Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses.
Rational therapeutic approaches based on synthetic lethality may improve cancer management. On the basis of a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL, and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and obatoclax) or selective (ABT199, WEHI-539, and A1210477), along with the established mitochondrial matrix chaperone inhibitor gamitrinib-TPP. Drug combinations were tested in various therapy-resistant tumors in vitro and in vivo in murine model systems of melanoma, triple-negative breast cancer, and patient-derived orthotopic xenografts (PDX) of human glioblastoma. We found that combining BH3 mimetics and gamitrinib-TPP blunted cellular proliferation in a synergistic manner by massive activation of intrinsic apoptosis. In like manner, suppressing either Bcl-2, Bcl-xL, or Mcl-1 recapitulated the effects of BH3 mimetics and enhanced the effects of gamitrinib-TPP. Mechanistic investigations revealed that gamitrinib-TPP activated a PERK-dependent integrated stress response, which activated the proapoptotic BH3 protein Noxa and its downstream targets Usp9X and Mcl-1. Notably, in the PDX glioblastoma and BRAFi-resistant melanoma models, this drug combination safely and significantly extended host survival. Our results show how combining mitochondrial chaperone and Bcl-2 family inhibitors can synergize to safely degrade the growth of tumors recalcitrant to other treatments. Cancer Res; 77(13); 3513-26. ©2017 AACR.


Transport and retention of nanoscale C60 aggregates in water-saturated porous media.
Experimental and mathematical modeling studies were performed to investigate the transport and retention of nanoscale fullerene aggregates (nC60) in water-saturated porous media. Aqueous suspensions of nC60 aggregates (95 nm diameter, 1 to 3 mg/L) were introduced into columns packed with either glass beads or Ottawa sand at a Darcy velocity of 2.8 m/d. In the presence of 1.0 mM CaCl2, nC60 effluent breakthrough curves (BTCs) gradually increased to a maximum value and then declined sharply upon reintroduction of nC60-free solution. Retention of nC60 in glass bead columns ranged from 8 to 49% of the introduced mass, while up to 77% of the mass was retained in Ottawa sand columns. When nC60 suspensions were prepared in deionized water alone, effluent nC60 BTCs coincided with those of a nonreactive tracer (Br-), with minimal nC60 retention. Observed differences in nC60 transport and retention behavior in glass beads and Ottawa sand were consistent with independent batch retention data and theoretical calculations of electrostatic interactions between nC60 and the solid surfaces. Effluent concentration and retention profile data were accurately simulated using a numerical model that accounted for nC60 attachment kinetics and a limiting retention capacity.


Protein turnover and sensory traits of longissimus muscle from implanted and nonimplanted heifers.
Primary bovine muscle cell culture studies were conducted to determine whether implanting heifers had a direct effect on in vitro protein synthesis and degradation and to determine the effect of implanting heifers on longissimus muscle palatability. Feedlot heifers (n = 96) were administered one of six implant regimens to characterize their effect on in vitro amino acid uptake and protein degradation. Treatments consisted of: 1) a nonimplanted control (NI/NI); 2) no implant on d 1 and Revalor-H administered on d 84 of the experiment (NI/Rev); 3) Revalor-H on d 1, but no implant given at d 84 (Rev/NI); 4) Revalor-H administered on d 1 and d 84 (Rev/Rev); 5) Revalor-IH administered on d 1 and Revalor-H at d 84 (RIH/Rev); and 6) Synovex-H given at d 1 and Revalor-H administered at d 84 (Syn/Rev). Blood and longissimus lumborum muscle were collected 20 min postmortem, and serum and muscle extracts were incubated with primary bovine muscle cells. Implant treatments had minimal effects on shear force and sensory traits; however, steaks from Rev/Rev heifers were 0.31 kg more tender (P < 0.05) than steaks from NI/NI heifers. Serum protein synthesis and degradation were not affected (P > 0.10) by any implant treatment. When primary bovine muscle cells were treated with muscle extract, amino acid uptake was greater for heifers implanted with Rev/ Rev than for the average of all other treatments (P < 0.01). The Rev/Rev implant regimen also increased (P < 0.05) amino acid uptake compared with heifers treated with RIH/Rev, Syn/Rev, NI/NI, NI/Rev, or Rev/NI. Cellular protein degradation of the muscle cell culture treated with muscle extract tended (P < 0.10) to be higher in NI/NI-treated cells compared with the average of all implant treatments. In addition, cells treated with muscle extract from heifers implanted with Rev/Rev had lower (P < 0.05) protein degradation than the NI/NI control heifers. These results indicate that anabolic implant strategies can directly affect both muscle protein synthesis and degradation via effects that seem to be more autocrine than paracrine in nature.


The social psychology of stigma.
This chapter addresses the psychological effects of social stigma. Stigma directly affects the stigmatized via mechanisms of discrimination, expectancy confirmation, and automatic stereotype activation, and indirectly via threats to personal and social identity. We review and organize recent theory and empirical research within an identity threat model of stigma. This model posits that situational cues, collective representations of one's stigma status, and personal beliefs and motives shape appraisals of the significance of stigma-relevant situations for well-being. Identity threat results when stigma-relevant stressors are appraised as potentially harmful to one's social identity and as exceeding one's coping resources. Identity threat creates involuntary stress responses and motivates attempts at threat reduction through coping strategies. Stress responses and coping efforts affect important outcomes such as self-esteem, academic achievement, and health. Identity threat perspectives help to explain the tremendous variability across people, groups, and situations in responses to stigma.


Measuring refractive index using the focal displacement method.
A simple technique is introduced for measuring the refractive index of plane-parallel samples having thickness of the order of a millimeter. The refractive index values are reported for six bulk semiconductors, each index measured at two infrared wavelengths using this method. The values are found to be within a few percent of those in literature for four semiconductors. The other two semiconductors were newly grown ternary alloys (CdMgTe and CdMnTe), for which the refractive index values have not been reported previously at the wavelengths studied here.


Quantifying quality of life and disability of patients with advanced schistosomiasis japonica.
The Chinese government lists advanced schistosomiasis as a leading healthcare priority due to its serious health and economic impacts, yet it has not been included in the estimates of schistosomiasis burden in the Global Burden of Disease (GBD) study. Therefore, the quality of life and disability weight (DW) for the advanced cases of schistosomiasis japonica have to be taken into account in the re-estimation of burden of disease due to schistosomiasis. A patient-based quality-of-life evaluation was performed for advanced schistosomiasis japonica. Suspected or officially registered advanced cases in a Schistosoma japonicum-hyperendemic county of the People's Republic of China (P.R. China) were screened using a short questionnaire and physical examination. Disability and morbidity were assessed in confirmed cases, using the European quality of life questionnaire with an additional cognitive dimension (known as the "EQ-5D plus"), ultrasonography, and laboratory testing. The age-specific DW of advanced schistosomiasis japonica was estimated based on patients' self-rated health scores on the visual analogue scale of the questionnaire. The relationships between health status, morbidity and DW were explored using multivariate regression models. Of 506 candidates, 215 cases were confirmed as advanced schistosomiasis japonica and evaluated. Most of the patients reported impairments in at least one health dimension, such as pain or discomfort (90.7%), usual activities (87.9%), and anxiety or depression (80.9%). The overall DW was 0.447, and age-specific DWs ranged from 0.378 among individuals aged 30-44 years to 0.510 among the elderly aged ≥ 60 years. DWs are positively associated with loss of work capacity, psychological abnormality, ascites, and active hepatitis B virus, while splenectomy and high albumin were protective factors for quality of life. These patient-preference disability estimates could provide updated data for a revision of the GBD, as well as for evidence-based decision-making in P.R. China's national schistosomiasis control program.


Enabling screening in 3D microenvironments: probing matrix and stromal effects on the morphology and proliferation of T47D breast carcinoma cells.
During breast carcinoma progression, the three-dimensional (3D) microenvironment is continuously remodeled, and changes in the composition of the extracellular matrix (ECM) occur. High throughput screening platforms have been used to decipher the complexity of the microenvironment and to identify ECM components responsible for cancer progression. However, traditional screening platforms are typically limited to two-dimensional (2D) cultures, and often exclude the influence of ECM and stromal components. In this work, a system that integrates 3-dimensional cell culture techniques with an automated microfluidic platform was used to create a new ECM screening platform that cultures cells in more physiologically relevant 3D in vitro microenvironments containing stromal cells and different ECM molecules. This new ECM screening platform was used to culture T47D breast carcinoma cells in mono- and co-culture with human mammary fibroblasts (HMF) with seven combinations of three different ECM proteins (collagen, fibronectin, laminin). Differences in the morphology of T47D clusters, and the proliferation of T47D cells were found in ECM compositions rich in fibronectin or laminin. In addition, an MMP enzyme activity inhibition screening showed the capabilities of the platform for small molecule screening. The platform presented in this work enables screening for the effects of matrix and stromal compositions and show promises for providing new insights in the identification of key ECM components involved in breast cancer.


The erbB-2 mitogenic signaling pathway: tyrosine phosphorylation of phospholipase C-gamma and GTPase-activating protein does not correlate with erbB-2 mitogenic potency.
The erbB-2 gene product, gp185erbB-2, unlike the structurally related epidermal growth factor (EGF) receptor (EGFR), exhibits constitutive kinase and transforming activity. We used a chimeric EGFR/erbB-2 expression vector to compare the mitogenic signaling pathway of the erbB-2 kinase with that of the EGFR, at similar levels of expression, in response to EGF stimulation. The EGFR/erbB-2 chimera was significantly more active in inducing DNA synthesis than the EGFR when either was expressed in NIH 3T3 cells. Analysis of biochemical pathways implicated in signal transduction by growth factor receptors indicated that both phospholipase C type gamma (PLC-gamma) and the p21ras GTPase-activating protein (GAP) are substrates for the erbB-2 kinase in NIH 3T3 fibroblasts. However, under conditions in which activation of the erbB-2 kinase induced DNA synthesis at least fivefold more efficiently than the EGFR, the levels of erbB-2- or EGFR-induced tyrosine phosphorylation of PLC-gamma and GAP were comparable. In addition, the stoichiometry of tyrosine phosphorylation of these putative substrates by erbB-2 appeared to be at least an order of magnitude lower than that induced by platelet-derived growth factor receptors at comparable levels of mitogenic potency. Thus, our results indicate that differences in tyrosine phosphorylation of PLC-gamma and GAP do not account for the differences in mitogenic activity of the erbB-2 kinase compared with either the EGFR or platelet-derived growth factor receptor in NIH 3T3 fibroblasts.


Common pre-diagnostic features in individuals with different rare diseases represent a key for diagnostic support with computerized pattern recognition?
Rare diseases (RD) result in a wide variety of clinical presentations, and this creates a significant diagnostic challenge for health care professionals. We hypothesized that there exist a set of consistent and shared phenomena among all individuals affected by (different) RD during the time before diagnosis is established. We aimed to identify commonalities between different RD and developed a machine learning diagnostic support tool for RD. 20 interviews with affected individuals with different RD, focusing on the time period before their diagnosis, were performed and qualitatively analyzed. Out of these pre-diagnostic experiences, we distilled key phenomena and created a questionnaire which was then distributed among individuals with the established diagnosis of i.) RD, ii.) other common non-rare diseases (NRO) iii.) common chronic diseases (CD), iv.), or psychosomatic/somatoform disorders (PSY). Finally, four combined single machine learning methods and a fusion algorithm were used to distinguish the different answer patterns of the questionnaires. The questionnaire contained 53 questions. A total sum of 1763 questionnaires (758 RD, 149 CD, 48 PSY, 200 NRO, 34 healthy individuals and 574 not evaluable questionnaires) were collected. Based on 3 independent data sets the 10-fold stratified cross-validation method for the answer-pattern recognition resulted in sensitivity values of 88.9% to detect the answer pattern of a RD, 86.6% for NRO, 87.7% for CD and 84.2% for PSY. Despite the great diversity in presentation and pathogenesis of each RD, patients with RD share surprisingly similar pre-diagnosis experiences. Our questionnaire and data-mining based approach successfully detected unique patterns in groups of individuals affected by a broad range of different rare diseases. Therefore, these results indicate distinct patterns that may be used for diagnostic support in RD.


Secretory products of macrophages and their physiological functions.
Macrophages secrete a variety of biologically active substances into their local milieu, including proteins, lipids, nucleotide metabolites, and oxygen metabolites. To date, more than 50 substances secreted by macrophages have been reported: enzymes; enzyme inhibitors; plasma proteins such as complement components, coagulation factors, and apolipoprotein E; factors that regulate the functions of other cells such as interferon, interleukin 1, mitogens, and angiogenesis factor; and low molecular weight substances such as reactive metabolites of oxygen and derivatives of arachidonic acids. Macrophage-derived products are probably important in the local environment, and they are believed to be important in the physiological and pathological functions of macrophages in inflammation, tissue repair, lipoprotein metabolism, acute phase response, and in microbicidal, antiviral, tumoricidal, and immunoregulatory activities; however, macrophages may not be the sole source for the secretion of some of these products. The secretion of these products is intricately regulated, developmentally and environmentally.


Experimental investigation and modeling of dissolved organic carbon removal by coagulation from seawater.
Coagulation removes colloidal matters and dissolved organic carbon (DOC) which can cause irreversible membrane fouling. However, how DOC is removed by coagulant is not well-known. Jar test was used to study the removal of hydrophobic and hydrophilic DOC fractions at various doses (0.5-8.0 mg-Fe(+3) L(-1)) of ferric chloride (FeCl3) and pH (5.0-9.0). Natural organic matter (NOM) in seawater and treated seawater were fractionated by liquid chromatography-organic carbon detector (LC-OCD). Compared to surface water, the removal of DOC in seawater by coagulation was remarkably different. Majority of DOC could be easily removed with very low coagulant dose (<5.0 mg-Fe(+3) L(-1)) and the removal efficiency did not vary with pH, but the DOC composition in treated water had significantly changed. Hydrophobic fraction (HB) was better removed at high pH while hydrophilic fraction (HF) was better removed at low pH. A modified model of Kastl et al. (2004) which assumed that the removal occurred by adsorption of un-dissociated compounds onto ferric hydroxide was formulated and successfully validated against the jar test data.


[Acute and chronic pancreatitis in the elderly patient].
Normal pancreatic ageing is characterized by functional and morphological changes of the pancreatic parenchyma and of the ductal system, which, however, do not interfere with normal exocrine pancreatic function. It can be speculated that 'pancreatic lithiasis in the aged' as well as the 'senile idiopathic chronic pancreatitis', two conditions of chronic pancreatitis in the elderly, may represent more extreme forms of these normal age-related changes in pancreatic structure and function. In elderly people, acute and chronic pancreatitis are only rarely related to alcohol abuse, in contrast to the situation in a younger patient population. The presence of gallstones represents the most frequent cause of acute pancreatitis in the elderly. In most aged patients with acute biliary pancreatitis, endoscopic sphincterotomy is the treatment of choice, even when bile duct stones cannot clearly be demonstrated at ERCP. Endoscopic sphincterotomy has been shown to reduce morbidity as well as mortality rates in acute biliary pancreatitis. This technique can even be considered as treatment of choice in elderly patients with an increased operative risk. An elective laparoscopic cholecystectomy should be performed in elderly patients with an acceptable operative risk.


Collagenase-1 and stromelysin distribution in fresh human herniated intervertebral disc: a possible link to the in vivo inflammatory reactions.
Chondrocytes may play an important role in the inflammatory reactions involving intervertebral discs: the role of metalloproteases (MMP) and the imbalance between proteases and their inhibitors seems to play a crucial role in the disc degenerative process. In the present study we have analysed the production of collagenase-1 and stromelysin in different parts of herniated intervertebral discs. Ten samples of herniated lumbar discs were obtained from adult patients operated on for primary microdiscectomy because of persistent radicular symptoms and subdivided into three samples: 1. The nearest to the nerve root in close contact with it, 2. the sample obtained from the intervertebral space, and 3. the sample obtained from the vertebral plates. The DNA content of each specimen was measured in order to obtain the best estimate of the cell content as well as to normalise the content of collagenase-1 and stromelysin found in the same tissues with respect to the number of cells. In 9 out of the 10 cases the DNA content was significantly higher in samples obtained from the intervertebral plates than in samples obtained near the nerve root or the intervertebral space. DNA content did not show any significant difference considering disc samples contiguous to the nerve root and samples obtained from the intervertebral space. The production of collagenase-1 did not show a specific pattern, being produced in similar quantities in the three disc compartments. The production of stromelysin was significantly lower in disc samples obtained from the intervertebral plates. In conclusion the results of the present study suggest firstly that in the herniated lumbar disc the reactivity and the production of pro-inflammatory agents is independent of DNA content, i.e. the cellularity of the sample, and secondly that activated cells in the intervertebral space and in the part of the disc in contact with the nerve root, even if scarce in number, are able to synthesise a proportionally higher quantity of MMP than the high-cellular disc fragments from the intervertebral plates, potentially playing a specific role in the inflammatory reactions.


Inhibition of HDM2 and activation of p53 by ribosomal protein L23.
The importance of coordinating cell growth with proliferation has been recognized for a long time. The molecular basis of this relationship, however, is poorly understood. Here we show that the ribosomal protein L23 interacts with HDM2. The interaction involves the central acidic domain of HDM2 and an N-terminal domain of L23. L23 and L11, another HDM2-interacting ribosomal protein, can simultaneously yet distinctly interact with HDM2 together to form a ternary complex. We show that, when overexpressed, L23 inhibits HDM2-induced p53 polyubiquitination and degradation and causes a p53-dependent cell cycle arrest. On the other hand, knocking down L23 causes nucleolar stress and triggers translocation of B23 from the nucleolus to the nucleoplasm, leading to stabilization and activation of p53. Our data suggest that cells may maintain a steady-state level of L23 during normal growth; alternating the levels of L23 in response to changing growth conditions could impinge on the HDM2-p53 pathway by interrupting the integrity of the nucleolus.


The recombinant antigen ASPND1r from Aspergillus nidulans is specifically recognized by sera from patients with aspergilloma.
A 996 bp Aspergillus nidulans cDNA encoding the ASPND1 immunodominant antigen was cloned and expressed in Escherichia coli as a fusion protein with the enzyme glutathione S-transferase (GST) from Schistosoma japonicum. The GST-ASPND1 fusion protein was purified from isolated bacterial inclusion bodies by preparative SDS-PAGE. After cleavage with thrombin, the ASPND1 recombinant antigen (ASPND1r) and the GST protein were separated by SDS-PAGE and immunoblotted with a number of different human sera. The sera from 22 (88%) of 25 patients with an aspergilloma recognized the ASPND1r recombinant antigen on immunoblots. Forty-nine normal human sera and 14 sera from patients with other infections were unreactive. The ASPND1r expressed in E. coli could therefore be used, in combination with previously reported recombinant antigens, as a standardized antigen for serological and clinical diagnosis of Aspergillus-associated diseases.


Oxidation of elemental sulfur to thiosulfate by Streptomyces.
Streptomyces sioyaensis, which produces the antibiotic siomycin, oxidizes elemental sulfur when added to the culture medium and accumulates thiosulfate in the fermented broth. The accumulated thiosulfate was isolated as the ammonium salt and was identified by melting point, IR spectrum, and paper chromatography. A variety of other streptomycetes also oxidized elemental sulfur and accumulated thiosulfate.


Essential arterial hypertension patients present higher cell adhesion forces, contributing to fibrinogen-dependent cardiovascular risk.
The increase of erythrocyte aggregation by high fibrinogen levels may be an indicator of cardiovascular risk. γ' fibrinogen variant has been considered as a possible player in enhancing aggregation. Here, we assessed, at the single-cell level, the influence of fibrinogen on erythrocyte aggregation in essential arterial hypertension. We also aimed at understanding how γ' fibrinogen is altered in this disease. Using atomic force microscopy (AFM), we show that the work and force necessary for erythrocyte-erythrocyte detachment is higher for patients than for healthy donors, with these parameters further increasing in both groups when higher fibrinogen concentrations are present. This can be associated with changes in blood flow, due to transient bridging of two erythrocytes by fibrinogen, representing an important cardiovascular risk factor. γ' fibrinogen can influence the increased risk in essential arterial hypertension, as we demonstrate that its levels are significantly increased in these patients' blood. Nevertheless, this cannot be the only cause for the changes observed in the AFM data.


Laparoscopic herniorrhaphy. Diagnostic and therapeutic technology assessment.
To provide clinicians with a technology assessment of the safety and effectiveness of laparoscopic herniorrhaphy for the surgical repair of inguinal hernias. A literature review and a Diagnostic and Therapeutic Technology Assessment (DATTA) survey questionnaire were mailed to 75 physicians with expertise in surgical repair of inguinal hernias. These panelists had been nominated to the DATTA panel by the appropriate specialty societies and medical schools. A total of 55 panelists (73%) responded. Assessment was based on the expert opinion of the panelists, as well as on published literature (available as of February 8, 1996). Published studies were identified by a MEDLINE search using the terms laparoscopic surgery, inguinal hernia, and laparoscopic herniorrhaphy and by review of the references cited in these primary sources. The respondents completed a DATTA survey questionnaire; the survey results were tabulated, analyzed, and interpreted by American Medical Association staff. The DATTA panelists rated the use of laparoscopic herniorrhaphy as promising for safety and investigational for effectiveness for two indications: the repair of primary inguinal hernias and the repair of bilateral inguinal hernias. The use of laparoscopic herniorrhaphy to repair recurrent inguinal hernias was rated as investigational for both safety and effectiveness by the panel. This technique was rated as promising for safety and effectiveness as a method for decreasing postoperative tenderness and time until return to full activity.


Macrophage-targeted overexpression of urokinase causes accelerated atherosclerosis, coronary artery occlusions, and premature death.
Human atherosclerotic lesions contain elevated levels of urokinase plasminogen activator (uPA), expressed predominantly by macrophages. To test the hypothesis that macrophage-expressed uPA contributes to the progression and complications of atherosclerosis, we generated transgenic mice with macrophage-targeted overexpression of uPA. The uPA transgene was bred into the apolipoprotein E-null background, and transgenic mice and nontransgenic littermate controls were fed an atherogenic diet. uPA-transgenic mice had significantly elevated uPA activity in the atherosclerotic artery wall, of a magnitude similar to elevations reported in atherosclerotic human arteries. Compared with littermate controls, uPA-transgenic mice had accelerated atherosclerosis, dilated aortic roots, occlusive proximal coronary artery disease, myocardial infarcts, and early mortality. These data support the hypothesis that overexpression of uPA by artery wall macrophages is atherogenic and suggest that uPA inhibitors might be therapeutically useful.


Interpreting and managing blood lead levels < 10 microg/dL in children and reducing childhood exposures to lead: recommendations of CDC's Advisory Committee on Childhood Lead Poisoning Prevention.
Lead is a common environmental contaminant, and exposure to lead is a preventable risk that exists in all areas of the United States. Lead is associated with negative outcomes in children, including impaired cognitive, motor, behavioral, and physical abilities. In 1991, CDC defined the blood lead level (BLL) that should prompt public health actions as 10 microg/dL. Concurrently, CDC also recognized that a BLL of 10 microg/dL did not define a threshold for the harmful effects of lead. Research conducted since 1991 has strengthened the evidence that children's physical and mental development can be affected at BLLs < or =10 microg/dL. This report summarizes the findings of a review of clinical interpretation and management of BLLs < or =10 microg/dL conducted by CDC's Advisory Committee on Childhood Lead Poisoning Prevention. This report provides information to help clinicians understand BLLs < or =10 microg/dL, identifies gaps in knowledge concerning lead levels in this range, and outlines strategies to reduce childhood exposures to lead. In addition, this report summarizes scientific data relevant to counseling, blood lead screening, and lead exposure risk assessment. To aid in the interpretation of BLLs, clinicians should understand the laboratory error range for blood lead values and, if possible, select a laboratory that achieves routine performance within +/-2 microg/dL. Clinicians should obtain an environmental history on all children they examine, provide families with lead prevention counseling, and follow blood lead screening recommendations established for their areas. As local and patient circumstances permit, clinicians should consider early referral to developmental programs for children at high risk for exposure to lead and consider more frequent rescreening of children with BLLs approaching 10 microg/dL, depending on the potential for exposure to lead, child age, and season of testing. In addition, clinicians should direct parents to agencies and sources of information that will help them establish a lead-safe environment for their children. For these preventive strategies to succeed, partnerships between health-care providers, families, and local public health and housing programs should be strengthened.


Association between PPAR-γ2 Pro12Ala genotype and insulin resistance is modified by circulating lipids in Mexican children.
The Pro12Ala (rs1801282) polymorphism in peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) has been convincingly associated with insulin resistance (IR) and type 2 diabetes (T2D) among Europeans, in interaction with a high-fat diet. Mexico is disproportionally affected by obesity and T2D however, whether the Pro12Ala polymorphism is associated with early metabolic complications in this population is unknown. We assessed the association of PPAR-γ2 Pro12Ala with metabolic traits in 1457 Mexican children using linear regression models. Interactions between PPAR-γ2 Pro12Ala and circulating lipids on metabolic traits were determined by adding an interaction term to regression models. We observed a high prevalence of overweight/obesity (49.2%), dyslipidemia (34.9%) and IR (11.1%). We detected nominally significant/significant interactions between lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol), the PPAR-γ2 Pro12Ala genotype and waist-to-hip ratio, fasting insulin, HOMA-IR and IR (9.30 × 10(-4) ≤ Pinteraction ≤ 0.04). Post-hoc subgroup analyses evidenced that the association between the PPAR-γ2 Pro12Ala genotype and fasting insulin, HOMA-IR and IR was restricted to children with total cholesterol or LDL-cholesterol values higher than the median (0.02 ≤ P ≤ 0.03). Our data support an association of the Pro12Ala polymorphism with IR in Mexican children and suggest that this relationship is modified by dyslipidemia.


Erl1, a novel era-like GTPase from Magnaporthe oryzae, is required for full root virulence and is conserved in the mutualistic symbiont Glomus intraradices.
Comparative analyses of genome sequences from several plant-infecting fungi have shown conservation and expansion of protein families with plant disease-related functions. Here, we show that this hypothesis can be extended to mutualistic symbiotic fungi. We have identified a gene encoding an Era (Escherichia coli Ras)-like GTPase in the rice blast fungus Magnaporthe oryzae and found that it is orthologous to the mature amino terminal part of the Gin1 protein from the arbuscular mycorrhizal (AM) fungus Glomus intraradices. M. oryzae Erl1 is required for full root virulence. Appressoria formation was not severely affected in Deltaerl1 strains, but invasive hyphae grew slower than in the wild type. Root browning defect of Deltaerl1 strains could be complemented by the AM gene under the control of the ERL1 promoter. Erl1 and Gin-N localized to the nucleus when carboxy-terminally labeled with green fluorescent protein (GFP). However, amino-terminal GFP-tagged versions of the proteins expressed in Aspergillus nidulans were shown to localize in the cytoplasm and to cause polarity defects. These data suggest that Erl1 and Gin-N are orthologs and might be involved in the control of hyphal growth in planta. This is the first characterization of an Era-like GTPase in filamentous fungi.


T cell requirements for generation of helper factor(s) in man: analysis of the subsets involved.
Lymphocyte mitogenic factor functions as a nonspecific helper molecule generated from antigen stimulation of T lymphocytes. As such, it induces proliferation of all major lymphocyte subclasses (T, B, and Null cells) and B cell immunoglobulin synthesis. In the present study, the specific T cell subset requirements for LMF production were determined in man. By utilizing the OKT4 monoclonal antibody directed at the human inducer T cell subset, T lymphocytes were separated into OKT4+ and OKT4- subpopulations. The antigen stimulated OKT4+ subset generated LMF in a fashion comparable to the unfractionated T cell population and was itself capable of directly inducing B cell proliferation and antibody production. In contrast, LMF could not be generated from the OKT4-T cell subset although this population accounted for 40% of the unfractionated T cell population. In addition, the OKT4- subset was unable to facilitate B cell differentiation in the presence of soluble antigen. These studies provide the first report of T cell subset restriction for generation of helper factors in man and further stress the importance of the OKT4+ inducer population in regulation of the human immune response.


Probabilistic accounting of uncertainty in forecasts of species distributions under climate change.
Forecasts of species distributions under future climates are inherently uncertain, but there have been few attempts to describe this uncertainty comprehensively in a probabilistic manner. We developed a Monte Carlo approach that accounts for uncertainty within generalized linear regression models (parameter uncertainty and residual error), uncertainty among competing models (model uncertainty), and uncertainty in future climate conditions (climate uncertainty) to produce site-specific frequency distributions of occurrence probabilities across a species' range. We illustrated the method by forecasting suitable habitat for bull trout (Salvelinus confluentus) in the Interior Columbia River Basin, USA, under recent and projected 2040s and 2080s climate conditions. The 95% interval of total suitable habitat under recent conditions was estimated at 30.1-42.5 thousand km; this was predicted to decline to 0.5-7.9 thousand km by the 2080s. Projections for the 2080s showed that the great majority of stream segments would be unsuitable with high certainty, regardless of the climate data set or bull trout model employed. The largest contributor to uncertainty in total suitable habitat was climate uncertainty, followed by parameter uncertainty and model uncertainty. Our approach makes it possible to calculate a full distribution of possible outcomes for a species, and permits ready graphical display of uncertainty for individual locations and of total habitat.


Automatic segmentation of corneal deposits from corneal stromal dystrophy images via deep learning.
Granular dystrophy is the most common stromal dystrophy. To perform automated segmentation of corneal stromal deposits, we trained and tested a deep learning (DL) algorithm from patients with corneal stromal dystrophy and compared its performance with human segmentation. In this retrospective cross-sectional study, we included slit-lamp photographs by sclerotic scatter from patients with corneal stromal dystrophy and real-world slit-lamp photographs via various techniques (diffuse illumination, tangential illumination, and sclerotic scatter). Our data set included 1007 slit-lamp photographs of semi-automatically generated handcraft masks on granular and linear lesions from corneal stromal dystrophy patients (806 for the training set and 201 for test set). For external test (140 photographs), we applied the DL algorithm and compared between automated and human segmentation. For performance, we estimated the intersection of union (IoU), global accuracy, and boundary F1 (BF) score for segmentation. In 201 internal test set, IoU, global accuracy, and BF score with 95 % confidence Interval were 0.81 (0.79-0.82), 0.99 (0.98-0.99), and 0.93 (0.92-0.95), respectively. In 140 heterogenous external test set as a real-world data, those were 0.64 (0.61-0.67), 0.95 (0.94-0.96), and 0.70 (0.64-0.76) via DL algorithm and 0.56 (0.51-0.61), 0.95 (0.94-0.96), and 0.70 (0.65-0.74) via human rater, respectively. We developed an automated segmentation DL algorithm for corneal stromal deposits in patients with corneal stromal dystrophy. Segmentation on corneal deposits was accurate via the DL algorithm in the well-controlled dataset and showed reasonable performance in a real-world setting. We suggest this automatic segmentation of corneal deposits helps to monitor the disease and can evaluate possible new treatments.


Secondary solid tumors after allogeneic hematopoietic SCT in Japan.
To evaluate the incidence and risk factors for secondary solid tumors in Japan after allogeneic hematopoietic SCT (allo-HSCT), 2062 patients who had received allo-HSCT between 1984 and 2005 were retrospectively analyzed. Twenty-eight patients who developed 30 solid tumors were identified a median of 5.6 years after transplantation. The risk for developing tumors was 2.16-fold higher than that of the age- and sex-adjusted general population. The cumulative incidence of solid tumors at 10 years after allo-HSCT was 2.4%. The risk was significantly higher for tumors of the skin, oral cavity and esophagus (standard incidental ratio 40.23, 35.25 and 10.73, respectively). No increase in gastric, colon or lung cancer, despite being the most prevalent neoplasm in the Japanese, was observed. In multivariate analysis, occurrence of chronic GVHD and malignant lymphoma as a primary disease was associated with a higher risk for developing solid tumors. Eighteen patients are still alive, and their 5-year probability of survival since diagnosis of solid tumors is 59.7%. Our data suggest that the incidence and risk factors of secondary solid tumors in Japanese allo-HSCT recipients are comparable to those reported in Western countries and emphasize that the early detection of solid tumors has a crucial role in improving OS.


Phytofiltration of cadmium from water by Limnocharis flava (L.) Buchenau grown in free-floating culture system.
A hydroponics experiment was conducted to examine the phytofiltration of Cd by Limnocharis flava (L.) Buchenau grown in low-level Cd-contaminated water. For this, 45 d old seedlings of L .flava were transferred to a floating-support culture system containing nutrient solution spiked with four levels of Cd (0.5, 1, 2 and 4 mg l(-1)) and were separately harvested after 3, 7, 21 and 30 d. After 30 d harvesting, the percentage removal of Cd from the above four treatments reached up to 98, 96, 95 and 93%, respectively. Interestingly, all treatments had higher growth rate than control at 95% confidence level and plants still remained healthy at 4 mg l(-1) Cd exposure. The bioaccumulation study showed a linear relationship of Cd (R(2)=0.896-0.999) in all plant parts with the exposure time (3-30 d) and Cd concentrations in hydroponics system (0.5-4 mg l(-1)). Although, the root of L. flava had higher Cd concentration than leaf and peduncles, the total Cd concentrations in aerial plant parts were higher than the roots. The maximum bioconcentration factor (BCF) and translocation factor (TF) value of L. flava were calculated as 984.42 and 1.43, respectively. Estimated Cd accumulation capacity of L. flava per unit area (m(2)) was found to be in the range of 218. 35-1698.92 mg m(-2).The experimental results demonstrated that L. flava is a suitable candidate for the phytofiltartion (>93%) of Cd from low-level Cd-contaminated water.


Parasite-specific immunomodulatory functions of filarial cystatin.
Cystatins of parasitic nematodes are well-described pathogenicity factors which contribute to downregulation of T-cell proliferation of their hosts and induce anti-inflammatory cytokine responses. We compared the immunomodulatory effects of two cystatins of the filarial nematodes Onchocerca volvulus and Acanthocheilonema viteae with two homologous proteins of the free-living nematode Caenorhabditis elegans. Like filarial cystatins, the C. elegans cystatins (rCysele1 and rCysele2) possessed domains relevant for inhibition of papain-like proteases and were biologically active inhibitors of human cathepsins B, L, and S. However, the inhibition of cathepsin B by C. elegans cystatin was much stronger. C. elegans cystatins lacked a domain involved in inhibition of legumain-like proteases that was present in O. volvulus cystatin. Filarial cystatins suppressed the proliferation of human peripheral blood mononuclear cells (PBMC) and murine spleen cells, while the C. elegans cystatins had this effect to a much lesser extent. Whereas filarial cystatins markedly increased the production of interleukin (IL)-10, C. elegans cystatins increased the production of IL-12 and gamma interferon (IFN-gamma) by human PBMC. The cystatins of both the filariae and C. elegans induced an upregulation of inducible nitric oxide by IFN-gamma-stimulated murine macrophages. These data suggest that filarial cystatins but not the C. elegans cystatins downregulate proliferative responses of host cells due to characteristics which might reflect an adaptation of filariae to their parasitic life style.


Molecular Epidemiology of Citrus Leprosis Virus C: A New Viral Lineage and Phylodynamic of the Main Viral Subpopulations in the Americas.
Despite the importance of viral strains/variants as agents of emerging diseases, genetic and evolutionary processes affecting their ecology are not fully understood. To get insight into this topic, we assessed the population and spatial dynamic parameters of citrus leprosis virus C (CiLV-C, genus Cilevirus, family Kitaviridae). CiLV-C is the etiological agent of citrus leprosis disease, a non-systemic infection considered the main viral disorder affecting citrus orchards in Brazil. Overall, we obtained 18 complete or near-complete viral genomes, 123 complete nucleotide sequences of the open reading frame (ORF) encoding the putative coat protein, and 204 partial nucleotide sequences of the ORF encoding the movement protein, from 430 infected Citrus spp. samples collected between 1932 and 2020. A thorough examination of the collected dataset suggested that the CiLV-C population consists of the major lineages CRD and SJP, unevenly distributed, plus a third one called ASU identified in this work, which is represented by a single isolate found in an herbarium sample collected in Asuncion, Paraguay, in 1937. Viruses from the three lineages share about 85% nucleotide sequence identity and show signs of inter-clade recombination events. Members of the lineage CRD were identified both in commercial and non-commercial citrus orchards. However, those of the lineages SJP were exclusively detected in samples collected in the citrus belt of São Paulo and Minas Gerais, the leading Brazilian citrus production region, after 2015. The most recent common ancestor of viruses of the three lineages dates back to, at least, ∼1500 years ago. Since citrus plants were introduced in the Americas by the Portuguese around the 1520s, the Bayesian phylodynamic analysis suggested that the ancestors of the main CiLV-C lineages likely originated in contact with native vegetation of South America. The intensive expansion of CRD and SJP lineages in Brazil started probably linked to the beginning of the local citrus industry. The high prevalence of CiLV-C in the citrus belt of Brazil likely ensues from the intensive connectivity between orchards, which represents a potential risk toward pathogen saturation across the region.


Metabolic derangements mediate cognitive impairment and Alzheimer's disease: role of peripheral insulin-resistance diseases.
Herein, we review evidence that systemic insulin-resistance diseases linked to obesity, type 2 diabetes, and non-alcoholic steatohepatitis promote neurodegeneration. Insulin-resistance dysregulates lipid metabolism, which promotes ceramide accumulation with attendant inflammation and endoplasmic reticulum (ER) stress. Mechanistically, we propose that toxic ceramides generated in extra-CNS tissues, e.g. liver, get released into peripheral blood, and subsequently transit across the blood-brain barrier into the brain where they induce brain insulin-resistance, inflammation, and cell death (extrinsic pathway). These abnormalities establish or help propagate a cascade of neurodegeneration associated with increased ER stress and ceramide generation, which exacerbate brain insulin-resistance, cell death, myelin degeneration, and neuro-inflammation. The data suggest that a mal-signaling network mediated by toxic ceramides, ER stress, and insulin-resistance should be targeted to disrupt positive feedback loops that drive the AD neurodegeneration cascade.


CHADS2 and CHA2DS2-VASc scoring systems for predicting atrial fibrillation following cardiac valve surgery.
Clinical use of CHADS2 and CHA2DS2-VASc scoring systems for predicting AF following cardiac surgery have been reported in previous studies and demonstrated well-validated predictive value. We sought to investigate whether the two scoring systems are effective for predicting new-onset of AF following cardiac valve surgery and to demonstrate its potential utility of clinical assessment. Medical records of all patients underwent cardiac valve surgeries during the period of January 2003 and December 2013 without preoperative AF at the cardiac center of our university were reviewed. The main outcome end point of our study was the early new-onset of AF following cardiac valve surgery. There were overall 518 patients involved in this study, with 234 (45.17%) developed POAF following valve surgery. Patients with POAF had older age (P=0.23) and higher BMI (P=0.013) than those without POAF. History of heart failure (P=0.025), hypertension (P=0.021), previous stroke or TIA (P=0.032), coronary artery disease (P=0.001), carotid artery disease (P=0.024) and preoperative medication of statins (P=0.021) were significantly more recorded in POAF group. Patients with POAF also had higher LAD (P=0.013) and E/e' ratio (P<0.001). The CHADS2 and CHA2DS2-VASc scores were significantly higher in patients with POAF (P=0.002; P<0.001), and under univariate and multivariate regression analysis the CHADS2 and CHA2DS2-VASc scores were significant predictors of POAF (P=0.001; P<0.001). Based on stratification of CHADS2 and CHA2DS2-VASc scores, the Kaplan-Meier analysis obtained a higher POAF rate on patients with higher stratification of CHADS2 and CHA2DS2-VASc scores (P<0.001; P<0.001). In conclusion, CHADS2 and CHA2DS2-VASc scores were directly associated with the incidence of POAF following valve surgery and a higher score was strongly predictive of POAF.


[Protection of azithromycin against pulmonary II epithelial cell injuries induced by cigarette smoke extract and relevant mechanisms].
Cigarette smoke extract (CSE) can induce injuries of pulmonary II epithelial cells, activate nuclear factor-kappaB and increase tumor necrosis factor-alpha(TNF-alpha) secretion. This study aimed to investigate whether azithromycin can protect pulmonary II epithelial cells from injuries induced by CSE and relevant mechanisms. Pulmonary II epithelial cells (A549 cells) were cultured in vitro. After 48 hrs of culture the cells were randomly treated with serum-free DMEM only (blank control group), azithromycin + serum-free DMEM, CSE+ serum-free DMEM or CSE+azithromycin. Eight hours later the morphology of A549 cells, the activity of NF-kappaB and the levels of TNF-alpha were measured by inverted microscope, immunohistochemistry and ELISA. The morphology and structure of A549 cells were changed, NF-kappaB activity increased (dark brown staining ) and TNF-alpha levels (0.307 +/- 0.036 pg/mL vs 0.234 +/- 0.028 pg/mL)increased in the CSE+ serum-free DMEM group compared with the blank control group (P < 0.01). CSE together with azithromycin treatment recovered partly the morphological injuries of A549 cells. It also attenuated NF-kappaB staining and decreased TNF-alpha levels from 0.307 +/- 0.036 pg/mL (CSE+serum-free DMEM group) to 0.269 +/- 0.009 pg/mL (P < 0.05). Azithromycin may inhibit NF-kappaB activity, decrease TNF-alpha secretion and thus lessen cytotoxicity of CSE to A549 cells.


Pharmacoeconomic evaluation of immunoglobulin treatment in patients with antibody deficiencies from the perspective of the German statutory health insurance.
Primary antibody deficiencies are the most common forms of primary immunodeficiencies. Substitution therapy with polyvalent immunoglobulins has been established as the standard therapy for antibody deficiencies for several decades. Until now mainly intravenous immunoglobulins (IVIG) have been used in Germany, and the majority of patients receive treatment in hospital outpatient clinics. In recent years subcutaneous administration of immunoglobulins (SCIG) has been developed which is administered as home self-infusion. Studies indicate no significant differences in immunoglobulin substitution therapy between SCIG and IVIG concerning outcome. We carried out a cost-minimization analysis to compare the two treatment alternatives in Germany. Under base case assumptions the treatment with SCIG is cost saving from the perspective of the German statutory health insurance. The main cost drivers are IVIG and SCIG; the incremental cost of SCIG compared to IVIG is most sensitive to changes in the immunoglobulin price and changes in the body weight of the patient.


Safety of biologics in rheumatoid arthritis: data from randomized controlled trials and registries.
Over the past decade, the use of biologics has significantly changed the management of rheumatoid arthritis (RA). Biologics selectively target components of the immune system, resulting in better disease control. However, the growing use of biologics in RA has increased safety concerns among rheumatologists. Randomized controlled trials (RCTs) and registries are the most reliable sources of clinical safety data. Although safety data from RCTs provide certain insights into the clinical safety profile of an agent, strict constraints in study design (eg, exclusion criteria and restrictive treatment protocols) often do not accurately reflect possible safety issues in the use of the agent, either in the clinical setting or over long-term treatment. Registries, on the other hand, are not restrictive regarding patient enrollment, making them more reliable in evaluating long-term safety. A number of registries have been established globally: in Europe, the United States, and Asia. However, the availability of registry data from Eastern Europe is lacking. The notable exceptions so far are registries from the Czech Republic (ATTRA, a registry of patients treated with anti-tumor necrosis factor-alpha drugs) and Serbia (National registry of patients with rheumatoid arthritis in Serbia [NARRAS]). The current report provides an overview of safety data with biologics in RA from RCTs and registries. Availability of regional safety data from Eastern Europe is of great importance to its clinicians for making evidence-based treatment decisions in RA.


The ninth component of complement and the pore-forming protein (perforin 1) from cytotoxic T cells: structural, immunological, and functional similarities.
The ninth component of complement (C9) and the pore-forming protein (PFP or perforin) from cytotoxic T lymphocytes polymerize to tubular lesions having an internal diameter of 100 A and 160 A, respectively, when bound to lipid bilayers. Polymerized C9, assembled by slow spontaneous or rapid Zn2+-induced polymerization, and polyperforin, which is assembled only in the presence of Ca2+, constitute large aqueous pores that are stable, nonselective for solutes, and insensitive to changes of membrane potential. Monospecific polyclonal antibodies to purified C9 and PFP show cross-reactivity, suggesting structural homology between the two molecules. The structural and functional homologies between these two killer molecules imply an active role for pore formation during cell lysis.


Lizards on newly created islands independently and rapidly adapt in morphology and diet.
Rapid adaptive changes can result from the drastic alterations humans impose on ecosystems. For example, flooding large areas for hydroelectric dams converts mountaintops into islands and leaves surviving populations in a new environment. We report differences in morphology and diet of the termite-eating gecko Gymnodactylus amarali between five such newly created islands and five nearby mainland sites located in the Brazilian Cerrado, a biodiversity hotspot. Mean prey size and dietary prey-size breadth were larger on islands than mainlands, expected because four larger lizard species that also consume termites, but presumably prefer larger prey, went extinct on the islands. In addition, island populations had larger heads relative to their body length than mainland populations; larger heads are more suited to the larger prey taken, and disproportionately larger heads allow that functional advantage without an increase in energetic requirements resulting from larger body size. Parallel morphological evolution is strongly suggested, because there are indications that, before flooding, relative head size did not differ between future island and future mainland sites. Females and males showed the same trend of relatively larger heads on islands, so the difference between island and mainland sites is unlikely to be due to greater male-male competition for mates on islands. We thus discovered a very fast (at most 15 y) case of independent parallel adaptive change in response to catastrophic human disturbance.


Penetrating keratoplasty using 37 C organ cultured cornea.
Sixty-three penetrating keratoplasties were performed in 63 patients using donor corneas stored by 37 C organ culture incubation for an average of 13 days (range 2 to 35 days). No grafts failed before four weeks, except one which was stored at 4 C for 48 hours prior to transplantation, indicating that endothelial viability is maintained when proper storage conditions are maintained. Sixteen grafts have failed as a result of factors other than the storage method. This clinical study confirms our previous laboratory conclusions that 37 C OC incubation up to 35 days improves the quality of donor endothelium compared with other methods of storage, and it represents a significant advance in corneal preservation.


High amplitude contractions in the middle third of the oesophagus: a manometric marker of chronic alcoholism?
Oesophageal motor abnormalities have been reported in alcoholism. To investigate the effects of chronic alcoholism and its withdrawal on oesophageal disease. 23 chronic alcoholic patients (20 men and three women; mean age 43, range 23 to 54). Endoscopy, manometry, and 24 hour pH monitoring 7-10 days and six months after ethanol withdrawal. Tests for autonomic and peripheral neuropathy were also performed. Motility and pH tracings were compared with those of age and sex matched control groups: healthy volunteers, nutcracker oesophagus, and gastro-oesophageal reflux disease. 14 (61%) alcoholic patients had reflux symptoms, and endoscopy with biopsy showed oesophageal inflammation in 10 patients. One patient had an asymptomatic squamous cell carcinoma. Oesophageal motility studies in the alcoholic patients showed that peristaltic amplitude in the middle third was > 150 mm Hg (95th percentile (P95) of healthy controls) in 13 (57%), the ratio lower/ middle amplitude was < 0.9 in 15 (65%) (> 0.9 in all control groups), and the lower oesophageal sphincter was hypertensive (> 23.4 mm Hg, P95 of healthy controls) in 13 (57%). All three abnormalities were present in five (22%). Abnormal reflux (per cent reflux time > 2.9, P95 of healthy controls) was shown in 12 (52%) alcoholic patients, and was unrelated to peristaltic dysfunction. Subclinical neuropathy in 10 patients did not effect oesophageal abnormalities. Oesophageal motility abnormalities persisted at six months in six patients with ongoing alcoholism, whereas they reverted towards normal in 13 who remained abstinent; reflux, however, was unaffected. Oesophageal peristaltic dysfunction and reflux are frequent in alcoholism. High amplitude contractions in the middle third of the oesophagus seem to be a marker of excessive alcohol consumption, and tend to improve with abstinence.


Intrauterine Growth Restriction Causes Abnormal Embryonic Dentate Gyrus Neurogenesis in Mouse Offspring That Leads to Adult Learning and Memory Deficits.
Human infants who suffer from intrauterine growth restriction (IUGR), which is a failure to attain their genetically predetermined weight, are at increased risk for postnatal learning and memory deficits. Hippocampal dentate gyrus (DG) granule neurons play an important role in memory formation; however, it is unknown whether IUGR affects embryonic DG neurogenesis, which could provide a potential mechanism underlying abnormal postnatal learning and memory function. Using a mouse model of the most common cause of IUGR, induced by hypertensive disease of pregnancy, we first assessed adult learning and memory function. We quantified the percentages of embryonic hippocampal DG neural stem cells (NSCs) and progenitor cells and developing glutamatergic granule neurons, as well as hippocampal volumes and neuron cell count and morphology 18 and 40 d after delivery. We characterized the differential embryonic hippocampal transcriptomic pathways between appropriately grown and IUGR mouse offspring. We found that IUGR offspring of both sexes had short-term adult learning and memory deficits. Prenatally, we found that IUGR caused accelerated embryonic DG neurogenesis and Sox2+ neural stem cell depletion. IUGR mice were marked by decreased hippocampal volumes and decreased doublecortin+ neuronal progenitors with increased mean dendritic lengths at postnatal day 18. Consistent with its known molecular role in embryonic DG neurogenesis, we also found evidence for decreased Wnt pathway activity during IUGR. In conclusion, we have discovered that postnatal memory deficits are associated with accelerated NSC differentiation and maturation into glutamatergic granule neurons following IUGR, a phenotype that could be explained by decreased embryonic Wnt signaling.


Interstitial retinol-binding protein (IRBP) in retinoblastoma.
Interstitial retinol-binding protein (IRBP) is an extracellular glycoprotein that appears to be synthesized by the photoreceptors in the normal retina and may be involved in shuttling retinoids through the interphotoreceptor matrix between the retina and pigment epithelium. The present work demonstrated immunochemically that IRBP of the same molecular weight as normal human IRBP (135,000) was present in three retinoblastomas, irrespective of their degree of differentiation. Tumor 1 was classified as differentiated; Tumors 2 and 3 were classified as poorly differentiated. The level of IRBP in the soluble proteins of Tumor 2 was about 8 times that in Tumor 1 and about one-half that in the soluble proteins (including adhering interphotoreceptor matrix) from a pair of normal retinas from a 31-year-old donor. IRBP occurred in the interstitial space of Tumor 3. Most of the IRBP in this tumor was recovered from the medium in which the undifferentiated cells were dispersed. Incubation of the isolated cells from Tumor 3 in medium containing [(3)H]leucine demonstrated that [(3)H]IRBP was secreted into the medium. The [(3)H]IRBP was immunoreactive with rabbit antibovine IRBP antibodies. It was inferred that the [(3)H]IRBP was glycosylated because it was bound by immobilized concanavalin A and could be displaced with ?-methylmannopyranoside. Since IRBP is not normally found in retinas until the time of photoreceptor differentiation, regulation of its gene may be defective in this malignant neuroectodermal neoplasm. The present findings are relevant to the possible role of retinoids and their binding proteins in neoplastic cells, because they demonstrate for the first time the presence of an extracellular retinoid-binding protein in tumor tissue.


Evidence against genetic anticipation in familial colorectal cancer.
Anecdotal reports of hereditary colorectal cancer suggest that genetic anticipation (earlier appearance in successive generations) occurs, but ascertainment bias and cohort effects confound this interpretation. Using approaches that correct for such biases, we examined the age at diagnosis of colorectal cancer from family history questionnaires completed by subjects in the Johns Hopkins Hereditary Colorectal Cancer Registry; 475 parent-offspring pairs in 308 pedigrees were studied. We observed the expected cohort effect among offspring, in that the mean ages at diagnosis of those born before 1921, between 1921 and 1930, and after 1930 were 63 +/- 13 (SD), 57 +/- 10, and 42 +/- 10 years, respectively, while their parents' mean ages were 65 +/- 14, 66 +/- 14, and 58 +/- 15 years, respectively. In the cohort born before 1921, in which observation periods for both parents and offspring were comparable, there was no difference in age at diagnosis by pairwise comparison or life table analysis (P = 0.15 and 0.23, respectively; r = 0.32). Subgroup analysis of 67 pairs from 38 families that met the International Collaborative Group (ICG) criteria for hereditary nonpolyposis colorectal cancer (HNPCC) and of 14 pairs from 7 families with known germline mutations of DNA mismatch repair genes also showed no significant differences (mean age at diagnosis: 56 +/- 14 years for parents and 57 +/- 16 years for offspring from ICG families, and 45 +/- 10 years for parents and 44 +/- 12 years for offspring in families with known mutations). We also found no evidence for effect of parental gender on age at diagnosis in offspring of either gender, nor a secular trend toward younger onset colorectal cancer in this sample. In conclusion, there is no evidence for genetic anticipation or genomic imprinting of age at diagnosis in this sample of colorectal cancer families. Apparent anticipation appears to reflect a birth cohort bias of ascertainment.


Behavioural interventions for primary and secondary dysmenorrhoea.
Dysmenorrhoea refers to the occurrence of painful menstrual cramps of uterine origin and is a common gynaecological condition with considerable morbidity. The behavioural approach assumes that psychological and environmental factors interact with, and influence, physiological processes. Behavioural interventions for dysmenorrhoea may include both physical and cognitive procedures and focus on both physical and psychological coping strategies for dysmenorrhoeic symptoms rather than modification of any underlying organic pathology. To determine the effectiveness of any behavioural interventions for the treatment of primary or secondary dysmenorrhoea when compared to each other, placebo, no treatment, or conventional medical treatments for example non-steroidal anti-inflammatory drugs (NSAIDs). We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched April 2005), Cochrane Central Register of Controlled Trials (CENTRAL on The Cochrane Library, Issue 2, 2005), MEDLINE (1966 to April 2005), EMBASE (1980 to April 2005), Social Sciences Index (1980 to April 2005), PsycINFO (1972 to April 2005) and CINAHL (1982 to April 2005) and reference lists of articles. Randomised controlled trials comparing behavioural interventions with placebo or other interventions in women with dysmenorrhoea. Two authors independently assessed trial quality and extracted data. Five trials involving 213 women were included. Behavioural intervention vs control: One trial of pain management training reported reduction in pain and symptoms compared to a control. Three trials of relaxation compared to control reported varied results, two trials showed no difference in symptom severity scores however one trial reported relaxation was effective for reducing symptoms in menstrual sufferers with spasmodic symptoms. Two trials reported less restriction in daily activities following treatment with either relaxation of pain management training compared to a control. One trial also reported less time absent from school following treatment wit pain management training compared to a control. Behavioural intervention vs other behavioural interventions: Three trials showed no difference between behavioural interventions for the outcome of improvement in symptoms. One trial showed that relaxation resulted in a decrease in the need for resting time compared to the relaxation and imagery. There is some evidence from five RCTs that behavioural interventions may be effective for dysmenorrhoea however results should be viewed with caution as they varied greatly between trials due to inconsistency in the reporting of data, small trial size, poor methodological quality and age of the trials.


Nonpharmacological interventions to improve the psychological well-being of women accessing abortion services and their satisfaction with care: A systematic review.
How women perceive and experience abortion impacts their subsequent psychological well-being. This systematic review evaluated nonpharmacological interventions designed to support women undergoing abortion services and improve their psychological well-being and satisfaction with care. Searches were conducted in MEDLINE, CINAHL, the Cochrane Library, PsycINFO, Sociological Abstracts, Social Services Abstracts, and PTSD Pubs. All searches were limited to peer-reviewed articles published in English from January 2010 to February 2020. Two reviewers independently assessed study eligibility. Ten studies were included, involving four types of interventions: music therapy; social support; information support; and mandated waiting and counseling requirements on abortion access. Outcome measures were divided into four categories comprised of cognitive domains, emotional and psychological well-being, clinical symptoms, and satisfaction with care. However, there is limited evidence on intervention effects. Most studies report null or mixed intervention effects. Even though some positive effects on women's cognitive outcomes and satisfaction with care were seen, findings across studies were inconclusive. Findings also show that methodological limitations such as lack of theoretical basis, inadequate reporting and no power sample size calculation were apparent across studies. There is limited evidence about nonpharmacological interventions designed to improve women's satisfaction with abortion services or psychological outcomes subsequent to accessing abortion services. Well-designed interventions that meet the needs of service-users should be developed and rigorously tested.


Turkish women's perceptions of antenatal education.
Antenatal education is considered essential for expectant women. Although there are a number of studies on the effects of antenatal education, there are few studies featuring substantial evidence in this area. For this reason, the benefits have not been clearly defined. To describe women's perceptions of the effectiveness of antenatal education on pregnancy, childbirth and the post-partum period, and also to describe their impressions on the type of education received. A qualitative approach was used. The study featured 15 primipara women who had attended antenatal education. Data were gathered through semi-structured interviews and analysed using the content analysis method. The results of this study showed that education provided a basis of knowledge about pregnancy, childbirth and the post-partum period. It was found that education could have positive effects on pregnancy, childbirth, breastfeeding, motherhood and infant care, and that it could at the same time have a positive or negative effect on fear of childbirth. Although different advantages were found to be perceived in both individual and group education, it was discovered that the study participants were much more satisfied with attending group sessions. Antenatal education should be planned in such a way that its content and methodology do not increase fear. When the lower costs incurred and the higher satisfaction level attained are considered, group education appears to be the type of antenatal education that should be preferred.


Soybean Proteome Database 2012: update on the comprehensive data repository for soybean proteomics.
The Soybean Proteome Database (SPD) was created to provide a data repository for functional analyses of soybean responses to flooding stress, thought to be a major constraint for establishment and production of this plant. Since the last publication of the SPD, we thoroughly enhanced the contents of database, particularly protein samples and their annotations from several organelles. The current release contains 23 reference maps of soybean (Glycine max cv. Enrei) proteins collected from several organs, tissues, and organelles including the maps for plasma membrane, cell wall, chloroplast, and mitochondrion, which were analyzed by two-dimensional polyacrylamide gels. Furthermore, the proteins analyzed with gel-free proteomics technique have been added and are available online. In addition to protein fluctuations under flooding, those of salt and drought stress have been included in the current release. A case analysis employing a portion of those newly released data was conducted, and the results will be shown. An 'omics table has also been provided to reveal relationships among mRNAs, proteins, and metabolites with a unified temporal-profile tag in order to facilitate retrieval of the data based on the temporal profiles. An intuitive user interface based on dynamic HTML enables users to browse the network as well as the profiles of the multiple "omes" in an integrated fashion. The SPD is available at: http://proteome.dc.affrc.go.jp/Soybean/


Single dose bioavailability and pharmacokinetic study of a innovative formulation of α-lipoic acid (ALA600) in healthy volunteers.
α-Lipoic acid is an important micronutrient with several pharmacological as well as antioxidant properties. The present study was aimed to examine the human bioavailability, pharmacokinetics (PK) and tolerability of an innovative oral formulation (ALA600) containing racemic α-lipoic acid 600 mg. After a single 600-mg oral administration in healthy volunteers, blood samples were collected up to 8 hours post dosing, and plasma α-lipoic acid concentrations were determined by Liquid Chromatography-Mass Spectrometry (LC-MS) detection. The PK data revealed a short time to reach plasma peak oncentrations (50.8± 4.2 min) with a C(max) of 6.86±1.29 µg/mL. The C(max) implying that the new pharmaceutical form positively influences absorption and absorption time. The AUC value of 5.65±0.79 µg/mL*h is the more reliable measure of new formulation bioavailability. The half-life and MRT values further show that new formulation is absorbed consistently and rapidly and is eliminated efficiently. These PK data appear to promote further refinement of present formulation. Should the authors compare the obtained data with the recent published data, the new formulation of α-lipoic acid tends to show an improvement of C(max) value (2.5-5.4 times) and AUC (1.8 times). ALA600 formulation is characterized by rapid absorption, high bioavailability, brief half-life and low toxicity. These PK parameters could significantly increase clinical use of lipoic acid with improvement of the therapeutic effects at the cellular level and might also prove to be the most suitable formulation for chronic administration such as peripheral neuropathies.


Smoking before surgery predicts poor long-term survival in patients with stage I non-small-cell lung carcinomas.
The majority of lung carcinoma patients requiring resection have smoking habits prior to surgical treatment, and the correlation of smoking with postoperative complications is well known. However, few studies have investigated the correlation between long-term survival and cigarette smoking in patients with primary, resected lung carcinoma. We analyzed the relationship between clinical factors, including cigarette smoking before surgery, and 10-year survival in stage I non-small-cell lung carcinoma (NSCLC). Cigarette smoking habit and other factors influencing either the overall survival or the disease-specific survival rates of patients with stage I primary, resected NSCLC were evaluated according to the Cox proportional hazards model using a total of 369 patients with stage I-NSCLC. Comparison of the cause of death in patients with 30 or more pack-years and patients with less than 30 pack-years showed significant differences in the prevalence of recurrent disease and onset of nonmalignant disease. Multivariate analysis demonstrated significant correlations between overall survival and age and pack-years. Disease-specific survival showed significant correlations with age, tumor classification, and visceral pleural invasion. Smoking pack-years is an important clinical prognostic factor in evaluating overall long-term survival in patients with stage I primary, resected NSCLC.


Characterization, distribution, biology and impact on Italian walnut orchards of the invasive North-American leafminer Coptodisca lucifluella (Lepidoptera: Heliozelidae).
The leafminer Coptodisca sp. (Lepidoptera: Heliozelidae), recently recorded for the first time in Europe on Italian black and common walnut trees, is shown to be the North-American Coptodisca lucifluella (Clemens) based on morphological (forewing pattern) and molecular (cytochrome oxidase c subunit I sequence) evidence. The phylogenetic relatedness of three species feeding on Juglandaceae suggests that C. lucifluella has likely shifted, within the same host plant family, from its original North-American hosts Carya spp. to Juglans spp. Over the few years since its detection, it has established in many regions in Italy and has become a widespread and dominant invasive species. The leafminer completes three to four generations per year, with the first adults emerging in April-May and mature larvae of the last generation starting hibernation in September-October. Although a high larval mortality was recorded in field observations (up to 74%), the impact of the pest was substantial with all leaves infested at the end of the last generation in all 3 years tested. The distribution of the leafminer in the canopy was homogeneous. The species is redescribed and illustrated, a lectotype is designated and a new synonymy is established.


Depression Among Medical Students of Karachi A Cross Sectional Study.
This article was migrated. The article was marked as recommended. Depression is a mood disorder characterized by loss of interest in daily activity, feeling of hopelessness and helplessness, decreased appetite, anger and irritability. The risk factors which leads to depression include academic demands, daily habits, sleeping hours, sedentary lifestyle, inability to cope, helplessness, increased psychological pressure, mental tension and increased work load etc. The objective of current study is to find out the prevalence of depression among students of different medical colleges of Karachi and its association with life style, habits and coping mechanisms. A descriptive cross-sectional study was conducted in 6 months i.e. April 2018 to September 2018, using a self-designed, self-explanatory questionnaire which also included Public Health Questionnaire (PHQ-9) for identification of depression. The coefficient of reliability including Cronbach alpha was 0.839 for the questionnaire. The data was analyzed by using mean with standard deviation and frequency with percentages while association was calculated by using Chi-square test. The mean age of participants was 21.43 ±1.803. About 2/3 of the participants were female with marital status of 3/4th of participants being single. 92% of the medical students were found to be depressed while 26% of them have suicidal thoughts. Symptoms of depression were compared with depression score, which showed strong positive correlation. Depression scores were also compared with lifestyle habits of participants, including sleeping hours, exercise, recent trauma and multiple coping mechanisms, presented significant association with depression scores (p-value ≤ 0.01). It is concluded that depression is highly prevalent amongst medical student populations while the lifestyle habits, sleeping hours, physical activities, recent trauma and coping mechanism showed significant positive association with depression.


Quantitative biodistribution of nanoparticles in plants with lanthanide complexes.
The inefficient distribution of fertilizers, nutrients, and pesticides on crops is a major challenge in modern agriculture that leads to reduced productivity and environmental pollution. Nanoformulation of agrochemicals is an attractive approach to enable the selective delivery of agents into specific plant organs, their release in those tissues, and improve their efficiency. Already commercialized nanofertilizers utilize the physiochemical properties of metal nanoparticles such as size, charge, and the metal core to overcome biological barriers in plants to reach their target sites. Despite their wide application in human diseases, lipid nanoparticles are rarely used in agricultural applications and a systematic screening approach to identifying efficacious formulations has not been reported. Here, we developed a quantitative metal-encoded platform to determine the biodistribution of different lipid nanoparticles in plant tissues. In this platform lanthanide metal complexes were encapsulated into four types of lipid nanoparticles. Our approach was able to successfully quantify payload accumulation for all the lipid formulations across the roots, stem, and leaf of the plant. Lanthanide levels were 20- to 57-fold higher in the leaf and 100- to 10,000-fold higher in the stem for the nanoparticle encapsulated lanthanide complexes compared to the unencapsulated, free lanthanide complex. This system will facilitate the discovery of nanoparticles as delivery carriers for agrochemicals and plant tissue-targeting products.


Absorption measurements in liquid core waveguides using cavity ring-down spectroscopy.
Short liquid core waveguides (LCWs) were included into a fiber-loop cavity ring-down absorption spectrometer to reduce the detection limit over, both, single pass absorption in a LCW and cavity-enhanced absorption using a conventional fiber-loop cavity. LCWs of 5 and 10 cm length were interfaced with a pressure-flow system and a multimode fiber-loop cavity using concave fiber lenses with matching numerical apertures and diameters. Two red dyes, Allura Red AC and Congo Red, were detected with a 532 nm pulsed laser at a 5 nM limit of detection in a detection volume of less than 1 μL, corresponding to a minimal detectable absorbance of less than 4 × 10(-4) cm(-1) and a minimal detectable change in absorption cross section, σ(min) = V(det) × ε × C(LOD), of about 14 μm(2) (Allura Red AC) and 37 μm(2) (Congo Red).


[Detection of visual anomalies in children of 10 months, 2 and 4 years of age. Child health evaluation].
Ophthalmological examination is part of a comprehensive examination in children under 4 years of age. Screening priorities are: strabismus examination at 10 months and 2 years of age; assessment of distant visual acuity at 2 years of age; assessment of monocular far and near acuity in association with colored vision screening at 4 years of age. Out of 130 000 check ups carried out by ophthalmologists in the Bilan de Santé de l'Enfant: At 10 months and 2 years of age: one child out of five presented ophthalmological anomalies of various degrees; At 4 years of age, one child out of four. One anomaly out of five required immediate treatment. Strabismus was noted in one child out of 28 for all ages considered. In the first year of age, the risk factors for ophthalmological anomalies were: prematurity, dysmaturity, neo-natal pathology, a familial past history of ophthalmic anomalies. These children must be routinely examined prior to the age of 2 years by an ophthalmologist trained in the examination of young children. The decision to refer to the ophthalmologist is the pediatrician's responsibility.


Metabolic response to anaesthesia and lower abdominal surgery in Nigerians. Changes in plasma cortisol and blood sugar.
In ten Nigerian patients undergoing prostatectomy, plasma cortisol was slightly decreased by pre-medication with atropine and pethidine and during general anaesthesia without surgery. This decrease was not statistically significant. There was, however, a statistically significant increase in plasma cortisol after 1 h of surgery and also in the post-operative period. The blood sugar was elevated by pre-medication and surgery though the rise was not significant. There was a significant rise of blood sugar after 30 min of surgery and in the post-operative period. These findings in general are similar to those observed in ten Nigerian patients undergoing upper abdominal surgery, although the rise in plasma cortisol was higher following upper abdominal surgery, and the rise in blood sugar higher following lower abdominal surgery.


Baseline Comparison of Exercisers and Nonexercisers With Spinal Cord Injury Enrolled in a Group Tele-Exercise Program.
Individuals with SCI are 1.5 times more likely to be sedentary compared to adults without disabilities or chronic health conditions. It is therefore imperative to develop and evaluate innovative facilitation strategies for physical activity behavior in this population. As an insightful step to creating and evaluating tailored physical activity interventions for individuals with SCI, we evaluated demographic, psychosocial, and physical characteristics of those who choose to engage in physical activity by enrolling in a group exercise study. We conducted a cross-sectional analysis detailing demographic features and baseline outcomes of those with SCI enrolled in a group tele-exercise study who were classified as regular exercisers versus nonregular exercisers per the American College of Sports Medicine exercise guidelines. Between-group differences for psychosocial and physical outcomes were assessed with chi-square and Mann-Whitney U tests (p < .05). Twenty-seven adult volunteers enrolled in the study (exercisers = 14, nonexercisers = 13). Groups were comparable for biological sex, gender identity, self-reported racial group(s), and current age. Exercisers demonstrated significantly shorter duration of injury compared to nonexercisers (p = .012). Exercisers exhibited significantly higher exercise self-efficacy (p = .017) and increased reported weekly minutes in vigorous intensity leisure time physical activity (p = .029). Nonexercisers with SCI demonstrate increased injury duration and reduced exercise self-efficacy compared to active peers. These factors should be addressed in the design and delivery of SCI-specific physical activity interventions to increase the likelihood of this critical health behavior over time.


The effect of ultraviolet light (PRK-2) on pentoses in the presence of various minerals.
4.0 X 10(-2) M solutions (pH 5.8) of ribose, arabinose and xylose were irradiated in UV light (1.84 X 10(9) erg cm-2 to 6.12 X 10(9) erg cm-2) in the presence of 5 mg/ml of Al2O3, SiO2, TiO2, V2O5, Cr2O3, Fe2O3, CuO, ZnO, schist and feldspar oxides. The resulting substance had an absorption spectrum with lambda max 245 nm and lambda min 288 nm. In the presence of all the oxides except that of V2O5 lambda max shifted to 265-268 nm. When irradiation was carried out in an alkaline medium (pH 10.0-11.0) containing no oxides the absorption band showed lambda max 265 nm as well. The photolysis was followed by the oxidative breakdown of pentoses resulting in the formation of H2CO, carbonyl substances, organic peroxides and acids. The quantum yield (phi) during photolysis without sensitizers for ribose, arabinose and xylose respectivelywas: phi (H2CO) - 2.32 X 10(-3), 1.99 X 10(-3), 1.69 X 10(-3) and phi (C=O) -1.58 X 10(-3), 1.46 X 10(-3), 1.43 X 10(-3). By the ability to sensitize formation of oxydation products of pentoses, the oxides are arranged as follows: Fe2O3 > or = V2O5 > or = TiO2 > or = SiO2 > Cr2O3 > CuO > pentose > or = ZnO. By their effect on phi (-m) of pentoses the oxides make up the sequence: Fe2O3 > or = TiO2 > or = V2O5 > or = SiO2 > feldspar > schist > Al2O3 > Cr2O3 > pentose > ZnO. By the increase of phi (-m) pentoses are arranged in a row: ribose (6.4 X 10(-3) > arabinose (2.5 X 10(-3)) > xylose (2.1 X 10(-3)). Photolysis in various gases has shown that oxidative destruction of pentoses increases according to: air > N2 > Ar. The results show that in the prebiological period on Earth, and possibly even at present on some other planets, various minerals could produce a photosensitizing effect on the breakdown of pentoses synthesized abiogenically from formaldehyde. Ribose proved to be the least resistant to photolysis. This fact is of interest in relation to studying the chemical evolution of carbohydrates and their interaction with purine and pyrimidine bases.


Update on bioterrorism preparedness.
Knowledge and preparation are the best defense against a biological attack. By understanding the epidemiology of biological warfare agents and diseases, strategies can be planned to decrease the morbidity and mortality associated with them. There is an urgent need for developing rapid diagnostic tests, effective vaccines, and drug therapy to defend against biological weapon attacks. The CDC, along with other agencies and partners, are defining how the public health system is to prepare for and respond to public health threats posed by terrorism.


A workplace incivility roadmap: Identifying theoretical speedbumps and alternative routes for future research.
Andersson and Pearson's (1999) seminal article on workplace incivility has paved the way for nearly two decades of research focusing on rude and discourteous behavior at work. We now have a better understanding of the dynamics associated with uncivil workplace interactions including the characteristics of those who instigate and are targeted with workplace incivility, the negative consequences of incivility, the mechanisms that link incivility and negative outcomes, and the boundary conditions that affect these relationships. The present article provides a "roadmap" for workplace incivility researchers by identifying five assumptions that we propose are acting as "speedbumps" in current workplace incivility research by limiting advancements about what workplace incivility is and how it functions. We then introduce five "alternative routes" for future workplace incivility research based on these identifications. Our goal is to guide and accelerate research toward a more nuanced understanding of workplace incivility as behavior that occurs within an organizational system. (PsycINFO Database Record


Dysbetalipoproteinaemia: a mixed hyperlipidaemia of remnant lipoproteins due to mutations in apolipoprotein E.
Atherosclerosis is strongly associated with dyslipoproteinaemia, and especially with increasing concentrations of low-density lipoprotein and decreasing concentrations of high-density lipoproteins. Its association with increasing concentrations of plasma triglyceride is less clear but, within the mixed hyperlipidaemias, dysbetalipoproteinaemia (Fredrickson type III hyperlipidaemia) has been identified as a very atherogenic entity associated with both premature ischaemic heart disease and peripheral arterial disease. Dysbetalipoproteinaemia is characterized by the accumulation of remnants of chylomicrons and of very low-density lipoproteins. The onset occurs after childhood and usually requires an additional metabolic stressor. In women, onset is typically delayed until menopause. Clinical manifestations may vary from no physical signs to severe cutaneous and tendinous xanthomata, atherosclerosis of coronary and peripheral arteries, and pancreatitis when severe hypertriglyceridaemia is present. Rarely, mutations in apolipoprotein E are associated with lipoprotein glomerulopathy, a condition characterized by progressive proteinuria and renal failure with varying degrees of plasma remnant accumulation. Interestingly, predisposing genetic causes paradoxically result in lower than average cholesterol concentration for most affected persons, but severe dyslipidaemia develops in a minority of patients. The disorder stems from dysfunctional apolipoprotein E in which mutations result in impaired binding to low-density lipoprotein (LDL) receptors and/or heparin sulphate proteoglycans. Apolipoprotein E deficiency may cause a similar phenotype. Making a diagnosis of dysbetalipoproteinaemia aids in assessing cardiovascular risk correctly and allows for genetic counseling. However, the diagnostic work-up may present some challenges. Diagnosis of dysbetalipoproteinaemia should be considered in mixed hyperlipidaemias for which the apolipoprotein B concentration is relatively low in relation to the total cholesterol concentration or when there is significant disparity between the calculated LDL and directly measured LDL cholesterol concentrations. Genetic tests are informative in predicting the risk of developing the disease phenotype and are diagnostic only in the context of hyperlipidaemia. Specialised lipoprotein studies in reference laboratory centres can also assist in diagnosis. Fibrates and statins, or even combination treatment, may be required to control the dyslipidaemia.


Role of organisational factors on uptake and implementation of the B.strong brief intervention training program in Queensland Indigenous primary health care services.
The B.strong Program was an Indigenous health worker brief intervention (BI) training program delivered in Queensland from 2017-2020. This study examines the organisational factors of participating Indigenous primary health care (PHC) services that impacted on B.strong's uptake and implementation in those services. Semi-structured interviews were conducted from 2019-2020 with 20 B.strong Program trainees and four health service managers from eight purposively sampled Queensland PHC services, and one Queensland Department of Health manager, to examine their perceptions of uptake and implementation of the B.strong Program. The Consolidated Framework for Implementation Research was used as a framework for the evaluation. Data analysis was conducted using NVivo 11. Although strong PHC service support was evident for the uptake of face-to-face workshop training, it was not available to support trainees to complete online modules or for ongoing BI delivery to clients. Key organisational factors associated with both program uptake and implementation of BIs in PHC services were leadership engagement and implementation climate. Within these themes, embedding B.strong into operational practices of health services, having policies, processes and consistent administrative support to facilitate implementation, and addressing gaps in knowledge and skills of health workers were identified as needing to be improved. The study identified the lack of application of continuous quality improvement (CQI) processes to BIs at these health services as a barrier to effective implementation. The study supports the establishment of BI specific CQI initiatives in health services and supports better engagement with organisational leadership in BI training to ensure their ongoing support of both the training and implementation of BI.


Mitral valve replacement with the Hancock stabilized glutaraldehyde valve. Clinical and laboratory evaluation.
From March 1971 through April 1975, one hundred twenty patients underwent mitral valve replacement with a Hancock "stabilized glutaraldehyde process" porcine aortic xenograft. A simultaneous canine experimental series was also carried out. In the clinical series, the early mortality was 8.3%. Actuarial analyses of all patients predicts survival at two years of 81.0% and at four years of 70.0%. The predicted survival for patients without coronary disease or prior prosthetic valve replacement is 87.5% at two years and 77.5% at four years. There were four thromboembolic episodes, a rate of 2.4% per patient-year. None were fatal. No valve failure were noted. Histologic examination and shrink temperature analysis of recovered valves show excellent tissue preservation at 40 months. The data indicate that the Hancock valve is durable, enjoys a low incidence of thromboembolism, and may be the valve of choice for mitral valve replacement.


The Delhi Declaration 2018: "Healthcare for All Rural People" - Alma Ata Revisited.
In the 40th anniversary year of Alma Ata: Health for All by 2000 conference, Academy of Family Physicians of India organized the 15th WONCA World Rural Health conference in New Delhi from 26 to 29th April 2018. More than a thousand delegates (1044) from 40 countries participated in this international conference. The conference attracted a multidisciplinary participation from various backgrounds with an interest in rural primary healthcare. Theme of this conference was "Healing the Heart of Healthcare-Leaving No one behind". The conference aspired to bring rural healthcare on global agenda. This was the first ever World Rural Health Conference organized in South Asia, incidentally a quarter of human population lives in South Asia, majority of which is based in rural habitat. The conference culminated with the unanimous adoption of the Delhi Declaration; calling for people living in rural and isolated parts of the to be given special priority, if nations are to achieve universal health coverage. The declaration has been cited at the website of the World Health Organization and is available in six languages (Chinese, English, French, Japanese, Portuguese, and Spanish.


[Low-molecular peptides in food as factors altering the resistance of rats to emotional stress].
The authors studied the resistance of animals to emotional stress when they were given in the diet, as a source of protein, casein and a protein fraction composed of a mixture of amino acids and low-molecular peptides (18 and 2.7%) obtained by reprocessing Saccharomyces cerevisiae yeasts, biomass. The ECG, rheovasogram, systolic arterial pressure, and respiratory rate were studied in rats given a diet containing 18 and 2.7% low-molecular peptides (controls) and in the same animals after 24-hour immobilization. Addition of low-molecular peptides in the indicated concentration to the diet reduced the resistance of animals to emotional stress.


On-target digestion of collected bacteria for MALDI mass spectrometry.
An on-target protein digestion system was developed for the identification of microorganisms in collected bioaerosols using off-line matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). Bacteria analysis techniques based on MALDI-MS were adapted for use with an orthogonal MALDI quadrupole-time-of-flight mass spectrometer. Bioaerosols were generated using a pneumatic nebulizer and infused into a chamber for sampling. An Andersen N6 single-stage impactor was used to collect the bioaerosols on a MALDI target. On-target digestion was carried out inside temporary mini-wells placed over the impacted samples. The wells served as miniature reactors for proteolysis. Collected test aerosol particles containing the protein cytochrome c and E. coli bacteria were proteolyzed in situ using trypsin or cyanogen bromide. A total of 19 unique proteins were identified for E. coli. Using the TOF-MS spectra of the digested samples, peptide mass mapping was performed using the MASCOT search engine and an iterative search technique.


[Effect of central and surrounding gratings of test stimulus on appearance of motion aftereffect].
We conducted three experiments to examine the effect of spatial arrangement of test stimulus on the motion aftereffect (MAE). The adaptation and test stimuli were presented to subjects successively. Each adaptation stimulus consisted of a set of three gratings; a central stationary grating was located between the two surrounding gratings, one above and the other below respectively, which were arranged to move leftward for two minutes. The location and/or the shape of the test stimulus were varied to examine the effects of the spatial arrangement. The first and second experiments revealed that the MAE lasted longer when the surrounding gratings for the test were superimposed on those for the adaptation than when they were not superimposed. Further, the results of both experiments showed that the duration was not affected by the distance between the central grating and surrounding one. The results of the third experiment showed that the MAE lasted longer when the central grating for the test was identical with that for the adaptation than when not, and that the surrounding for the test need not to be identical with that for the adaptation. These results support Wade's hypothesis for explaining how MAE occurs.