Effect of Almond Supplementation on Non-Esterified Fatty Acid Values and Exercise Performance.
Several studies have investigated the effects of fat intake before exercise on subsequent substrate oxidation and exercise performance. While some studies have reported that unsaturated fatty acid supplementation slightly increases fat oxidation, the changes have not been reflected in the maximum oxygen uptake or in other performance and physiological parameters. We selected almonds as a fatty acid (FA) source for acute supplementation and investigated their effect on non-esterified fatty acid (NEFA) values and exercise performance. Five physically active male subjects (age 32.9 ± 12.7 years, height 178.5 ± 3.3 cm, and weight 81.3 ± 9.7 kg) were randomly assigned to take an almond or placebo supplement 2 h before participating in two cycling resistance training sessions separated by an interval of 7-10 days. Their performance was evaluated with a maximal incremental test until exhaustion. Blood samples collected before, during, and after testing were biochemically analysed. The results indicated a NEFA value average increase of 0.09 mg·dL-1 (95% CI: 0.05-0.14; p < 0.001) after active supplement intake and enhanced performance (5389 ± 1795 W vs. placebo 4470 ± 2053 W, p = 0.043) after almond supplementation compared to the placebo. The almond supplementation did not cause gastrointestinal disturbances. Our study suggests that acute almond supplementation 2 h before exercise can improve performance in endurance exercise in trained subjects.


Amyloid β Ion Channels in a Membrane Comprising Brain Total Lipid Extracts.
Amyloid β (Aβ) oligomers are the predominant toxic species in the pathology of Alzheimer's disease. The prevailing mechanism for toxicity by Aβ oligomers includes ionic homeostasis destabilization in neuronal cells by forming ion channels. These channel structures have been previously studied in model lipid bilayers. In order to gain further insight into the interaction of Aβ oligomers with natural membrane compositions, we have examined the structures and conductivities of Aβ oligomers in a membrane composed of brain total lipid extract (BTLE). We utilized two complementary techniques: atomic force microscopy (AFM) and black lipid membrane (BLM) electrical recording. Our results indicate that Aβ1-42 forms ion channel structures in BTLE membranes, accompanied by a heterogeneous population of ionic current fluctuations. Notably, the observed current events generated by Aβ1-42 peptides in BTLE membranes possess different characteristics compared to current events generated by the presence of Aβ1-42 in model membranes comprising a 1:1 mixture of DOPS and POPE lipids. Oligomers of the truncated Aβ fragment Aβ17-42 (p3) exhibited similar ion conductivity behavior as Aβ1-42 in BTLE membranes. However, the observed macroscopic ion flux across the BTLE membranes induced by Aβ1-42 pores was larger than for p3 pores. Our analysis of structure and conductance of oligomeric Aβ pores in a natural lipid membrane closely mimics the in vivo cellular environment suggesting that Aβ pores could potentially accelerate the loss of ionic homeostasis and cellular abnormalities. Hence, these pore structures may serve as a target for drug development and therapeutic strategies for AD treatment.


Computing Bayes factors using thermodynamic integration.
In the Bayesian paradigm, a common method for comparing two models is to compute the Bayes factor, defined as the ratio of their respective marginal likelihoods. In recent phylogenetic works, the numerical evaluation of marginal likelihoods has often been performed using the harmonic mean estimation procedure. In the present article, we propose to employ another method, based on an analogy with statistical physics, called thermodynamic integration. We describe the method, propose an implementation, and show on two analytical examples that this numerical method yields reliable estimates. In contrast, the harmonic mean estimator leads to a strong overestimation of the marginal likelihood, which is all the more pronounced as the model is higher dimensional. As a result, the harmonic mean estimator systematically favors more parameter-rich models, an artefact that might explain some recent puzzling observations, based on harmonic mean estimates, suggesting that Bayes factors tend to overscore complex models. Finally, we apply our method to the comparison of several alternative models of amino-acid replacement. We confirm our previous observations, indicating that modeling pattern heterogeneity across sites tends to yield better models than standard empirical matrices.


Using LTI Dynamics to Identify the Influential Nodes in a Network.
Networks are used for modeling numerous technical, social or biological systems. In order to better understand the system dynamics, it is a matter of great interest to identify the most important nodes within the network. For a large set of problems, whether it is the optimal use of available resources, spreading information efficiently or even protection from malicious attacks, the most important node is the most influential spreader, the one that is capable of propagating information in the shortest time to a large portion of the network. Here we propose the Node Imposed Response (NiR), a measure which accurately evaluates node spreading power. It outperforms betweenness, degree, k-shell and h-index centrality in many cases and shows the similar accuracy to dynamics-sensitive centrality. We utilize the system-theoretic approach considering the network as a Linear Time-Invariant system. By observing the system response we can quantify the importance of each node. In addition, our study provides a robust tool set for various protective strategies.


iOCT-assisted macular hole surgery: outcomes and utility from the DISCOVER study.
This study aimed to characterise the clinical outcomes and utility of intraoperative optical coherence tomography (iOCT)-assisted macular hole (MH) repair. This was a post hoc analysis of eyes in the D etermination of feasibility of I ntraoperative S pectral domain microscope C ombined/integrated O CT V isualization during E n face R etinal and ophthalmic surgery (DISCOVER) study undergoing surgical MH repair with use of iOCT. Functional and surgical outcome data were collected through 12 months postoperatively. MH closure rate, postoperative visual acuity (VA), percentage of cases in which iOCT provided valuable feedback and altered surgical decision making were measured. Eighty-four eyes were included in this study. The mean preoperative VA measured 20/114. The mean postoperative VA improved to 20/68 (p<0.001) at month 1, 20/48 (p<0.001) at month 3 and 20/45 (p<0.001) at month 12 or later. In 43 cases (51%), surgeons reported that iOCT provided valuable information (eg, confirming release of vitreomacular traction and identification of occult residual membranes). In 10 cases (12%), iOCT data specifically altered surgical decision making. Postoperative day 1 transtamponade OCT confirmed tissue apposition and apparent hole closure in 74% of eyes (21/26). All five open holes on postoperative day 1 closed following positioning. Single-surgery MH closure was achieved in 97.6% of cases. One persistent MH was successfully closed with a subsequent surgical repair for a final overall closure rate of 98.8%. Due to chronicity and MH size, additional repair was not recommended for the single remaining persistent MH. This study suggests that iOCT may have important utility in MH surgery, including impacting surgical decision making. iOCT-assisted MH surgery resulted in significant improvement in VA and high single-surgery success rate.


Polymorphisms of the vitamin D receptor gene predict the onset of surgical menopause in Caucasian females.
We tested association of four single nucleotide polymorphisms (SNPs) of the vitamin D receptor gene (VDR) with age at surgical and natural menopause in a sample of Caucasians composed of 153 women with surgical and 260 with natural menopause. A significant association was observed between age at surgical menopause and two SNPs, rs1544410 (BsmI) and rs731236 (TaqI) (p < 0.05). For rs1544410, homozygotes of the minor allele, AA, had about two-fold higher risk of surgical menopause than homozygotes of the major allele, GG (95% confidence ratio (CI) 1.09-3.82). For rs731236, the CC subjects had a greater chance of surgical menopause than the TT subjects (odds ratio = 2.01, 95% CI 1.07-3.78). Since rs1544410 and rs731236 are in strong linkage disequilibrium, the haplotypes based on these two loci were also tested. The haplotype AC was highly significantly associated with age at surgical menopause (p = 0.008). Women with this haplotype had surgical menopause on average 2.8 years earlier than non-carriers. These results reveal the potential effect of the VDR gene on ovaries and uterus, and suggest that its SNPs can be used as predictors of genetic susceptibility for early surgical menopause and respective causal health problems.


State-space modelling reveals proximate causes of harbour seal population declines.
Declines in large vertebrate populations are widespread but difficult to detect from monitoring data and hard to understand due to a multiplicity of plausible biological explanations. In parts of Scotland, harbour seals (Phoca vitulina) have been in decline for 10 years. To evaluate the contributions of different proximate causes (survival, fecundity, observation artefacts) to this decline, we collated behavioural, demographic and population data from one intensively studied population in part of the Moray Firth (north-east Scotland). To these, we fit a state-space model comprising age-structured dynamics and a detailed account of observation errors. After accounting for culling (estimated by our model as 14% of total mortality), the main driver of the historical population decline was a decreasing trend in survival of young individuals combined with (previously unrecognised) low levels of pupping success. In more recent years, the model provides evidence for considerable increases in breeding success and consistently high levels of adult survival. However, breeding success remains the most volatile demographic component of the population. Forecasts from the model indicate a slow population recovery, providing cautious support for recent management measures. Such investigations of the proximate causes of population change (survival, fecundity and observation errors) provide valuable short-term support for the management of population declines, helping to focus future data collection on those ultimate causal mechanisms that are not excluded by the demographic evidence. The contribution of specific ultimate drivers (e.g. shooting mortality or competitors) can also be quantified by including them as covariates to survival or fecundity.


Dysregulation of In Vitro Decidualization of Human Endometrial Stromal Cells by Insulin via Transcriptional Inhibition of Forkhead Box Protein O1.
Insulin resistance and compensatory hyperinsulinemia are characteristic features of obesity and polycystic ovary syndrome, and both are associated with reduced fertility and implantation. There is little knowledge about the effect of insulin on the decidualization process and previous findings are contradictory. We investigated the effect of insulin on the regulation of forkhead box protein O1 (FOXO1), one of the most important transcription factors during decidualization. Endometrial stromal cells were isolated from six healthy, regularly menstruating women and decidualized in vitro. Gene expression levels of six putative FOXO1 target genes (including insulin-like growth factor binding protein-1 (IGFBP1) and prolactin (PRL)) were measured with Real-Time PCR following FOXO1 inhibition or insulin treatment. PI3K inhibition was used to identify the possible mechanism behind regulation. Subcellular localization of FOXO1 was analyzed with immunofluorescence. All the genes (IGFBP1, CTGF, INSR, DCN, LEFTY2), except prolactin, were evaluated as FOXO1 target genes in decidualizing stromal cells. Insulin caused a significant dose-dependent inhibition of the verified FOXO1 target genes. It was also demonstrated that insulin regulated FOXO1 target genes by transcriptional inactivation and nuclear export of FOXO1 via PI3K pathway. However, insulin did not inhibit the morphological transformation of endometrial stromal cells via transcriptional inactivation of FOXO1. This study provides new insights on the action of insulin on the endometrium via regulation of FOXO1. It is suggested that hyperinsulinemia results in dysregulation of a high number of FOXO1 controlled genes that may contribute to endometrial dysfunction and reproductive failure. Our findings may illuminate possible reasons for unexplained infertility.


Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease.
To characterize antibodies produced in humans in response to Abeta42 vaccination, we carried out immunohistochemical examinations of the brains of both transgenic mice and human patients with beta-amyloid pathology. We collected sera from patients with Alzheimer disease who received a primary injection of pre-aggregated Abeta42 followed by one booster injection in a placebo-controlled study. Antibodies in immune sera recognized beta-amyloid plaques, diffuse Abeta deposits and vascular beta-amyloid in brain blood vessels. The antibodies did not cross-react with native full-length beta-amyloid precursor protein or its physiological derivatives, including soluble Abeta42. These findings indicate that vaccination of AD patients with Abeta42 induces antibodies that have a high degree of selectivity for the pathogenic target structures. Whether vaccination to produce antibodies against beta-amyloid will halt the cognitive decline in AD will depend upon clinical assessments over time.


Passive component based multifunctional Jones matrix swept source optical coherence tomography for Doppler and polarization imaging.
We present a fiber based multifunctional Jones matrix swept source optical coherence tomography (SS-OCT) system for Doppler and polarization imaging. Jones matrix measurement without using active components such as electro-optic modulators is realized by incident polarization multiplexing based on independent delay of two orthogonal polarization states and polarization diversity detection. In addition to polarization sensitivity, this system measures Doppler flow without extra hardware for phase stabilized SS-OCT detection. An eighth-wave plate was measured to demonstrate the polarization detection accuracy. The optic nerve head of a retina was measured in vivo. Detailed vasculature and birefringent structures were investigated simultaneously.


Regulation of a dpp target gene in the Drosophila embryo.
In Drosophila, two TGF-beta growth factors, dpp and screw, function synergistically to subdivide the dorsal ectoderm into two embryonic tissues, the amnioserosa and dorsal epidermis. Previous studies have shown that peak dpp activity is required for the localized expression of zerknüllt (zen), which encodes a homeodomain transcription factor. We present evidence that zen directly activates the amnioserosa-specific expression of a downstream target gene, Race (Related to angiotensin converting enzyme). A 533 bp enhancer from the Race promoter region is shown to mediate selective expression in the amnioserosa, as well as the anterior and posterior midgut rudiments. This enhancer contains three zen protein binding sites, and mutations in these sites virtually abolish the expression of an otherwise normal Race-lacZ fusion gene in the amnioserosa, but not in the gut. Genetic epistasis experiments suggest that zen is not the sole activator of Race, although a hyperactivated form of zen (a zen-VP16 fusion protein) can partially complement reduced levels of dpp activity. These results suggest that dpp regulates multiple transcription factors, which function synergistically to specify the amnioserosa.


A Solvent-Mediated Coarse-Grained Model of DNA Derived with the Systematic Newton Inversion Method.
We present a new class of coarse-grained (CG) force fields (FFs) for B-DNA with explicit ions suited for large-scale mesoscale simulations at microsecond-micrometer scale using a wide spectrum of particle simulation methods from molecular dynamics to dissipative particle dynamics. The effective solvent-mediated pairwise interactions making up the FFs are obtained by inverting radial distribution functions and other particle-particle distributions obtained from all-atom simulations of numbers of octadecamer DNA fragments from the Ascona B-DNA library. The inverse Monte Carlo (IMC) method, later known as Newton inversion (NI) (Lyubartsev, A. P.; Laaksonen, A. Phys. Rev. E, 1995, 52, 3730-3737), was used together with the iterative Boltzmann inversion (IBI) scheme to compute the effective CG potentials. We show that this systematic structure-based approach is capable of providing converged potentials that accurately reproduce the structural features of the underlying atomistic system within a few percents of relative difference. We also show that a simple one-site-per-nucleotide model with 10 intramolecular pair interaction potentials is able to reproduce key features of DNA, for example, the persistence length and its dependence on the ionic concentration, experimentally determined around 50 nm at physiological salt concentration.


Structure and function predictions of the Msa protein in Staphylococcus aureus.
Staphylococcus aureus is a human pathogen that causes a wide variety of life-threatening infections using a large number of virulence factors. One of the major global regulators used by S. aureus is the staphylococcal accessory regulator (sarA). We have identified and characterized a new gene (modulator of sarA: msa) that modulates the expression of sarA. Genetic and functional analysis shows that msa has a global effect on gene expression in S. aureus. However, the mechanism of Msa function is still unknown. Function predictions of Msa are complicated by the fact that it does not have a homologous partner in any other organism. This work aims at predicting the structure and function of the Msa protein. Preliminary sequence analysis showed that Msa is a putative membrane protein. It would therefore be very difficult to purify and crystallize Msa in order to acquire structure information about this protein. We have used several computational tools to predict the physico-chemical properties, secondary structural features, topology, 3D tertiary structure, binding sites, motifs/patterns/domains and cellular location. We have built a consensus that is derived from analysis using different algorithms to predict several structural features. We confirm that Msa is a putative membrane protein with three transmembrane regions. We also predict that Msa has phosphorylation sites and binding sites suggesting functions in signal transduction. Based on our predictions we hypothesise that Msa is a novel signal transducer that might be involved in the interaction of the S. aureus with its environment.


Potential pediatric intensive care unit demand/capacity mismatch due to novel pH1N1 in Canada.
To investigate the possibility of pediatric intensive care unit shortfalls, using pandemic models for a range of attack rates and durations. The emergence of the swine origin pH1N1 virus has led to concerns about shortfalls in our ability to provide pediatric ventilation and critical care support. Modeling of pediatric intensive care demand based on pH1N1 predictions using simulation techniques. Simulation laboratory. None. None. Data collected during the first wave of the pH1N1 in children in Canada were applied to several second wave pandemic models to explore potential pediatric intensive care unit ventilatory demands for Canada and to investigate the impact of vaccination upon these demands. In almost all cases studied, even for relatively low attack rates of 15%, significant pediatric intensive care unit shortages would be expected to occur. Vaccination strategies targeting 50% of the population significantly reduced demand, but shortages may still be expected. Although shortfalls can occur in all provinces, Ontario and British Columbia may experience the greatest supply-demand difference, even at low attack rates. Reducing the attack rate among children, whether through vaccination or additional measures, such as social distancing, will be critical to ensure sufficient pediatric intensive care unit capacity for continued pediatric care.


Inverse agonist activity of beta-adrenergic antagonists.
Agonist-independent properties of the human beta 2-adrenergic receptor (beta 2AR) were studied using the baculovirus expression system in Sf9 cells. In the absence of agonist but in the presence of GTP, membranes from cells expressing the beta 2AR exhibited higher levels of cAMP production than did membranes from uninfected cells or from cells infected with wild-type baculovirus. The increase in cAMP production was proportional to the number of beta 2AR expressed, up to 40 pmol/mg of membrane protein, and it could be inhibited in a dose-dependent manner by beta AR antagonists. The increase and its reversal both were independent of the possible presence of contaminating catecholamines in the culture medium and thus appear to reflect spontaneous beta 2AR activity and direct antagonist-receptor interactions, respectively. The maximal level of inhibition varied among the beta AR ligands tested, to yield the following rank order of "inverse efficacy"; timolol > or = propranolol > alprenolol > or = pindolol > labetalol > dichloroisoproterenol. The same rank order was observed using membranes prepared from Chinese hamster fibroblasts expressing beta 2AR. The effect of timolol was partly blocked by labetalol and dichloroisoproterenol, in an apparently competitive manner. The intracellular cAMP content of Sf9 cells cultured in serum-free medium was also increased by the expression of beta 2AR, and that increase was reversed by timolol and propranolol, consistent with observations in membrane preparations. The properties revealed by the expression of the beta 2AR in Sf9 cells suggest two agonist-independent traits of G protein-linked receptors, i.e., 1) that unliganded receptors are able to activate G proteins both in membrane preparations and in whole cells and 2) that antagonists may mediate their effects not only by preventing the binding of agonists but also by decreasing the propensity of the receptor to assume an active state.


Conversion after off-pump coronary artery bypass grafting: the CORONARY trial experience.
Emergent and late conversions form OFF-to-ON pump coronary artery bypass grafting (CABG) have been associated with worse outcomes, however, it remains unclear as to which risk factors are associated with conversion and how to prevent them. Among 4718 patients who randomly underwent off- or on-pump CABG, the incidence of off-pump to on-pump cross-over, or 'OFF-to-ON conversion', was 7.9% (186/2356). The primary outcome was a composite of death, stroke, myocardial infarction, or new renal failure requiring dialysis. We assessed the risk factors and outcomes of converted patients. Emergent OFF-to-ON conversions, defined as conversions for hypotension or ischaemia, were required for 3.2% of patients ( n = 75), while most elective conversions were due to small or intramuscular coronaries ( n = 83). OFF-to-ON converted patients required increased surgery time, blood transfusions, intensive care unit stay, and presented a higher incidence at 1 year of the composite outcome compared with non-converted off-pump patients (all P < 0.01), especially if the conversion was emergent. Conversely, elective conversions outcomes were no different compared with non-converted off-pump patients ( P = 0.35). Independent predictors of emergent conversions included higher heart rate or chronic atrial fibrillation, urgent surgery, more grafts planned and surgeon experience with off-pump CABG. Emergent OFF-to-ON conversion is associated with worse outcomes compared with elective conversion or no conversion. In the presence of risk factors for emergent conversion, an early and elective conversion approach is a judicious strategy.


Mouse models of colorectal cancer as preclinical models.
In this review, we discuss the application of mouse models to the identification and pre-clinical validation of novel therapeutic targets in colorectal cancer, and to the search for early disease biomarkers. Large-scale genomic, transcriptomic and epigenomic profiling of colorectal carcinomas has led to the identification of many candidate genes whose direct contribution to tumourigenesis is yet to be defined; we discuss the utility of cross-species comparative 'omics-based approaches to this problem. We highlight recent progress in modelling late-stage disease using mice, and discuss ways in which mouse models could better recapitulate the complexity of human cancers to tackle the problem of therapeutic resistance and recurrence after surgical resection.


[Approaching the family in the Family Health Strategy: an integrative literature review].
Today there is consensus regarding the idea that there is mutual influence between the health-disease conditions of family members and family union. Establishing health practice centered on family care is a way to revert the hegemonic disease-centered model, which divides individuals and separate them from their context and socio-cultural values. The Family Health Strategy (FHS) was implemented to reorganize the Brazilian public health system (Sistema Único de Saúde), an each of its teams becomes acquainted with the true situation of the families for which they are responsible. In this sense, an integrative literature was performed to identify the concept of family and the factors associated with the family approach in the FHS. The review identified aspects that contribute to maintaining the fragmented approach in the FHS, as well as aspects that could help overcome towards a model using a family-centered approached.


LEF1 identifies androgen-independent epithelium in the developing prostate.
Lymphoid enhancer-binding factor (LEF)1 is a major mediator and a target in canonical Wnt/β-catenin pathway. Interactions between the androgen receptor (AR) and canonical Wnt pathways have been implicated in the development of the genitourinary organs. Here, we investigated the localization and role of LEF1-positive cells during development of the prostate gland in human and in the murine model. We show that during human prostate development, LEF1 is restricted to the basal epithelial layer of the urogenital sinus. During mouse development, Lef1 is also present in the urogenital mesenchyme in addition to the basal epithelial layer of the urogenital sinus. In the course of elongation and branching of the prostatic ducts, Lef1 is localized to the proliferating epithelium at the distal tips of the buds. Notably, during branching morphogenesis, domains of Lef1 and AR are mutually exclusive. We further employed the TOPGAL reporter strain to examine the dynamics of Wnt signaling in the context of prostate regression upon a 7-d treatment with a competitive AR inhibitor, bicalutamide. We found that Wnt/Lef1-positive basal cells are not dependent upon androgen for survival. Furthermore, upon bicalutamide treatment, Wnt/Lef1-positive basal progenitors repopulated the luminal compartment. We conclude that Wnt/Lef1 activity identifies an androgen-independent population of prostate progenitors, which is important for embryonic development and organ maintenance and regeneration in the adult.


Supplementation with tomato-based products increases lycopene, phytofluene, and phytoene levels in human serum and protects against UV-light-induced erythema.
Carotenoids are suitable photoprotectants, and beta-carotene supplements are used for protection against ultraviolet (UV) light-induced erythema. Protective effects are also observed when carotenoids are provided with the diet. Here, we investigated the photoprotective effects of synthetic lycopene in comparison with a tomato extract (Lyc-o-Mato) and a drink containing solubilized Lyc-o-Mato (Lyc-o-Guard-Drink). With these different sources, the volunteers ingested similar amounts of lycopene (about 10 mg/day). After 12 weeks of supplementation, significant increases in lycopene serum levels and total skin carotenoids were observed in all groups. Significant increases in the serum levels of phytofluene and phytoene occurred in the Lyc-o-Mato and the Lyc-o-Guard-Drink group. At weeks 0, 4, and 12 an erythema was induced with a solar light simulator. Dorsal skin of each subject was irradiated with 1.25 minimal erythemal dose (MED). Reddening of the skin was evaluated before and 24 hours after irradiation by chromametry and expressed as positive a-values (red/green-axis). delta a-values (difference of a-value before irradiation and after 24 hours) were used as an index of erythema intensity. A decrease in the delta a-value from week 0 to week 12, indicating prevention of erythema formation, was observed in all groups. Compared to week 0, the delta a-value at week 12 was 25% lower in the synthetic lycopene group. The protective effect was more pronounced in the Lyc-o-Mato (38%) and Lyc-o-Guard-Drink (48%) groups. In the two latter groups, phytofluene and phytoene may have contributed to protection. Both of these carotenoids exhibit absorption maxima at wavelengths of UV light. Absorption of UV light protects skin from photodamage and might explain the differences observed between groups.


Focal decline of cortical thickness in Alzheimer's disease identified by computational neuroanatomy.
Alzheimer's disease (AD) is characterized by a heterogeneous distribution of pathological changes throughout the brain. Magnetic resonance imaging can be used to investigate the regional distribution of cortical atrophy in AD in vivo. One marker for the disease-specific atrophy is the thickness of the cortical mantle across the brain, obtained with automated 3-D image processing. Here, we present data from 36 subjects (17 controls and, 19 patients diagnosed as probable AD) investigated for cortical thickness across the entire brain. We show significant cortical thickness decline in AD in temporal, orbitofrontal and parietal regions, with the most pronounced changes occurring in the allocortical region of the medial temporal lobes, outlining the parahippocampal gyrus, and representing a loss of >1.25 millimeters of cortical thickness. Moreover, focal cortical areas decline with progression of the disease as measured by time from baseline scan as well as the Mini-Mental State Exam. The results demonstrate the ability of this method to detect changes in cortical thickness in AD, across the entire brain, without need of prior anatomical definitions. The regional distribution of changes reported here is consistent with independent findings on the distribution of neuropathological alterations in AD. Using cortical thickness, moreover, we provide a direct quantitative index of atrophy in the disease.


Challenges for providing effective hemostasis in surgery and trauma.
Vascular injury, whether surgical or traumatic, triggers a complex series of regulatory events. The understanding of these events, their interdependence, and their effect on hemostasis and thrombosis, is slowly being unraveled. The current understanding of these processes is reviewed in this paper. The application of this knowledge to the operating theatre has been slow and is severely limited by the lack of effective tools to monitor the coagulopathic status of individual patients. Hence, the initial treatment of patients with severe hemorrhage relies on improving the patient's physiological status and on basic surgical techniques. Should these efforts fail, then a number of topical hemostatic agents, selective inhibitors of fibrinolysis, and procoagulant molecules, such as recombinant factor VIIa, may be utilized. However, many of these agents have not yet been tested in clinical trials and studies are urgently needed to determine efficacy, safety, optimal dosage and time of administration.


In situ growth of metallic Ag0 intercalated CoAl layered double hydroxides as efficient electrocatalysts for the oxygen reduction reaction in alkaline solutions.
Metallic Ag0 intercalated CoAl-layered double hydroxides (CoAl LDHs) have been successfully synthesized in situ through a simple redox process with ethylene glycol (EG) and triethanolamine (TEOA). The Ag(CN)2- anion-exchanged precursor was reduced by EG to form metallic Ag0. Furthermore, the effect of TEOA on confining the particle size of Ag0 was demonstrated. The oxygen reduction reaction (ORR) property of metallic Ag0 intercalated CoAl LDHs was examined in alkaline aqueous solution. A typical sample synthesized by the addition of TEOA for 180 min exhibited excellent ORR catalytic activity with a high current density of 5.5 mA cm-2 at 0.2 V (vs. a reversible hydrogen electrode (RHE)) and good stability. Koutecky-Levich (K-L) calculations and rotating ring-disk electrode (RRDE) measurements further revealed that the ORR of the as-prepared catalyst proceeded mainly via an almost ideal four-electron transfer process. The enhanced electrocatalytic activity was ascribed to the intercalated Ag0, confined nanoparticle size and the expanded interlayer space, which effectively facilitate the reactant transfer and electron migration.


Case report: pelvic congestion syndrome as an unusual etiology for chronic hip pain in 2 active, middle-age women.
The past 2 decades have shown a dramatic increase in the number of pelvic and hip injuries in female athletes. Accurate diagnosis of hip pain in active women has proven to be a challenge, as there is an extensive differential including both musculoskeletal and visceral problems. While the incidence of pelvic congestion syndrome (PCS) is not known, this condition may manifest as chronic hip pain in this patient population. A PubMed search was undertaken for articles published in English from 1980 to 2012. Additional references were accrued from reference lists of research articles. Case series. Level 3. Diagnosis was established using magnetic resonance imaging. Both women were evaluated and treated by interventional radiology with gonadal vein embolization. Initial evaluation and subsequent follow-up was completed in the Sports Medicine Clinic to monitor chronic hip pain symptoms. Both patients experienced significant alleviation of chronic hip pain symptoms within several months after gonadal vein embolization, allowing for a return to the previous level of activity. Although PCS most commonly presents as pelvic pain, it is important to consider this condition in athletes with persistent hip pain. PCS may also present with the primary symptom of hip pain as in the 2 case reports described. With more awareness of this condition and appropriate diagnosis, PCS as an unusual etiology of chronic hip pain may be effectively treated with gonadal vein embolization.


IL-12 stimulates an antiviral type 1 cytokine response but lacks adjuvant activity in IFN-gamma-receptor-deficient mice.
Cytokines can be used as adjuvants to enhance and direct protective immune responses induced by vaccines. IL-12, a cytokine that favors the maturation of Th1-type cells and stimulates associated cell-mediated responses was evaluated as immunologic adjuvant for a viral vaccine in a mouse challenge model. When it was administered together with inactivated pseudorabies virus, a herpes simplex virus related alpha-herpesvirus, increased production of IFN-gamma by ex vivo-stimulated splenocytes was observed as well as augmented production of antiviral serum lgG2a. This was associated with increased protection against a lethal challenge infection. Infection of IfN-gamma-neutralizing Ab reduced the increased antiviral resistance in IL-12-treated mice. Also, in mice bearing an inactivated IFN-gamma-receptor gene IL-12 failed to stimulate protection against challenge and the synthesis of antiviral lgG2a. However, in these IFN-gamma-receptor knockout mice, increased antiviral lgG2b levels and enhanced IFN-gamma-secretion, with minimal IL-4 production, by ex vivo-stimulated splenocytes was observed. In wild-type mice administration of recombinant IFN-gamma but not IL-2 mimicked the immune-stimulating activity of IL-12; it is therefore likely that the IL-12 adjuvant activity is largely mediated by physiologic IFN-gamma.


Atomic-scale observation of multiconformational binding and energy level alignment of ruthenium-based photosensitizers on TiO2 anatase.
Dye-sensitized solar cells constitute a promising approach to sustainable and low-cost solar energy conversion. Their overall efficiency crucially depends on the effective coupling of the photosensitizers to the photoelectrode and the details of the dye's energy levels at the interface. Despite great efforts, the specific binding of prototypical ruthenium-based dyes to TiO2, their potential supramolecular interaction, and the interrelation between adsorption geometry and electron injection efficiency lack experimental evidence. Here we demonstrate multiconformational adsorption and energy level alignment of single N3 dyes on TiO2 anatase (101) revealed by scanning tunnelling microscopy and spectroscopy. The distinctly bound molecules show significant variations of their excited state levels associated with different driving forces for photoelectron injection. These findings emphasize the critical role of the interfacial coupling and suggest that further designs of dye-sensitized solar cells should target a higher selectivity in the dye-substrate binding conformations in order to ensure efficient electron injection from all photosensitizers.


Distribution and prevalence of malaria parasites among long-tailed macaques (Macaca fascicularis) in regional populations across Southeast Asia.
Plasmodium knowlesi and Plasmodium cynomolgi are two malaria parasites naturally transmissible between humans and wild macaque through mosquito vectors, while Plasmodium inui can be experimentally transmitted from macaques to humans. One of their major natural hosts, the long-tailed macaque (Macaca fascicularis), is host to two other species of Plasmodium (Plasmodium fieldi and Plasmodium coatneyi) and is widely distributed in Southeast Asia. This study aims to determine the distribution of wild macaques infected with malarial parasites by examining samples derived from seven populations in five countries across Southeast Asia. Plasmodium knowlesi, P. cynomolgi, P. coatneyi, P. inui and P. fieldi, were detected using nested PCR assays in DNA samples from 276 wild-caught long-tailed macaques. These samples had been derived from macaques captured at seven locations, two each in the Philippines (n = 68) and Indonesia (n = 70), and one each in Cambodia (n = 54), Singapore (n = 40) and Laos (n = 44). The results were compared with previous studies of malaria parasites in long-tailed macaques from other locations in Southeast Asia. Fisher exact test and Chi square test were used to examine the geographic bias of the distribution of Plasmodium species in the macaque populations. Out of 276 samples tested, 177 were Plasmodium-positive, with P. cynomolgi being the most common and widely distributed among all long-tailed macaque populations (53.3 %) and occurring in all populations examined, followed by P. coatneyi (20.4 %), P. inui (12.3 %), P. fieldi (3.4 %) and P. knowlesi (0.4 %). One P. knowlesi infection was detected in a macaque from Laos, representing the first documented case of P. knowlesi in wildlife in Laos. Chi square test showed three of the five parasites (P. knowlesi, P. coatneyi, P. cynomolgi) with significant bias in prevalence towards macaques from Malaysian Borneo, Cambodia, and Southern Sumatra, respectively. The prevalence of malaria parasites, including those that are transmissible to humans, varied among all sampled regional populations of long-tailed macaques in Southeast Asia. The new discovery of P. knowlesi infection in Laos, and the high prevalence of P. cynomolgi infections in wild macaques in general, indicate the strong need of public advocacy in related countries.


Expression profiling reveals altered satellite cell numbers and glycolytic enzyme transcription in nemaline myopathy muscle.
The nemaline myopathies (NMs) are a clinically and genetically heterogeneous group of disorders characterized by nemaline rods and skeletal muscle weakness. Mutations in five sarcomeric thin filament genes have been identified. However, the molecular consequences of these mutations are unknown. Using Affymetrix oligonucleotide microarrays, we have analyzed the expression patterns of >21,000 genes and expressed sequence tags in skeletal muscles of 12 NM patients and 21 controls. Multiple complementary approaches were used for data analysis, including geometric fold analysis, two-tailed unequal variance t test, hierarchical clustering, relevance network, and nearest-neighbor analysis. We report the identification of high satellite cell populations in NM and the significant down-regulation of transcripts for key enzymes of glucose and glycogen metabolism as well as a possible regulator of fatty acid metabolism, UCP3. Interestingly, transcript level changes of multiple genes suggest possible changes in Ca(2+) homeostasis. The increased expression of multiple structural proteins was consistent with increased fibrosis. This comprehensive study of downstream molecular consequences of NM gene mutations provides insights in the cellular events leading to the NM phenotype.


Distribution of renal lesions in idiopathic systemic vasculitis: A three-dimensional analysis of 87 glomeruli.
Extracapillary proliferation and fibrinoid necrosis are the main diagnostic glomerular lesions in renal biopsy specimens of patients with idiopathic systemic vasculitis. Neither the incidence nor the correlation between extracapillary proliferation and fibrinoid necrosis in renal biopsy specimens from patients with systemic vasculitis has been systematically evaluated. By means of a three-dimensional analysis, we made a topographic reconstruction of the distribution of extracapillary proliferation and fibrinoid necrosis in affected glomeruli and tested different biopsy-processing protocols to optimize histopathologic analysis in clinical practice. Paraffin blocks of renal biopsy specimens from six patients diagnosed with systemic vasculitis were completely and serially sectioned in 2-microm thick sections and stained with the Gomori trichrome method. Glomeruli were scored per section for the presence of fibrinoid necrosis and extracapillary proliferation. Subsequently, a three-dimensional reconstruction was obtained for 87 glomeruli. In only one glomerulus did fibrinoid necrosis occur without extracapillary proliferation; in 51%, a combination of the two lesions was found; in 22%, extracapillary proliferation occurred in the absence of fibrinoid necrosis; and 26% did not show either lesion. Using the standard protocol from our department (ie, evaluation of 20 consecutive sections in various stainings), the chance of finding extracapillary proliferation was 100% and that of finding fibrinoid necrosis was 73%. If 5 sections stained with the Gomori trichrome were added, the latter percentage increased to 86%. Using skip-serial sections, even better results (87% to 92%) were obtained, with four skips as the best option (92%). In conclusion, our finding that fibrinoid necrosis rarely occurs in the absence of extracapillary proliferation may imply that both lesions are etiologically related. In addition, our observations indicate that the incidence of fibrinoid necrosis may be underestimated in clinical practice, depending on the number of sections evaluated.


The epidemiology of a coronary waiting list. A description of all of the patients.
To describe the characteristics and the severity of symptoms amongst patients on the waiting list for possible coronary revascularization. All the patients were sent a postal questionnaire for symptom evaluation. All hospitals in western Sweden. All patients in western Sweden on the waiting list in September 1990, who had been referred for coronary angiography or revascularization (n = 904) and a sex- and age-matched reference group (n = 809). More than half of the patients had daily attacks of chest pain, whereas 16% reported less than one attack per week or no pain at all. However, other symptoms such as dyspnoea, tachycardia and nervous reactions were also common and 25% of all patients used sedatives. A long waiting time for a given procedure was not associated with more pain but with more nervous symptoms such as restlessness and insomnia (P < 0.0001) and greater use of sedatives and cigarettes (P < 0.05). We conclude that a long waiting time for possible coronary revascularization is associated with more nervous symptoms but not with more pain.


Comparison between preemptive gabapentin and paracetamol for pain control after adenotonsillectomy in children.
Tonsillectomy is the most commonly performed surgical procedure in ENT practice. Postoperative pain remains the major problem following tonsillectomy, if not treated. Different methods and many drugs have been used to control the postoperative pain. In this study, we evaluate the role of gabapentin premedication vs paracetamol in management of postoperative pain following adenotonsillectomy in children. In a double blind randomized study, 70 children were subjected for adenotonsillectomy classified into two equal groups. Group I: Gabapentin 10 mg/kg was given orally 2 hours before induction of anesthesia (Gabapentin syrup 250 mg/5 ml); Group II: Oral paracetamol 20 mg/kg was given orally 2 hours before induction of anesthesia. All children underwent general anesthesia. Pain score was assisted postoperatively 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 18 hours after recovery using visual analogue scale (VAS). Pain score in gabapentin group was significantly less in 2 hours, 4 hours, 6 hours, and 8 hours postoperatively than in paracetamol group (P=0.0003, <0.0001, 0.0004, <0.0001, respectively). The time to first analgesia was longer in the gabapentin group than paracetamol group (7.95±2.06 hours vs 5.85±1.87 hours; P<0.0001) and the total amount of pethedine was less in gabapentin group than in paracetamol group (8±10.05 mg vs 16.25±11.57 mg; P=0.002). Gabapentin premedication improves postoperative analgesia following adenotonsillectomy in children and reduce analgesic requirements in comparison with paracetamol premedication, with no reported side effects.


Natural and synthetic compounds such as trimethoprim behave as inhibitors of efflux in Gram-negative bacteria.
We hypothesized that small heterocyclic or nitrogen-containing compounds could act as RND efflux pump inhibitors (EPIs). To ascertain possible EPIs, we sought to identify compounds that synergized with substrates of RND efflux pumps for wild-type bacteria and those that overexpress an efflux pump, but had no synergistic activity against strains in which a gene encoding a component of the AcrAB-TolC efflux pump had been inactivated. Twenty-six compounds plus L-phenylalanyl-L-arginyl-beta-naphthylamide (PAbetaN) and carbonyl cyanide m-chlorophenylhydrazone (CCCP) were screened by bioassay to identify compounds that synergized with ciprofloxacin for a range of Enterobacteriaceae and Pseudomonas aeruginosa. The MICs of ciprofloxacin, tetracycline, chloramphenicol, erythromycin and ethidium bromide+/-synergizing compounds were determined, and the ability to inhibit the efflux of Hoechst 33342 was measured. Two compounds, trimethoprim and epinephrine, consistently showed synergy with antibiotics for most strains. The combinations did not show synergy for Salmonella enterica serovar Typhimurium in which the AcrAB-TolC efflux pump was inactive. Both compounds inhibited the efflux of Hoechst 33342. Two compounds, trimethoprim and epinephrine, which are already licensed for use in man, may warrant further analysis as EPIs. The combination of trimethoprim with another antibiotic is a well-used combination in anti-infective chemotherapy, and so combination with another agent, such as a quinolone, may be a viable option and further studies are now required.


Development of epithelial tissues: How are cleavage planes chosen?
The cross-section of a cell in a monolayer epithelial tissue can be modeled mathematically as a k-sided polygon. Empirically studied distributions of the proportions of k-sided cells in epithelia show remarkable similarities in a wide range of evolutionarily distant organisms. A variety of mathematical models have been proposed for explaining this phenomenon. The highly parsimonious simulation model of (Patel et al., PLoS Comput. Biol., 2009) that takes into account only the number of sides of a given cell and cell division already achieves a remarkably good fit with empirical distributions from Drosophila, Hydra, Xenopus, Cucumber, and Anagallis. Within the same modeling framework as in that paper, we introduce additional options for the choice of the endpoints of the cleavage plane that appear to be biologically more realistic. By taking the same data sets as our benchmarks, we found that combinations of some of our new options consistently gave better fits with each of these data sets than previously studied ones. Both our algorithm and simulation data are made available as research tools for future investigations.


New insights into the developmental biology and transmission mechanisms of Leishmania.
Leishmania alternates between two main morphological forms in its life cycle: intracellular amastigotes in the mammalian host and motile promastigotes in the sandfly vector. Several different forms of promastigote can be recognised in sandfly infections. The first promastigote forms, which are found in the sandfly in the bloodmeal phase, are multiplicative procyclic promastigotes. These differentiate into nectomonad promastigotes, which are a non-dividing migratory stage moving from the posterior to the anterior midgut. When nectomonad promastigotes arrive at the anterior midgut they differentiate into leptomonad forms, a newly named life cycle stage, which resume replication. Leptomonad promastigotes, which are found in the anterior midgut, are the developmental precursors of the metacyclic promastigotes, the mammal-infective stages. Leptomonad forms also produce promastigote secretory gel, a substance that plays a key role in transmission by forming a physical obstruction in the gut, forcing the sandfly to regurgitate metacyclic promastigotes during bloodfeeding.


Temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells.
Most isolates of human rhinovirus, the common cold virus, replicate more robustly at the cool temperatures found in the nasal cavity (33-35 °C) than at core body temperature (37 °C). To gain insight into the mechanism of temperature-dependent growth, we compared the transcriptional response of primary mouse airway epithelial cells infected with rhinovirus at 33 °C vs. 37 °C. Mouse airway cells infected with mouse-adapted rhinovirus 1B exhibited a striking enrichment in expression of antiviral defense response genes at 37 °C relative to 33 °C, which correlated with significantly higher expression levels of type I and type III IFN genes and IFN-stimulated genes (ISGs) at 37 °C. Temperature-dependent IFN induction in response to rhinovirus was dependent on the MAVS protein, a key signaling adaptor of the RIG-I-like receptors (RLRs). Stimulation of primary airway cells with the synthetic RLR ligand poly I:C led to greater IFN induction at 37 °C relative to 33 °C at early time points poststimulation and to a sustained increase in the induction of ISGs at 37 °C relative to 33 °C. Recombinant type I IFN also stimulated more robust induction of ISGs at 37 °C than at 33 °C. Genetic deficiency of MAVS or the type I IFN receptor in infected airway cells permitted higher levels of viral replication, particularly at 37 °C, and partially rescued the temperature-dependent growth phenotype. These findings demonstrate that in mouse airway cells, rhinovirus replicates preferentially at nasal cavity temperature due, in part, to a less efficient antiviral defense response of infected cells at cool temperature.


[Antiepileptic drugs in North America].
In this review study, second-generation antiepileptic drugs (AEDs) (levetiracetam, gabapentin, topiramate, lamotrigine, zonisamide, oxcarbazepine, vigabatrin, pregabalin, rufinamide, tiagabine, lacosamide, and felbamate) and injectable AEDs (levetiracetam, lacosamide, fosphenytoin, lorazepam, and valproic acid) available in North America were compared with those available in Japan. Three second-generation AEDs (gabapentin, topiramate, and lamotrigine) were recently approved in Japan. Levetiracetam is currently under review for approval by the Japanese regulatory agency. An ideal AED would have a broad-spectrum activity to control multiple types of seizures, favorable safety profile, limited potential for drug-drug interaction, many bioequivalent formulations, long half life to allow infrequent administration, and antiepileptogenic effects that may provide a fundamental cure of epileptic patients by suppressing the development of epileptogenic network and neutralizing previously established epileptogenic foci in the brain. The second-generation AEDs have been developed to possess some of these ideal properties. All the second-generation AEDs are efficacious for the treatment of patients with partial seizures. In addition, levetiracetam, topiramate, lamotrigine, and zonisamide are effective for the treatment of patients with generalized tonic-clonic seizures, absences, myoclonic seizures, Lennox-Gastaut syndrome, and West syndrome; however, lamotrigine is not effective for the treatment of patients with myoclonic seizures. Rufinamide and felbamate are useful for the treatment of patients with Lennox-Gastaut syndrome; however owing to its serious adverse effects, including aplastic anemia and hepatic failure, felbamate is used as the last resort for the treatment of patients with intractable seizures. Vigabatrin is particularly effective for the treatment of patients with West syndrome; however, the patients need to be regularly monitored for the development of peripheral visual field defect. Gabapentin, oxcarbazepine, vigabatrin, and tiagabine are ineffective for the treatment of patients with absences and/or myoclonic seizures and may aggravate these conditions. Treatment with levetiracetam or topiramate (off-label use) is the new option for patients with refractory status epilepticus, which is characterized by downregulation of the inhibitory gamma-aminobutyric acid system, because these drugs act via different mechanisms and are rapidly titratable, especially intravenous levetiracetam. The pharmacokinetic profiles of levetiracetam, gabapentin, and pregabalin are favorable: these drugs exhibit minimal protein binding, do not undergo hepatic metabolism, are not involved in any clinically relevant drug interactions, and rarely lead to the development of serious adverse effects. In general, levetiracetam is probably the closest to being the ideal AED because of its broad-spectrum favorable pharmacokinetic profile and safety profile as well as because of the availability of its parenteral formulation. Among the injectable AEDs, fosphenytoin is a water-soluble prodrug and is used to treat patients with status epilepticus. Systemic and local side effects of this drug are fewer than those of phenytoin. Lorazepam, a benzodiazepine is used as the first-line AED for the treatment of patients with status epilepticus. The effects of this drug are more prolonged than those of diazepam. Intravenous administration of valproic acid is regarded as a new treatment option for patients with status epilepticus, because sedative and negative effects on the cardiorespiratory system of this drug are lesser than those of the traditional injectable AEDs. These novel medications will aid the improvement of the quality of life of epileptic patients through improved seizure control and reduced adverse effects.


Association of decreased membrane protein phosphorylation with red blood cell spherocytosis.
A close association between sphering of human red cells and deficient phosphorylation of their membrane proteins has been documented in three spearate situations. Red cells rendered spheroidal by exposure to: (1) elevated temperatures; (2) two sulfhydryl inhibitors (N-ethylmaleimide or paramercuribenzoate); or (3) in the genetic situation of hereditary spherocytosis--all manifest deficient phosphorylation of endogenous membrane proteins by ATP. In the two former cases, we have noted an exact association between the onset of red cell sphering (e.g., as temperatures rose above 48 degrees C or N-ethylmaleimide concentrations exceeded 2 mumoles/ml RBC) and the development of deficient ghost protein phosphorylation.


Effect of Sibling Birth on BMI Trajectory in the First 6 Years of Life.
This study examined the longitudinal association between birth of a sibling and changes in body mass index z-score (BMIz) trajectory during the first 6 years of life. Children (n = 697) were recruited across 10 sites in the United States at the time of birth. Sibship composition was assessed every 3 months. Anthropometry was completed when the child was age 15 months, 24 months, 36 months, 54 months, and in first grade. Children were classified based on the timing of their sibling's birth. A piecewise quadratic regression model adjusted for potential confounders examined the association of the birth of a sibling with subsequent BMIz trajectory. Children whose sibling was born when they were 24 to 36 months or 36 to 54 months old, compared with children who did not experience the birth of a sibling by first grade, had a lower subsequent BMIz trajectory and a significantly lower BMIz at first grade (0.27 vs 0.51, P value = 0.04 and 0.26 vs 0.51, P value = 0.03, respectively). Children who did not experience the birth of a sibling by the time they were in first grade had 2.94 greater odds of obesity (P value = 0.046) at first grade compared with children who experienced the birth of a sibling when they were between 36 to 54 months old. A birth of a sibling when the child is 24 to 54 months old is associated with a healthier BMIz trajectory. Identifying the underlying mechanism of association can help inform intervention programs.


Oval cells compensate for damage and replicative senescence of mature hepatocytes in mice with fatty liver disease.
Hepatic steatosis may have a generally benign prognosis, either because most hepatocytes are not significantly injured or mechanisms to replace damaged hepatocytes are induced. To determine the relative importance of these mechanisms, we compared hepatocyte damage and replication in ethanol-fed and ob/ob mice with very indolent fatty liver disease to that of healthy control mice and PARP-1(-/-) mice with targeted disruption of the DNA repair enzyme, poly(ADP-ribose) polymerase. Compared to the healthy controls, both groups with fatty livers had significantly higher serum alanine aminotransferase values, hepatic mitochondrial H(2)O(2) production, and hepatocyte oxidative DNA damage. A significantly smaller proportion of the hepatocytes from fatty livers entered S phase when cultured with mitogens. Moreover, this replicative senescence was not reversed by treating cultured hepatocytes with agents (i.e., betaine or leptin) that improve liver disease in intact ethanol-fed or leptin-deficient mice. Hepatocytes from PARP1(-/-) mice also had more DNA damage and reduced DNA synthesis in response to mitogens. However, neither mice with fatty livers nor PARP-1-deficient mice had atrophic livers. All of the mice with senescent mature hepatocytes exhibited hepatic accumulation of liver progenitor (oval) cells and oval cell numbers increased with the demand for hepatocyte replacement. Therefore, although hepatic oxidant production and damage are generally increased in fatty livers, expansion of hepatic progenitor cell populations helps to compensate for the increased turnover of damaged mature hepatocytes. In conclusion, these results demonstrate that induction of mechanisms to replace damaged hepatocytes is important for limiting the progression of fatty liver disease.


The emergence of a global right to health norm--the unresolved case of universal access to quality emergency obstetric care.
The global response to HIV suggests the potential of an emergent global right to health norm, embracing shared global responsibility for health, to assist policy communities in framing the obligations of the domestic state and the international community. Our research explores the extent to which this global right to health norm has influenced the global policy process around maternal health rights, with a focus on universal access to emergency obstetric care. In examining the extent to which arguments stemming from a global right to health norm have been successful in advancing international policy on universal access to emergency obstetric care, we looked at the period from 1985 to 2013 period. We adopted a qualitative case study approach applying a process-tracing methodology using multiple data sources, including an extensive literature review and limited key informant interviews to analyse the international policy agenda setting process surrounding maternal health rights, focusing on emergency obstetric care. We applied John Kingdon's public policy agenda setting streams model to analyse our data. Kingdon's model suggests that to succeed as a mobilising norm, the right to health could work if it can help bring the problem, policy and political streams together, as it did with access to AIDS treatment. Our analysis suggests that despite a normative grounding in the right to health, prioritisation of the specific maternal health entitlements remains fragmented. Despite United Nations recognition of maternal mortality as a human rights issue, the relevant policy communities have not yet managed to shift the policy agenda to prioritise the global right to health norm of shared responsibility for realising access to emergency obstetric care. The experience of HIV advocates in pushing for global solutions based on right to health principles, including participation, solidarity and accountability; suggest potential avenues for utilising right to health based arguments to push for policy priority for universal access to emergency obstetric care in the post-2015 global agenda.


Microbiota analysis for risk assessment: evaluation of hazardous dietary substances and its potential role on the gut microbiome variability and dysbiosis.
The expansion of fields related to probiotics, microbiome-targeted interventions and an evolving landscape for implementation across policy, industry and end users, signifies an era of important clinical translational changes. Characteristics and perception of traditional probiotics stemmed from the historical long-term use of fermented products. Although the distinction between probiotic microorganisms and fermentation-associated microbes is important, it is often confused as not all fermented foods are probiotic supplements. Current innovation in area of biotechnology and bioinformatics is emerging outside of the classical definitions and new probiotics will emerge from novel sources, challenging scientific as well as regulatory instructions. At the same time, the search for individual and group microbiome signatures - biomarkers in order to predict disease incidence, progression and response to treatment is a key area of microbiological and multidisciplinary research, enabled by efficient and powerful processing of large data sets. However, the regulation of marketed beneficial microbes and probiotics differs among countries and the basic level of classification, which depend on probiotic classification is not globally harmonised. At the same time, the regulation is very demanding to evaluate the safety of products on the market, so that only those products with scientific evidence benefits can obtain positive recognition in ways of health claims. Collaborative experimental and theoretical approaches and case studies have assisted the progress in this crosscutting area of research. There is a requirement to clearly specify criteria and provide details about ways and approaches of achieving those criteria with the intention that manufacturers can benefit from a transparent way of communicating product quality to end users.


Understanding integrated care pathways in palliative care using realist evaluation: a mixed methods study protocol.
Policy- and evidence-based guidelines have highlighted the need for improved palliative and end-of-life care. However, there is still evidence of individuals dying undignified deaths with little pain control, therefore inflicting unnecessary suffering. New commissioning powers have enabled a 2-year pilot of an innovative integrated care pathway (ICP) designed to improve arrangements for individuals with life-limiting illnesses requiring palliative care. A novel feature of the ICP is its focus on palliative care over the last 6 months of life, aiming to intervene early to prepare for and ensure a good death. What is not known is if this pathway works, how it works and who it works for. A realist evaluation and a complex analytical framework will investigate and discover context, mechanism and outcome conjectures and configurations of the ICP and thus facilitate exploration of how it works and who it works for. A mixed methods approach will be used with small sample sizes to capture the breadth of the ICP. Phase 1 will identify if the pathway works through analysis of NHS Morbidity Information Query and Export Syntax data, locality Death Audit data and the Quality of Dying and Death Questionnaire. Phase 2 employs soft systems methodology with data from focus groups with health professionals to identify how the pathway works. Phase 3 uses the Miller Behavioural Style Scale and interviews with palliative care patients and bereaved relatives to analyse communication in palliative care. Ethical approval has been granted from the NHS local ethics committee (REC reference number: 11/NE/0318). Research & Development approval has been gained from four different trusts, and relevant voluntary organisations and the local council have been informed about the research. This protocol illustrates the complexity inherent in evaluating a palliative care ICP. Identification of whether the pathway works, how it works and who it works for will be beneficial to all practices and other care providers involved as it will give objective data on the impact of the ICP. Results will be disseminated throughout the study for continuous quality improvement of the ICP. Outcomes from each data collection phase will be disseminated separately if analysis warrants it; all data collection will be utilised in the realist evaluation. The research provides a potential for the dissemination of the pathway to other localities through the transferable knowledge it will generate, from its focus on the contexts that are crucial for successful implementation, the mechanisms that facilitate implementation and the outcomes achieved.


Mitochondrial protein BNIP3 regulates Chikungunya virus replication in the early stages of infection.
Chikungunya virus (CHIKV) is a human pathogen causing outbreaks of febrile illness for which vaccines and specific treatments remain unavailable. Autophagy-related (ATG) proteins and autophagy receptors are a set of host factors that participate in autophagy, but have also shown to function in other unrelated cellular pathways. Although autophagy is reported to both inhibit and enhance CHIKV replication, the specific role of individual ATG proteins remains largely unknown. Here, a siRNA screen was performed to evaluate the importance of the ATG proteome and autophagy receptors in controlling CHIKV infection. We observed that 7 out of 50 ATG proteins impact the replication of CHIKV. Among those, depletion of the mitochondrial protein and autophagy receptor BCL2 Interacting Protein 3 (BNIP3) increased CHIKV infection. Interestingly, BNIP3 controls CHIKV independently of autophagy and cell death. Detailed analysis of the CHIKV viral cycle revealed that BNIP3 interferes with the early stages of infection. Moreover, the antiviral role of BNIP3 was found conserved across two distinct CHIKV genotypes and the closely related Semliki Forest virus. Altogether, this study describes a novel and previously unknown function of the mitochondrial protein BNIP3 in the control of the early stages of the alphavirus viral cycle.


Solvent-dependent photo-induced dynamics in a non-rigidly linked zinc phthalocyanine-perylenediimide dyad probed using ultrafast spectroscopy.
In this work, we characterize the energy and electron transfer kinetics of a zinc phthalocyanine-perylenediimide dyad (ZnPc-PDI) in various solvents using steady-state and tunable narrowband pump-probe spectroscopy. We fit the ultrafast data with global analysis techniques and find that upon excitation of the PDI moiety (pump pulse at 540 nm), the excitation energy transfer (EET) rate to the ZnPc moiety displays a solvent sensitivity that we attribute to changes in the relative equilibrium moiety orientation. We rationalize these observations by considering the nature of the non-rigid bridge used to link the two moieties as well as the degenerate nature of the Q band transitions in the ZnPc species. By tuning the pulse into resonance with the ZnPc Q band (685 nm) we can directly photo-induce an electron transfer (ET) process back to the PDI moiety. Employing the same global analysis, we find that the dynamics of the ultrafast electron transfer are completely kinetically controlled according to the Bixon-Jortner model of barrierless solvent-controlled curve crossing, while the recombination to reform the ground state is well-described using the static energetic picture according to Marcus theory.


Soft diphosphine and diarsine complexes of niobium(V) and tantalum(V) fluorides: synthesis, properties, structures and comparisons with the corresponding chlorides.
The reactions of the soft diphosphines o-C6H4(PMe2)2, Me2P(CH2)2PMe2, Et2P(CH2)2PEt2 or o-C6H4(PPh2)2 with NbF5 or TaF5 in anhydrous MeCN solution produce [MF4(diphosphine)2][MF6] (M = Nb or Ta), which have been characterised by microanalysis, IR, (1)H, (19)F{(1)H}, (31)P{(1)H} and (93)Nb NMR spectroscopy. X-ray crystal structures are reported for the isomorphous [MF4{o-C6H4(PMe2)2}2][MF6], which confirm the presence of eight-coordinate (distorted dodecahedral) cations. The corresponding reactions using o-C6H4(AsMe2)2 produced [MF4{o-C6H4(AsMe2)2}2][MF6] which were similarly characterised, including by the X-ray structure of [NbF4{o-C6H4(AsMe2)2}2][NbF6]. These are very rare examples of arsine complexes of high valent metal fluorides. The chloro complexes [NbCl4{o-C6H4(PMe2)2}2]Cl, [TaCl4{o-C6H4(PMe2)2}2][TaCl6], [NbCl4{Me2P(CH2)2PMe2}2][NbCl6] and [MCl4{o-C6H4(AsMe2)2}2][MCl6] were prepared and their structural and spectroscopic properties compared with the fluoride analogues. Attempts to prepare diphosphine complexes of NbOF3 were unsuccessful, but the NbOCl3 complexes, [{{Me2P(CH2)2PMe2}NbOCl3}2{μ-Me2P(CH2)2PMe2}] and [{o-C6H4(PMe2)2}NbOCl3(μ-O)NbCl3(CH3CN){o-C6H4(PMe2)2}] were obtained. X-Ray structures are also reported for [NbCl4{o-C6H4(PMe2)2}2]Cl, [NbCl4{o-C6H4(AsMe2)2}2][NbCl5(OEt)], [NbCl4{o-C6H4(PMe2)2}2][NbOCl4(CH3CN)], [{{Me2P(CH2)2PMe2}NbOCl3}2{μ-Me2P(CH2)2PMe2}] and [{o-C6H4(PMe2)2}NbOCl3(μ-O)NbCl3(CH3CN){o-C6H4(PMe2)2}].


New insights into the role of motion and form vision in neurodevelopmental disorders.
A selective deficit in processing the global (overall) motion, but not form, of spatially extensive objects in the visual scene is frequently associated with several neurodevelopmental disorders, including preterm birth. Existing theories that proposed to explain the origin of this visual impairment are, however, challenged by recent research. In this review, we explore alternative hypotheses for why deficits in the processing of global motion, relative to global form, might arise. We describe recent evidence that has utilised novel tasks of global motion and global form to elucidate the underlying nature of the visual deficit reported in different neurodevelopmental disorders. We also examine the role of IQ and how the sex of an individual can influence performance on these tasks, as these are factors that are associated with performance on global motion tasks, but have not been systematically controlled for in previous studies exploring visual processing in clinical populations. Finally, we suggest that a new theoretical framework is needed for visual processing in neurodevelopmental disorders and present recommendations for future research.


Single motor unit responses underlying cervical vestibular evoked myogenic potentials produced by bone-conducted stimuli.
Cervical vestibular evoked myogenic potentials (cVEMPs) are muscle reflexes recorded from the sternocleidomastoid (SCM) neck muscles following vestibular activation with air- or bone-conducted (BC) stimulation. We investigated the effect of different forms of BC stimulation on the single motor unit response underlying the cVEMP. We tested 8 healthy human subjects with 5 different stimuli. Motor units were recorded with thin concentric needle electrodes; surface potentials were recorded simultaneously. The polarity of the initial change (at approx. 15 ms) in single motor unit activity reflected the polarity of the surface cVEMPs: a short-latency decrease in activity (inhibition) was seen with the four stimuli that produced a positive surface potential (p13), while an initial increase in activity (excitation) was seen with the stimulus that produced a negative surface potential. BC stimulation with common clinical stimuli usually produces an inhibition in single motor unit activity in the ipsilateral SCM muscle. However the projections activated by BC stimulation are not exclusively inhibitory in nature and depend upon the shape and direction of the stimulus. The utricle is likely to contribute to some BC cVEMPs, as some stimuli clearly evoke an excitation that is not likely to be saccular in origin.


Menkes' kinky hair disease: further definition of the defect in copper transport.
Duodenal mucosa obtained from two patients with Menkes' syndrome contained abnormally large amounts of copper. The defect in copper absorption in this disease must lie in the process of intracellular handling or of transport across the serosal cell membrane. Fibroblastic cells cultured from the skin of patients and of heterozygous females show intense metachromasia in primary culture which disappears in subculture. These cells may be useful for the study of copper transport in vitro and for the identification of heterozygotes in affected families.


[Management and care in hemodialysis units].
The study aimed at investigating a theoretical practical experience as well as the prospects concerning care management reported by nursing professionals working at hemodialysis units in Curitiba/Brazil. It is a practice-converging research; information was obtained by means of interviews, and team discussions and reflections during a workshop of educational practice. The approach of Collective Speech was used in order to organize data for the analysis. Research results pointed out the existence of a conflict between care management and care delivery to patients. This would result, according to the nurses, from the excess of administrative tasks, shortage of nursing staff and lack of effective planning.


Hormonal control of neutrophil chemotactic activity in the rat vagina.
A sexual-hormone-dependent neutrophil chemotactic factor(s), operative under physiological conditions, is described. Rat vaginal washouts were shown to be both chemotactic and chemokinetic for rat neutrophils in vitro, whereas macrophages were not attracted. Peak activity was observed at the end of estrus and preceded maximal neutrophil infiltration in the vagina. In order to mimic these events, gonadectomized animals were treated with estradiol for a week. They showed a similar peak of chemotactic activity 30-36 h after estradiol withdrawal, accompanied by a massive neutrophil accumulation. These data suggest that a decrease in estradiol level permits the expression of the chemotactic signal. There was no evidence for chemotaxis and/or migration inhibitors before and during estrus or during long-term estradiol treatment of gonadectomized rats. Induced neutrophil accumulation in the peritoneal cavity and chemotactic responsiveness of these cells in vitro were similar in all stages during the estrus cycle. Estradiol, progesterone, testosterone, and hydrocortisone neither promoted nor significantly inhibited the neutrophil migratory behavior over a wide range of concentrations. Our experiments suggest that the periodic neutrophil accumulation in the rat vagina after estrus is triggered by locally expressed chemotactic mechanisms that are controlled by sexual hormones. The data provide the first evidence that hormonal changes can control chemotactic factors and thus indirectly control cell migration.


Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma.
To determine if phosphodiesterase 5 (PDE5) inhibitors can augment immune function in patients with head and neck cancer through inhibition of myeloid-derived suppressor cells (MDSC). We performed a randomized, prospective, double blinded, placebo controlled, phase II clinical trial to determine the in vivo effects of systemic PDE5 inhibition on immune function in patients with head and neck squamous cell carcinoma (HNSCC). Tadalafil augmented immune response, increasing ex vivo T-cell expansion to a mean 2.4-fold increase compared with 1.1-fold in control patients (P = 0.01), reducing peripheral MDSC numbers to mean 0.81-fold change compared with a 1.26-fold change in control patients (P = 0.001), and increasing general immunity as measured by delayed type hypersensitivity response (P = 0.002). Tumor-specific immunity in response to HNSCC tumor lysate was augmented in tadalafil-treated patients (P = 0.04). These findings demonstrate that tadalafil augments general and tumor-specific immunity in patients with HNSCC and has therapeutic potential in HNSCC. Evasion of immune surveillance and suppression of systemic and tumor-specific immunity is a significant feature of head and neck cancer development. This study demonstrates that a PDE5 inhibitor, tadalafil, can reverse tumor-specific immune suppression in patients with head and neck cancer, with potential for therapeutic application.


A faster method to detect norovirus in oysters using probe hybridization to isolate target RNA before RT-PCR.
Human Noroviruses (HuNoVs) are the most frequent cause of outbreaks of acute gastroenteritis following the ingestion of raw or improperly cooked oysters. Although highly sensitive methods to detect HuNoV in oysters using reverse transcriptase-polymerase chain reaction (RT-PCR) are available, rapid methods to process samples for RT-PCR are still needed. The conventional approach is to concentrate the virus first before RNA purification to maximize assay sensitivity, but the procedures used are cumbersome. We developed a new hybridization method that is much faster and more effective compared to existing technology. The procedure includes an initial extraction of total RNA from the digestive diverticula of oysters using TRI Reagent, followed by HuNoV RNA purification using a capture probe and then HuNoV detection by real-time RT-PCR. The detection limit is approximately 100 PCR detection units of HuNoV per sample. Compared to published methods that require an initial virus concentration step before RNA extraction, the new method is much faster to complete. Approximately 3 h are needed to purify HuNoV RNA using the new method compared to at least 8 h using conventional methods. Coupled with real-time RT-PCR, the new method can detect HuNoV in contaminated oysters within 8 h. The effectiveness of the method was demonstrated using live artificially contaminated oysters and wild oysters.


Development and characterization of novel erythropoiesis stimulating protein (NESP).
Studies on human erythropoietin (EPO) demonstrated that there is a direct relationship between the sialic acid-containing carbohydrate content of the molecule and its serum half-life and in vivo biological activity, but an inverse relationship with its receptor-binding affinity. These observations led to the hypothesis that increasing the carbohydrate content, beyond that found naturally, would lead to a molecule with enhanced biological activity. Hyperglycosylated recombinant human EPO (rHuEPO) analogues were developed to test this hypothesis. Darbepoetin alfa (novel erythropoiesis stimulating protein, NESP, ARANESP, Amgen Inc, Thousand Oaks, CA), which was engineered to contain 5 N-linked carbohydrate chains (two more than rHuEPO), has been evaluated in preclinical animal studies. Due to its increased sialic acid-containing carbohydrate content, NESP is biochemically distinct from rHuEPO, having an increased molecular weight and greater negative charge. Compared with rHuEPO, it has an approximate 3-fold longer serum half-life, greater in vivo potency, and can be administered less frequently to obtain the same biological response. NESP is currently being evaluated in human clinical trials for treatment of anaemia and reduction in its incidence.


Degenerative arthritis in mice. Study of age and sex frequency in various strains with a genetic study of NZB/B1, NZY/B1, and hybrid mice.
Of a number of strains of mice studied for evidence of autoimmunity, NZY/B1 mice showed the highest frequency of degenerative arthritis of the knee, reaching a maximum of 68% at 18 months. 50% PN mice were affected at 24 months. Both breeds differed from previously described strains in not showing a sex difference. The NZB/B1 mice were rarely affected and hybrids to the NZY and the backcross to the NZB showed a recessive pattern of inheritance for knee arthritis and an additive pattern for carpal arthritis. Polygenic inheritance was postulated as at least three genes would be necessary to explain the findings. Joint disease was not related to red cell and nuclear antibodies, glomerulitis, or arteritis.


Dynamic distribution decomposition for single-cell snapshot time series identifies subpopulations and trajectories during iPSC reprogramming.
Recent high-dimensional single-cell technologies such as mass cytometry are enabling time series experiments to monitor the temporal evolution of cell state distributions and to identify dynamically important cell states, such as fate decision states in differentiation. However, these technologies are destructive, and require analysis approaches that temporally map between cell state distributions across time points. Current approaches to approximate the single-cell time series as a dynamical system suffer from too restrictive assumptions about the type of kinetics, or link together pairs of sequential measurements in a discontinuous fashion. We propose Dynamic Distribution Decomposition (DDD), an operator approximation approach to infer a continuous distribution map between time points. On the basis of single-cell snapshot time series data, DDD approximates the continuous time Perron-Frobenius operator by means of a finite set of basis functions. This procedure can be interpreted as a continuous time Markov chain over a continuum of states. By only assuming a memoryless Markov (autonomous) process, the types of dynamics represented are more general than those represented by other common models, e.g., chemical reaction networks, stochastic differential equations. Furthermore, we can a posteriori check whether the autonomy assumptions are valid by calculation of prediction error-which we show gives a measure of autonomy within the studied system. The continuity and autonomy assumptions ensure that the same dynamical system maps between all time points, not arbitrarily changing at each time point. We demonstrate the ability of DDD to reconstruct dynamically important cell states and their transitions both on synthetic data, as well as on mass cytometry time series of iPSC reprogramming of a fibroblast system. We use DDD to find previously identified subpopulations of cells and to visualise differentiation trajectories. Dynamic Distribution Decomposition allows interpretation of high-dimensional snapshot time series data as a low-dimensional Markov process, thereby enabling an interpretable dynamics analysis for a variety of biological processes by means of identifying their dynamically important cell states.


The patient-oriented clinician-researcher: advantages and challenges of being a double agent.
The number of clinically trained individuals who perform research is declining. Although it is often observed that the clinician-researcher is necessary, the reasons are rarely discussed. In this article, the authors critically consider the complexities of the role of the patient-oriented clinician-researcher at the interface of behavioral health treatment and research. The authors note that patient-oriented clinician-researchers can serve as effective "bridgers" between the research and practice communities and can facilitate both the development of clinically relevant research and the dissemination of evidence-based treatments into routine clinical services. However, care needs to be taken to address the potential for ethical and role conflicts. Programs can encourage trainees to become clinician-researchers by providing opportunities for them to meet with patient-oriented clinician-researchers and by including coursework that raises their awareness of ethical and role conflicts and provides them with the skills needed to be effective "bridgers."


The time course of the last contractions during incompletely fused tetani of motor units in rat skeletal muscle.
The time course of the contraction and the relaxation of individual contractions during incompletely fused tetani of motor units were analyzed. Investigations were performed on fast fatigable (FF), fast resistant (FR) and slow (S) motor units of the rat medial gastrocnemius muscle. Stimulation of a motor unit with a series of nine trains of stimuli at a frequency from 10 to 150 Hz was used and tetani fused to a variable degree were recorded. For fast motor units the procedure was repeated twice and observations were made on potentiated tetani in the second series of stimulation. For each tetanus, the amplitude of the tension increase, the peak amplitude of the contraction, the contraction time and the half-relaxation time were measured in the last contraction of the tension recording. It was observed in all three types of motor units that the last contraction was prolonged in parallel with the increase of fusion of a tetanus. In this contraction, the contraction time slightly decreased whereas the half-relaxation time strongly prolonged. The prolongation of the half-relaxation time was the strongest in tetani of slow units. Moreover, for the last contraction in a tetanus, the rate of changes in tension were studied. The rate of increase in tension during the contraction decreased in parallel with the increase of fusion of a tetanus, whereas the maximal rate of the tension decrease during the relaxation was found in tetani with fusion indices of 0.79, 0.98 and 0.95 for FF, FR and S motor units, respectively. Changes in the time course of contractions in tetani fused to a variable degree can shed light on processes of summation of contractions in unfused tetani at the level of individual motor units.


Genetic variants of human serum cholinesterase influence metabolism of the muscle relaxant succinylcholine.
People with genetic variants of cholinesterase respond abnormally to succinylcholine, experiencing substantial prolongation of muscle paralysis with apnea rather than the usual 2-6 min. The structure of usual cholinesterase has been determined including the complete amino acid and nucleotide sequence. This has allowed identification of altered amino acids and nucleotides. The variant most frequently found in patients who respond abnormally to succinylcholine is atypical cholinesterase, which occurs in homozygous form in 1 out of 3500 Caucasians. Atypical cholinesterase has a single substitution at nucleotide 209 which changes aspartic acid 70 to glycine. This suggests that Asp 70 is part of the anionic site, and that the absence of this negatively charged amino acid explains the reduced affinity of atypical cholinesterase for positively charged substrates and inhibitors. The clinical consequence of reduced affinity for succinylcholine is that none of the succinylcholine is hydrolyzed in blood and a large overdose reaches the nerve-muscle junction where it causes prolonged muscle paralysis. Silent cholinesterase has a frame shift mutation at glycine 117 which prematurely terminates protein synthesis and yields no active enzyme. The K variant, named in honor of W. Kalow, has threonine in place of alanine 539. The K variant is associated with 33% lower activity. All variants arise from a single locus as there is only one gene for human cholinesterase (EC 18.104.22.168). Comparison of amino acid sequences of esterases and proteases shows that cholinesterase belongs to a new family of serine esterases which is different from the serine proteases.


Effects of perinatal asphyxia and myoglobinuria on development of acute, neonatal renal failure.
Thirty four consecutive neonates with birth asphyxia or respiratory problems were examined in the first week of life to clarify the relation between neonatal myoglobinuria and acute renal failure. Investigations included determination of creatinine clearance, fractional sodium excretion, and N-acetyl-beta-D glucosaminidase index as an indicator of tubular injury. The infants' gestational ages ranged from 29 to 41 weeks (mean 36 weeks). Fifteen infants did not have myoglobinuria on the first day of life (group A); myoglobinuria was mild in eight infants (group B) and severe in eleven (group C). Two infants in group B and seven in group C developed acute renal failure (47%). Ten infants in group C (91%) had severe asphyxia, five of whom (45%) also suffered neonatal seizures and intracranial haemorrhage. We suggest that myoglobin derived from muscle breakdown in asphyxiated infants may lead to acute renal failure secondary to a reduction in renal blood flow, or to tubular damage.


Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance.
Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection.


Blood pressure response to chronic low-dose intrarenal noradrenaline infusion in conscious rats.
Sodium chloride solution (0.9%) or noradrenaline in doses of 4, 12 and 36 micrograms h-1 kg-1 was infused for five consecutive days, either intrarenally (by a new technique) or intravenously into rats with one kidney removed. Intrarenal infusion of noradrenaline caused hypertension at doses which did not do so when infused intravenously. Intrarenal compared with intravenous infusion of noradrenaline caused higher plasma noradrenaline concentrations and a shift of the plasma noradrenaline concentration-blood pressure effect curve towards lower plasma noradrenaline levels. These results suggest that hypertension after chronic intrarenal noradrenaline infusion is produced by relatively higher levels of circulating noradrenaline and by triggering of an additional intrarenal pressor mechanism.


Proteinaceous cysteine protease inhibitors.
Studies of proteinaceous cysteine protease inhibitors originated with the discovery of cystatins in the 1960s. Since that time, a rich and fascinating world of proteins that control and regulate a multitude of important physiological processes, ranging from the basics of protein turnover to development and brain function, has been uncovered. Failures in such important and complex systems inevitably lead to pathologies. Many threatening diseases such as cancer or neurological disorders, to mention only some, are attributed to deregulation of protease-inhibitor balance. Moreover, important aspects of infection pathology and host defense rely on proteolysis and protease inhibition. Recent advances in the field of protease inhibitors have drawn attention to the possible use of this collected knowledge to control related pathological processes. This review attempts to familiarize the reader with proteinaceous cysteine protease inhibitors by providing an overview of current knowledge. The work primarily highlights biological processes in which the inhibitors are involved and focuses on pathologies resulting from aberrant protease-inhibitor balance, pointing out emerging possibilities for their correction.


Do all schizophrenia patients need antipsychotic treatment continuously throughout their lifetime? A 20-year longitudinal study.
The prevailing standard of care in the field involves background assumptions about the importance of prolonged use of antipsychotic medications for all schizophrenia (SZ) patients. However, do all SZ patients need antipsychotics indefinitely? Are there factors that help to identify which SZ patients can enter into prolonged periods of recovery without antipsychotics? This 20-year longitudinal research studied these issues. A total of 139 early young psychotic patients from the Chicago Follow-up Study, including 70 patients with SZ syndromes and 69 with mood disorders, were assessed, prospectively, at the acute phase and then followed up six times over the next 20 years. Patients were assessed with standardized instruments for major symptoms, psychosocial functioning, personality, attitudinal variables, neurocognition and treatment. At each follow-up, 30-40% of SZ patients were no longer on antipsychotics. Starting at the 4.5-year follow-ups and continuing thereafter, SZ patients not on antipsychotics for prolonged periods were significantly less likely to be psychotic and experienced more periods of recovery; they also had more favorable risk and protective factors. SZ patients off antipsychotics for prolonged periods did not relapse more frequently. The data indicate that not all SZ patients need treatment with antipsychotics continuously throughout their lives. SZ patients not on antipsychotics for prolonged periods are a self-selected group with better internal resources associated with greater resiliency. They have better prognostic factors, better pre-morbid developmental achievements, less vulnerability to anxiety, better neurocognitive skills, less vulnerability to psychosis and experience more periods of recovery.


Race and ethnicity in fragile families.
Robert Hummer and Erin Hamilton note that the prevalence of fragile families varies substantially by race and ethnicity. African Americans and Hispanics have the highest prevalence; Asian Americans, the lowest; and whites fall somewhere in the middle. The share of unmarried births is lower among most foreign-born mothers than among their U.S.-born ethnic counterparts. Immigrant-native differences are particularly large for Asians, whites, and blacks. The authors also find racial and ethnic differences in the composition and stability of fragile families over time. Although most parents of all racial and ethnic groups are romantically involved at the time of their child's birth, African American women are less likely to be in a cohabiting relationship than are white and Hispanic mothers. Over time, these racial and ethnic differences become more pronounced, with African American mothers having the lowest rates of marriage and cohabitation and the highest breakup rates, and Mexican immigrant mothers having the highest rates of marriage and cohabitation and the lowest breakup rates. Fragile families have far fewer socioeconomic resources than married families, though resources vary within fragile families by race and ethnicity. White mothers, in general, have more socioeconomic resources than black, Mexican American, and Mexican immigrant mothers; they are more likely to have incomes above the poverty limit, more likely to own a car, less likely to have children from a prior relationship, and more likely to report living in a safe neighborhood. Access to health care and child care follows a similar pattern. The exception is education; black and white unmarried mothers are equally likely to have finished high school, and Mexican immigrant and Mexican American mothers are less likely to have done so. The authors argue that socioeconomic differences are by far the biggest driver of racial and ethnic differences in marriage and family stability, and they support reforms to strengthen parents' economic security. They also discuss how sex ratios and culture affect family formation and stability. In particular, they note that despite severe poverty, Mexican immigrant families have high rates of marriage and cohabitation--an advantage that erodes by the second generation with assimilation. To address the paradox that marriage declines as socioeconomic status improves, they support policies that reinforce rather than undermine the family ties of Mexican immigrants.