Glycemic index: overview of implications in health and disease.
The glycemic index concept is an extension of the fiber hypothesis, suggesting that fiber consumption reduces the rate of nutrient influx from the gut. The glycemic index has particular relevance to those chronic Western diseases associated with central obesity and insulin resistance. Early studies showed that starchy carbohydrate foods have very different effects on postprandial blood glucose and insulin responses in healthy and diabetic subjects, depending on the rate of digestion. A range of factors associated with food consumption was later shown to alter the rate of glucose absorption and subsequent glycemia and insulinemia. At this stage, systematic documentation of the differences that exist among carbohydrate foods was considered essential. The resulting glycemic index classification of foods provided a numeric physiologic classification of relevant carbohydrate foods in the prevention and treatment of diseases such as diabetes. Since then, low-glycemic-index diets have been shown to lower urinary C-peptide excretion in healthy subjects, improve glycemic control in diabetic subjects, and reduce serum lipids in hyperlipidemic subjects. Furthermore, consumption of low-glycemicindex diets has been associated with higher HDL-cholesterol concentrations and, in large cohort studies, with decreased risk of developing diabetes and cardiovascular disease. Case-control studies have also shown positive associations between dietary glycemic index and the risk of colon and breast cancers. Despite inconsistencies in the data, sufficient, positive findings have emerged to suggest that the dietary glycemic index is of potential importance in the treatment and prevention of chronic diseases.


Predictors of benefit following pulmonary rehabilitation for interstitial lung disease.
Pulmonary rehabilitation improves functional capacity and symptoms in the interstitial lung diseases (ILDs), however there is marked variation in outcomes between individuals. The aim of this study was to establish the impact of the aetiology and severity of ILD on response to pulmonary rehabilitation. Forty-four subjects with ILD, including 25 with idiopathic pulmonary fibrosis (IPF), underwent eight weeks of pulmonary rehabilitation. Relationships between disease aetiology, markers of disease severity and response to pulmonary rehabilitation were assessed after eight weeks and six months, regardless of program completion. In IPF, greater improvements in 6-minute walk distance (6MWD) immediately following pulmonary rehabilitation were associated with larger forced vital capacity (r = 0.49, p = 0.01), less exercise-induced oxyhaemoglobin desaturation (r(S) = 0.43, p = 0.04) and lower right ventricular systolic pressure (r = -0.47, p = 0.1). In participants with other ILDs there was no relationship between change in 6MWD and baseline variables. Less exercise-induced oxyhaemoglobin desaturation at baseline independently predicted a larger improvement in 6MWD at six month follow-up. Fewer participants with IPF had clinically important reductions in dyspnoea at six months compared to those with other ILDs (25% vs 56%, p = 0.04). More severe dyspnoea at baseline and diagnosis other than IPF predicted greater improvement in dyspnoea at six months. Patients with IPF attain greater and more sustained benefits from pulmonary rehabilitation when disease is mild, whereas those with other ILDs achieve benefits regardless of disease severity. Early referral to pulmonary rehabilitation should be considered in IPF.


First use of a divalent lanthanide for visible-light-promoted photoredox catalysis.
We report the first catalytic use of a divalent lanthanide in visible-light-promoted bond-forming reactions. Our new precatalyst uses europium in the +2 oxidation state and is active in the presence of blue light from light-emitting diodes. The use of low-energy visible light reduces the occurrence of potential side reactions that might be induced by higher-energy UV light. The system described here uses zinc metal as a sacrificial reductant and is tolerant to wet, protic solvents. The catalyst can be made in situ from relatively inexpensive and air-stable EuCl3·6H2O, and the ligand can be synthesized in large quantities in two steps. With 0.5% loading of precatalyst, an average of 120 turnovers was observed in six hours for reductive coupling of benzyl chloride. We expect that the results will initiate the study of visible-light-promoted photoredox catalysis using divalent europium in a variety of reactions.


Lyme disease: a neuropsychiatric illness.
Lyme disease is a multisystemic illness that can affect the central nervous system (CNS), causing neurologic and psychiatric symptoms. The goal of this article is to familiarize psychiatrists with this spirochetal illness. Relevant books, articles, and abstracts from academic conferences were perused, and additional articles were located through computerized searches and reference sections from published articles. Up to 40% of patients with Lyme disease develop neurologic involvement of either the peripheral or central nervous system. Dissemination to the CNS can occur within the first few weeks after skin infection. Like syphilis, Lyme disease may have a latency period of months to years before symptoms of late infection emerge. Early signs include meningitis, encephalitis, cranial neuritis, and radiculoneuropathies. Later, encephalomyelitis and encephalopathy may occur. A broad range of psychiatric reactions have been associated with Lyme disease including paranoia, dementia, schizophrenia, bipolar disorder, panic attacks, major depression, anorexia nervosa, and obsessive-compulsive disorder. Depressive states among patients with late Lyme disease are fairly common, ranging across studies from 26% to 66%. The microbiology of Borrelia burgdorferi sheds light on why Lyme disease can be relapsing and remitting and why it can be refractory to normal immune surveillance and standard antibiotic regimens. Psychiatrists who work in endemic areas need to include Lyme disease in the differential diagnosis of any atypical psychiatric disorder. Further research is needed to identify better laboratory tests and to determine the appropriate manner (intravenous or oral) and length (weeks or months) of treatment among patients with neuropsychiatric involvement.


Acupuncture in the treatment of upper-limb lymphedema: results of a pilot study.
Current treatments for lymphedema after breast cancer treatment are expensive and require ongoing intervention. Clinical experience and our preliminary published results suggest that acupuncture is safe and potentially useful. This study evaluates the safety and potential efficacy of acupuncture on upper-limb circumference in women with lymphedema. Women with a clinical diagnosis of breast cancer-related lymphedema (BCRL) for 0.5-5 years and with affected arm circumference ≥2 cm larger than unaffected arm received acupuncture treatment twice weekly for 4 weeks. Affected and unaffected arm circumferences were measured before and after each acupuncture treatment. Response, defined as ≥30% reduction in circumference difference between affected/unaffected arms, was assessed. Monthly follow-up calls for 6 months thereafter were made to document any complications and self-reported lymphedema status. Among 37 enrolled patients, 33 were evaluated; 4 discontinued due to time constraints. Mean reduction in arm circumference difference was 0.90 cm (95% CI, 0.72-1.07; P < .0005). Eleven patients (33%) exhibited a reduction of ≥30% after acupuncture treatment. Seventy-six percent of patients received all treatments; 21% missed 1 treatment, and another patient missed 2 treatments. During the treatment period, 14 of the 33 patients reported minor complaints, including mild local bruising or pain/tingling. There were no serious adverse events and no infections or severe exacerbations after 255 treatment sessions and 6 months of follow-up interviews. Acupuncture for BCRL appears safe and may reduce arm circumference. Although these results await confirmation in a randomized trial, acupuncture can be considered for women with no other options for sustained arm circumference reduction.


Sensory innervation of normal and hypospadiac prepuce: possible implications in hypospadiology.
Sensory innervation of the skin influences wound healing through the release of neuropeptides from the nerve endings. The purpose of this study was to investigate the differences in the sensory innervation of the normal and the hypospadiac prepuce. The prepuce from 10 healthy children undergoing routine circumcision and 10 age-matched children undergoing hypospadias repair were submitted for immunohistochemistry, using antibodies against protein gene product (PGP) 9.5, calcitonin gene-related peptide (CGRP), and substance P (SP). The hypospadiac prepuce was found to be hypo-innervated for PGP 9.5 and CGRP positive nerves when compared with the normal prepuce ( p<0.05). The number of SP-positive nerves were increased in the hypospadiac prepuce, but not to statistical significance ( p=0.06, confidence interval >95%). There may be differences in the sensory innervation of the normal and hypospadiac prepuce. These differences in tissue environment may partly explain the postoperative edema, poor wound healing leading to urethrocutaneous fistula (UF), and increased analgesia requirements in patients undergoing hypospadias surgery.


Wild-type and mutant in vitro products of an operon for ribonucleic acid polymerase subunits.
An in vitro protein-synthesizing system can synthesize two ribonucleic acid (RNA) polymerase subunits of Escherichia coli, beta and beta', when a transducing phage deoxyribonucleic acid (DNA) template containing the rpoB region of the bacterial chromosome is added. Recombinant rpoB transducing phages were isolated that carry "nonsense" mutations of the class rpo-rifampin zero amber (formally referred to as rifoam). DNA was extracted from two of these phages. These DNAs are unable to direct the synthesis of beta subunits, whereas beta' synthesis is unaffected. Both mutations can be efficiently suppressed in vitro by the addition of suppressor transfer RNA. One of the mutations (rpoB115) produces a detectable nonsense (or restart) fragment of the beta protein in the absence of suppression. It is concluded that rpoB115 is an amber mutation within the structural gene for the beta subunit of RNA polymerase.


Magnetic anisotropy in isotropic and nanopatterned strongly exchange-coupled nanolayers.
In this study, the fabrication of magnetic multilayers with a controlled value of the in-plane uniaxial magnetic anisotropy field in the range of 12 to 72 kA/m was achieved. This fabrication was accomplished by the deposition of bilayers consisting of an obliquely deposited (54°) 8-nm-thick anisotropic Co layer and a second isotropic Co layer that was deposited at a normal incidence over the first layer. By changing the thickness value of this second Co layer (X) by modifying the deposition time, the value of the anisotropy field of the sample could be controlled. For each sample, the thickness of each bilayer did not exceed the value of the exchange correlation length calculated for these Co bilayers. To increase the volume of the magnetic films without further modification of their magnetic properties, a Ta spacer layer was deposited between successive Co bilayers at 54° to prevent direct exchange coupling between consecutive Co bilayers. This step was accomplished through the deposition of multilayered films consisting of several (Co8 nm-54°/CoX nm-0°/Ta6 nm-54°) trilayers.


The distribution of individual threshold doses eliciting allergic reactions in a population with peanut allergy.
Hidden peanut in consumer products can endanger patients with peanut allergy. Individual threshold doses for eliciting allergic reactions need to be elucidated to assess the risks for development of allergic reactions after accidental ingestion of peanut in a population with peanut allergy. We sought to determine the distribution of individual threshold doses in a population with peanut allergy and to correlate these thresholds to the severity of peanut-induced symptoms. Twenty-six adult patients with a convincing history of peanut-related symptoms, a specific IgE level of 0.7 kU/L or greater, or a positive skin prick test response of 2+ or greater to peanut were included. These patients underwent double-blind, placebo-controlled food challenges with increasing doses of peanut. A threshold dose could be established when objective or repetitive subjective reactions occurred after active doses. All patients had subjective oral symptoms (n = 26), prior subjective gastrointestinal symptoms (n = 14), or objective symptoms (n = 5). Reactions started within 30 minutes after ingestion of peanut, but in 2 patients additional symptoms were delayed by 1 to 2 hours. Threshold doses for allergic reactions ranged from a dose as low as 100 microg up to 1 g of peanut protein. Fifty percent of the study population (95% CI, 30%-70%) already had an allergic reaction after ingestion of 3 mg of peanut protein. Patients with severe symptoms had lower threshold doses compared with those of patients with mild symptoms (P =.027). A substantial part of a population with peanut allergy will react to very low amounts of peanut, requiring accurate declaration of peanut content in consumer products. This is even more important because patients with severe reactions react to lower doses than patients with mild symptoms.


Therapeutic effect of paclitaxel and propolis on lipid peroxidation and antioxidant system in 7,12 dimethyl benz(a)anthracene-induced breast cancer in female Sprague Dawley rats.
Breast cancer is one of the most common cancers in women of developed and developing countries. The optimum management of which requires a multidisciplinary approach including the use of certain biochemical and molecular markers. The effect of propolis along with paclitaxel on 7,12 dimethyl benz(a)anthracene (DMBA) induced experimental breast cancer was investigated in female Sprague Dawley rats. Female Sprague Dawley rats were divided into five groups of six animals each. Group I served as normal control animal. Group II animals received DMBA (20 mg in 0.5 ml sunflower oil and 0.5 ml of saline) i.p. to develop mammary tumor by the end of 90 days. Group III were breast cancer animals treated with 33 mg paclitaxel/kg body weight (bw) weekly once for 4 weeks. Group IV were breast cancer-bearing animals treated with 50 mg propolis/kg bw for 30 days. Group V were breast cancer-bearing animals treated with both paclitaxel and propolis as mentioned above. Administration of paclitaxel and propolis effectively suppressed breast cancer, which is revealed by the decrease in the extent of lipid peroxidation (LPO) with concomitant increase in the activities of enzymic antioxidants (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)) and non-enzymic antioxidants (reduced glutathione (GSH), Vitamin C and Vitamin E) levels when compared to breast cancer-bearing animals treated with either paclitaxel or propolis alone. From our results, we conclude that propolis is a potent antioxidant and, when given in combination with paclitaxel, offers maximum protection against DMBA induced mammary carcinogenesis.


Noninvasive imaging of 5-HT3 receptor trafficking in live cells: from biosynthesis to endocytosis.
Sequential stages in the life cycle of the ionotropic 5-HT(3) receptor (5-HT(3)R) were resolved temporally and spatially in live cells by multicolor fluorescence confocal microscopy. The insertion of the enhanced cyan fluorescent protein into the large intracellular loop delivered a fluorescent 5-HT(3)R fully functional in terms of ligand binding specificity and channel activity, which allowed for the first time a complete real-time visualization and documentation of intracellular biogenesis, membrane targeting, and ligand-mediated internalization of a receptor belonging to the ligand-gated ion channel superfamily. Fluorescence signals of newly expressed receptors were detectable in the endoplasmic reticulum about 3 h after transfection onset. At this stage receptor subunits assembled to form active ligand binding sites as demonstrated in situ by binding of a fluorescent 5-HT(3)R-specific antagonist. After novel protein synthesis was chemically blocked, the 5-HT(3) R populations in the endoplasmic reticulum and Golgi cisternae moved virtually quantitatively to the cell surface, indicating efficient receptor folding and assembly. Intracellular 5-HT(3) receptors were trafficking in vesicle-like structures along microtubules to the cell surface at a velocity generally below 1 mum/s and were inserted into the plasma membrane in a characteristic cluster distribution overlapping with actin-rich domains. Internalization of cell surface 5-HT(3) receptors was observed within minutes after exposure to an extracellular agonist. Our orchestrated use of spectrally distinguishable fluorescent labels for the receptor, its cognate ligand, and specific organelle markers can be regarded as a general approach allowing subcellular insights into dynamic processes of membrane receptor trafficking.


Short-Term Dynamic and Local Epidemiological Trends in the South American HIV-1B Epidemic.
The human displacement and sexual behavior are the main factors driving the HIV-1 pandemic to the current profile. The intrinsic structure of the HIV transmission among different individuals has valuable importance for the understanding of the epidemic and for the public health response. The aim of this study was to characterize the HIV-1 subtype B (HIV-1B) epidemic in South America through the identification of transmission links and infer trends about geographical patterns and median time of transmission between individuals. Sequences of the protease and reverse transcriptase coding regions from 4,810 individuals were selected from GenBank. Maximum likelihood phylogenies were inferred and submitted to ClusterPicker to identify transmission links. Bayesian analyses were applied only for clusters including ≥5 dated samples in order to estimate the median maximum inter-transmission interval. This study analyzed sequences sampled from 12 South American countries, from individuals of different exposure categories, under different antiretroviral profiles, and from a wide period of time (1989-2013). Continentally, Brazil, Argentina and Venezuela were revealed important sites for the spread of HIV-1B among countries inside South America. Of note, from all the clusters identified about 70% of the HIV-1B infections are primarily occurring among individuals living in the same geographic region. In addition, these transmissions seem to occur early after the infection of an individual, taking in average 2.39 years (95% CI 1.48-3.30) to succeed. Homosexual/Bisexual individuals transmit the virus as quickly as almost half time of that estimated for the general population sampled here. Public health services can be broadly benefitted from this kind of information whether to focus on specific programs of response to the epidemic whether as guiding of prevention campaigns to specific risk groups.


Enzymatic manganese(II) oxidation by metabolically dormant spores of diverse Bacillus species.
Bacterial spores are renowned for their longevity, ubiquity, and resistance to environmental insults, but virtually nothing is known regarding whether these metabolically dormant structures impact their surrounding chemical environments. In the present study, a number of spore-forming bacteria that produce dormant spores which enzymatically oxidize soluble Mn(II) to insoluble Mn(IV) oxides were isolated from coastal marine sediments. The highly charged and reactive surfaces of biogenic metal oxides dramatically influence the oxidation and sorption of both trace metals and organics in the environment. Prior to this study, the only known Mn(II)-oxidizing sporeformer was the marine Bacillus sp. strain SG-1, an extensively studied bacterium in which Mn(II) oxidation is believed to be catalyzed by a multicopper oxidase, MnxG. Phylogenetic analysis based on 16S rRNA and mnxG sequences obtained from 15 different Mn(II)-oxidizing sporeformers (including SG-1) revealed extensive diversity within the genus Bacillus, with organisms falling into several distinct clusters and lineages. In addition, active Mn(II)-oxidizing proteins of various sizes, as observed in sodium dodecyl sulfate-polyacrylamide electrophoresis gels, were recovered from the outer layers of purified dormant spores of the isolates. These are the first active Mn(II)-oxidizing enzymes identified in spores or gram-positive bacteria. Although extremely resistant to denaturation, the activities of these enzymes were inhibited by azide and o-phenanthroline, consistent with the involvement of multicopper oxidases. Overall, these studies suggest that the commonly held view that bacterial spores are merely inactive structures in the environment should be revised.


Neuromelanin, neurotransmitter status and brainstem location determine the differential vulnerability of catecholaminergic neurons to mitochondrial DNA deletions.
Deletions of the mitochondrial DNA (mtDNA) accumulate to high levels in dopaminergic neurons of the substantia nigra pars compacta (SNc) in normal aging and in patients with Parkinson's disease (PD). Human nigral neurons characteristically contain the pigment neuromelanin (NM), which is believed to alter the cellular redox-status. The impact of neuronal pigmentation, neurotransmitter status and brainstem location on the susceptibility to mtDNA damage remains unclear. We quantified mtDNA deletions (ΔmtDNA) in single pigmented and non-pigmented catecholaminergic, as well as non-catecholaminergic neurons of the human SNc, the ventral tegmental area (VTA) and the locus coeruleus (LC), using laser capture microdissection and single-cell real-time PCR. In healthy aged individuals, ΔmtDNA levels were highest in pigmented catecholaminergic neurons (25.2 ± 14.9%), followed by non-pigmented catecholamergic (18.0 ± 11.2%) and non-catecholaminergic neurons (12.3 ± 12.3%; p < 0.001). Within the catecholaminergic population, ΔmtDNA levels were highest in dopaminergic neurons of the SNc (33.9 ± 21.6%) followed by dopaminergic neurons of the VTA (21.9 ± 12.3%) and noradrenergic neurons of the LC (11.1 ± 11.4%; p < 0.001). In PD patients, there was a trend to an elevated mutation load in surviving non-pigmented nigral neurons (27.13 ± 16.73) compared to age-matched controls (19.15 ± 11.06; p = 0.052), but levels where similar in pigmented nigral neurons of PD patients (41.62 ± 19.61) and controls (41.80 ± 22.62). Catecholaminergic brainstem neurons are differentially susceptible to mtDNA damage. Pigmented dopaminergic neurons of the SNc show the highest ΔmtDNA levels, possibly explaining the exceptional vulnerability of the nigro-striatal system in PD and aging. Although loss of pigmented noradrenergic LC neurons also is an early feature of PD pathology, mtDNA levels are not elevated in this nucleus in healthy controls. Thus, ΔmtDNA are neither an inevitable consequence of catecholamine metabolism nor a universal explanation for the regional vulnerability seen in PD.


Particulate photocatalyst sheets for Z-scheme water splitting: advantages over powder suspension and photoelectrochemical systems and future challenges.
Water splitting using semiconductor photocatalysts has been attracting growing interest as a means of solar energy based conversion of water to hydrogen, a clean and renewable fuel. Z-scheme photocatalytic water splitting based on the two-step excitation of an oxygen evolution photocatalyst (OEP) and a hydrogen evolution photocatalyst (HEP) is a promising approach toward the utilisation of visible light. In particular, a photocatalyst sheet system consisting of HEP and OEP particles embedded in a conductive layer has been recently proposed as a new means of obtaining efficient and scalable redox mediator-free Z-scheme solar water splitting. In this paper, we discuss the advantages and disadvantages of the photocatalyst sheet approach compared to conventional photocatalyst powder suspension and photoelectrochemical systems through an examination of the water splitting activity of Z-scheme systems based on SrTiO3:La,Rh as the HEP and BiVO4:Mo as the OEP. This photocatalyst sheet was found to split pure water much more efficiently than the powder suspension and photoelectrochemical systems, because the underlying metal layer efficiently transfers electrons from the OEP to the HEP. The photocatalyst sheet also outperformed a photoelectrochemical parallel cell during pure water splitting. The effects of H+/OH- concentration overpotentials and of the IR drop are reduced in the case of the photocatalyst sheet compared to photoelectrochemical systems, because the HEP and OEP are situated in close proximity to one another. Therefore, the photocatalyst sheet design is well-suited to efficient large-scale applications. Nevertheless, it is also noted that the photocatalytic activity of these sheets drops markedly with increasing background pressure because of reverse reactions involving molecular oxygen under illumination as well as delays in gas bubble desorption. It is shown that appropriate surface modifications allow the photocatalyst sheet to maintain its water splitting activity at elevated pressure. Accordingly, we conclude that the photocatalyst sheet system is a viable option for the realisation of efficient solar fuel production.


JNK, cytoskeletal regulator and stress response kinase? A Drosophila perspective.
c-Jun N-terminal kinases (JNKs) are intracellular stress-activated signalling molecules, which are controlled by a highly evolutionarily conserved signalling cascade. In mammalian cells, JNKs are regulated by a wide variety of cellular stresses and growth factors and have been implicated in the regulation of remarkably diverse biological processes, such as cell shape changes, immune responses and apoptosis. How can such different stimuli activate the JNK pathway and what roles does JNK play in vivo? Molecular genetic analysis of the Drosophila JNK gene has started to provide answers to these questions, confirming the role of this molecule in development and stress responses and suggesting a conserved function for JNK signalling in processes such as wound healing. Here, we review this work and discuss how future experiments in Drosophila should reveal the cell type-specific mechanisms by which JNKs perform their diverse functions.


Virologic and serologic markers of rapid progression to AIDS after HIV-1 seroconversion.
The association between early virologic and immunologic events after human immunodeficiency virus type 1 (HIV-1) infection and progression of HIV-1 infection to acquired immunodeficiency syndrome (AIDS) was studied among 59 homosexual men with documented time of seroconversion. Epidemiologic factors, such as number of lifetime sexual partners, history of sexually transmitted diseases, and other factors, also were studied. All 17 seroconverters in the cohort who developed AIDS within 3 years (rapid progressors = RPs) were compared with 42 men without AIDS for at least 6 years seroconversion (nonrapid progressors = non-RPs). Plasma levels of HIV-1 RNA, p24 antigen, antibodies to HIV-1 structural genes, beta-2 microglobulin, neopterin, and interferon-alpha were measured at four time points: (a) the last seronegative visit, (b) the first seropositive visit, (c) the visit closest to AIDS (or the corresponding visit for the non-RPs) and (d) 6 years after seroconversion (for non-RPs). Up to seroconversion, the RPs had a significantly higher number of lifetime sexual partners than non-RPs (503 versus 171, respectively). At the first seropositive visit, RPs had significantly higher concentrations of plasma HIV-1 RNA (p < 0.01) and prevalence of p24 antigenemia (p < 0.001) and significantly lower levels of antibodies to the HIV-1 gag proteins p17 and p24 (p < 0.01-0.001) compared with non-RPs. These differences increased during follow-up visits. Antibodies to p66 and gp120 were significantly different only at the visit closet to AIDS (p < 0.001), as were beta-2 microglobulin and interferon alpha. These findings suggest that early virologic-immunologic events after HIV-1 infection may determine the rate of progression to AIDS. Anti-gag immune response may prevent rapid progression of HIV-1 disease and should be considered for future vaccine studies.


Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine.
Testicular germ cell tumors (TGCTs) are the most common cancers of young males. A substantial portion of TGCT patients are refractory to cisplatin. There are no effective therapies for these patients, many of whom die from progressive disease. Embryonal carcinoma (EC) are the stem cells of TGCTs. In prior in vitro studies we found that EC cells were highly sensitive to the DNA methyltransferase inhibitor, 5-aza deoxycytidine (5-aza). Here, as an initial step in bringing demethylation therapy to the clinic for TGCT patients, we evaluated the effects of the clinically optimized, second generation demethylating agent guadecitabine (SGI-110) on EC cells in an animal model of cisplatin refractory testicular cancer. EC cells were exquisitely sensitive to guadecitabine and the hypersensitivity was dependent on high levels of DNA methyltransferase 3B. Guadecitabine mediated transcriptional reprogramming of EC cells included induction of p53 targets and repression of pluripotency genes. As a single agent, guadecitabine completely abolished progression and induced complete regression of cisplatin resistant EC xenografts even at doses well below those required to impact somatic solid tumors. Low dose guadecitabine also sensitized refractory EC cells to cisplatin in vivo. Genome-wide analysis indicated that in vivo antitumor activity was associated with activation of p53 and immune-related pathways and the antitumor effects of guadecitabine were dependent on p53, a gene rarely mutated in TGCTs. These preclinical findings suggest that guadecitabine alone or in combination with cisplatin is a promising strategy to treat refractory TGCT patients.


Pyelonephritis in Pregnancy: Clinical and Laboratorial Aspects and Perinatal Results.
Objective To identify the prevalence of pyelonephritis during pregnancy and to analyze the clinical and laboratorial aspects, perinatal results and complications. Methods A transversal study of 203 pregnant women who had pyelonephritis during pregnancy and whose labor took place between 2010 and 2016 at a hospital in the state of Santa Catarina, Brazil. The analysis was based on medical records as well as on the hospital's database. Clinical and laboratory conditions, antibiotics, bacterial resistance, perinatal outcomes and complications were all taken into account. The data was compared using the Mann-Whitney test and the Chi-square test. Results A prevalence of 1.97% with pyelonephritis was evidenced, with most patients having it during the second trimester of gestation. The bacteria most commonly found in the urine cultures was Escherichia coli, in 76.6% of cases, followed by Klebsiella pneumoniae (8.7%). Ceftriaxone had the lowest bacterial resistance (only 3.5% of the cases). On the other hand, ampicillin and cephalothin presented higher bacterial resistance, 52% and 36.2%, respectively. The risk of very premature delivery was more than 50% higher in patients with pyelonephritis. Conclusion Ampicillin and first-generation cephalosporins are associated with a higher bacterial resistance while ceftriaxone proved to have a high efficacy for the treatment of pyelonephritis due to low bacterial resistance. Patients with pyelonephritis showed a higher risk for very premature delivery (< 32 weeks). In this casuistry, there were no others significant differences in the overall perinatal outcomes when compared with the routine service series.


Induction of cerebral ischemic tolerance by erythromycin preconditioning reprograms the transcriptional response to ischemia and suppresses inflammation.
A single dose of the macrolide antibiotic erythromycin can induce tolerance against cerebral ischemia in vivo (pharmacologic preconditioning). This study identified potential mechanisms of tolerance induction by assessing effects of erythromycin preconditioning on the cerebral transcriptional response to transient global cerebral ischemia. Preconditioned and nonpreconditioned rats were exposed to 15 min of global cerebral ischemia, and changes in cerebral gene expression were identified by complementary DNA expression array and quantified by real-time reverse-transcription polymerase chain reaction. Ischemia caused a widespread up-regulation of transcription in nonpreconditioned brains in this model. Tolerance induction by erythromycin preconditioning reversed this pattern and caused a net down-regulation of a majority of genes, effectively reprogramming the brain's response pattern to ischemia. The most striking change in transcriptional response found in preconditioned animals was an almost complete suppression of the otherwise profound induction of proinflammatory genes by global ischemia. In contrast, the same treatment had little effect on the expression of apoptosis-inducing genes after ischemia. These findings present a new molecular correlate for the induction of ischemic tolerance achieved by erythromycin preconditioning and will further the understanding of this clinically important new regimen of preemptive neuroprotection.


Evidence for antibody-catalyzed ozone formation in bacterial killing and inflammation.
Recently, we showed that antibodies catalyze the generation of hydrogen peroxide (H2O2) from singlet molecular oxygen (1O2*) and water. Here, we show that this process can lead to efficient killing of bacteria, regardless of the antigen specificity of the antibody. H2O2 production by antibodies alone was found to be not sufficient for bacterial killing. Our studies suggested that the antibody-catalyzed water-oxidation pathway produced an additional molecular species with a chemical signature similar to that of ozone. This species is also generated during the oxidative burst of activated human neutrophils and during inflammation. These observations suggest that alternative pathways may exist for biological killing of bacteria that are mediated by potent oxidants previously unknown to biology.


How to select patients for antireflux surgery? The ICARUS guidelines (international consensus regarding preoperative examinations and clinical characteristics assessment to select adult patients for antireflux surgery).
Antireflux surgery can be proposed in patients with GORD, especially when proton pump inhibitor (PPI) use leads to incomplete symptom improvement. However, to date, international consensus guidelines on the clinical criteria and additional technical examinations used in patient selection for antireflux surgery are lacking. We aimed at generating key recommendations in the selection of patients for antireflux surgery. We included 35 international experts (gastroenterologists, surgeons and physiologists) in a Delphi process and developed 37 statements that were revised by the Consensus Group, to start the Delphi process. Three voting rounds followed where each statement was presented with the evidence summary. The panel indicated the degree of agreement for the statement. When 80% of the Consensus Group agreed (A+/A) with a statement, this was defined as consensus. All votes were mutually anonymous. Patients with heartburn with a satisfactory response to PPIs, patients with a hiatal hernia (HH), patients with oesophagitis Los Angeles (LA) grade B or higher and patients with Barrett's oesophagus are good candidates for antireflux surgery. An endoscopy prior to antireflux surgery is mandatory and a barium swallow should be performed in patients with suspicion of a HH or short oesophagus. Oesophageal manometry is mandatory to rule out major motility disorders. Finally, oesophageal pH (±impedance) monitoring of PPI is mandatory to select patients for antireflux surgery, if endoscopy is negative for unequivocal reflux oesophagitis. With the ICARUS guidelines, we generated key recommendations for selection of patients for antireflux surgery.


Variables related to increased mortality following out-patient pulmonary rehabilitation.
Although patients with advanced pulmonary diseases have significant improvement in exercise ability and functional status following comprehensive out-patient pulmonary rehabilitation (OPR), their long-term prognosis once they have reached this stage of their diseases remains poor. To further evaluate predictors of increased mortality in these patients, we related patient characteristics and short-term outcome obtained during OPR assessment of 158 patients to subsequent survival. The time period from OPR to death or collection of survival data was 40.0 +/- 17.1 months. The following variables were tested individually and in stepwise fashion using a proportional hazards model: 1) age; 2) gender; 3) pulmonary diagnosis; 4) prebronchodilator forced expiratory volume in one second (FEV1); 5) arterial oxygen tension (Pa,O2) and arterial carbon dioxide tension (Pa,CO2); 6) body mass index (BMI); 7) pre- and post-OPR 12 min walking distance (12-MW); 8) pre- and post-OPR quality of life, using the Chronic Respiratory Disease Questionnaire (CRDQ); 9) number and type of nonpulmonary diagnoses; and 10) number of medications. Separate survival analyses were performed for all deaths (the total group), respiratory deaths only (nonrespiratory deaths excluded), and nonrespiratory deaths only (respiratory deaths excluded). Forty three patients (27%) died during the study period; and the 3 year survival was 80%. For all three survival analyses, the post-OPR 12-MW was the most significant variable related to prognosis: patients with low timed walking distance had increased mortality both from respiratory and nonrespiratory causes. Other variables related to increased mortality included: elevated Pa,CO2; low pre-OPR 12-MW; reduced Pa,O2; low FEV1; low BMI, increased number of medications, and increased CRDQ dyspnoea. These results indicate that the timed walking distance following out-patient pulmonary rehabilitation is an important predictor of survival in patients with advanced pulmonary disease.


Clinical and genetic features of pediatric acute lymphoblastic leukemia in Down syndrome in the Nordic countries.
Children with Down syndrome (DS) have an increased risk for acute lymphoblastic leukemia (ALL). Although previous studies have shown that DS-ALL differs clinically and genetically from non-DS-ALL, much remains to be elucidated as regards genetic and prognostic factors in DS-ALL. To address clinical and genetic differences between DS-ALL and non-DS-ALL and to identify prognostic factors in DS-ALL, we ascertained and reviewed all 128 pediatric DS-ALL diagnosed in the Nordic countries between 1981 and 2010. Their clinical and genetic features were compared with those of the 4,647 B-cell precursor (BCP) ALL cases diagnosed during the same time period. All 128 DS-ALL were BCP ALL, comprising 2.7% of all such cases. The 5-year event-free survival (EFS) and overall survival (OS) were significantly (P = 0.026 and P = 0.003, respectively) worse for DS-ALL patients with white blood cell counts ≥50 × 109/l. The age distributions varied between the DS and non-DS cases, with age peaks at 2 and 3 years, respectively; none of the DS patients had infant ALL (P = 0.029). The platelet counts were lower in the DS-ALL group (P = 0.005). Abnormal karyotypes were more common in non-DS-ALL (P < 0.0001), and there was a significant difference in the modal number distribution, with only 2% high hyperdiploid DS-ALL cases (P < 0.0001). The 5-year EFS and 5-year OS were significantly worse for DS-ALL (0.574 and 0.691, respectively) compared with non-DS-ALL (0.783 and 0.894, respectively) in the NOPHO ALL-1992/2000 protocols (P < 0.001). The present study adds further support for genetic and clinical differences between DS-ALL and non-DS-ALL.


Structure of the Kti11/Kti13 heterodimer and its double role in modifications of tRNA and eukaryotic elongation factor 2.
The small, highly conserved Kti11 alias Dph3 protein encoded by the Kluyveromyces lactis killer toxin insensitive gene KTI11/DPH3 is involved in the diphthamide modification of eukaryotic elongation factor 2 and, together with Kti13, in Elongator-dependent tRNA wobble base modifications, thereby affecting the speed and accuracy of protein biosynthesis through two distinct mechanisms. We have solved the crystal structures of Saccharomyces cerevisiae Kti13 and the Kti11/Kti13 heterodimer at 2.4 and 2.9 Å resolution, respectively, and validated interacting residues through mutational analysis in vitro and in vivo. We show that metal coordination by Kti11 and its heterodimerization with Kti13 are essential for both translational control mechanisms. Our structural and functional analyses identify Kti13 as an additional component of the diphthamide modification pathway and provide insight into the molecular mechanisms that allow the Kti11/Kti13 heterodimer to coregulate two consecutive steps in ribosomal protein synthesis.


Diagnosis of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: Why liver biopsy is essential.
The pattern of non-alcoholic fatty liver disease is complex with an association of several lesions, each of them related to different pathophysiological mechanisms. Despite the progress in non-invasive tools, liver biopsy remains the only diagnostic procedure that can reliably assess these various patterns, their related severity and associations. The most important difficulties of liver biopsy can be avoided if this procedure is performed by an experienced hepatologist and read by a liver pathologist. However, for obvious reasons, biopsy should be restricted to selected patients, especially in the context of clinical trials. Indeed, liver biopsy is considered mandatory by regulatory authorities as a surrogate to assess drug efficacy in Phase 3 clinical trials. In addition to the clinical diagnosis, liver biopsy can be used to score the various histological patterns of disease (NASH-CRN, SAF scores) and accurately assess the extent of fibrosis, both of which are useful when follow-up biopsies are performed. When treatment becomes available in the near future, liver biopsy could remain useful for choosing the most suitable therapeutic option based on the main predominant histological features (activity, steatosis, fibrosis).


Melanin-concentrating hormone enhances sucrose intake.
Melanin-concentrating hormone (MCH) is known to be an important regulator for feeding and energy balance. MCH was recently reported to stimulate water intake independent of food intake. The purpose of the present study is to examine the dipsogenic response of MCH with special emphasis on sweetened beverages, the preference for which is well documented in diabetic animals. Our results showed that intracerebroventricular injection of MCH acutely increased food as well as water intake. Human (h)MCH and salmon (s)MCH increased water intake independent of food intake, which was not suppressed by angiotensin antagonists. hMCH and sMCH significantly increased both sucrose solution and food intake; on the other hand, agouti-related protein (AgRP) stimulated food but not sucrose intake when provided simultaneously. MCH-treated rats significantly increased the ingestion of sucrose and glucose solution, but not of saccharin, indicating that MCH-induced dipsogenic response is more related to caloric content than sweet taste per se. Significant correlation was observed between the sucrose intake and the mRNA expression of MCH and MCHR1 in normal rats. These results indicate that MCH may be an important regulator of sugar intake in normal as well as in obese diabetic animals.


Accuracy of screening mammography in older women.
The objective of our study was to determine the accuracy and cancer detection rate of screening mammography in women as they age. Using data from the Vermont Breast Cancer Surveillance System (1996-2006), we calculated the sensitivity, specificity, positive predictive value, negative predictive value, and cancer detection rate by decade of age for 403,448 mammograms of 96,193 women 50-101 years old. Confounding variables were assessed using logistic regression analysis. The sensitivity of screening mammography increased from 77.3% for the 50- to 59-year-old group to 93.8% for the 90- to 101-year-old group (p = 0.015). Specificity increased from 98.7% to 98.8% at age 50-59 compared with age 90-101 (p < 0.001), respectively. The cancer detection rate increased from 3.7 cases per 1000 mammograms at age 50-59 to 14.4 cases per 1000 mammograms at age 90-101 (p < 0.001). The prevalence of breast cancer increased from 4.8% to 15.4% across age groups (p < 0.001) as did the positive predictive value from 22.2% to 55.6% (p <0.001). There was no evidence of confounding by body mass index, breast density, or other factors. Tumors were more likely to be small, hormone receptor-positive, and more invasive as women aged. Accuracy parameters were all associated with age without evidence of confounding by regression analysis. Screening mammography is more accurate in older women than in younger women, suggesting that it may be of value in assessing women in all age groups. These data do not address the impact of mammography screening on mortality or breast cancer outcomes.


Safe surgery for cystic tumors of the pancreas.
Cystic tumors of the pancreas are a common indication for pancreatic surgery, and many of them are incidentally-discovered. Some of these tumors are malignant, and many others are pre-malignant. Less than two generations ago, pancreatic surgery was risky business. Surgical mortality, even in some of the best institutions in the world, was about 25%. Complications were very common and not infrequently patients required reoperations and had to remain in the hospital for weeks or even months. They emerged from this highly debilitated, and often went on to have a very poor quality of life. Not surprisingly, for these reasons, pancreatic resection was used only as a "last resort", and mostly for cancer.


Molecular phylogenetic study at the generic boundary between the lichen-forming fungi Caloplaca and Xanthoria (Ascomycota, Teloschistaceae).
A molecular phylogenetic analysis of rDNA was performed for seven Caloplaca, seven Xanthoria, one Fulgensia and five outgroup species. Phylogenetic hypotheses are constructed based on nuclear small and large subunit rDNA, separately and in combination. Three strongly supported major monophyletic groups were revealed within the Teloschistaceae. One group represents the Xanthoria fallax-group. The second group includes three subgroups: (1) X. parietina and X. elegans; (2) basal placodioid Caloplaca species followed by speciations leading to X. polycarpa and X. candelaria; and (3) a mixture of placodioid and endolithic Caloplaca species. The third main monophyletic group represents a heterogeneous assemblage of Caloplaca and Fulgensia species with a drastically different metabolite content. We report here that the two genera Caloplaca and Xanthoria, as well as the subgenus Gasparrinia, are all polyphyletic. The taxonomic significance of thallus morphology in Teloschistaceae and the current delimitation of the genus Xanthoria is discussed in light of these results.


The effect of increased alcohol availability on alcohol-related health problems up to the age of 42 among children exposed in utero: a natural experiment.
To examine whether exposure to increased alcohol availability in utero is associated with later alcohol-related health problems. Register-linked population-based longitudinal study using data from a natural experiment setting, including 363 286 children born 1965-71. An experimental alcohol policy change was piloted in two regions of Sweden in 1967-68, where access to strong beer increased for 16-20 year old. Children exposed in utero to the policy change were compared to children born elsewhere in Sweden (excluding a border area), and to children born before and after the policy change. The outcome was obtained from the National Hospital Discharge Register using the Swedish index of alcohol-related inpatient care. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated by Cox regression analysis. The results suggest that children conceived by young mothers prior to the policy change but exposed to it in utero had a slightly increased risk of alcohol-related health problems later in life (HR 1.26, 95% CI 0.94-1.68). A tendency towards an inverse association was found among children conceived by older mothers (HR 0.88, 95% CI 0.74-1.06). Results obtained from a natural experiment setting found no consistent evidence of long-term health consequences among children exposed in utero to an alcohol policy change. Some evidence however suggested an increased risk of alcohol-related health problems among the exposed children of young mothers.


Charge-Transfer Plasmon Polaritons at Graphene/α-RuCl3 Interfaces.
Nanoscale charge control is a key enabling technology in plasmonics, electronic band structure engineering, and the topology of two-dimensional materials. By exploiting the large electron affinity of α-RuCl3, we are able to visualize and quantify massive charge transfer at graphene/α-RuCl3 interfaces through generation of charge-transfer plasmon polaritons (CPPs). We performed nanoimaging experiments on graphene/α-RuCl3 at both ambient and cryogenic temperatures and discovered robust plasmonic features in otherwise ungated and undoped structures. The CPP wavelength evaluated through several distinct imaging modalities offers a high-fidelity measure of the Fermi energy of the graphene layer: EF = 0.6 eV (n = 2.7 × 1013 cm-2). Our first-principles calculations link the plasmonic response to the work function difference between graphene and α-RuCl3 giving rise to CPPs. Our results provide a novel general strategy for generating nanometer-scale plasmonic interfaces without resorting to external contacts or chemical doping.


Patient complaints about hospital services: applying a complaint taxonomy to analyse and respond to complaints.
To explore the applicability of a patient complaint taxonomy to data on serious complaint cases. Qualitative descriptive study. Complaints made to the New South Wales (NSW) Health Care Complaints Commission, Australia between 2005 and 2010. All 138 cases of serious complaints by patients about public hospitals and other health facilities investigated in the 5-year period. A thematic analysis of the complaints was conducted to identify particular complaint issues and the Reader et al. (Patient complaints in healthcare systems: a systematic review and coding taxonomy. BMJ Qual Saf 2014;23:678-89.) patient complaint taxonomy was then used to classify these issues into categories and sub-categories. The 138 investigated cases revealed 223 complaint issues. Complaint issues were distributed into the three domains of the patient complaint taxonomy: clinical, management and relationships. Complaint issue most commonly related to delayed diagnosis, misdiagnosis, medication errors, inadequate examinations, inadequate/nil treatment and quality of care including nursing care. The types of complaints from patients about their healthcare investigated by the NSW Commission were similar to those received by other patient complaint entities in Australia and worldwide. The application of a standard taxonomy to large numbers of complaints cases from different sources would enable the creation of aggregated data. Such data would have better statistical capacity to identify common safety and quality healthcare problems and so point to important areas for improvement. Some conceptual challenges in devising and using a taxonomy must be addressed, such as inherent problems in ensuring coding consistency, and giving greater weight to patient concerns about their treatment.


New Insight Into the Biology, Risk Stratification, and Targeted Treatment of Myelodysplastic Syndromes.
In myelodysplastic syndromes (MDS), somatic mutations occur in five major categories: RNA splicing, DNA methylation, activated cell signaling, myeloid transcription factors, and chromatin modifiers. Although many MDS cases harbor more than one somatic mutation, in general, there is mutual exclusivity of mutated genes within a class. In addition to the prognostic significance of individual somatic mutations, more somatic mutations in MDS have been associated with poor prognosis. Prognostic assessment remains a critical component of the personalization of care for patient with MDS because treatment is highly risk adapted. Multiple methods for risk stratification are available with the revised International Prognostic Scoring System (IPSS-R), currently considered the gold standard. Increasing access to myeloid gene panels and greater evidence for the diagnostic and predictive value of somatic mutations will soon make sequencing part of the standard evaluation of patients with MDS. In the absence of formal guidelines for their prognostic use, well-validated mutations can still refine estimates of risk made with the IPSS-R. Not only are somatic gene mutations advantageous in understanding the biology of MDS and prognosis, they also offer potential as biomarkers and targets for the treatment of patients with MDS. Examples include deletion 5q, spliceosome complex gene mutations, and TP53 mutations.


Predicting later-life outcomes of early-life exposures.
In utero exposure of the fetus to a stressor can lead to disease in later life. Epigenetic mechanisms are likely mediators of later-life expression of early-life events. We examined the current state of understanding of later-life diseases resulting from early-life exposures in order to identify in utero and postnatal indicators of later-life diseases, develop an agenda for future research, and consider the risk assessment implications of this emerging knowledge. This review was developed based on our participation in a National Research Council workshop titled "Use of in Utero and Postnatal Indicators to Predict Health Outcomes Later in Life: State of the Science and Research Recommendations." We used a case study approach to highlight the later-life consequences of early-life malnutrition and arsenic exposure. The environmental sensitivity of the epigenome is viewed as an adaptive mechanism by which the developing organism adjusts its metabolic and homeostatic systems to suit the anticipated extrauterine environment. Inappropriate adaptation may produce a mismatch resulting in subsequent increased susceptibility to disease. A nutritional mismatch between the prenatal and postnatal environments, or early-life obesogen exposure, may explain at least some of the recent rapid increases in the rates of obesity, type 2 diabetes, and cardiovascular diseases. Early-life arsenic exposure is also associated with later-life diseases, including cardiovascular disease and cancer. With mounting evidence connecting early-life exposures and later-life disease, new strategies are needed to incorporate this emerging knowledge into health protective practices.


Dietary prevention of allergic diseases in infants and small children.
Because of scientific fraud four trials have been excluded from the original Cochrane meta-analysis on formulas containing hydrolyzed protein for prevention of allergy and food intolerance in infants. Unlike the conclusions of the revised Cochrane review the export group set up by the Section on Paediatrics, European Academy of Allergology and Clinical Immunology (SP-EAACI) do not find that the exclusion of the four trials demands a change of the previous recommendations regarding primary dietary prevention of allergic diseases. Ideally, recommendations on primary dietary prevention should be based only on the results of randomized and quasi-randomized trials (selection criteria in the Cochrane review). However, regarding breastfeeding randomization is unethical, Therefore, in the development of recommendations on dietary primary prevention, high-quality systematic reviews of high-quality cohort studies should be included in the evidence base. The study type combined with assessment of the methodological quality determines the level of evidence. In view of some methodological concerns in the Cochrane meta-analysis, particularly regarding definitions and diagnostic criteria for outcome measures and inclusion of non peer-reviewed studies/reports, a revision of the Cochrane analysis may seem warranted. Based on analysis of published peer-reviewed observational and interventional studies the results still indicate that breastfeeding is highly recommended for all infants irrespective of atopic heredity. A dietary regimen is effective in the prevention of allergic diseases in high-risk infants, particularly in early infancy regarding food allergy and eczema. The most effective dietary regimen is exclusively breastfeeding for at least 4-6 months or, in absence of breast milk, formulas with documented reduced allergenicity for at least the first 4 months, combined with avoidance of solid food and cow's milk for the first 4 months.


Feasibility of implementing a community-based randomized trial of yoga for women undergoing chemotherapy for breast cancer.
Treatment-related symptoms and decreased health-related quality of life (HRQoL) frequently occur during chemotherapy for breast cancer. Although research findings suggest that yoga can reduce symptoms and Improve HRQoL after treatment, potential benefits of yoga during chemotherapy have received minimal attention. To estimate accrual, adherence, study retention, and preliminary efficacy of a yoga intervention compared with an active control group for breast cancer patients during chemotherapy. Women with stage I-III breast cancer were recruited from 3 community cancer clinics and randomized to 10 weeks of gentle yoga or wellness education. Depressive symptoms, fatigue, sleep, and HRQoL were assessed at baseline, mid-intervention (Week 5), and after intervention (Week 10). 40 women aged 29-83 years (median, 48 years; 88% white) were randomized to yoga (n = 22) or wellness education (n = 18). The groups did not differ significantly on baseline characteristics, adherence, or study retention. Participant feedback was positive and comparable between groups. Meaningful within-group differences were identified For sleep adequacy and quantity in yoga participants and for somnolence in wellness-education participants. Small sample size and lack of a usual-care control group. This study established Feasibility of a community-based randomized trial of yoga and an active comparison group for women undergoing chemotherapy for breast cancer. Preliminary efficacy estimates suggest that yoga improves sleep adequacy Symptom severity and interference remained stable during chemotherapy for the yoga group and snowed a trend toward increasing in the control group. The study highlighted obstacles to multisite yoga research during cancer treatment. National Cancer Institute (3U10 CA081851, PI; Shaw; R25 CA122061, PI: Avis); Translational Science Institute, Wake Forest School of Medicine.


Emergence of Carbapenem Resistant Non-Fermenting Gram-Negative Bacilli Isolated in an ICU of a Tertiary Care Hospital.
The emergence and spread of Multi-Drug Resistant (MDR) Non-Fermenting Gram-Negative Bacilli (NFGNB) in Intensive Care Units (ICU) and their genetic potential to transmit diverse antibiotic resistance regardless of their ability to ferment glucose poses a major threat in hospitals. The complex interplay of clonal spread, persistence, transmission of resistance elements and cell-cell interaction leads to the difficulty in controlling infections caused by these multi drug-resistant strains. Among non-fermenting Gram-negative rods, the most clinically significant species Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia are increasingly acquiring resistant to carbapenems. Carbapenems once considered as a backbone of treatment of life threatening infections appears to be broken as the resistance to carbapenems is on rise. To document the prevalence of carbapenem resistance in non-fermenting Gram-negative bacilli isolated from patients with respiratory tract infections in the ICU of Himalayan Institute of Medical Sciences, Dehradun. This is a cross-sectional study conducted in ICU patients between October 2015 to March 2016. A total of 366 lower respiratory tract samples were collected from 356 patients with clinical evidence of lower respiratory tract infections in form of Endotracheal (ET) aspirate, Tracheal Tube (TT) aspirate and Bronchoalveolar Lavage (BAL) specimen. Organism identification and the susceptibility testing was done by using an automated system VITEK 2. Out of 366 samples received 99 NFGNB were isolated and most common sample was ET aspirate sample 256 (64.5%). Acinetobacter baumannii was the most common NFGNB isolated 63 (63.63%) followed by Pseudomonas aeruginosa 25 (25.25%), Elizabethkingia meningoseptica seven (7.07%) and Strenotrophomonas maltophilia four (4.04%). We observed that 90.5% Acinetobacter baumannii were resistant to imipenem and 95.2% resistant to meropenem, Pseudomonas aeruginosa came out to be 52% resistant to imipenem and 56% resistant to meropenem while Stenotrophomonas maltophilia and Elizabethkingia meningoseptica were 100% resistant to carbapenems as they are intrinsically resistant to carbapenems. The resistance rate of carbapenems for NFGNB infections is very high in our study and variable in different regions. Overall carbapenem resistance is on rise. So, the infection control team and microbiologist needs to work together to determine the risk carried by multi drug resistant non-fermenting gram-negative infections and the resistance surveillance programs are mandatory to control these bacteria in ICU settings.


Type II collagen peptide Coll2-1 is an actor of synovitis.
We evaluated the ability of Coll2-1, a type II collagen peptide, to activate pro-inflammatory pathways in synovial cells and to induce arthritis in Lewis rats. Human synoviocytes and chondrocytes from knee OA patients were cultured for 24 h with/without Coll2-1 and/or purified immunoglobulin G (AS0619) binding specifically this peptide, and/or CLI-095, a TLR-4 signaling inhibitor and/or apocynin and diphenyleneiodonium, Reactive oxygen species (ROS) production inhibitors. The Interleukin (IL)-8 and Vascular Endothelium Growth Factor (VEGF) expression, the IL-8 production, the IκB-α and p65 phosphorylation and ROS were evaluated. Coll2-1 peptide, bovine type II collagen (CIA), streptococcal cell wall (SCW) or saline solution were injected into Lewis rats. The Coll2-1 peptide was injected subcutaneously (SC; 20-200μg/100μl/animal) or intra-articularly (IA; 0.5-5μg/50μl/animal) and compared to CIA injected in SC (200μg/100μl/animal) and SCW in IA (5μg/50μl/animal). The animals were injected on day 0 and monitored for 28 days. Histological lesions assessment was performed using an arthritis score. Coll2-1 peptide significantly increased IL-8 gene expression and production by synoviocytes. AS0619 and CLI-095 significantly decreased IL-8 expression. Coll2-1 induced p65 and IκBα phosphorylation and oxidative stress inhibitors decreased it. In human chondrocytes culture, Coll2-1 significantly increased MMP-3 and VEGF gene expression. In Lewis rats, CIA, SCW or Coll2-1 injection triggered arthritis. Like CIA or SCW, Coll2-1 induced synovitis, loss of cartilage proteoglycans, cartilage structure lesion and subchondral bone remodeling. Coll2-1 activates synoviocytes to produce IL-8 and induces arthritis in rat. These findings suggest that neutralizing Coll2-1 could be a therapeutic approach of arthritis.


Alcohol and proactive interference: a test of response eccentricity theory of alcohol's psychological effects.
A theory is offered which proposes that alcohol induces eccentricity in the neurophysiological mechanism by which responses are selected for emission by the nervous system. Hence, in a specific stimulus situation, normally high probability responses decrease in frequency, while lower probability responses increase in frequency. From this postulate, the prediction is derived that in a verbal paired-associate learning task administered over two days, alcohol will decrease proactive interference from first-day learning (high probability associate) and result in enhanced acquisition of second day items. This paper reports two experimental tests of the prediction, each of which employs four subject groups tested over two days. Experiment 1 (n = 24) provides tentative support while ruling out some potential confounds. With these confounds eliminated, Experiment 2 (n = 40) confirms the prediction in a more direct test. A variety of possible alternative explanations for the counter-intuitive finding of improved cognitive performance under alcohol are evaluated against the theory proposed, as are other recent theories which address the variable behavioral effects of alcohol. Finally, the new data gathered on the effects of imagery instructions on proactive interference are considered.


Adsorption of Pb(2+) from aqueous solution using spinel ferrite prepared from steel pickling sludge.
In this paper, spinel ferrite with high crystallinity and high saturation magnetization was successfully prepared from steel pickling sludge by adding iron source and precipitator in the hydrothermal condition. The obtained spinel ferrite was characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), vibrating sample magnetometer (VSM), and Zeta potential methods and investigated as an adsorbent for removal of Pb(2+) from aqueous solution. Batch experiments were performed by varying the pH values, contact time, temperature and initial metal concentration. The result of pH impact showed that the adsorption of Pb(2+) was a pH dependent process, and the pH 5.8 ± 0.2 was found to be the optimum condition. The achieved experimental data were analyzed with various kinetic and isotherm models. The kinetic studies revealed that Pb(2+) adsorption onto spinel ferrite followed a pseudo-second order model, and the Langmuir isotherm model provided the perfect fit to the equilibrium experimental data. At different temperatures, the maximum Pb(2+) adsorption capacities calculated from the Langmuir equation were in the range of 126.5-175.4 mg/g, which can be in competition with other adsorbents. The thermodynamic results showed that the spinel ferrite could spontaneously and endothermically adsorb Pb(2+) from aqueous solution. The regeneration studies showed that spinel ferrite could be used five times (removal efficiency (%) >90%) by desorption with HNO3 reagent.


Neonatal mortality and coverage of essential newborn interventions 2010 - 2013: a prospective, population-based study from low-middle income countries.
Approximately 3 million neonatal deaths occur each year worldwide. Simple interventions have been tested and found to be effective in reducing the neonatal mortality. In order to effectively implement public health interventions, it is important to know the rates of neonatal mortality and understand the contributing risk factors. Hence, this prospective, population-based, observational study was carried out to inform these needs. The Global Network's Maternal Newborn Health Registry was initiated in the seven sites in 2008. Registry administrators (RAs) attempt to identify and enroll all eligible women by 20 weeks gestation and collect basic health data, and outcomes after delivery and at 6 weeks post-partum. All study data were collected, reviewed, and edited by staff at each study site. The study was reviewed and approved by each sites' ethics review committee. Overall, the 7-day neonatal mortality rate (NMR) was 20.6 per 1000 live births and the 28-day NMR was 25.7 per 1000 live births. Higher neonatal mortality was associated with maternal age > 35 and <20 years relative to women 20-35 years of age. Preterm births were at increased risk of both early and 28-day neonatal mortality (RR 8.1, 95% CI 7.5-8.8 and 7.5, 95% CI 6.9-8.1) compared to term as were those with low birth weight (<2500g). Neonatal resuscitation rates were 4.8% for hospital deliveries compared to 0.9% for home births. In the hospital, 26.5% of deliveries were by cesarean section with an overall cesarean section rate of 12.5%. Neonatal mortality rates were highest in the Pakistan site and lowest in Argentina. Using prospectively collected data with high follow up rates (99%), we documented characteristics associated with neonatal mortality. Low birth weight and prematurity are among the strongest predictors of neonatal mortality. Other risk factors for neonatal deaths included male gender, multiple gestation and major congenital anomalies. Breech presentation/transverse lie, and no antenatal care were also significant risk factors for neonatal death. Coverage of interventions varied by setting of delivery, with the overall population rate of most evidence-based interventions low. This study informs about risk factors for neonatal mortality which can serve to design strategies/interventions to reduce risk of neonatal mortality. The trial is registered at clinicaltrials.gov. ClinicalTrial.gov NCT01073475.


Racial differences in lens opacity incidence and progression: the Salisbury Eye Evaluation (SEE) study.
To evaluate racial differences in nuclear and cortical lens opacity incidence and progression over a 2-year period in an older American population. Prospective population-based cohort study of a multiethnic population of 2520 people (26% African-American and 74% Caucasian), 65 to 84 years of age, living in Salisbury, Maryland. Data at baseline included race, education level, past steroid use, smoking status, alcohol status, sunlight exposure, and history of hypertension and diabetes. Lens photographs were taken at baseline and at 2-year follow-up and were graded using the Wilmer grading scheme. Multiple logistic regression models were used to examine the independent associations between race, as well as other risk factors, and incidence and progression of cortical and nuclear opacities. AFRICAN-AMERICANS HAD LOWER RATES OF NUCLEAR OPACITY INCIDENCE (ODDS RATIO [OR]: 0.52; 95% Confidence Interval [CI]: 0.35-0.76) and nuclear opacity progression (OR: 0.60; 95% CI: 0.38-0.92) compared with Caucasians. African-Americans had higher rates of cortical opacity incidence (OR: 1.90; 95% CI: 1.21-2.98) and cortical opacity progression (OR: 1.72; 95% CI: 1.21-2.45) compared with Caucasians. Additionally, nuclear opacity incidence was associated with age, female sex, and current smoking status. Nuclear progression was associated with past smoking and current smoking. Cortical opacity incidence was associated with female sex, Ultraviolet-B exposure, and a history of diabetes. Cortical opacity progression was associated with current smoking status. Differences by race in the type of cataract incidence and progression, even adjusting for personal and environmental risk factors, deserve further exploration.


Social withdrawal in major depressive disorder: a case-control study of hikikomori in japan.
Social withdrawal is a feature of a number of psychiatric disorders including major depressive disorder (MDD), yet research examining social withdrawal as a feature of MDD is rare. This was a retrospective case-control study. Participants (N = 67) were recruited through an outpatient clinic at an academic medical center in Japan. Major depressive disorder (MDD) and social withdrawal were established with the Structured Clinical Interview for DSM-IV Axis I Disorders and a semi-structured psychiatric interview, respectively. Participants also completed self-report measures. We classified 24 participants as cases (MDD with social withdrawal) and 43 participants as controls (MDD without social withdrawal). Cases, on average, were more likely to have lower education level, prior episodes of depression, and higher suicidal ideation at baseline than controls. In unadjusted regression models, cases had significantly less social connection, less reward dependence, less self-directedness, and higher scores on scales of modern-type depression and hikikomori. In adjusted regression models, associations between social withdrawal and hikikomori (p<0.01) and reward dependence (p = 0.03) remained significant. The sample was limited in size and drawn from a single site. In patients with MDD, social withdrawal may have subtle associations with clinical symptoms, social connection, and personality traits. Developing a better understanding of social withdrawal's phenotype in depression requires more in-depth examination.


Mechanism-based traps enable protease and hydrolase substrate discovery.
Hydrolase enzymes, including proteases, are encoded by 2-3% of the genes in the human genome and 14% of these enzymes are active drug targets1. However, the activities and substrate specificities of many proteases-especially those embedded in membranes-and other hydrolases remain unknown. Here we report a strategy for creating mechanism-based, light-activated protease and hydrolase substrate traps in complex mixtures and live mammalian cells. The traps capture substrates of hydrolases, which normally use a serine or cysteine nucleophile. Replacing the catalytic nucleophile with genetically encoded 2,3-diaminopropionic acid allows the first step reaction to form an acyl-enzyme intermediate in which a substrate fragment is covalently linked to the enzyme through a stable amide bond2; this enables stringent purification and identification of substrates. We identify new substrates for proteases, including an intramembrane mammalian rhomboid protease RHBDL4 (refs. 3,4). We demonstrate that RHBDL4 can shed luminal fragments of endoplasmic reticulum-resident type I transmembrane proteins to the extracellular space, as well as promoting non-canonical secretion of endogenous soluble endoplasmic reticulum-resident chaperones. We also discover that the putative serine hydrolase retinoblastoma binding protein 9 (ref. 5) is an aminopeptidase with a preference for removing aromatic amino acids in human cells. Our results exemplify a powerful paradigm for identifying the substrates and activities of hydrolase enzymes.


Abetalipoproteinemia: two case reports and literature review.
Abetalipoproteinemia (ABL, OMIM 200100) is a rare, autosomal recessive disorder, characterized by fat malabsorption, acanthocytosis and hypocholesterolemia in infancy. Later in life, deficiency of fat-soluble vitamins is associated with development of atypical retinitis pigmentosa, coagulopathy, posterior column neuropathy and myopathy. ABL results from mutations in the gene encoding the large subunit of microsomal triglyceride transfer protein (MTP; OMIM 157147). To date at least 33 MTP mutations have been identified in 43 ABL patients. We describe the clinical progress of two patients, both currently in the fifth decade of life, who were diagnosed with ABL as children and were treated with high oral doses of fat soluble vitamins, including vitamin E over the last three decades. Treatment appears to have been associated with arrest of the neuropathy and other complications in both patients. Because pharmacologic inhibition of MTP is being developed as a novel approach to reduce plasma cholesterol for prevention of cardiovascular disease, defining the long-term clinical features of patients with a natural deficiency in MTP might provide some insight into the possible effects of such treatments. We review the range of clinical, biochemical and molecular perturbations in ABL.


Swiss Medical Board Mammography screening predictions for Switzerland: importance of time-periods.
In 2013, the Swiss Medical Board (SMB) concluded that for three breast cancer screens over 13 years in Switzerland, cost-effectiveness was negative, with no additional benefits in quality-adjusted life-years gained. We compared these suggested predicted effects with other estimates. We used an extensively validated model on the natural history of breast cancer in Switzerland, comparing a 13-year time frame, a life-time perspective, and a continuous screening programme, per 10,000 Swiss women. Both approaches used the Swedish randomized controlled trials for the theoretical effect. Over 13 years, both approaches yield comparable life-years gained (56 versus 67), but in expectation in 10,000 women's lifetimes 444 life-years are gained, and in a continuous screening programme (instead of three screens) 839 years. The SMB estimate of 56 life-years gained is counterweighted by 57 negative quality of life adjusted years, primarily resulting from a 5% annual loss for 10% of women, being false-positive results. International literature is consistent with more than four times lower losses on false-positives. The estimate of overdiagnosed cases in the 13-year time frame was four times higher than in the long-term perspective. By restricting life-years gained to a 13-year time frame the SMB prediction on benefits of mammography screening is unrealistically low. Predicting long-term harms and benefits, specifically tailored to observations, regarding the clinical situation before screening commences, and possible data during a screening programme, are crucial for women, professionals, and policymakers.


Impregnated central venous catheters for prevention of bloodstream infection in children (the CATCH trial): a randomised controlled trial.
Impregnated central venous catheters are recommended for adults to reduce bloodstream infections but not for children because there is not enough evidence to prove they are effective. We aimed to assess the effectiveness of any type of impregnation (antibiotic or heparin) compared with standard central venous catheters to prevent bloodstream infections in children needing intensive care. We did a randomised controlled trial of children admitted to 14 English paediatric intensive care units. Children younger than 16 years were eligible if they were admitted or being prepared for admission to a participating paediatric intensive care unit and were expected to need a central venous catheter for 3 or more days. Children were randomly assigned (1:1:1) to receive a central venous catheter impregnated with antibiotics, a central venous catheter impregnated with heparin, or a standard central venous catheter with computer generated randomisation in blocks of three and six, stratified by method of consent, site, and envelope storage location within the site. The clinician responsible for inserting the central venous catheter was not masked to allocation, but allocation was concealed from patients, their parents, and the paediatric intensive care unit personnel responsible for their care. The primary outcome was time to first bloodstream infection between 48 h after randomisation and 48 h after central venous catheter removal with impregnated (antibiotic or heparin) versus standard central venous catheters, assessed in the intention-to-treat population. Safety analyses compared central venous catheter-related adverse events in the subset of children for whom central venous catheter insertion was attempted (per-protocol population). This trial is registered with ISRCTN number, ISRCTN34884569. Between Nov 25, 2010, and Nov 30, 2012, 1485 children were recruited to this study. We randomly assigned 502 children to receive standard central venous catheters, 486 to receive antibiotic-impregnated catheters, and 497 to receive heparin-impregnated catheters. Bloodstream infection occurred in 18 (4%) of those in the standard catheters group, 7 (1%) in the antibiotic-impregnated group, and 17 (3%) assigned to heparin-impregnated catheters. Primary analyses showed no effect of impregnated (antibiotic or heparin) catheters compared with standard central venous catheters (hazard ratio [HR] for time to first bloodstream infection 0.71, 95% CI 0.37-1.34). Secondary analyses showed that antibiotic central venous catheters were better than standard central venous catheters (HR 0.43, 0.20-0.96) and heparin central venous catheters (HR 0.42, 0.19-0.93), but heparin did not differ from standard central venous catheters (HR 1.04, 0.53-2.03). Clinically important and statistically significant absolute risk differences were identified only for antibiotic-impregnated catheters versus standard catheters (-2.15%, 95% CI -4.09 to -0.20; number needed to treat [NNT] 47, 95% CI 25-500) and antibiotic-impregnated catheters versus heparin-impregnated catheters (-1.98%, -3.90 to -0.06, NNT 51, 26-1667). Nine children (2%) in the standard central venous catheter group, 14 (3%) in the antibiotic-impregnated group, and 8 (2%) in the heparin-impregnated group had catheter-related adverse events. 45 (8%) in the standard group, 35 (8%) antibiotic-impregnated group, and 29 (6%) in the heparin-impregnated group died during the study. Antibiotic-impregnated central venous catheters significantly reduced the risk of bloodstream infections compared with standard and heparin central venous catheters. Widespread use of antibiotic-impregnated central venous catheters could help prevent bloodstream infections in paediatric intensive care units. National Institute for Health Research, UK.


Driving Adsorbed Gold Nanoparticle Assembly by Merging Lipid Gel/Fluid Interfaces.
Surface forces between inorganic nanoparticles and lipid bilayer is of great relevance to biophysics, medicine, and nanobiotechnology. Adsorbed nanoparticles may influence the fluidity of the underlying lipids, which may in turn influence nanoparticle assembly. Herein three types of lipids (DOPC, Tc = -20 °C; DMPC, Tc = 23 °C; and DPPC, Tc = 41 °C) are used, all with the same phosphocholine (PC) headgroup. Gold nanoparticle (AuNP) color change is monitored as a function of lipid phase transition temperature (Tc), surface ligands on AuNPs, and temperature. Liposomes with higher fluidity induce much faster aggregation of AuNPs. Aside from the kinetic aspect of faster diffusion on fluid bilayers, this faster color change is attributed to the local lipid gelation and merging of gelled regions to eliminate the interface between different lipid phases.


Time-lapse imaging of cleavage divisions in embryo quality assessment.
In vitro fertilization (IVF) is one of the most important procedures for treating infertility. As several embryos are usually produced in a single IVF cycle, it is crucial to select only the most viable ones for transfer to the patient. Morphokinetics, i.e. analysis of the dynamics of cleavage divisions and processes such as compaction and cavitation, has provided both biologists and clinicians with a new set of data regarding embryonic behaviour during preimplantation development and its association with embryo quality. In the current review, we focus on biological significance of morphokinetic parameters and show how they can be used to predict a reproductive outcome. We also explain the statistics behind the predictive algorithms and discuss the future perspectives of morphokinetics.


Comparison of restriction enzyme analysis versus pulsed-field gradient gel electrophoresis as a typing system for Torulopsis glabrata and Candida species other than C. albicans.
Candida species have recently emerged as important nosocomial pathogens. Because of the lack of a reliable system for detecting differences within the same species, little is known about the epidemiology of infection with Candida species. We describe a typing system for Torulopsis glabrata and the non-C. albicans Candida species that uses contour-clamped homogeneous electric field electrophoresis (CHEF), a version of pulsed-field gradient gel electrophoresis, and compared it with restriction enzyme analysis (REA) of genomic DNA. One hundred seventeen clinical isolates from 40 patients were evaluated. CHEF and REA were performed on each of the isolates, and the results of the two procedures were compared. The REA procedure revealed 8 different types of Candida lusitaniae, 20 of Torulopsis glabrata, 5 of Candida tropicalis, 3 of Candida parapsilosis, and 7 of Candida kefyr, whereas the CHEF method revealed 14 different types of C. lusitaniae, 16 of T. glabrata, 10 of C. tropicalis, 10 of C. parapsilosis, and 7 of C. kefyr. The CHEF technique yielded unique patterns of electrophoretic karyotypes that could be used to distinguish intraspecies variations. When compared with REA, CHEF demonstrated greater sensitivity in recognizing subtle strain-to-strain variations in most isolates and will be a useful epidemiologic tool for studying non-C. albicans Candida species and T. glabrata.


Proteomic analysis of peripheral T-lymphocytes in patients with asthma.
Asthma is chronic airway inflammation that occurs together with reversible airway obstruction. T-lymphocytes play an important role in the pathogenesis of asthma. Proteomic technology has rapidly developed in the postgenomic era, and it is now widely accepted as a complementary technology to genetic profiling. We investigated the changes of proteins in T-lymphocytes of asthma patients by using standard proteome technology: two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), and a database search. The proteins of CD3+ T-lymphocytes were isolated from whole blood of six steroid-naive asthmatic patients and of six healthy volunteers. 2D-PAGE was performed and the silver-stained protein spots were comparatively analyzed between the asthma and control groups using an image analyzer. Some differentially expressed spots were identified by MALDI-TOF-MS and database search. The messenger RNA expressions of some identified proteins were examined by real-time polymerase chain reaction (RT-PCR). Thirteen protein spots in the T-lymphocytes of the asthmatic patients were increased and 12 spots were decreased compared to those of the normal subjects. Among the identified proteins, the increased expression of the messenger RNA of phosphodiesterase 4C and thioredoxin-2 and the decreased expression of the messenger RNA of glutathione S-transferase M3 were confirmed by RT-PCR in the asthmatic patients. Proteomic examination of the peripheral T-lymphocytes revealed some differentially expressed proteins in the asthmatic patients. The possibility of using the differentially expressed proteins as important biomarkers and therapeutic targets in asthma patients warrants further studies.


A SARS-CoV-2 Spike Binding DNA Aptamer that Inhibits Pseudovirus Infection by an RBD-Independent Mechanism*.
The receptor binding domain (RBD) of the spike glycoprotein of the coronavirus SARS-CoV-2 (CoV2-S) binds to the human angiotensin-converting enzyme 2 (ACE2) representing the initial contact point for leveraging the infection cascade. We used an automated selection process and identified an aptamer that specifically interacts with CoV2-S. The aptamer does not bind to the RBD of CoV2-S and does not block the interaction of CoV2-S with ACE2. Nevertheless, infection studies revealed potent and specific inhibition of pseudoviral infection by the aptamer. The present study opens up new vistas in developing SARS-CoV2 infection inhibitors, independent of blocking the ACE2 interaction of the virus, and harnesses aptamers as potential drug candidates and tools to disentangle hitherto inaccessible infection modalities, which is of particular interest in light of the increasing number of escape mutants that are currently being reported.


FAM210A Regulates Mitochondrial Translation and Maintains Cardiac Mitochondrial Homeostasis.
Mitochondria play a vital role in cellular metabolism and energetics and support normal cardiac function. Disrupted mitochondrial function and homeostasis cause a variety of heart diseases. Fam210a (family with sequence similarity 210 member A), a novel mitochondrial gene, is identified as a hub gene in mouse cardiac remodeling by multi-omics studies. Human FAM210A mutations are associated with sarcopenia. However, the physiological role and molecular function of FAM210A remain elusive in the heart. We aim to determine the biological role and molecular mechanism of FAM210A in regulating mitochondrial function and cardiac health in vivo . Tamoxifen-induced αMHC MCM -driven conditional knockout of Fam210a in the mouse cardiomyocytes induced progressive dilated cardiomyopathy and heart failure, ultimately causing mortality. Fam210a deficient cardiomyocytes exhibit severe mitochondrial morphological disruption and functional decline accompanied by myofilament disarray at the late stage of cardiomyopathy. Furthermore, we observed increased mitochondrial reactive oxygen species production, disturbed mitochondrial membrane potential, and reduced respiratory activity in cardiomyocytes at the early stage before contractile dysfunction and heart failure. Multi-omics analyses indicate that FAM210A deficiency persistently activates integrated stress response (ISR), resulting in transcriptomic, translatomic, proteomic, and metabolomic reprogramming, ultimately leading to pathogenic progression of heart failure. Mechanistically, mitochondrial polysome profiling analysis shows that FAM210A loss of function compromises mitochondrial mRNA translation and leads to reduced mitochondrial encoded proteins, followed by disrupted proteostasis. We observed decreased FAM210A protein expression in human ischemic heart failure and mouse myocardial infarction tissue samples. To further corroborate FAM210A function in the heart, AAV9-mediated overexpression of FAM210A promotes mitochondrial-encoded protein expression, improves cardiac mitochondrial function, and partially rescues murine hearts from cardiac remodeling and damage in ischemia-induced heart failure. These results suggest that FAM210A is a mitochondrial translation regulator to maintain mitochondrial homeostasis and normal cardiomyocyte contractile function. This study also offers a new therapeutic target for treating ischemic heart disease. Mitochondrial homeostasis is critical for maintaining healthy cardiac function. Disruption of mitochondrial function causes severe cardiomyopathy and heart failure. In the present study, we show that FAM210A is a mitochondrial translation regulator required for maintaining cardiac mitochondrial homeostasis in vivo . Cardiomyocyte-specific FAM210A deficiency leads to mitochondrial dysfunction and spontaneous cardiomyopathy. Moreover, our results indicate that FAM210A is downregulated in human and mouse ischemic heart failure samples and overexpression of FAM210A protects hearts from myocardial infarction induced heart failure, suggesting that FAM210A mediated mitochondrial translation regulatory pathway can be a potential therapeutic target for ischemic heart disease.


Structure and mapping of the G protein gamma3 subunit gene and a divergently transcribed novel gene, gng3lg.
The mammalian nervous system is rich in signaling mediated by heterotrimeric (alphabetagamma) G proteins. As an initial step to define the roles that particular gamma subunit types play in signaling, we have begun to clone and characterize those genes that encode gamma subunits enriched within neural tissue. In the present study, we have isolated and characterized the mouse gamma3 subunit gene (Gng3). The gamma3 subunit is expressed abundantly in the brain and at low levels in testes. Gng3 is composed of three exons spanning approximately 1.4 kb. A comparison of Gng3 with the gene structure for five other gamma subtypes indicates that although these proteins are diverse at the amino acid level, their exon-intron boundaries are conserved. Sequence analysis of the 5' flanking region of Gng3 revealed the presence of a novel gene, the gamma3 linked gene (Gng3lg). Gng3 and Gng3lg are organized in a head-to-head fashion with major transcription initiation sites separated by approximately 133 bp. Sequence analysis of a Gng3lg cDNA clone revealed an open reading frame encoding a 410-amino-acid protein of unknown function. Gng3lg transcripts are expressed in a variety of tissues including both brain and testes. Using an interspecific backcross panel, we localized both Gng3 and Gng3lg to the same locus on chromosome 19. The orientation, close proximity, and expression pattern of these two genes raise the distinct possibility that shared regulatory elements are used to control their expression.


A microRNA-mRNA expression network during oral siphon regeneration in Ciona.
Here we present a parallel study of mRNA and microRNA expression during oral siphon (OS) regeneration in Ciona robusta, and the derived network of their interactions. In the process of identifying 248 mRNAs and 15 microRNAs as differentially expressed, we also identified 57 novel microRNAs, several of which are among the most highly differentially expressed. Analysis of functional categories identified enriched transcripts related to stress responses and apoptosis at the wound healing stage, signaling pathways including Wnt and TGFβ during early regrowth, and negative regulation of extracellular proteases in late stage regeneration. Consistent with the expression results, we found that inhibition of TGFβ signaling blocked OS regeneration. A correlation network was subsequently inferred for all predicted microRNA-mRNA target pairs expressed during regeneration. Network-based clustering associated transcripts into 22 non-overlapping groups, the functional analysis of which showed enrichment of stress response, signaling pathway and extracellular protease categories that could be related to specific microRNAs. Predicted targets of the miR-9 cluster suggest a role in regulating differentiation and the proliferative state of neural progenitors through regulation of the cytoskeleton and cell cycle.


Ignored faces produce figural face aftereffects.
Following adaptation to faces with contracted (or expanded) internal features, faces previously perceived as normal appear distorted in the opposite direction. This figural face aftereffect suggests face-coding mechanisms adapt to changes in the spatial relations of features and/or the global structure of faces. Here, we investigated whether the figural aftereffect requires spatial attention. Participants ignored a distorted adapting face and performed a highly demanding letter-count task. Before and after adaptation, participants rated the normality of morphed distorted faces ranging from 50% contracted through undistorted to 50% expanded. A robust aftereffect was observed. These results suggest that the figural face aftereffect can occur in the absence of spatial attention, even when the attentional demands of the relevant task are high.


Studies of the chemical composition of a healing skin wound in rats, and of the concentrations of some constituents of tissues distant from the healing wound.
1. A skin lesion was made in rats by dorsal incision and the insertion of a polythene tube. 2. Over a period of 25 days after wounding, assays were performed for ascorbic acid, DNA, hydroxyproline, methionine, tryptophan, tyrosine and free amino acids in the lesion tissue. 3. The neutral-salt-soluble proteins of the lesion tissue were fractionated on DEAE-Sephadex, with the separation of fibrinogen and gamma-globulin from a serum protein fraction. 4. Over a period of 20 days after wounding, in wounded rats and in controls, assays were conducted for: ascorbic acid in lens and liver, hydroxyproline, soluble protein, methionine and water in muscle and tendon, and free amino acids in muscle. 5. Relative to controls there was a decrease in lens and liver ascorbic acid, a rise in tendon hydroxyproline, a rise in muscle free amino acids, a fall in muscle protein and a rise in tendon and muscle water.


The Limiting Speed of the Bacterial Flagellar Motor.
Recent experiments on the bacterial flagellar motor have shown that the structure of this nanomachine, which drives locomotion in a wide range of bacterial species, is more dynamic than previously believed. Specifically, the number of active torque-generating complexes (stators) was shown to vary across applied loads. This finding brings under scrutiny the experimental evidence reporting that limiting (zero-torque) speed is independent of the number of active stators. In this study, we propose that, contrary to previous assumptions, the maximum speed of the motor increases as additional stators are recruited. This result arises from our assumption that stators disengage from the motor for a significant portion of their mechanochemical cycles at low loads. We show that this assumption is consistent with current experimental evidence in chimeric motors, as well as with the requirement that a processive motor driving a large load via an elastic linkage must have a high duty ratio.


Silver linings: how mental health activists can help us navigate wicked problems.
This article explores how 'wicked problems' such as climate change might force psychiatry to rethink some of its fundamental ideas and ways of working, including clinical boundaries, understandings of psychopathology and ways of organising. We use ethnographic evidence to explore how mental health service 'survivor' activists are already rethinking some of these issues by therapeutically orienting themselves towards social problems and collective understandings of well-being, rejecting 'treatment as usual' approaches to distress. In this way we provide an example of the potential of activists to help psychiatry negotiate the climate crisis.