantly shorter for the TTA Rapid procedure (p < 0.0001). There was no significant difference in the occurrence of complications between groups. Lameness scores were significantly higher during the first 3 days after surgery for the TPLO group (p = 0.01 at day 1, p = 0.01 at day 2 and p = 0.003 at day 3). One month after surgery, the symmetry index between healthy and affected limbs for the relative stance time during the gait cycle (symmetry index/%) was significantly higher for the TTA Rapid group (p < 0.01). No gait parameters were significantly different between the two groups 6 months after surgery. All of the owners of dogs in the TPLO group were completely satisfied, whereas only 11/13 owners of dogs in the TTA rapid group were completely satisfied. Tibial plateau levelling osteotomy and TTA Rapid were associated with high long-term success rates in dogs. The immediate postoperative recovery seemed faster with TTA Rapid, but thereafter there was no difference.


Genetic and environmental factors in alcohol abuse and antisocial personality.
Previous analyses of adoptees from Lutheran Social Services of Iowa developed a multifactorial model of adoptee alcohol abuse that related abuse to three factors: biologic background of alcohol-related problems, biologic background of antisocial problems and exposure to an adoptive family where family members had alcohol-related problems. The present study examines an independently collected sample of adoptees from a different agency--the Iowa Children's and Family Services, and confirms the multifactorial model previously found in the Lutheran Social Service data. The model shows a specificity of type of inheritance and type of environmental influence: biologic family alcohol-related problems predict increased alcohol abuse in adoptee, biologic family antisocial behaviors predict increased antisocial personality diagnoses in adoptee, and environmental factors of alcohol-related problems in the adoptive family predict increased adoptee alcohol abuse.


Dynamic cerebral autoregulation estimates derived from near infrared spectroscopy and transcranial Doppler are similar after correction for transit time and blood flow and blood volume oscillations.
We analysed mean arterial blood pressure, cerebral blood flow velocity, oxygenated haemoglobin and deoxygenated haemoglobin signals to estimate dynamic cerebral autoregulation. We compared macrovascular (mean arterial blood pressure-cerebral blood flow velocity) and microvascular (oxygenated haemoglobin-deoxygenated haemoglobin) dynamic cerebral autoregulation estimates during three different conditions: rest, mild hypocapnia and hypercapnia. Microvascular dynamic cerebral autoregulation estimates were created by introducing the constant time lag plus constant phase shift model, which enables correction for transit time, blood flow and blood volume oscillations (TT-BF/BV correction). After TT-BF/BV correction, a significant agreement between mean arterial blood pressure-cerebral blood flow velocity and oxygenated haemoglobin-deoxygenated haemoglobin phase differences in the low frequency band was found during rest (left: intraclass correlation=0.6, median phase difference 29.5° vs. 30.7°, right: intraclass correlation=0.56, median phase difference 32.6° vs. 39.8°) and mild hypocapnia (left: intraclass correlation=0.73, median phase difference 48.6° vs. 43.3°, right: intraclass correlation=0.70, median phase difference 52.1° vs. 61.8°). During hypercapnia, the mean transit time decreased and blood volume oscillations became much more prominent, except for very low frequencies. The transit time related to blood flow oscillations was remarkably stable during all conditions. We conclude that non-invasive microvascular dynamic cerebral autoregulation estimates are similar to macrovascular dynamic cerebral autoregulation estimates, after TT-BF/BV correction is applied. These findings may increase the feasibility of non-invasive continuous autoregulation monitoring and guided therapy in clinical situations.


Effects of exposure to vinyl chloride. An assessment of the evidence.
This paper reviews the possible effects of vinyl chloride on the mortality of occupationally exposed men and the carcinogenic effects that might be observed in the general population as a result of environmental pollution with vinyl chloride. The results of four studies fulfilling the criteria of providing substantial numbers of observations more than 25 years after first exposure and covering a period long enough for more than 10% of the workers to have been expected to die constitute the basis for the assessment of the occupational hazards. Other studies provide only supplementary information. The data permit two conclusions. First, men occupationally exposed to vinyl chloride have experienced a specific hazard of angiosarcoma of the liver. Second, any other occupational hazards that may have existed have been small. No positive evidence of a hazard of any nonmalignant disease or any type of cancer other than angiosarcoma of the liver has been found except possibly for a small hazard of lung cancer when exposure was heavy. More definite conclusions might be reached if those who have studied exposed employees could present their results in appropriate and comparable ways. A very small risk of angiosarcoma may have occurred as a result of vinyl chloride escaping into the environment around plants handling vinyl chloride in the past, but the evidence indicates that the current risk to the general public (if any) must be negligible.


Peptide sequences binding to MHC class I proteins.
Motifs for peptides which bind specifically to the human class I major histocompatibility complex molecules HLA-A2 and B7 were determined by sequence analysis of class I-bound peptides selected from a random synthetic library of nonamers. Thirteen individual peptides were sequenced for HLA-A2, twelve individual and nine pooled peptides were sequenced for HLA-B7. Analysis of sequence alignment implicated four peptide positions in potential contact with the class I HLA-A2 molecule and three positions for the HLA-B7 molecule. The results demonstrate that a synthetic peptide library can be used to identify allele-specific motifs for class I molecules, providing information comparable to the results obtained from sequencing endogenous peptides. This method utilizes denatured class I heavy chains, and similar results were obtained using a class I protein purified from mammalian cells or by expression in Escherichia coli. This method has the potential to detect peptides which may not be generated physiologically, but due to their binding properties, may be valuable to predict or engineer immunomodulatory T cell epitopes.


Littre hernia--a rare cause of unexpected death in the elderly.
A rare case of sudden and unexpected death is reported in an 87-year-old woman who was found dead at her home. At autopsy, the most striking finding was of a right-sided direct inguinal hernia containing a 20 mm infarcted Meckel diverticulum, with proximal small intestinal obstruction. Significant stenosing atherosclerosis was present in all three major epicardial coronary arteries, but with no histological evidence of acute or chronic ischemic myocardial damage. Death was attributed to small intestinal obstruction due to direct inguinal herniation (and infarction) of a Meckel diverticulum (a Littre hernia), complicating ischemic heart disease. Although Littre hernias are not a reported cause of sudden death in the elderly, congenital gastrointestinal anomalies may rarely play a significant role in terminal episodes well beyond childhood years. The autopsy assessment of sudden death at any age involves detailed examination of the entire length of the intestinal tract.


Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human Liver Microphysiological System.
In this work, we first describe the population variability in hepatic drug metabolism using cryopreserved hepatocytes from five different donors cultured in a perfused three-dimensional human liver microphysiological system, and then show how the resulting data can be integrated with a modeling and simulation framework to accomplish in vitro-in vivo translation. For each donor, metabolic depletion profiles of six compounds (phenacetin, diclofenac, lidocaine, ibuprofen, propranolol, and prednisolone) were measured, along with metabolite formation, mRNA levels of 90 metabolism-related genes, and markers of functional viability [lactate dehydrogenase (LDH) release, albumin, and urea production]. Drug depletion data were analyzed with mixed-effects modeling. Substantial interdonor variability was observed with respect to gene expression levels, drug metabolism, and other measured hepatocyte functions. Specifically, interdonor variability in intrinsic metabolic clearance ranged from 24.1% for phenacetin to 66.8% for propranolol (expressed as coefficient of variation). Albumin, urea, LDH, and cytochrome P450 mRNA levels were identified as significant predictors of in vitro metabolic clearance. Predicted clearance values from the liver microphysiological system were correlated with the observed in vivo values. A population physiologically based pharmacokinetic model was developed for lidocaine to illustrate the translation of the in vitro output to the observed pharmacokinetic variability in vivo. Stochastic simulations with this model successfully predicted the observed clinical concentration-time profiles and the associated population variability. This is the first study of population variability in drug metabolism in the context of a microphysiological system and has important implications for the use of these systems during the drug development process.


The importance of problem-focused treatments: A meta-analysis of anxiety treatments.
One explanation for differences in treatment effectiveness for targeted symptoms is that more-effective treatments are more focused on patients' problems than are less-effective treatments. This conjecture was examined meta-analytically. Comparisons of two treatments of adults with anxiety disorders were included. Effect sizes for targeted symptoms, nontargeted symptoms, and global outcomes (e.g., quality of life and well-being) as well as the relative focus on patients' problems and researcher allegiance were coded. Metaregressions were conducted to predict effect sizes from (a) variables related to the focus on patients' problems and (b) researcher allegiance. For symptom measures, the relative focus on patients' problems predicted the relative effectiveness of the treatments, with the expectations created by explanation appearing more predictive than specific therapeutic actions focused on patients' problems, although conclusions about relative importance were difficult to determine given collinearity of predictors. Researcher allegiance also predicted the effects of the comparisons. For global outcomes, both the focus on patients' problems and researcher allegiance seemed to have smaller roles. A focus on patients' problems appears to be important for the reductions of symptoms. Clinical trials comparing treatments need to balance the focus on patients' problems and reduce researcher allegiance. (PsycINFO Database Record


Psychometric assessment and behavioral experiments using a free virtual reality platform and computational science.
Virtual Reality has been extensively used in a wide range of psychological experiments. In this study, we aimed to introduce NeuroVirtual 3D, a platform that clinicians could use free of charge. The platform we developed relies on NeuroVR software, but we extended it to apply to experiments. The software is available free of charge to researchers and clinical practitioners who can also use a large number of virtual environments and objects already developed. The platform has been developed to connect to virtually every device ever produced by the means of Virtual-Reality Peripheral Network (VRPN) protocols; however, a number of these have already been included and tested in the platform. Among the available devices, the Microsoft Kinect low-cost sensor has already been configured for navigation through the virtual environments and to trigger specific action (sounds, videos, images, and the like) when a specific gesture is recognized, e.g., a step forward or an arm up. A task for neglect and a task for spatial abilities assessment were already implemented within the platform. Moreover, NeuroVirtual 3D integrated a TCP-IP-based module (bridge) to collect the data from virtually any existent biosensor (Thought-Technology, Zephyr and StarStim devices have already been included in the platform). It is able to record any psychophysiological signal during any experiment using also the computed indices in real time. NeuroVirtual 3D is able to record external and internal (e.g., coordinates, keys-press, timestamp) data with a millisecond precision, representing de facto the most advanced technology for experimental psychology using virtual environments available without the needs to program code.


Mechanistic understanding in clinical practice: complementing evidence-based medicine with personalized medicine.
In the last century, medicine has undergone an unprecedented wave of radical changes. From the implementation of surgery up to the development of single gene-targeted therapies, clinical decision making has become increasingly complex to handle. Today, this complexity needs to be rethought in the light of two emerging paradigms: evidence-based medicine (EBM) and personalized medicine (P-Med). The new availability of diverse sources of scientific evidence raises significant issues concerning how clinicians will compare, evaluate and orient their decisions in front of a rapidly growing plethora of therapies, procedures, medical technologies and drugs. In this paper, we compare the background visions behind these two paradigms, evaluating their respective relevance for present and future clinical decision making. In particular, we argue that EBM and P-Med are driven by two diverse modes of reasoning about 'evidence making' in medicine. EBM is grounded on statistical notions and epidemiological data, generally gathered through systematic meta-reviews of randomized controlled trials; P-Med, instead, is grounded on mechanistic explanations of molecular interactions, metabolic pathways and biomarkers. While both paradigms are epistemically sound, we argue that they cannot, and should not, be hybridized into a unique model. Rather, they ought to represent two compatible, but alternative ways of informing the clinical practice. Hence, we conclude that clinicians may expect to see their responsibility increasing as they will deal with diverse, but equally compelling, ways of reasoning and deciding about which intervention will qualify as the 'best one' in each individual case.


A proposal for using the ratio of attempted to completed suicides across several countries worldwide.
Completed suicide (CS) is a leading cause of death worldwide and its rates are available for most developed countries. On the other hand, attempted suicide (AS) is a risk factor for CS but there are limited data on its rates in various countries. In constructing a ratio for AS/CS rates, most would agree that for CS, the denominator should be the annual suicide rate (per 100 000). As for the ratio's numerator (AS) per 100 000, there are three possible calculations: (1) annual prevalence from population surveys, (2) annual prevalence from national clinical registers or (3) lifetime prevalence from population surveys. We think that the first possibility would probably be the best choice but, unfortunately, surveys providing the annual prevalence of AS are lacking for most countries. Annual prevalence from national registers is also lacking for most countries and is contaminated by under-reporting. Therefore, in this editorial, we are left with only the last option, a ratio for lifetime prevalence of AS (per 100 000) divided by annual rate of CS (per 100 000). This ratio for AS/CS rates appears to differ substantially across countries worldwide but presents no big regional differences other than two remarkable exceptions, one per continent. In Europe, Spain and France had greater ratios (174.4 and 152.5, respectively) than Italy (64.1). In Asia/Pacific, New Zealand has a higher ratio (345.9) compared with China (75.8) and Japan (76.9). The ratio for AS/CS rates could be a good index for implementing evidence-informed decision-making regarding suicidal behaviour (SB) among health service managers, and for helping them in the allocation of health resources for the prevention of SB.


Calcitonin: physiology or fantasy?
Calcitonin, a potent hypocalcemic hormone produced by the C-cells of the thyroid, was first discovered by Harold Copp in 1962. The physiological significance of calcitonin has been questioned, but recent studies using genetically modified mouse models have uncovered additional actions of calcitonin acting through its receptor (CTR) that are of particular significance to the regulation of bone and calcium homeostasis. Mice in which the CTR is deleted in osteoclasts are more susceptible to induced hypercalcemia and exogenous calcitonin is able to lower serum calcium in younger animals. These data are consistent with the hypothesis that calcitonin can regulate serum calcium by inhibiting the efflux of calcium from bone, and that this action is most important when bone turnover is high. Calcitonin has also been implicated in protecting the skeleton from excessive loss of bone mineral during times of high calcium demand, such as lactation. This action may be linked to an intriguing and as yet unexplained observation that calcitonin inhibits bone formation, because deletion of the CTR leads to increased bone formation. We propose several mechanisms by which calcitonin could protect the skeleton by regulating bone turnover, acting within the bone and/or centrally. A new more holistic notion of the physiological role of calcitonin in bone and calcium homeostasis is required and we have highlighted some important knowledge gaps so that future calcitonin research will help to achieve such an understanding.


Identifying adaptive alleles in the human genome: from selection mapping to functional validation.
The suite of phenotypic diversity across geographically distributed human populations is the outcome of genetic drift, gene flow, and natural selection throughout human evolution. Human genetic variation underlying local biological adaptations to selective pressures is incompletely characterized. With the emergence of population genetics modeling of large-scale genomic data derived from diverse populations, scientists are able to map signatures of natural selection in the genome in a process known as selection mapping. Inferred selection signals further can be used to identify candidate functional alleles that underlie putative adaptive phenotypes. Phenotypic association, fine mapping, and functional experiments facilitate the identification of candidate adaptive alleles. Functional investigation of candidate adaptive variation using novel techniques in molecular biology is slowly beginning to unravel how selection signals translate to changes in biology that underlie the phenotypic spectrum of our species. In addition to informing evolutionary hypotheses of adaptation, the discovery and functional annotation of adaptive alleles also may be of clinical significance. While selection mapping efforts in non-European populations are growing, there remains a stark under-representation of diverse human populations in current public genomic databases, of both clinical and non-clinical cohorts. This lack of inclusion limits the study of human biological variation. Identifying and functionally validating candidate adaptive alleles in more global populations is necessary for understanding basic human biology and human disease.


Titanium superoxide--a stable recyclable heterogeneous catalyst for oxidative esterification of aldehydes with alkylarenes or alcohols using TBHP as an oxidant.
Titanium superoxide efficiently catalysed the oxidative esterification of aldehydes with alkylarenes or alcohols, under truly heterogeneous conditions, to afford the corresponding benzyl and alkyl esters in excellent yields. Mechanistic studies have established that this "one pot" direct oxidative esterification process proceeds through a radical pathway, proven by a FTIR spectral study of a titanium superoxide-aldehyde complex as well as spin trapping experiments with TEMPO. The intramolecular version of this protocol has been successfully demonstrated in the concise synthesis of 3-butylphthalide, an anti-convulsant drug.


p53 and RB expression predict progression in T1 bladder cancer.
The optimal clinical management of minimally invasive (stage T1) bladder cancer is controversial. T1 bladder cancers share characteristics of both noninvasive (Ta) papillary cancer and high stage, muscle-invasive bladder cancers. Patients with T1 bladder cancer have a higher risk of cancer progression and death than do patients with Ta bladder cancer. However, this risk is much lower than that of patients with high-stage bladder cancers. Methods of identifying T1 bladder cancer patients at greatest risk for progression may significantly improve clinical management. We retrospectively evaluated two tumor suppressor genes, p53 and RB, as potential prognostic markers for progression in a cohort of 45 patients with pT1 bladder cancer. Median follow-up for these individuals was greater than 3.5 years. Of this group, 58% had altered p53 expression based on positive p53 immunostaining. Three patterns for RB nuclear protein staining were observed: absent, heterogeneous (normal), and strongly homogeneous. Progression-free survival was similar for patients with loss of RB protein expression and those with apparent overexpression of RB protein. Therefore, both staining patterns were considered abnormal. Patients with normal expression of both proteins (i.e., p53 negative and RB heterogeneously positive) had an excellent outcome, with no patient showing disease progression, whereas patients with abnormal expression of either or both proteins had a significant increase in progression (P = 0.04 and P = 0.005, respectively). These data support the stratification of T1 bladder cancer patients based on p53 and RB nuclear protein status and suggest that patients with normal protein expression for both genes can be managed conservatively, whereas patients with alterations in one and particularly both genes require more aggressive treatment.


The molecular machinery of autophagy: unanswered questions.
Autophagy is a process in which cytosol and organelles are sequestered within double-membrane vesicles that deliver the contents to the lysosome/vacuole for degradation and recycling of the resulting macromolecules. It plays an important role in the cellular response to stress, is involved in various developmental pathways and functions in tumor suppression, resistance to pathogens and extension of lifespan. Conversely, autophagy may be associated with certain myopathies and neurodegenerative conditions. Substantial progress has been made in identifying the proteins required for autophagy and in understanding its molecular basis; however, many questions remain. For example, Tor is one of the key regulatory proteins at the induction step that controls the function of a complex including Atg1 kinase, but the target of Atg1 is not known. Although autophagy is generally considered to be nonspecific, there are specific types of autophagy that utilize receptor and adaptor proteins such as Atg11; however, the means by which Atg11 connects the cargo with the sequestering vesicle, the autophagosome, is not understood. Formation of the autophagosome is a complex process and neither the mechanism of vesicle formation nor the donor membrane origin is known. The final breakdown of the sequestered cargo relies on well-characterized lysosomal/vacuolar proteases; the roles of lipases, by contrast, have not been elucidated, and we do not know how the integrity of the lysosome/vacuole membrane is maintained during degradation.


Abnormal coagulation profile in brain tumor patients during surgery.
Neurosurgical patients are at high risk for the development of thrombosis and thromboembolism. We compared the perioperative clotting factor and coagulation parameters of 20 patients undergoing elective craniotomy for brain tumors to those of 20 patients undergoing elective abdominal surgery. We also measured the levels of plasma arginine vasopressin to determine if changes in this hormone might be associated with changes in clotting factors, activated partial thromboplastin times, or bleeding times. The results demonstrated a significant reduction in partial thromboplastin times and bleeding times in the neurosurgery group, which began at the initiation of surgery and lasted to the end of the study (12 h postoperatively). Elevations in factor assays and plasma arginine vasopressin occurred in both groups during surgery, but there were no differences between the neurosurgical and abdominal surgical patients, except with Factor IX levels, which were elevated only in the neurosurgical patients. Serum osmolality and hemoglobin levels were significantly higher in the neurosurgical cohort. These results suggest that there are hemostatic differences between neurosurgical patients with brain tumors and abdominal surgery patients that cannot be explained solely by elevations in plasma arginine vasopressin or the clotting factors measured; these differences may be the consequence of perioperative variables such as dehydration and hyperosmolality.


Left atrial volume index as a predictor of ventricle repolarization abnormalities in adult dialyzed patients.
This study was performed to investigate the relationship between left atrium (LA) volume index (LAVI) and left ventricle electrical activity presumably repolarization in end-stage renal disease patients. Study group was consisted of 120 dialyzed patients divided into two subgroups: 57 (age 50.7 ± 7.1) were on continuous ambulatory peritoneal dialysis (CAPD) and 73 (age 51.6 ± 7.6) were hemodialyzed (HD). All patients were undergoing three-dimensional vectorcardiographic (VCG) monitoring to assess parameters concerning T vector: QRS-T angle, Tel, and Taz. Standard echocardiography was performed to assess: LAmax, LAshort, LAlong. LAVI was calculated due to formula: LAVI = (π/6X [LAmax × LAshort × LAlong])/m2. LAVI in HD as well as in CAPD patients was significantly higher compared with controls (respectively: 36.29 ± 10.92; 36.41 ± 11.06; 20.64 ± 6.77 mL/m2). The calculated cutoff value of LAVI was 36.32 mL/m2. In HD patients, the strong correlations between LAVI and QRS-T angle and Tel were determined (respectively: r = 0.407, P < 0.001 and r = 0.359, P = 0.006). Similarly in CAPD group were significant associations between LAVI and QRS-T angle and Tel (respectively: r = 0.423, P < 0.001 and r = 0.374, P = 0.004). The QRS-T angle, Tel and Taz are independently and markedly associated with LAVI in both HD and CAPD patients. LAVI and VCG indices are higher in both HD and CAPD patients. Correlation between QRS-T angle and LAVI may reflect unfavorable influence on the electrical activity of the heart in dialyzed patients with left ventricle diastolic dysfunction. LAVI cutoff value is useful biomarker for stratification of ventricle repolarization disturbances in those patients.


Survey of extreme solvent tolerance in gram-positive cocci: membrane fatty acid changes in Staphylococcus haemolyticus grown in toluene.
We exploited the unique ecological niche of oil fly larval guts to isolate a strain of Staphylococcus haemolyticus which may be the most solvent-tolerant gram-positive bacterium yet described. This organism is able to tolerate 100% toluene, benzene, and p-xylene on plate overlays and saturating levels of these solvents in monophasic liquid cultures. A comparison of membrane fatty acids by gas chromatography after growth in liquid media with and without toluene showed that in cells continuously exposed to solvent the proportion of anteiso fatty acids increased from 25.8 to 33.7% while the proportion of 20:0 straight-chain fatty acids decreased from 19.3 to 10.1%. No changes in the membrane phospholipid composition were noted. Thus, S. haemolyticus alters its membrane fluidity via fatty acid composition to become more fluid when it is exposed to solvent. This response is opposite that commonly found in gram-negative bacteria, which change their fatty acids so that the cytoplasmic membrane is less fluid. Extreme solvent tolerance in S. haemolyticus is not accompanied by abnormal resistance to anionic or cationic detergents. Finally, six strains of Staphylococcus aureus and five strains of Staphylococcus epidermidis, which were not obtained by solvent selection, also exhibited exceptional solvent tolerance.


Management of radiation-induced ulcers by singlestage reconstructive surgery: a prospective study.
Radiation-induced ulcers are a late-stage skin reaction after radiation therapy for cancer treatment. The present study examined the possibility of using a single-stage reconstructive procedure to manage radiation-related wounds. This prospective study recruited 30 participants who underwent radiation treatment for cancer or hemangioma. The patients ranged in age from 15 to 80 years. They were admitted to the Plastic, Reconstructive, and Regenerative Centre of Viet Nam National Burn Hospital from October 2013 to September 2017. For each patient, the surgeons discussed which reconstructive method would yield the best outcome. Patients' demographic data and information on the radiation-induced ulcer, the reconstructive method used, complications, and length of hospital stay were recorded. The mean age of all participants was 50 ± 36.3 years, and female patients were predominant (83.3%). Eighteen perforator flaps, five random-pattern flaps, three free flaps, three tissue expander flaps, and one full-thickness skin graft were employed, with no instances of recurrence or complications, except for total flap loss in two cases. The median length of stay was 43 days. These data suggest that immediate reconstruction may be a valuable option for managing radiation-induced ulcers.


GABAergic neurons from mouse embryonic stem cells possess functional properties of striatal neurons in vitro, and develop into striatal neurons in vivo in a mouse model of Huntington's disease.
Huntington's disease (HD) is a neurodegenerative disease where GABAergic medium spiny neurons (MSNs) in the striatum degenerate. Embryonic stem cell-derived neural transplantation may provide an appropriate therapy for HD. Here we aimed to develop a suitable protocol to obtain a high percentage of functional GABAergic neurons from mouse embryonic stem cells (mESCs), and then tested their differentiation potential in vivo. The monolayer method was compared with the embryoid body and five stage method for its efficiency in generating GABAergic neurons from mESCs. All three methods yielded a similar percentage of GABAergic neurons from mESCs. Monolayer method-derived GABAergic neurons expressed the MSN marker dopamine- and cyclic AMP-regulated phosphoprotein (DARPP32). The pluripotent stem cell population could be eliminated in vitro by treating cells with puromycin and retinoic acid. Using patch-clamp recordings, the functional properties of GABAergic neurons derived from mESCs were compared to GABAergic neurons derived from primary lateral ganglionic eminence. Both types of neurons showed active membrane properties (voltage-gated Na(+) and K(+) currents, Na(+)-dependent action potentials, and spontaneous postsynaptic currents) and possessed functional glutamatergic receptors and transporters. mESC-derived neural progenitors were transplanted into a mouse model of HD. Grafted cells differentiated to mature neurons expressing glutamate decarboxylase, dopamine type 1 receptors, and DARPP32. Also, neural precursors and dividing populations were found in the grafts. In summary, mESCs are able to differentiate efficiently into functional GABAergic neurons using defined in vitro conditions, and these survive and differentiate following grafting to a mouse model of HD.


Oral Function for Diagnosing Oral Hypofunction in Healthy Young Adults: A Comparison with the Literature.
This study investigated decline in oral function in healthy young adults and compared it with that observed in an earlier studies employing older adults. The participants comprised 130 young healthy adults (mean age 24.1±2.9 yr), all with complete dentition. All participants underwent the oral hypofunction test established by the Japanese Society of Gerodontology, which evaluates oral hygiene, oral dryness, occlusal force, tongue-lip motor function (oral diadochokinetic rate; ODK), tongue pressure, and masticatory and swallowing function. The average value for and rate of hypofunction of each parameter were calculated. In healthy young adults, the scores were 28.9±17.1% for oral hygiene; 28.8±2.2 for oral dryness; 959.9±499.8 N for occlusal force; 7.0±0.8 times/sec for ODK /pa/, 7.6±0.8 times/sec for /ta/, and 6.9±0.9 times/sec for /ka/; 41.8±8.4 kPa for tongue pressure; 249.8±94.1 mg/dl for masticatory function; and 0.2±0.7 for swallowing function. No sign or symptom of change in oral function was observed at a high rate in young adults. Occlusal force, tongue-lip motor function, and tongue pressure showed a large difference in the rate of hypofunction between younger and older adults, however.


Comparison of Cardiorespiratory Fitness between Patients with Mitral Valve Prolapse and Healthy Peers: Findings from Serial Cardiopulmonary Exercise Testing.
Individuals with mitral valve prolapse (MVP) have exercise intolerance even without mitral valve regurgitation. Mitral valve degeneration may progress with aging. We aimed to evaluate the influence of MVP on the cardiopulmonary function (CPF) of individuals with MVP through serial follow-ups from early to late adolescence. Thirty patients with MVP receiving at least two cardiopulmonary exercise tests (CPETs) using a treadmill (MVP group) were retrospectively analyzed. Age-, sex-, and body mass index-matched healthy peers, who also had serial CPETs, were recruited as the control group. The average time from the first CPET to the last CPET was 4.28 and 4.06 years in the MVP and control groups, respectively. At the first CPET, the MVP group had a significantly lower peak rate pressure product (PRPP) than the control group (p = 0.022). At the final CEPT, the MVP group had lower peak metabolic equivalent (MET, p = 0.032) and PRPP (p = 0.031). Moreover, the MVP group had lower peak MET and PRPP as they aged, whereas healthy peers had higher peak MET (p = 0.034) and PRPP (p = 0.047) as they aged. Individuals with MVP had poorer CPF than healthy individuals as they develop from early to late adolescence. It is important for individuals with MVP to receive regular CPET follow-ups.


Modeling isovolumetric phases in cardiac flows by an Augmented Resistive Immersed Implicit Surface method.
A major challenge in the computational fluid dynamics modeling of the heart function is the simulation of isovolumetric phases when the hemodynamics problem is driven by a prescribed boundary displacement. During such phases, both atrioventricular and semilunar valves are closed: consequently, the ventricular pressure may not be uniquely defined, and spurious oscillations may arise in numerical simulations. These oscillations can strongly affect valve dynamics models driven by the blood flow, making unlikely to recovering physiological dynamics. Hence, prescribed opening and closing times are usually employed, or the isovolumetric phases are neglected altogether. In this article, we propose a suitable modification of the Resistive Immersed Implicit Surface (RIIS) method (Fedele et al., Biomech Model Mechanobiol 2017, 16, 1779-1803) by introducing a reaction term to correctly capture the pressure transients during isovolumetric phases. The method, that we call Augmented RIIS (ARIIS) method, extends the previously proposed ARIS method (This et al., Int J Numer Methods Biomed Eng 2020, 36, e3223) to the case of a mesh which is not body-fitted to the valves. We test the proposed method on two different benchmark problems, including a new simplified problem that retains all the characteristics of a heart cycle. We apply the ARIIS method to a fluid dynamics simulation of a realistic left heart geometry, and we show that ARIIS allows to correctly simulate isovolumetric phases, differently from standard RIIS method. Finally, we demonstrate that by the new method the cardiac valves can open and close without prescribing any opening/closing times.


[The allelic polymorhism of IL-1alpha and IL-beta genes in patients with chronic inflammatory periodontal diseases].
The researchers studied the polymorphism of IL-1alpha and Il-beta genes in patients of different ages with severe chronic generalized periodontitis and people with healthy periodontium. They used molecular and genetic techniques such as polymerase chain reaction and reverse hybridization with Geno Type PRT reagents (Germany). The study demonstrated a correlation between high frequency of genetic polymorphism in IL-1A -899 and IL-1B +3953 loci and the development of severe periodontitis in patients less than 35 years of age, and a possibility of using this parameter in complex assessment of patients with periodontal diseases. The research suggests that Geno TypeR PRT test system should be recommended for evaluation of patients with a high risk of aggressive periodontal diseases, as well as patients with therapy-resistant periodontitis.


The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Aβ oligomers through Tau phosphorylation.
Amyloid-β 1-42 (Aβ42) oligomers are synaptotoxic for excitatory cortical and hippocampal neurons and might play a role in early stages of Alzheimer's disease (AD) progression. Recent results suggested that Aβ42 oligomers trigger activation of AMP-activated kinase (AMPK), and its activation is increased in the brain of patients with AD. We show that increased intracellular calcium [Ca²⁺](i) induced by NMDA receptor activation or membrane depolarization activates AMPK in a CAMKK2-dependent manner. CAMKK2 or AMPK overactivation is sufficient to induce dendritic spine loss. Conversely, inhibiting their activity protects hippocampal neurons against synaptotoxic effects of Aβ42 oligomers in vitro and against the loss of dendritic spines observed in the human APP(SWE,IND)-expressing transgenic mouse model in vivo. AMPK phosphorylates Tau on KxGS motif S262, and expression of Tau S262A inhibits the synaptotoxic effects of Aβ42 oligomers. Our results identify a CAMKK2-AMPK-Tau pathway as a critical mediator of the synaptotoxic effects of Aβ42 oligomers.


Familial arteriovenous malformations of the brain--two case reports.
Familial arteriovenous malformation (AVM) of the brain is an uncommon entity. A 24-year-old female presented with sudden onset of left hemiparesis due to an AVM with a hematoma in the right frontal lobe, which was surgically removed. Her 23-year-old younger sister presented with motor aphasia and right hemiparesis due to an AVM with a hematoma in the left frontoparietal lobes, which was surgically removed. Thirty-two patients in 15 families have been described in total. The mean age of these patients was 28 years, with 15 males and 17 females. Multiple AVMs occurred in four patients (12.5%), more frequently than in non-familial cases.


Role of tumor necrosis factor-alpha in acute pancreatitis: from biological basis to clinical evidence.
Tumor necrosis factor (TNF)-alpha is a pleiotropic cytokine that exerts host-damaging effects in different autoimmune and inflammatory diseases. It is a key regulator of other proinflammatory cytokines and of leukocyte adhesion molecules, and it is a priming activator of immune cells. In recent years, several research lines-mostly derived from animal models and in vitro studies-suggested that TNF-alpha plays a pivotal role in the pathogenesis of acute pancreatitis. In particular, it contributes to the systemic progression of the inflammatory response and to the end-organ dysfunction often observed in severe disease. Current clinical applications of TNF-alpha in acute pancreatitis include the assessment of blood concentrations to predict disease severity and to identify individuals prone to develop complications such as multiple organ failure and septic shock. However, TNF-alpha is rapidly cleared from the bloodstream, and sensitivity and overall accuracy of its measurement seem strictly time dependent, thereby being of potential prognostic value only in the first days after the onset of the disease. In parallel, TNF-alpha has been evaluated as a novel pharmacologic target for treating pancreatitis. Although promising results have been observed in the laboratory, transition to clinical practice seems problematic, in particular, in the light of divergent results obtained in sepsis trials. Therefore, in future clinical trials pertaining to TNF-alpha neutralization in acute pancreatitis, timing of intervention should be related to changes in TNF-alpha serum levels, and inclusion and exclusion criteria should be accurately selected to better define the population most likely to benefit.


Risk factor investigation for cardiovascular health through WHO STEPS approach in Ardabil, Iran.
Reliable evidence is the keystone for any noncommunicable disease (NCD) prevention plan to be initiated. In this study we carried out a risk factor investigation based on the WHO Stepwise approach to Surveillance (STEPS). The study was conducted on 1000 adults between 15 and 64 years of age living in Ardabil province, north-west Iran during 2006, based on the WHO STEPS approach to surveillance of risk factors for NCD. At this stage only the first and second steps were carried out. Data were collected through standard questionnaires and methods analyzed using STATA version 8 statistical software package. 29.0% of men and 2.6% of women were current daily tobacco smokers. The mean number of manufactured cigarettes smoked per day was 18.9 among current daily smokers. Smoking was most prevalent among men of low-income families and those of lower education. The mean body mass index (BMI) was 26.6 kg/m(2), and was significantly correlated with systolic blood pressure. 58.9% were overweight or obese; 18.0% had raised blood pressure and 3.7% had isolated systolic hypertension. The mean number of servings of fruit consumed per day was 1.1; 33.1% had low levels of activity. Combined risk factor analysis showed that 4.1% of participants were in the low-risk group (up to 5.1% among men and 3.2% among women). Those in the high-risk group comprised 25.6% in the 25- to 44-year age group and 49.7% in the 45- to 64-year age group. Mean BMI increased by age in both sexes at least at the first three decades of adult life. Based on observed status of risk for cardiovascular health, burden of cardiovascular diseases is expected to increase if an effective prevention strategy is not undertaken.


Lumbar computerized adaptive test and Modified Oswestry Low Back Pain Disability Questionnaire: relative validity and important change.
Retrospective analysis of longitudinal, observational cohort data. To compare discriminating ability and minimal clinically important improvement (MCII) calculated using functional status (FS) measures estimated from the lumbar computerized adaptive test (LCAT) and Modified Oswestry Low Back Pain Disability Questionnaire (ODQ). The LCAT and ODQ are commonly used to estimate FS in patients seeking outpatient therapy but have not been compared directly. Data from 8198 adult patients who completed the LCAT and ODQ at intake were analyzed, 3379 (41%) of whom completed both surveys at discharge. Global ratings of change data were available for 980 patients. Discriminating ability of FS estimates from the LCAT and ODQ was estimated using relative validity, calculated by dividing F values from LCAT and ODQ analyses of covariance for important risk-adjustment variables. MCII was estimated using receiver-operating-characteristic analyses by quartiles of intake FS values, and areas under the curves were compared. Relative validity ratios favored the LCAT for age (3.7; 95% confidence interval [CI]: 2.0, 8.9), acuity (1.3; 95% CI: 1.1, 1.6), comorbidities (1.8; 95% CI: 1.3, 2.6), and surgical history (1.8; 95% CI: 1.2, 2.9). MCII cut scores per quartile favored the LCAT. Receiver-operating-characteristic areas under the curves were not different. FS measures estimated by both questionnaires had similar psychometric characteristics. The LCAT FS estimates tended to be more discriminating than ODQ FS estimates. MCII cut scores by quartile of intake FS favored the LCAT. Given the need to be efficient and precise in estimating measures of FS, particularly in older patients, results favor the LCAT in busy, automated outpatient therapy clinics, which are increasingly serving an aging population.


Integrin Adhesions Suppress Syncytium Formation in the Drosophila Larval Epidermis.
Integrins are critical for barrier epithelial architecture. Integrin loss in vertebrate skin leads to blistering and wound healing defects. However, how integrins and associated proteins maintain the regular morphology of epithelia is not well understood. We found that targeted knockdown of the integrin focal adhesion (FA) complex components β-integrin, PINCH, and integrin-linked kinase (ILK) caused formation of multinucleate epidermal cells within the Drosophila larval epidermis. This phenotype was specific to the integrin FA complex and not due to secondary effects on polarity or junctional structures. The multinucleate cells resembled the syncytia caused by physical wounding. Live imaging of wound-induced syncytium formation in the pupal epidermis suggested direct membrane breakdown leading to cell-cell fusion and consequent mixing of cytoplasmic contents. Activation of Jun N-terminal kinase (JNK) signaling, which occurs upon wounding, also correlated with syncytium formation induced by PINCH knockdown. Further, ectopic JNK activation directly caused epidermal syncytium formation. No mode of syncytium formation, including that induced by wounding, genetic loss of FA proteins, or local JNK hyperactivation, involved misregulation of mitosis or apoptosis. Finally, the mechanism of epidermal syncytium formation following JNK hyperactivation and wounding appeared to be direct disassembly of FA complexes. In conclusion, the loss-of-function phenotype of integrin FA components in the larval epidermis resembles a wound. Integrin FA loss in mouse and human skin also causes a wound-like appearance. Our results reveal a novel and unexpected role for proper integrin-based adhesion in suppressing larval epidermal cell-cell fusion--a role that may be conserved in other epithelia.


Tempo of magma degassing and the genesis of porphyry copper deposits.
Porphyry deposits are copper-rich orebodies formed by precipitation of metal sulphides from hydrothermal fluids released from magmatic intrusions that cooled at depth within the Earth's crust. Finding new porphyry deposits is essential because they are our largest source of copper and they also contain other strategic metals including gold and molybdenum. However, the discovery of giant porphyry deposits is hindered by a lack of understanding of the factors governing their size. Here, we use thermal modelling and statistical simulations to quantify the tempo and the chemistry of fluids released from cooling magmatic systems. We confirm that typical arc magmas produce fluids similar in composition to those that form porphyry deposits and conclude that the volume and duration of magmatic activity exert a first order control on the endowment (total mass of deposited copper) of economic porphyry copper deposits. Therefore, initial magma enrichment in copper and sulphur, although adding to the metallogenic potential, is not necessary to form a giant deposit. Our results link the respective durations of magmatic and hydrothermal activity from well-known large to supergiant deposits to their metal endowment. This novel approach can readily be implemented as an additional exploration tool that can help assess the economic potential of magmatic-hydrothermal systems.


The somatization in primary care study: a tale of three diagnoses.
Somatization is a common phenomenon that has been defined in many ways. The two most widely used diagnoses, Somatization Disorder (SD) and Abridged Somatization Disorder (ASD), are based on lifetime unexplained symptoms. However, reports indicate instability in lifetime symptom recall among somatizing patients. Multisomatoform disorder (MSD) is a new diagnosis based on current unexplained symptoms. To understand how knowledge about SD and ASD translates to MSD, we examined the diagnostic concordance, impairment and health care utilization of these groups in a sample from the Somatization in Primary Care Study. The diagnostic concordance was high between MSD and SD, but lower between MSD and ASD. All three groups reported considerable physical impairment (measured using the PCS subscale of the SF-36). The mental health (MCS) scores for the three groups were only slightly lower than those of the general population. Over the course of one year, physical functioning fell significantly for all three groups. Mental functioning did not change significantly for any of the three groups over this period. Utilization patterns were very similar for the three groups. The high prevalence, serious impairment, and worsening physical functioning over the course of one year suggest the importance of developing interventions in primary care to alleviate the impaired physical functioning and reduce utilization in somatizing patients. MSD should be a useful diagnosis for targeting these interventions because it identifies a sizable cohort of somatizing patients reporting impairment of comparable severity to full SD, using a more efficient diagnostic algorithm based on current symptoms.


PDC-Net+: Enhanced Probabilistic Dense Correspondence Network.
Establishing robust and accurate correspondences between a pair of images is a long-standing computer vision problem with numerous applications. While classically dominated by sparse methods, emerging dense approaches offer a compelling alternative paradigm that avoids the keypoint detection step. However, dense flow estimation is often inaccurate in the case of large displacements, occlusions, or homogeneous regions. In order to apply dense methods to real-world applications, such as pose estimation, image manipulation, or 3D reconstruction, it is therefore crucial to estimate the confidence of the predicted matches. We propose the Enhanced Probabilistic Dense Correspondence Network, PDC-Net+, capable of estimating accurate dense correspondences along with a reliable confidence map. We develop a flexible probabilistic approach that jointly learns the flow prediction and its uncertainty. In particular, we parametrize the predictive distribution as a constrained mixture model, ensuring better modelling of both accurate flow predictions and outliers. Moreover, we develop an architecture and an enhanced training strategy tailored for robust and generalizable uncertainty prediction in the context of self-supervised training. Our approach obtains state-of-the-art results on multiple challenging geometric matching and optical flow datasets. We further validate the usefulness of our probabilistic confidence estimation for the tasks of pose estimation, 3D reconstruction, image-based localization, and image retrieval.


Stability of sodium and potassium in lyophilized quality control serum. A study of data from the Quality Assurance Service Program of the College of American Pathologists.
The long-term prereconstitution stability of sodium and potassium in large pools of lyophilized quality control serum used in Regional Quality Control Programs, conducted between 1977 and 1980 is reviewed. In approximately one third of 27 pools studied, minimal but significant increases in sodium concentration were detected, these increases averaged less than 0.50 per year and confirmed our previously reported results from pools analyzed between 1973 and 1976. Results relating to potassium stability have been inconsistent. The previously reported tendency for potassium to increase in some pools was again suggested by data obtained from laboratories using automated flame-emission photometry procedures. This was not confirmed, however, by the data reflecting manual/semi-automated flame-emission photometry procedures or automated electrode methods. It is postulated, that the source of sodium causing the increases in concentration is the glass containers in which control materials are stored between the time of manufacture and reconstitution. Regression analysis against time of monthly interlaboratory means, from participants in Regional Quality Control Programs, is a useful tool for evaluating postmanufacture stability of analytes in pools used for daily internal quality control procedures.


Intergenerational neuroimaging study: mother-infant functional connectivity similarity and the role of infant and maternal factors.
Mother and infant neural and behavioral synchrony is important for infant development during the first years of life. Recent studies also suggest that neural risk markers associated with parental psychopathology may be transmitted across generations before symptoms emerge in offspring. There is limited understanding of how early similarity in brain functioning between 2 generations emerges. In the current study, using functional magnetic resonance imaging, we examined the functional connectivity (FC) similarity between mothers and newborns during the first 3 months after the infant's birth. We found that FC similarity between mothers and infants increased as infant age increased. Furthermore, we examined whether maternal factors such as maternal socioeconomic status and prenatal maternal depressive symptoms may influence individual differences in FC similarity. For the whole-brain level, lower maternal education levels were associated with greater FC similarity. In previous literature, lower maternal education levels were associated with suboptimal cognitive and socioemotional development. Greater FC similarity may reflect that the infants develop their FC similarity prematurely, which may suboptimally influence their developmental outcomes in later ages.


Two-dimensional transition metal honeycomb realized: Hf on Ir(111).
Two-dimensional (2D) honeycomb systems made of elements with d electrons are rare. Here, we report the fabrication of a transition metal (TM) 2D layer, namely, hafnium crystalline layers on Ir(111). Experimental characterization reveals that the Hf layer has its own honeycomb lattice, morphologically identical to graphene. First-principles calculations provide evidence for directional bonding between adjacent Hf atoms, analogous to carbon atoms in graphene. Calculations further suggest that the freestanding Hf honeycomb could be ferromagnetic with magnetic moment μ/Hf = 1.46 μ(B). The realization and investigation of TM honeycomb layers extend the scope of 2D structures and could bring about novel properties for technological applications.


Fecal transplantation: digestive and extradigestive clinical applications.
Fecal transplantation or fecal material transplantation (FMT) became a hot topic in gastroenterology in recent years. Therefore it is important to disseminate the up-to-date information on FMT. The aim of the paper is to review the knowledge on FMT and its clinical applications. An extensive review of the literature was carried out. Titles from Pubmed were searched and analyzed. A narrative review has been written with emphasis on indications of FMT in different conditions. The guidelines recommend FMT in relapsing infection with Clostridium difficile. Several attempts to use FMT in other conditions have been analyzed. Attempts were recorded in other bowel disorders like IBD, IBS, chronic constipation and even colorectal cancer. The attempt to change the microbiota by FMT in diabetes and obesity represent challenges for the future. Fecal transplantation represents an important therapeutic method, intensively investigated these years. Beside the indication for persistent and recurrent Clostridium difficile infection, several attempts were undertaken in other intestinal diseases and in metabolic conditions. The efficiency of these applications has to be demonstrated.


Immunocytochemistry on scrape cytology in breast cancer: will it unearth the weaker positives?
To standardize the technique of immunocytochemical (ICC) assessment of estrogen (ER) and progesterone receptor (PR) status in breast cancer by scrape cytology and to compare the results with immunohistochemistry on paraffin blocks. ICC assessment for ER and PR was done on scrape smears from tissue samples in 200 cases of primary breast cancer. The results were compared to those obtained from immunohistochemical (IHC) evaluation of formalin-fixed paraffin same tissue samples. ER/PR positivity rates as well as staining scores were compared between the scrape smears and tissue sections. The concordance between cytology and histology was 84% for ER and 90% for PR. Both the positivity rates and the staining intensity scores were higher for cytochemistry than for histochemistry. The ICC method on scrape smears is a simple test with rapid turnaround time. The sample required is small, and antigen loss due to fixation and processing is minimal. This new method gives a higher yield of hormone receptor positivity and, when used in conjunction with the IHC method, may improve the pickup rate of ER-positive cases, thereby playing an important role in risk stratification and therapeutic decision making in patients with breast cancer.


Causal Vaccine Effects on Binary Postinfection Outcomes.
The effects of vaccine on postinfection outcomes, such as disease, death, and secondary transmission to others, are important scientific and public health aspects of prophylactic vaccination. As a result, evaluation of many vaccine effects condition on being infected. Conditioning on an event that occurs posttreatment (in our case, infection subsequent to assignment to vaccine or control) can result in selection bias. Moreover, because the set of individuals who would become infected if vaccinated is likely not identical to the set of those who would become infected if given control, comparisons that condition on infection do not have a causal interpretation. In this article we consider identifiability and estimation of causal vaccine effects on binary postinfection outcomes. Using the principal stratification framework, we define a postinfection causal vaccine efficacy estimand in individuals who would be infected regardless of treatment assignment. The estimand is shown to be not identifiable under the standard assumptions of the stable unit treatment value, monotonicity, and independence of treatment assignment. Thus selection models are proposed that identify the causal estimand. Closed-form maximum likelihood estimators (MLEs) are then derived under these models, including those assuming maximum possible levels of positive and negative selection bias. These results show the relations between the MLE of the causal estimand and two commonly used estimators for vaccine effects on postinfection outcomes. For example, the usual intent-to-treat estimator is shown to be an upper bound on the postinfection causal vaccine effect provided that the magnitude of protection against infection is not too large. The methods are used to evaluate postinfection vaccine effects in a clinical trial of a rotavirus vaccine candidate and in a field study of a pertussis vaccine. Our results show that pertussis vaccination has a significant causal effect in reducing disease severity.


CART Peptides and Drugs of Abuse: A Review of Recent Progress.
Earlier studies suggesting an involvement of cocaine and amphetamine regulated transcript peptide (CARTp) in the actions of drugs of abuse are confirmed in the most recent publications. This seems especially true for the psychostimulants where CARTp in the nucleus accumbens inhibits or regulates the actions of these drugs; the regulation is lost after repeated drug use which may be an important mechanism in addiction. The other drugs, including nicotine, alcohol, opiates, and perhaps caffeine can affect CARTp or CART mRNA levels. While the exact mechanism is not always clear, the hope is that these findings may provide some insight for the development of medications. While binding studies indicate the existence of specific G-protein coupled receptors (GPCR) receptors for CARTp, major work to be done is the cloning of these receptors.


A Quiescent, Regeneration-Responsive Tissue Engineered Mesenchymal Stem Cell Bone Marrow Niche Model via Magnetic Levitation.
The bone marrow niche represents a specialized environment that regulates mesenchymal stem cell quiescence and self-renewal, yet fosters stem cell migration and differentiation upon demand. An in vitro model that embodies these features would open up the ability to perform detailed study of stem cell behavior. In this paper we present a simple bone marrow-like niche model, which comprises of nanomagnetically levitated stem cells cultured as multicellular spheroids within a type I collagen gel. The stem cells maintained are nestin positive and remain quiescent until regenerative demand is placed upon them. In response to coculture wounding, they migrate and appropriately differentiate upon engraftment. This tissue engineered regeneration-responsive bone marrow-like niche model will allow for greater understanding of stem cell response to injury and also facilitate as a testing platform for drug candidates in a multiwell plate format.


Schistosomiasis causes remodeling of pulmonary vessels in the lung in a heterogeneous localized manner: Detailed study.
Schistosomiasis is a global parasitic disease with high impact on public health in tropical areas. Schistosomiasis is a well-described cause of pulmonary arterial hypertension (PAH). The exact pathogenesis is still unclear, though inflammatory mechanisms are suspected. Another unknown is whether the changes in the pulmonary vasculature are generalized or localized. We studied 13 mice infected with cercariae for 12 weeks compared with 10 control mice. In our model, we observed that the liver was a target during infection and was enlarged more than two-fold after infection. However, right heart hypertrophy as measured by RV/(LV + S) ratio was not observed at this time point. Moreover, we noticed that 72% of the sampled lobes (92% of the lungs) harvested from these animals costained evidence of granulomatous changes, secondary to egg deposition. We systemically mapped the distribution of granulomatous lesions in right lung lobes (n = 43) of infected mice. We observed that the distribution of the granulomatous lesions was heterogeneous. Remodeled pulmonary vessels were seen in 26% of the lobes (46% of the lungs) and were observed only in close proximity to the granuloma. No remodeling was observed in the absence of granulomas. These findings support the view that pulmonary vascular remodeling is caused by the local presence of granulomas in PAH associated with schistosomiasis. The heterogeneous nature of the remodeling partly explains why many patients with schistosomiasis do not develop pulmonary hypertension.