MKK7γ1 reverses nerve growth factor signals: proliferation and cell death instead of neuritogenesis and protection.
c-Jun N-terminal kinases (JNKs) are the exclusive downstream substrates of mitogen-activated protein kinase kinase 7 (MKK7). Recently, we have shown that a single MKK7 splice variant, MKK7γ1, substantially changes the functions of JNKs in naïve PC12 cells. Here we provide evidence that MKK7γ1 blocks NGF-mediated differentiation and sustains proliferation by interfering with the NGF-triggered differentiation programme at several levels: (i) down-regulation of the NGF receptors TrkA and p75; (ii) attenuation of the differentiation-promoting pathways ERK1/2 and AKT; (iii) increase of JNK1 and JNK2, especially the JNK2 54kDa splice variants; (iv) repression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1), which normally supports NGF-mediated cell cycle arrest; (v) strong induction of the cell cycle promoter CyclinD1, and (vi) profound changes of p53 functions. Moreover, MKK7γ1 substantially changes the responsiveness to stress. Whereas NGF differentiation protects PC12 cells against taxol-induced apoptosis, MKK7γ1 triggers an escape from cell cycle arrest and renders transfected cells sensitive to taxol-induced death. This stress response completely differs from naïve PC12 cells, where MKK7γ1 protects against taxol-induced cell death. These novel aspects on the regulation of JNK signalling emphasise the importance of MKK7γ1 in its ability to reverse basic cellular programmes by simply using JNKs as effectors. Furthermore, our results highlight the necessity for the cells to balance the expression of JNK activators to ensure precise intracellular processes.


Author Correction: Neighborhood Preference of Amino Acids in Protein Structures and its Applications in Protein Structure Assessment.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Smoking abstinence after hospitalization: predictors of success.
Our objective was to explore the relationship between baseline characteristics of hospitalized smokers and 6-month to 2-year self-reported quit rates. We surveyed adult smokers (n = 154) admitted to the Medicine service of an urban public hospital. We used the pharmacy database, a follow-up telephone survey, and medical records to characterize nicotine patch use and post-discharge smoking abstinence. Among the 102 patients for whom smoking status at least 6 months after discharge was known, 18 (18%) were not smoking at last contact (mean follow-up 20 months). Individual factors associated with quitting include confidence to quit within 1 week, stage of change other than precontemplation, filling a nicotine patch prescription after discharge, number of previous quit attempts, and increasing age. With multivariate modeling, only confidence to quit [OR 9.8, confidence interval (CI), 2.8-35.0] and the number of previous quit attempts (OR 1.3 per attempt, 95% CI, 1.0-1.5) remained significantly associated with future abstinence. A high level of confidence to quit and multiple prior quit attempts are strongly associated with future abstinence among hospitalized patients who smoke. Using a simple confidence-to-quit scale to target interventions to patients with high confidence may improve the effectiveness of smoking cessation programs.


Lipid, kilocalorie, and selected mineral intakes of rural black schoolgirls.
Dietary intakes of nutrients implicated in cardiovascular disease were studied in 143 Black females, age 9 years. Dietary recall interviews were conducted and data compared with recommendations of several authoritative groups. A majority of subjects reported intakes: exceeding recommendations for total fat, saturated fat, and sodium; within recommendations for potassium and cholesterol; and below recommendations for kilocalories.


Impact of residential greenness on preschool children's emotional and behavioral problems.
This study investigated the effects of the proximity to city parks and the influence of residential greenness on children's emotional and behavioral problems. This cross-sectional study included 1,468 mothers of children (ages 4 to 6) who were residents of the city of Kaunas, Lithuania. The mothers and their children were enrolled in the FP7 PHENOTYPE project study. The mothers reported on their parenting stress and their children's mental health. Residential greenness was characterized as an average of the satellite-derived normalized difference vegetation index (NDVI) in a 300 m buffer around each home address, and the proximity to city parks was defined as the distance from the subject's residence to the nearest park. Linear regression models were used to investigate the association among the residence distances from city parks, greenness and children's mental health problems. Farther residential distance from city parks was associated with worse mental health (except for the emotional problems subscale) in children whose mothers had a lower education level. More residential greenness was associated with worse mental health (more conditional problems and less prosocial behavior) in children whose mothers had a higher education level. These relationships have important implications for the prevention of emotional and behavioral problems in children.


Follow-up of adverse drug reactions from peginterferon alfa-2b-ribavirin therapy.
To investigate the adverse drug reactions (ADRs) from peginterferon alfa-2b plus ribavirin in patients infected with the hepatitis C virus (HCV). Prospective, observational, pharmacovigilance study. Gastroenterology department of a French university hospital. A cohort of consecutive outpatients who were treated with peginterferon alfa-2b plus ribavirin for viral hepatitis. During the 1-year period of HCV therapy visits, a medical staff member trained in pharmacovigilance interviewed the patients about all ADRs and their use of other drugs. The ADRs assessed as serious were confirmed from regular review of the medical records. A total of 87 patients were treated for HCV. Among these, peginterferon alfa-2b plus ribavirin therapy was started in 51 patients; one patient was lost to follow-up after 1 month. The ADRs were assessed as serious in 10 patients (20%): suicide (one patient), hospitalization (three patients), and definitive discontinuation of peginterferon alfa-2b plus ribavirin (six patients). The ADRs contributed to or were the main reason for withdrawing HCV drugs in 8 patients (16%). Dosage reductions of ribavirin and/or peginterferon alfa-2b were required in 10 patients (20%) and seemed less frequent than that needed in clinical trials. Compared with results of clinical trials, a similar frequency of hair loss, higher frequency of injection-site reactions, lower frequency of depression or insomnia, and higher frequency of endocrine ADRs or blurred vision were detected. Results suggest some differences in the frequencies of ADRs compared with data from clinical trials. A longer period of monitoring is warranted to improve knowledge about ADRs of pegylated interferon. A medical staff member trained in pharmacovigilance is useful to collect quantitative and qualitative data about ADRs.


Orthogonal test design for the optimization of superparamagnetic chitosan plasmid gelatin microspheres that promote vascularization of artificial bone.
The optimal conditions for the preparation of superparamagnetic chitosan plasmid (pReceiver-M29-VEGF165/DH5a) gelatin microspheres (SPCPGMs) were determined. Then, the performance of the SPCPGMs during neovascularization was evaluated in vivo. The SPCPGMs were prepared through a cross-linking curing method and then filled into the hollow scaffold of an artificial bone. Neovascularization at the bone defect position was histologically examined in samples collected 2, 4, 6, and 8 weeks after the operation. The cellular magnetofection rate of superparamagnetic chitosan nanoparticles/plasmid (pReceiver-M29-VEGF165/DH5a) complexes reached 1-3% under static magnetic field (SMF). Meanwhile, the optimal conditions for SPCPGM fabrication were 20% Fe3 O4 (w/v), 4 mg of plasmid, 5.3 mg of glutaraldehyde, and 500 rpm of emulsification rotate speed. Under oscillating magnetic fields (OMFs), 4-6 μg of plasmids was released daily for 21 days. Under the combined application of SMF and OMF, evident neovascularization occurred at the bone defect position 6 weeks after the operation. This result is expected to provide a new type of angiogenesis strategy for the research of bone tissue engineering.


Bi-variate approach to negative interference of bilirubin towards an acetaminophen assay.
It is well known that enzymatic assays for acetaminophen are positively interfered by bilirubin. The effect on acetaminophen not only depends on the concentration of bilirubin but also on that of acetaminophen. We demonstrated a negative interference instead of a positive one in a commonly used routine analyzer and investigated the recovery of acetaminophen in an enzymatic assay by a bi-variate regression. Commercially available blank serum specimens were spiked with acetaminophen and bilirubin at various concentrations, and were analyzed in the Beckman Coulter AU5822 analyzer. The specimens were run in duplicates. The results were then analyzed by least-square analysis and was built into a bi-variate quadratic model. The recovery of acetaminophen in this experiment ranged from 38.9% to 100% throughout a range of 23 μmol/L to 2052 μmol/L (for acetaminophen) and 19 μmol/L to 570 μmol/L (for bilirubin). A contour map, as well as a bi-variate equation was established, describing the relationship between acetaminophen recovery, acetaminophen concentration, and bilirubin concentration. It was shown that the degree of bilirubin interference in a commercially available acetaminophen assay is dependent on both bilirubin and acetaminophen concentrations. There was a decrease in the apparent acetaminophen concentration by an average of 30% at a bilirubin concentration of 420 μmol/L in the Beckman Coulter AU5822 analyzer. The complex relationship can be modeled by mathematical means. This allows the laboratory staff to estimate the recovery of acetaminophen when bilirubin level is concurrently measured.


Digestion & fermentation characteristics of sulfated polysaccharides from Gracilaria chouae using two extraction methods in vitro and in vivo.
The sulfated polysaccharides extracted from Gracilaria chouae using critic acid extraction and water extraction, respectively, and their digestion and fermentation characteristics were compared in vitro and in vivo. The molecular weight of water extracted polysaccharide of G. chouae (WGCP) was 1.73 × 103 kDa while critic acid extracted polysaccharide (CGCP) was 31.5 kDa. During stimulated gastrointestinal digestion in vitro, WGCP and CGCP were lightly degraded. However, the glycemic index (GI) of WGCP and CGCP were 17.7 and 36.12, respectively. After 24 h of fermentation in vitro, the pH values of CGLP in the fecal culture decreased from 6.89 to 4.82, similar to the inulin but significantly (p < 0.05) lower than those of the WGCP and normal control. In addition, CGCP and inulin showed similar microbial fermentation characteristics according to the microbiome compositions and contents of short-chain fatty acids (SCFAs). Nevertheless, CGCP gavage for four weeks could also promote the growth of microbes producing the SCFAs such as Peptococcus, Roseburia and Butyricicoccus in the cecum of KM mice. The present study suggests that polysaccharides prepared by acid-extraction method could potentially be used as a good source of prebiotics.


On the activation of human leuserpin-2, a thrombin inhibitor, by glycosaminoglycans.
Human leuserpin-2 (hLS2) cDNA variants generated by site-directed mutagenesis were expressed in a transient COS cell system. Functional analysis of the mutants revealed two regions in the NH2-terminal half of hLS2 which are essential for glycosaminoglycan-enhanced thrombin inhibition by hLS2. One of these regions, which encompasses a dimeric structure enriched in basic amino acids, is required for both glycosaminoglycan binding and glycosaminoglycan-mediated acceleration of thrombin inhibition. Deletion of another dimeric region, which spans a sequence with a high negative charge density, resulted in a strong reduction in the glycosaminoglycan-enhanced activity of hLS2. This polyanionic region displays structural and functional similarities to the COOH-terminal end of hirudin, another potent thrombin inhibitor, indicating that both inhibitors may have a common binding site on thrombin. Based on our observations we propose a model for the activation of hLS2 by glycosaminoglycans. The key feature of this model is the suggestion that the glycosaminoglycan-enhanced reaction between hLS2 and thrombin is mediated by at least two regions of contact, involving both the reactive center region and the acidic domain of hLS2. Binding of glycosaminoglycans to hLS2 is suggested to result first in the release of the acidic region from intramolecular interactions. Then, amino acid sequences in thrombin are proposed to interact with the acidic dimer of hLS2.


Altered thymic activity in early life: how does it affect the immune system in young adults?
The thymus is responsible for the maturation of lymphoid precursors into T cells, and is necessary to establish the T cell pool during prenatal and early postnatal life in humans. With the years, it undergoes a natural shrinking process, referred to as involution, suspected to be central in the decline of immune competence with aging, or immunosenescence. Here, we review the recent studies focusing on the immunological consequences of abnormal thymic development and thymectomy shortly after birth. These works highlight the importance of the thymic function in preserving immune efficacy throughout life, and provide insights into the development of immune aging.


Postinfectious and chronic fatigue syndromes: clinical experience from a tertiary-referral centre in Norway.
We aimed to compare patients reporting acute infection with those reporting no infection at onset of chronic fatigue syndrome (CFS). This study includes 873 patients with CFS referred to a tertiary centre on average 4.8 years after symptom onset. Assessment was by both observer query and self-reports. Antibody analyses against infectious agents including Epstein-Barr virus and enterovirus were performed in a majority of patients. Females comprised 75.3% of the patient group, and the mean age was 33 years. Initial infection was reported by 77%. There was no difference as to antibody analyses. Logistic regression showed that initial infection was independently associated with acute onset of fatigue, improvement of fatigue at referral, and the following symptoms at referral: fever, tender lymph nodes, and myalgia. CFS patients with initial infection as a precipitating factor more often report acute onset of fatigue, more frequent accompanying symptoms, and more frequent improvement on referral than do patients without initial infection.


Systems biology of the endoplasmic reticulum stress response.
The endoplasmic reticulum (ER) is the first sub-cellular compartment encountered by secretory proteins en route to the plasma membrane. Newly synthesized secretory proteins translocate into the ER lumen and acquire their correct conformation prior to being exported to later compartments. When folding is not properly achieved, proteins accumulate in the ER due to resident quality control machineries and terminally misfolded proteins are ultimately degraded through the ER-associated degradation pathway. All these molecular machines function in a coordinated fashion to restore and maintain ER homeostasis. A fifth molecular machine plays a coordinating role in the ER. Indeed, the ER stress signaling machinery signals ER dysfunction to the rest of the cell and consequently integrates the functions of the four other molecular machines to improve their operation in stressful conditions. In this work, we have attempted to define the ER as a molecular biological system regulated by its own specific signaling pathways defined as the Unfolded Protein Response to delineate a systems biology approach of ER stress signaling.


The AAA ATPase Afg1 preserves mitochondrial fidelity and cellular health by maintaining mitochondrial matrix proteostasis.
Mitochondrial functions are critical for cellular physiology; therefore, several conserved mechanisms are in place to maintain the functional integrity of mitochondria. However, many of the molecular details and components involved in ensuring mitochondrial fidelity remain obscure. Here, we identify a novel role for the conserved mitochondrial AAA ATPase Afg1 in mediating mitochondrial protein homeostasis during aging and in response to various cellular challenges. Saccharomyces cerevisiae cells lacking functional Afg1 are hypersensitive to oxidative insults, unable to tolerate protein misfolding in the matrix compartment and exhibit progressive mitochondrial failure as they age. Loss of the Afg1 ortholog LACE-1 in Caenorhabditis elegans is associated with reduced lifespan, impeded oxidative stress tolerance, impaired mitochondrial proteostasis in the motor neuron circuitry and altered behavioral plasticity. Our results indicate that Afg1 is a novel protein quality control factor, which plays an important evolutionarily conserved role in mitochondrial surveillance, and cellular and organismal health.


A new rejection of moral expertise.
There seem to be two clearly-defined camps in the debate over the problem of moral expertise. On the one hand are the "Professionals", who reject the possibility entirely, usually because of the intractable diversity of ethical beliefs. On the other hand are the "Ethicists", who criticise the Professionals for merely stipulating science as the most appropriate paradigm for discussions of expertise. While the subject matter and methodology of good ethical thinking is certainly different from that of good clinical thinking, they argue, this is no reason for rejecting the possibility of a distinctive kind of expertise in ethics, usually based on the idea of good justification. I want to argue that both are incorrect, partly because of the reasons given by one group against the other, but more importantly because both neglect what is most distinctive about ethics: that it is personal in a very specific way, without collapsing into relativism.


Activation and desensitization of hippocampal kainate receptors.
We have used whole-cell recordings and rapid agonist applications to characterize the physiological properties of kainate receptors expressed by rat hippocampal neurons in dissociated cell culture. Activation of NMDA and AMPA receptors was prevented by inclusion of the noncompetitive antagonists MK-801 (2 microM) and GYKI 53655 (100 microM), respectively. In the presence of these inhibitors, both kainate (EC50 = 23 microM) and glutamate (EC50 = 310 microM) evoked desensitizing currents. Maximal peak currents for kainate with GYKI 53655 were 15 +/- 3% as large as in control solutions without GYKI. In contrast to currents mediated by AMPA receptors, kainate currents recorded in GYKI were blocked potently by lanthanum (IC50 = 2 microM) and were desensitized by 1 microM 2S,4R-4-methylglutamate (SYM 2081). Coapplication of either 5 microM AMPA or 500 microM aspartate had little effect on responses to kainate, although AMPA alone elicited current at 1 mM. In most cells, the currents evoked by kainate, glutamate, and SYM 2081 varied linearly with membrane potential and reversed near 0 mV. Kainate elicited substantial current at steady state (approximately 30% of peak), whereas responses to glutamate and SYM 2081 desensitized almost completely within 0.2-2 sec. Inhibition produced by a 10 sec desensitizing prepulse was half-maximal at 0.22 microM for SYM 2081 and 13 microM for glutamate. Recovery from desensitization to kainate and glutamate was >80% complete within 60 sec but was three- to fourfold slower after exposure to SYM 2081. Exposure to Concanavalin A blocked desensitization of the currents but also reduced the peak current amplitudes. Collectively, these results confirm that kainate-preferring receptors underlie the currents evoked by kainate, glutamate, or SYM-2081 in the presence of GYKI 53655; they are not mediated by electrogenic transport or by AMPA-preferring receptors that are insensitive to GYKI. In contrast to previous work on embryonic hippocampal neurons, our results show that the properties of kainate receptors expressed by cells from older animals are distinct from those displayed by homomeric assemblies of the GluR6 subunit.


Current status of extracorporeal ventricular assist devices in Japan.
Extracorporeal VADs are less expensive, their prices reimbursable by the health insurance being about one-sixth of those of implantable VADs in Japan. However, a disadvantage is that, in Japan, their use is restricted to hospitals, necessitating prolonged hospitalization, reducing the patients' quality of life. According to the Japanese registry for Mechanically Assisted Circulatory Support, the survival rate does not differ significantly between patients with extracorporeal and implantable VADs. As in Europe and North America, extracorporeal VADs in Japan are commonly used as Bridge to Decision or Bridge to Recovery. Extracorporeal VADs are switched to implantable VADs as a Bridge-to-Bridge strategy after stabilization or when cardiac function recovery fails. They are also used as right ventricular assist devices (RVADs) in patients with right heart failure. A special characteristic of extracorporeal VADs in Japan is their frequent use as a Bridge to Candidacy. In Japan, indications for implantable VADs are restricted to patients registered for heart transplantation. Therefore, in patients who cannot be registered for transplantation because of transient renal dysfunction, etc., due to heart failure, extracorporeal VADs are used first, and then replaced by implantable VADs after transplant registry is done. Here, we describe the current status of extracorporeal VADs in Japan, focusing on the environmental backgrounds, along with a review of the relevant literature.


Dietary effect on mixed function P450 1A2 activity assayed by estimation of caffeine metabolism in man.
Two studies were performed in order to evaluate cytochrome P450 1A2 mediated caffeine metabolism during different nutritional conditions. 1. In the first study, 23 healthy male non-smokers, mean age 25, changed from a customary mixed diet to a standard diet in 6 days. The 6 day's standard diet was based on bread, potatoes, rice and boiled meat. Thus, broccoli, cabbage and other cruciferous vegetables, spinach, leeks, onion, parsley, grapefruit, toasted bread, fried and charcoal grilled food, smoked fish and meat, ham and sausages were avoided. 2. In the second study, 33 healthy non-smoking subjects, 24 men and nine women mean age 25 years, volunteered. The study was designed to compare a customary home dietary period with the 6 day period of low dietary P450 induction and with a 5 day supplementary dietary period, i.e. ingestion of known dietary inducers. None of the women were using oral contraceptives or were pregnant during the experimental period. In the period of diet supplementation, the volunteers received charcoal grilled hamburger as a supplement to the standard low induction diet for lunch for 5 days. The hamburgers were made with 150 g beef (18-20% fat) and were grilled on charcoal for 10 min on each side until they were 'well done'. In the present study P450 1A2 activity was estimated from the caffeine metabolic ratio, the so-called CYP 1A2 index:(AFMU + 1-MX + 1-MU/ 17 -DMU) of the caffeine metabolites formed after oral ingestion of 200 mg caffeine. Urine was collected 4-8 h after caffeine ingestion in study 1 and 5 h after caffeine ingestion in study 2. In study 1 the CYP 1A2 index decreased from 4.28 +/- 0.98 in the customary home dietary period to 3.87 +/- 0.69 in the standard dietary period corresponding to 10.6% (P < 0.06) decrease in the CYP 1A2 index. In study 2 the CYP 1A2 index decreased from 4.47 +/- 1.76 in the customary home dietary period to 3.90 +/- 1.12 in the standard dietary period corresponding to a 14.6% decrease (P < 0.2) in P450 1A2 activity. The female subjects had a mean index value of 3.89 +/- 1.14 which was 16.8% (P = 0.09) lower than the mean male index value of 4.68 +/- 1.76 during the home dietary period. After the 5 day period with charcoal grilled hamburgers as a dietary supplement, the CYP 1A2 index increased to almost the same level as in the customary home dietary period. The index increased to 4.45 +/- 1.57 in the whole group of volunteers, corresponding to a 14.1% (P < 0.05) increase. The mean increase in the CYP 1A2 index covered a large inter-individual variation in response to ingestion of charcoal grilled meat ranging from a 29% decrease to a 147% increase.


Redox regulation of hemodynamics response to diadenosine tetraphosphate an agonist of P2 receptors and renal function in diet-induced hypercholesterolemic rats.
Hypercholesterolemia and oxidative stress may lead to disturbances in the renal microvasculature in response to vasoactive agents, including P2 receptors (P2R) agonists. We investigated the renal microvascular response to diadenosine tetraphosphate (Ap4 A), an agonist of P2R, in diet-induced hypercholesteremic rats over 28 days, supplemented in the last 10 days with tempol (2 mM) or DL-buthionine-(S,R)-sulfoximine (BSO, 20 mM) in the drinking water. Using laser Doppler flowmetry, renal blood perfusion in the cortex and medulla (CBP, MBP) was measured during the infusion of Ap4 A. This induced a biphasic response in the CBP: a phase of rapid decrease was followed by one of rapid increase extended for 30 min in both the normocholesterolemic and hypercholesterolemic rats. The phase of decreased CBP was not affected by tempol or BSO in either group. Early and extended increases in CBP were prevented by tempol in the hypercholesterolemia rats, while, in the normocholesterolemic rats, only the extended increase in CBP was affected by tempol; BSO prevented extended increase in CBP in normocholesterolemic rats. MBP response is not affected by hypercholesterolemia. The hypercholesterolemic rats were characterized by increased urinary albumin and 8-isoPGF2α excretion. Moreover, BSO increased the urinary excretion of nephrin in the hypercholesterolemic rats but, similar to tempol, did not affect the excretion of albumin in their urine. The results suggest the important role of redox balance in the extracellular nucleotide regulation of the renal vasculature and glomerular injury in hypercholesterolemia.


Visualization and exploratory analysis of epidemiologic data using a novel space time information system.
BACKGROUND: Recent years have seen an expansion in the use of Geographic Information Systems (GIS) in environmental health research. In this field GIS can be used to detect disease clustering, to analyze access to hospital emergency care, to predict environmental outbreaks, and to estimate exposure to toxic compounds. Despite these advances the inability of GIS to properly handle temporal information is increasingly recognised as a significant constraint. The effective representation and visualization of both spatial and temporal dimensions therefore is expected to significantly enhance our ability to undertake environmental health research using time-referenced geospatial data. Especially for diseases with long latency periods (such as cancer) the ability to represent, quantify and model individual exposure through time is a critical component of risk estimation. In response to this need a STIS - a Space Time Information System has been developed to visualize and analyze objects simultaneously through space and time. RESULTS: In this paper we present a "first use" of a STIS in a case-control study of the relationship between arsenic exposure and bladder cancer in south eastern Michigan. Individual arsenic exposure is reconstructed by incorporating spatiotemporal data including residential mobility and drinking water habits. The unique contribution of the STIS is its ability to visualize and analyze residential histories over different temporal scales. Participant information is viewed and statistically analyzed using dynamic views in which values of an attribute change through time. These views include tables, graphs (such as histograms and scatterplots), and maps. In addition, these views can be linked and synchronized for complex data exploration using cartographic brushing, statistical brushing, and animation. CONCLUSION: The STIS provides new and powerful ways to visualize and analyze how individual exposure and associated environmental variables change through time. We expect to see innovative space-time methods being utilized in future environmental health research now that the successful "first use" of a STIS in exposure reconstruction has been accomplished.


Report of two co-operative trials of a gel permeation chromatographic method for the isolation of pesticide residues from oils and fats. Committee for Analytical Methods for Residues of Pesticides in Foodstuffs of the Ministry of Agriculture, Fisheries and Food.
A gel permeation chromatographic (GPC) method for the determination of pesticide residues in fats and oils was subjected to two co-operative trials. Results for organochlorine pesticides (beta-HCH, gamma-HCH, dieldrin, p,p'-DDE and heptachlor) were compared with those obtained using an alumina column clean-up method. No significant differences in the mean values were found between the two techniques using the t-test (5% significance level). Horrat values demonstrated acceptable inter- and intralaboratory precisions for both clean-up techniques. Two organophosphorus pesticides (diazinon and propetamphos) and the synthetic pyrethroid deltamethrin were also determined using the GPC method. However, these compounds were not recoverable using the alumina column method, so no comparisons between the two methods were possible.


The influence of gratitude on pre-service teachers' career goal self-efficacy: Chained intermediary analysis of meaning in life and career calling.
The aim of the study was to explore the relationship among gratitude, meaning in life (MIL), career calling, and career goal self-efficacy (CGSE) of the pre-service teachers in the Free Teacher Education program in China and the internal mechanism of action. In this study, gratitude, MIL, career calling, and CGSE questionnaires were used to investigate 801 pre-service teachers. IBM SPSS 25.0 and AMOS 24.0 were used for data processing, and SPSS macro program Model 6 was used for the mediating mechanism. (1) Gratitude was positively correlated with MIL and career calling. MIL was positively correlated with career calling. Gratitude, MIL, and career calling were significantly and positively associated with CGSE. (2) Gratitude influences pre-service teachers' CGSE mainly through the independent intermediary of MIL and career calling, and the chain intermediary of MIL→career calling, three indirect effects. Gratitude indirectly predicts CGSE of pre-service teachers not only through the independent intermediary of MIL and career calling but also through the chain intermediary of MIL and career calling.


Cloning of a cDNA for a novel insulin-like peptide of the testicular Leydig cells.
We have isolated complementary DNA clones coding for a novel member of the insulin-like hormone super-family from a boar testis cDNA library. Northern blot analysis and in situ hybridization revealed that the gene is expressed exclusively in prenatal and postnatal Leydig cells. We have tentatively proposed the name Leydig insulin-like (Ley I-L) for the gene and its encoded protein. The Leydig insulin-like protein is synthesized as a 131-amino acid preproprotein, which contains a 24-amino acid signal peptide. Comparison of the deduced amino acid sequence of pro-Leydig insulin-like protein with members of the insulin-like hormone superfamily predicts that the biologically active protein, after proteolytic processing of the C-peptide, consists of a 32-residue-long B-chain and a 26-residue-long A-chain and has a molecular size of 6.25 kDa.


Challenging diagnosis and successful treatment of localised Mycobacterium avium subsp. hominissuis glossitis in a dog on long-term immunomodulatory therapy.
A 3-year-old, intact female mixed-breed dog, weighing 7 kg, was presented with generalised swelling of the tongue, leading to impaired deglutition and episodes of dyspnoea. From the age of 2 years, the dog had been under immunosuppressive therapy due to atopic dermatitis. Multiple nodular lesions at the apex of the tongue were noted as well as mandibular and retropharyngeal lymph node enlargement. Serum biochemistry results showed inflammatory changes. The results of several biopsies taken over 7 months indicated persistent pyogranulomatous and necrotising glossitis despite ongoing antimicrobial treatment, first with amoxicillin/clavulanic acid and then pradofloxacin. No foreign material, acid-fast bacteria or fungal hyphae were detected throughout. The final diagnosis of Mycobacterium avium subsp. hominissuis (Mah) was reached after PCR and bacterial culture were carried out on the third biopsy sample. Therapy was initiated with rifampicin, clarithromycin and doxycycline, leading to complete remission of the lesions. Severe chronic pyogranulomatous and necrotising glossitis associated with infection by Mah. This report describes challenges in the diagnosis and therapy of a localised Mah infection in an iatrogenically immunocompromised dog. Successful treatment was only achieved with a specific combination of antibiotics administered long-term. AF: Acid-fast; ALP: Alkaline phosphatase; CT: Computed tomography; MAC: Mycobacterium avium complex; Mah: Mycobacterium avium subsp. hominissuis.


Successful management of COVID-19 outbreak in a long-term care facility in Jeddah, Saudi Arabia: Epidemiology, challenges for prevention and adaptive management strategies.
The global transmission of SARS-COV-2 constitutes a highly challenging situation for long-term care facilities, especially with the lack of standardized and approved procedures. Residents in these facilities are at high risk for contamination due to proximity, and to morbidity and mortality given their advanced age and critical baseline health conditions. This paper exposes the experience and outcomes of a COVID-19 outbreak in a long-term facility in Jeddah, Saudi Arabia, which occurred after admission of a new resident despite high baseline level of alertness including systematic isolation and screening of all newly admitted residents. We highlight the challenges for case detection and application of protective measures, and describe the adaptive management strategies implemented to contain the outbreak.


Enhanced photothermal conversion properties of magnetic nanofluids through rotating magnetic field for direct absorption solar collector.
The direct absorption solar collector (DASCs) with nanofluids can remarkably improve the utilization efficiency of solar energy. However, in the actual applications, the temperature distribution of the receiver is extremely uneven when the concentration of nanofluids is high or the receiver is deep. This makes the temperature of upper layer much higher than that of the lower layer, resulting in much heat loss to the surrounding by convection. Here, we propose a magnetic forced convection nanofluids absorption system, where an external rotating magnetic field is used to change the heat transfer mechanism of working fluids from traditional heat conduction to the thermal convection. It is found that the photothermal conversion efficiency of FeNi/C-EG nanofluids is up to 58.1% in this system, which is 22.7% higher than non-external rotating magnetic field when the nanofluids concentration is 50 ppm. Furthermore, the agglomeration of nanofluids can be effectively reduced by an external rotating magnetic field.


Limitations of Nasal Nitric Oxide Measurement for Diagnosis of Primary Ciliary Dyskinesia with Normal Ultrastructure.
Rationale: Primary ciliary dyskinesia (PCD) is a heterogeneous, multisystem disorder characterized by defective ciliary beating. Diagnostic guidelines of the American Thoracic Society and European Respiratory Society recommend measurement of nasal nitric oxide (nNO) for PCD diagnosis. Several studies demonstrated low nNO production rates in PCD individuals, but underlying causes remain elusive. Objectives: To determine nNO production rates in a well-characterized PCD cohort, including subgroup analyses with regard to ultrastructural and ciliary beating phenotypes. Methods: This study included 301 individuals assessed according to European Respiratory Society guidelines. Diagnostic cutoffs for nNO production rates for this study cohort and subgroups with normal and abnormal ultrastructure were determined. Diagnostic accuracy was also tested for the widely used 77 nl/min cutoff in this study cohort. The relationship between nNO production rates and ciliary beat frequencies (CBFs) was evaluated. Results: The study cohort comprised 180 individuals with definite PCD diagnosis, including 160 individuals with genetic diagnosis, 16 individuals with probable PCD diagnosis, and 105 disease controls. The 77 nl/min nNO cutoff showed a test sensitivity of 0.92 and specificity of 0.86. Test sensitivity was lower (0.85) in the subgroup of 47 PCD individuals with normal ultrastructure compared with 133 PCD individuals with abnormal ultrastructure (0.95). The optimal diagnostic cutoff for the nNO production rate for the whole study cohort was 69.8 nl/min (sensitivity, 0.92; specificity, 0.89); however, it was 107.8 nl/min (sensitivity, 0.89; specificity, 0.78) for the subgroup of PCD with normal ultrastructure. PCD individuals with normal ultrastructure compared with abnormal ultrastructure showed higher ciliary motility. Consistently, PCD individuals with higher CBFs showed higher nNO production rates. In addition, laterality defects occurred less frequently in PCD with normal ultrastructure. Conclusions: Measurements of nNO below the widely used 77 nl/min cutoff are less sensitive in detecting PCD individuals with normal ultrastructure. Our findings indicate that higher nNO production in this subgroup with a higher cutoff for the nNO production rate (107.8 nl/min) and higher residual ciliary motility is dependent on the underlying molecular PCD defect. Higher nNO production rates, higher residual CBFs, and the lower prevalence of laterality defects hamper diagnosis of PCD with normal ultrastructure. Adjusting the cutoff of nNO production rate to 107.8 nl/min might promote diagnosing PCD with normal ultrastructure.


Invasive cervical cancer after conservative therapy for cervical intraepithelial neoplasia.
Conservative outpatient therapy for cervical intraepithelial neoplasia (CIN) by ablative or excisional techniques is widely used. The main objective of this treatment is the prevention of invasive cervical cancer. We assessed the rate of invasive disease and the duration of the risk of developing invasive cervical cancer after such treatment. Four UK centres have used life-table methods to analyse the long-term results of conservative treatment of CIN. We combined and updated data from these studies to investigate the rate of invasive disease after treatment and the duration of that risk. The data comprised 44 699 woman-years of follow-up, with 2116 women under observation 8 years after treatment. 33 women developed invasive cancer, 14 of whom had microinvasion. The cumulative rate of invasion 8 years after treatment was 5.8 per 1000 women and the rate of invasive cancer during this period was 85 (95% CI 60-119) per 100,000 woman-years. The risk of developing cancer did not change throughout the 8 years of follow-up. These data show that conservative outpatient therapy in women with CIN reduces the risk of invasive cancer of the cervix by 95% during the first 8 years after treatment. However, even with careful, long-term follow-up, the risk of invasive cervical cancer among these women is about five times greater than that among the general population of women throughout that period. Careful follow-up is essential for at least 10 years after conservative treatment of CIN.


The influence of EDDS on the metabolic and transcriptional responses induced by copper in hydroponically grown Brassica carinata seedlings.
To improve the knowledge about the use of plants for the removal of toxic metals from contaminated soils, metabolic and transcriptional responses of Brassica carinata to different forms of copper (Cu) were studied. Two-week-old hydroponically grown seedlings were exposed for 24 h to 30 μM CuSO₄ or CuEDDS. CuSO₄ appeared to be more toxic than CuEDDS as roots showed higher levels of thiobarbituric acid reactive substances (TBARS) and increased relative leakage ratios (RLR), although the superoxide dismutase (SOD, EC 184.108.40.206) activity increased following both exposures. In CuSO₄-exposed seedlings the higher toxicity was underlined by increased transcription of lipoxygenases (EC 220.127.116.11) and NADPH oxidases (EC 18.104.22.168) and by the higher Cu accumulation in both tissues compared to CuEDDS exposure. The presence of EDDS increased Cu translocation, which resulted 5-times higher than when exposed to CuSO₄. Decreases in catalase (CAT, EC 184.108.40.206), ascorbate peroxidase (APX, EC 184.108.40.206) and glutathione reductase (GR, EC 22.214.171.124) activities together with increases of reduced glutathione (GSH) and tocopherols and a reduction of lipoic acid (LA) were observed in roots of CuSO₄-exposed seedlings. On the contrary, CuEDDS exposure induced a general increase in enzyme activities and decreases in ascorbate (AsA) and tocopherol levels. In the primary leaves, in both exposures Cu differently affected the oxidative stress responses indicating that the cellular redox balance was anyway maintained. EDDS plays a crucial role in B. carinata tolerance to oxidative stress induced by Cu and might be proposed to improve the efficiency of Cu phytoextraction.


Evolution of maternal feed restriction practices over 60 years of selection for broiler productivity.
The effect of commercial selection by poultry breeders on the growth, efficiency, and sexual maturity of broiler breeders was studied using 2 University of Alberta Meat Control strains unselected since 1957 and 1978 (AMC-1957 and AMC-1978, respectively) and 2 strains originating from the University of Arkansas; 1995 Random-bred (1995RB) and 2015 Random-bred (2015RB). A study with a 4 × 2 factorial arrangement was conducted with the 4 strains fed at either ad libitum, or restricted levels to achieve a current commercial breeder target BW profile. Growth rate, feed intake, feed efficiency, age at sexual maturity, carcass components, and body conformation were measured. To assess reproductive development, birds were assigned to 2 fates: dissected at photostimulation or dissected after the second oviposition. At 22.4 wk of age, the restricted-fed AMC-1957, AMC-1978, 1995RB, and 2015RB reached 100, 61, 46, and 38% of their ad libitum-fed counterparts' BW, respectively. During the rearing phase, the amount of feed needed to maintain restricted-fed birds on the target BW was 99.4, 57, 29.5, and 24.9% of their ad libitum-fed counterparts for AMC-1957, AMC-1978, 1995RB, and 2015RB, respectively. Feed restricted birds in the 2015RB had lower heat production relative to the AMC-1957 and AMC-1978, which shows that modern strains utilized feed more efficiently compared to the antique strains. This might be related to the increasing severity of feed restriction of broiler breeders over the past 60 years. Relative to AMC-1957 and AMC-1978 strains, the 1995RB and 2015RB strains had heavier breast muscle and lower fat pad weight. Although the pubertal threshold for age and BW have increased over the last 6 decades, changes in selection programs for feed efficiency have resulted in broiler breeders that prioritize nutrient allocation to growth and breast development rather than adipose storage. As a result, feed restricted modern broiler breeders may have marginally sufficient fat resources to support reproduction.


Aged versus young skin before and after transplantation onto nude mice.
The behaviour of aged skin transplanted onto nude mice was investigated to determine whether the skin maintains its histological features. Split-thickness skin grafts obtained from the unexposed skin on the thighs of healthy aged and young volunteers were grafted onto nude mice. A significant difference between the mean thickness of young versus aged epidermis was noted before transplantation (P less than 0.001). The epidermis of aged and young skin showed an increase in thickness following engraftment with a mean increase in epidermal thickness of 18.8% in the young (P less than 0.01) and 142.5% in aged skin (P less than 0.001). The number of blood vessels in the aged skin was significantly lower than in the young skin, but a remarkable increase was found post-transplantation. These findings indicate that part of the typical histological changes of unexposed aged skin are reversible.


Perforator-based propeller flaps treating loss of substance in the lower limb.
Local flaps based on perforator vessels are raising interest in reconstructive surgery of the limbs. These flaps allow efficient coverage of large wounds without the need to sacrifice a major vascular axis. The operative technique does not require microvascular anastomosis and allows reconstruction of soft tissue defects using nearby similar tissues. The aim of this study was to evaluate the clinical results of local perforator flaps in the treatment of complex lower-limb defects. Twenty-two local perforator flaps were retrospectively studied. Loss of substance was due to postsurgical complications in seven cases, oncological resection in six, posttraumatic defect in five, pressure sores in three, and osteomyelitis in one. Postoperatively, two patients showed partial flap necrosis. In five patients, a superficial epidermolysis occurred. Minor complications were seen in three patients who showed transient venous congestion of the flap. Furthermore, transient leg edema was sometimes observed in patients with large propeller flaps. All but one patient healed without further major surgical procedures. In three cases, secondary skin grafts were performed. In most cases, the aesthetic result was optimal and patients were fully satisfied. When characteristics of the defect are suitable for treatment with a propeller-based local flap, this technique should be considered as one of reasonable options for surgical reconstruction. Microsurgical techniques facilitate the management of complex trauma in emergency and may allow planning reconstructive procedures and limb salvage in elective orthopedic surgery.


Outcome of Sublingual Immunotherapy in Allergic Rhinitis.
Allergic rhinitis (AR) is one of the most common types of allergy worldwide. It has significant negative impact on the quality of life (QOL). One of the available causal treatments of AR is allergen specific immunotherapy which remains effective even after the end of treatment course, unlike symptomatic drugs. AR patients aged above five years, allergic to unavoidable allergen like house dust, mite etc., and refractory to maximal pharmacotherapy were included in present study. Patients allergic to avoidable allergen, taking beta-blocker medication, having other immunological disease, and who were pregnant, breast-feeding or lost to follow up, were excluded from the study. All patients included in the study underwent sublingual immunotherapy (SLIT). The impact of treatment is measured by calculating the difference between SNOT-20 score before and after treatment (which is 6 months interval). Total 30 patients were studied. Paired-t test calculated value of cumulative score and nasal symptom score are 7.853 and 6.85 respectively. Both are greater than table value of 2.46. So paired-t test shows that SLIT is very much effective in treatment of AR. The present study re-establish the fact that SLIT not only reduces AR symptoms, it also improves the QOL. It has very good patient compliance with minimal side effects.


Extending the HKB model of coordinated movement to oscillators with different eigenfrequencies.
We study the dynamics of a system of coupled nonlinear oscillators that has been used to model coordinated human movement behavior. In contrast to earlier work we examine the case where the two component oscillators have different eigenfrequencies. Problems related to the decomposition of a time series (from an experiment) into amplitude and phase are discussed. We show that oscillations at multiples of the main frequency of the oscillator system may occur in the phase and amplitude due to the choice of a coordinate system and how these oscillations can be eliminated. We derive an explicit equation for the dynamics of the relative phase of the oscillator system in phase space that enables a direct comparison between theory and experiment.


Recent insights into eukaryotic translation initiation factors 5A1 and 5A2 and their roles in human health and disease.
The eukaryotic translation initiation factor 5A1 (eIF5A1) and its homolog eIF5A2 are the only two human proteins containing the unique post-translational modification-hypusination, which is essential for the function of these two proteins. eIF5A1 was initially identified as a translation initiation factor by promoting the first peptide bond formation of protein during translation; however, recent results suggest that eIF5A1 also functions as a translation elongation factor. It has been shown that eIF5A1 is implicated in certain human diseases, including diabetes, several human cancer types, viral infections and diseases of neural system. Meanwhile, eIF5A2 is overexpressed in many cancers, and plays an important role in the development and progression of cancers. As multiple roles of these two factors were observed among these studies, therefore, it remains unclear whether they act as oncogene or tumor suppressor. In this review, the recent literature of eIF5As and their roles in human diseases, especially in human cancers, will be discussed.


Dialects in Japanese monkeys: vocal learning and cultural transmission of locale-specific vocal behavior?
Differences were detected by ear in vocalizations made during artificial feeding of Japanese monkey troops at three locations. Tape recording and sound spectrographic analysis confirmed a distinctive vocal pattern specific to each site and used only in the provisioning situation. The 3 different acoustic morphologies are variations on a shared tonal theme. Vocal learning by Macaca fuscata may have occurred separately at each site regulated by species-wide constraints on vocal production.


Analysis of the context dependent sequence requirements of active site residues in the metallo-beta-lactamase IMP-1.
The metallo-beta-lactamase IMP-1 catalyzes the hydrolysis of a broad range of beta-lactam antibiotics to provide bacterial resistance to these compounds. In this study, 29 amino acid residue positions in and near the active-site pocket of the IMP-1 enzyme were randomized individually by site-directed mutagenesis of the corresponding codons in the bla(IMP-1) gene. The 29 random libraries were used to identify positions that are critical for the catalytic and substrate-specific properties of the IMP-1 enzyme. Mutants from each of the random libraries were selected for the ability to confer to Escherichia coli resistance to ampicillin, cefotaxime, imipenem or cephaloridine. The DNA sequence of several functional mutants was determined for each of the substrates. Comparison of the sequences of mutants obtained from the different antibiotic selections indicates the sequence requirements for each position in the context of each substrate. The zinc-chelating residues in the active site were found to be essential for hydrolysis of all antibiotics tested. Several positions, however, displayed context-dependent sequence requirements, in that they were essential for one substrate(s) but not others. The most striking examples included Lys69, Asp84, Lys224, Pro225, Gly232, Asn233, Asp236 and Ser262. In addition, comparison of the results for all 29 positions indicates that hydrolysis of imipenem, cephaloridine and ampicillin has stringent sequence requirements, while the requirements for hydrolysis of cefotaxime are more relaxed. This suggests that more information is required to specify active-site pockets that carry out imipenem, cephaloridine or ampicillin hydrolysis than one that catalyzes cefotaxime hydrolysis.


Willingness to get vaccinated against Covid-19 and attitudes toward vaccination in general.
High uptake of Covid-19 vaccination is required to reach herd immunity. A representative sample of 2,060 Belgians were surveyed in October 2020. Regression analyses identified the predictors associated with willingness to get vaccinated against Covid-19, and attitudes toward vaccination in general. 34% of the participants reported that they will definitely get vaccinated against Covid-19 and 39% that they would "probably". Intended uptake was strongly associated with age, opinion on the government's dealing with the Covid-19 pandemic, medical risk, spoken language, gender, and to a lesser extent with having known someone who was hospitalised because of Covid-19. Similar predictors were identified for attitudes to vaccination in general. Covid-19 vaccine hesitancy was more marked in age groups below 54 years old. We further analysed a sample of 17% (N = 349) found favourable to vaccination in general but not willing to be vaccinated against Covid-19. They were mainly female, young, French speaking, slightly less educated, working, and did not belong to a Covid-19 risk group. They were very dissatisfied with the government's dealing with the pandemic, and did not know someone who was hospitalised because of Covid-19. Vaccine hesitancy was higher for Covid-19 vaccines than for other vaccines. The part of the population being convinced of the utility of vaccination in general but hesitant about the Covid-19 vaccine is a primary interest group for tailored communication campaigns in order to reach the vaccine coverage needed for herd immunity.


Rigidity of the polypeptide backbone in the triple-stranded collagen molecule.
Conformational energy computations were carried out on collagen-like triple-stranded conformations of several polytripeptides with the structure CH3CO(GXY)3NHCH3, where X and Y can be Pro, Ala, or Gly. The computed minimum-energy conformations for various sequences are compared with that computed earlier for poly(Gly-Pro-Pro). Usually, substitution of Ala or Gly residues for Pro does not cause any strain or distortion of the conformation of the triple-stranded complex. Thus, the structure is a very stable and essentially rigid one. Unfavorable interactions were found only in the case of CH3CO(Gly-Ala-Pro)NHCH3. These interactions are a consequence of differences between the residue geometry of Ala and Pro. They result in small changes of some backbone dihedral angles and in an increase of intra- and interchain energies. The presence of a single Gly-Ala-Pro tripeptide within a sequence of Gly-Pro-Pro tripeptides is not sufficient, however, to cause even a small distoration of the triple strand. No deviation of the peptide groups from planarity is required to stabilize the triple-stranded structure.


Human Papillomavirus (HPV): unawareness of the causal role of HPV infection in cervical cancer, HPV vaccine availability, and HPV vaccine uptake among female schoolteachers in a Middle Eastern country.
Human papillomavirus (HPV) is the most common viral infection of the reproductive tract. This cross-sectional study among female schoolteachers assessed the prevalence of i) unawareness of HPV infection's causal role in cervical cancer; ii) unawareness of HPV vaccine availability and iii) examined the sociodemographic variables associated both the outcome variables. This cross-sectional study was conducted among female schoolteachers employed in public and private sectors schools in Kuwait using a structured questionnaire for data collection. Prevalence of each of the outcome variables was computed. Multivariable logistic regression analyses were used to evaluate independent predictors of two dependent variables. A total 1341 female schoolteachers were enrolled. Of the participants, 60% were unaware of HPV causal role in cervical cancer and 88% were unaware of HPV vaccine availability. Among those who were aware of HPV vaccine availability, 83.8% were unvaccinated. Multivariable logistic regression (MLR) model showed that 20-29 years old participants or those with low family income (< 500 KD/month) were significantly (p < 0.05) more likely to be unaware of HPV causal role in cervical cancer. Moreover, participants with family/ personal history of cervical cancer were significantly (p < 0.05) less likely to be unaware of HPV role in causation of cervical cancer. A separate MLR model revealed that the participants were significantly more likely to be unaware of HPV vaccine availability if they were Kuwaiti nationals or non-Kuwaiti Arabs (p < 0.05), employed in public schools (p = 0.003) or less likely to be unaware if they had personal or family history of cervical cancer (p < 0.001). High prevalences of unawareness of causal role of HPV in cervical cancer and unawareness of HPV vaccine availability were recorded. Targeted education among identified sociodemographic groups with high levels of unawareness is warranted. If undertaken, future studies may evaluate the impact of recommended efforts.


MRI in Early Onset of Creutzfeldt Jakob Disease.
Teaching point: Cortical diffusion restriction can be depicted by MRI in the early onset of Creutzfeld Jakob disease.


Incidence and effect of acute kidney injury after transcatheter aortic valve replacement using the new valve academic research consortium criteria.
Acute kidney injury (AKI) is associated with a poor prognosis after transcatheter aortic valve replacement (TAVR). A paucity of data exists regarding the incidence and effect of AKI after TAVR using the new recommended Valve Academic Research Consortium criteria. At Columbia University Medical Center, 218 TAVR procedures (64.2% transfemoral, 35.8% transapical) were performed from 2008 to July 2011. The creatinine level was evaluated daily until discharge. Using the Valve Academic Research Consortium definitions, the 30-day and 1-year outcomes were compared between patients with significant AKI (AKI stage 2 or 3) and those without significant AKI (AKI stage 0 or 1). Significant AKI occurred in 18 patients (8.3%). Of these 18 patients, 10 (55.6%) had AKI stage 3 and 9 (50%) required dialysis. AKI was associated with a lower baseline mean transvalvular gradient (37.6 ± 11.4 vs 45.6 ± 14.8 mm Hg for no AKI, p = 0.03). After TAVR, the AKI group had a greater hemoglobin decrease (3.6 ± 2.0 vs 2.4 ± 1.3 g/dl, p = 0.01), greater white blood cell elevation at 72 hours (21.09 ± 12.99 vs 13.18 ± 4.82 × 10(3)/μl, p = 0.001), a more severe platelet decrease (118 ± 40 vs 75 ± 43 × 10(3)/μl, p <0.0001), and longer hospitalization (10.7 ± 6.4 vs 7.7 ± 8.5 days, p <0.001). One stroke (5.6%) occurred in the AKI group compared with 3 (1.5%) in the group without AKI (p = 0.29). The 30-day and 1-year rates of death were significantly greater in the AKI group than in the no-AKI group (44.4% vs 3.0%, hazard ratio 18.1, 95% confidence interval 6.25 to 52.20, p <0.0001; and 55.6% vs 16.0%, hazard ratio 6.32, 95% confidence interval 3.06 to 13.10, p <0.0001, respectively). Periprocedural life-threatening bleeding was the strongest predictor of AKI after TAVR. In conclusion, the occurrence of AKI, as defined by the Valve Academic Research Consortium criteria, is associated with periprocedural complications and a poor prognosis after TAVR.


CED-4 CARD domain residues can modulate non-apoptotic neuronal regeneration functions independently from apoptosis.
A major challenge in regenerative medicine is the repair of injured neurons. Regeneration of laser-cut C. elegans neurons requires early action of core apoptosis activator CED-4/Apaf1 and CED-3/caspase. While testing models for CED-4 as a candidate calcium-sensitive activator of repair, we unexpectedly discovered that amino acid substitutions affecting alpha-helix-6 within the CED-4 caspase recruitment domain (CARD) confer a CED-4 gain-of-function (gf) activity that increases axonal regrowth without disrupting CED-4 apoptosis activity. The in vivo caspase reporter CA-GFP reveals a rapid localized increase in caspase activity upon axotomy, which is absent in ced-4 and ced-3 loss-of-function mutants but present in the ced-4(gf) mutant. The ced-3 loss-of-function mutation can significantly suppress the axonal regrowth of the ced-4(gf) mutant, indicating that CED-4(gf) regeneration depends on CED-3 caspase. Thus, we identified a subdomain within the CED-4 CARD that regulates the dynamic and controlled caspase activity required for efficient regeneration.


A little more conversation, a little less action--candidate roles for the motor cortex in speech perception.
The motor theory of speech perception assumes that activation of the motor system is essential in the perception of speech. However, deficits in speech perception and comprehension do not arise from damage that is restricted to the motor cortex, few functional imaging studies reveal activity in the motor cortex during speech perception, and the motor cortex is strongly activated by many different sound categories. Here, we evaluate alternative roles for the motor cortex in spoken communication and suggest a specific role in sensorimotor processing in conversation. We argue that motor cortex activation is essential in joint speech, particularly for the timing of turn taking.


Transcriptional analysis of the divergent cagAB genes encoded by the pathogenicity island of Helicobacter pylori.
Helicobacter pylori strains isolated from most patients with peptic ulcer disease and adenocarcinoma express the vacuolating toxin VacA and contain a pathogenicity island named cag. The cag pathogenicity island codes for more than 40 putative proteins with features similar to bacterial secretion systems. One of these proteins, CagA, is an immunodominant antigen with unknown function encoded by the cagA gene. In the present study, we have analysed the functional promoter elements of the H. pylori cagA gene as well as of the divergently transcribed cagB gene. Primer extension analyses identified a single 5' end of the cagA mRNA, while two initiation sites were mapped in the case of the cagB mRNA. The promoters deduced upstream of these start points of transcription contained conserved -10 regions but no -35 regions with respect to the Escherichia coli sigma70 consensus sequence. Nevertheless, they could be activated in E. coli and in vitro by purified E. coli RNA polymerase. Deletion analyses indicated that the cagA and cagB genes are transcribed by overlapping promoters and that full activation requires sequences up to -70 and -96 respectively. Instead, basal transcription is likely to be mediated by -10 extended promoter-like sequences. RNA polymerase is able to bind the -40 to -60 region of the cagA promoter, and its binding is mediated by the alpha-subunit. This region resembles the UP elements of prokaryotic promoters in location, sequence and mechanism of interaction with the RNA polymerase. We discuss the features of these promoters and propose that they could represent a class of minimum promoters, which ensures a basic level of transcription, while full activation requires regulatory elements or a defined promoter context.


Deep memory distortions.
Deep distortions are a new family of memory biases that comprise one of the two basic varieties of false memory. The first and older variety, surface distortions, are specific item or source memories that are erroneous because the events did not happen. The new variety, deep distortions, are emergent properties of multiple specific memories. They are relations among such memories that are false because they violate objective logical rules that real-world events must obey. I discuss four deep distortions for which substantial data have accumulated: overdistribution, super-overdistribution, non-additivity, and impossible conjunctions. These phenomena violate four axioms of classical probability (numerical bound, universal event, additivity, and countable additivity) and two rules that follow from them (empty set and monotonicity). Their psychological significance lies in four facts about them: (a) They demonstrate that although events in the real world are compensatory, our memories of them are not; (b) they establish that we persistently over remember experience; (c) they reveal that surface distortions are by-products of deep distortions; and (d) they pose the theoretical conundrum of how the structure of memory could so thoroughly misrepresent the objective structure of the events we are remembering.


A prospective cohort study of perceived noise exposure at work and cerebrovascular diseases among male workers in Japan.
This study prospectively examined the association between perceived noise exposure at work and cerebrovascular diseases among Japanese male workers. A baseline survey was conducted between 1988 and 1990, which involved 110,792 inhabitants (age range: 40-79 yr) from 45 areas throughout Japan. Subsequent causes of death were identified from death certificates. The analysis was restricted to 14,568 men free of a cerebrovascular diseases (age range: 40-59 yr) who were in work at the time of the baseline survey. All subjects completed a self-administered questionnaire at the baseline. This included a question regarding perceived noise exposure at work. The Cox proportional-hazards model was used to estimate the risks of perceived noise exposure for death due to cerebrovascular diseases. The model included age, smoking, alcohol consumption, educational level, perceived mental stress, past medical history, body mass index, hours of walking, hours of exercise, shift work, and job type. During the 190,777 person-years of follow-up, a total of 1,064 deaths were recorded, 98 from cerebrovascular diseases, 27 deaths from subarachnoid haemorrhage, 35 deaths from intracerebral haemorrhage, and 25 deaths from cerebral infarction. Noise exposure did not increase the risk of cerebrovascular diseases, subarachnoid haemorrhage, or cerebral infarction. However, perceived noise exposure increased the risk of intracerebral haemorrhage diseases (hazard ratio (HR)=2.38, 95%CI: 1.20, 4.71, p=0.013). Furthermore, individuals with hypertension were highly susceptible to the effect of perceived noise exposure on the risk of intracerebral hemorrhage, but this association was not observed among the subjects without hypertension. Although the underlying mechanisms are not clear, hypertensive individuals with perceived noise exposure at work should be regarded as a high-risk group for intracerebral hemorrhage.


Influence of walking speed on gait parameters.
Modern three-dimensional gait analysis systems give information on joint angles and moments in the sagittal and coronal planes, for which normal ranges may not be readily available in the literature. Since patients with joint disease tend to walk slowly and with a short stride, it is essential that normal ranges for gait parameters should be defined with reference to speed of walking. This we have done using a population of 10 normal male subjects aged from 18 to 63 years, walking at speeds which range from very slow to very fast. The ranges of knee angle and moment are given, together with the changes in these parameters with walking speed. Peak knee flexion moment is strongly related to walking speed, whereas coronal plane knee angle is virtually independent of it. The stride length is probably the best basis for deciding the normal range for a particular measurement.


Iron foam coupled hydrolysis acidification for trichloroacetaldehyde treatment: Strengthening characteristics and mechanism.
This research studied transformative characteristics and enhanced mechanism of trichloroacetaldehyde (TCAL), one of chlorinated acetaldehydes (CAAs), by coupled-type iron foam enhanced hydrolysis acidification (HA) reactor. Main results were given that better dechlorination and aldehyde removal were achieved at this process than coupled-type iron foam enhanced HA, alone iron foam and HA reactor. The reasons were due to better strengthening effects of iron foam and HA, iron foam reduced TCAL toxicity to microbes caused an improvement of microbial activity, therefore, volatile fatty acids (VFAs) content and acetate acid (Ac) ratio were increased compared with HA. Moreover, it promoted the enrichment of Actinobacteriota and Firmicutes, and more extracellular polymeric substance (EPS) and enzymes enhanced dechlorination and aldehyde removal. Certainly, microbes reduced iron foam passivation and facilitated its oxidation further improved the strengthening effect.


The hemolytic activity of Galleria mellonella hemolymph.
A hemolytic activity was identified in the hemolymph of normal and immune Galleria mellonella larvae. The hemolysin was active against sheep, human, guinea pig, and rabbit erythrocytes. Hemolysis occurred in the presence of 0.04M EDTA. Vaccination of the larvae with formalized Pseudomonas aeruginosa increased the hemolytic activity. The increase, and subsequent decline of this activity paralleled the pattern of induced in vivo antibacterial activity that is characteristic of the insect's immune response. The hemolytic activity was distinct from induced phospholipase A-like and phospholipase C-like activities that were detected in immune hemolymph and which were inhibited by EDTA. The hemolytically active material (HAM) was partially purified (apparent molecular weight range 69,000 to 75,000) and was found not to be antibacterial for P. aeruginosa. The physiological role of the HAM is as yet unknown. It is possible that it may act together with other hemolymph components to produce an immune state.


Quantitative changes in cerebral cortical microvasculature in ageing and dementia.
Brains were obtained postmortem from 25 mentally normal patients aged 26 to 96 years and from 3 patients with Alzheimer's disease. Although the number of pyramidal nerve cells within frontal and temporal cortex decreased significantly with age, measures of capillary density correlated only weakly with age. Stronger correlations, however, were noted between measures of capillary density and number of pyramidal cells, irrespective of age or disease. Capillary measures did not differ in 6 of the mentally normal patients who showed a few plaques and tangles in their cortex from those of 6 other patients of similar age who did not show such changes. It is concluded that the extent of the capillary network in the cerebral cortex alters to match the number and activity of functioning nerve cells; changes in quantity of capillary occurring with age or Alzheimer's disease may, therefore, secondarily reflect a primary loss of nerve cells and do not form, per se, part of the degenerative process.


Interpregnancy weight changes and impact on pregnancy outcome in a cohort of women with a macrosomic first delivery: a prospective longitudinal study.
To determine the median interpregnancy maternal weight change between first and second pregnancies, and second and third pregnancies and to assess the impact of this weight change on pregnancy outcome in a cohort of women with a macrosomic first delivery. Prospective longitudinal study conducted over three pregnancies from 2007 to 2015. Tertiary referral maternity hospital, Dublin, Ireland. Women were recruited if their first baby weighed >4.0 kg. The pregnancy outcomes in the second and third pregnancies were analysed separately. Data were also analysed for both interpregnancy intervals comparing outcomes for those who gained any weight, or more weight than the median, with those who did not. Recurrent fetal macrosomia ≥4.0 kg and gestational diabetes mellitus. There were 280 women who delivered a third baby between 2011 and 2015. There were no differences in pregnancy outcomes for the second pregnancy in women who gained interpregnancy weight compared with those who did not and those who gained more interpregnancy weight than the median compared with those who did not. There was a statistically significant increase in birth weight ≥4.0 kg (54.0% vs 39.6% p=0.03) in those women who gained any weight between the second and third pregnancies. In those women who gained more interpregnancy weight than the median (1.70 kg) between a second and third pregnancy, there was a significant increase in the rate of gestational diabetes (6.5% vs 1.4%, p=0.03). This longitudinal study demonstrates that within this cohort maternal interpregnancy weight change between a second and third pregnancy is associated with an increase in birth weight ≥4.0 kg. Additionally, a gain of more weight than the median (1.70 kg) is associated with a higher rate of gestational diabetes.


Perceptions of Canadian dental faculty and students about appropriate penalties for academic dishonesty.
The purpose of this investigation was to a) compare the opinions of Canadian faculty and students as regards to what they felt was an appropriate penalty for particular academic offenses and b) to analyze the results and create a jurisprudence grid to serve as a guideline for appropriate disciplinary action. Two hundred questionnaires were distributed to the ten dental colleges in Canada. Each college was asked to have ten faculty and ten students complete the survey. A response rate of 100 percent was achieved for students and 92 percent for faculty. The questionnaire required respondents to select what they felt were appropriate penalties for a list of fifteen academic offenses and to render judgment on three specific cases. Statistical analysis of survey responses led to the following conclusions: 1) students gave equal or more lenient penalties than faculty for the same offense; 2) extenuating circumstances introduced via case presentations altered penalty choice only slightly; and 3) offenses could be grouped to correspond with appropriate penalties, thereby establishing a jurisprudence grid that may serve as a guideline for adjudication committees.


Grip Constancy but Not Perceptual Size Constancy Survives Lesions of Early Visual Cortex.
Object constancies are central constructs in theories of visual phenomenology. A powerful example is "size constancy," in which the perceived size of an object remains stable despite changes in viewing distance [1-4]. Evidence from neuropsychology [5], neuroimaging [6-11], transcranial magnetic stimulation [12, 13], single-unit and lesion studies in monkey [14-20], and computational modeling [21] suggests that re-entrant processes involving reciprocal interactions between primary visual cortex (V1) and extrastriate visual areas [22-26] play an essential role in mediating size constancy. It is seldom appreciated, however, that object constancies must also operate for the visual guidance of goal-directed action. For example, when reaching out to pick up an object, the hand's in-flight aperture scales with size of the goal object [27-30] and is refractory to the decrease in retinal-image size with increased viewing distance [31-41] (Figure 1), a phenomenon we call "grip constancy." Does grip constancy, like perceptual constancy, depend on V1 or can it be mediated by pathways that bypass it altogether? We tested these possibilities in an individual, M.C., who has bilateral lesions encompassing V1 and much of the ventral visual stream. We show that her perceptual estimates of object size co-vary with retinal-image size rather than real-world size as viewing distance varies. In contrast, M.C. shows near-normal scaling of in-flight grasp aperture to object size despite changes in viewing distance. Thus, although early visual cortex is necessary for perceptual object constancy, it is unnecessary for grip constancy, which is mediated instead by separate visual inputs to dorsal-stream visuomotor areas [42-48].


The phosphopeptide-binding specificity of Src family SH2 domains.
Src homology 2 (SH2) domains mediate protein/protein interactions by binding phosphotyrosyl proteins with high specificity. The protein Lck, a Src-like lymphocyte-specific tyrosine kinase which is important in signals involved in T-cell development, contains one such domain. The crystal structure of a complex of the Lck SH2 domain with a high-affinity ligand, pY324, is known. This ligand has the sequence EPQpYEEIPIYL. We designed and synthesized a series of phosphopeptides with single amino-acid changes in the four residues C-terminal to the phosphotyrosine (pTyr) in pY324. Surprisingly, the Glu one residue C-terminal to the phosphotyrosine (at position pY + 1) is sensitive to substitution, whereas the Ile at position pY + 3 is much less sensitive, accommodating a Glu with only modest loss of binding affinity. Replacement of the Glu and Pro on either side of the Ile had little effect, as predicted. Truncated phosphopeptides that end at position pY + 5 and have only an acetyl group N-terminal to the pTyr bound with only slightly lower affinity than pY324. In addition, naturally occurring phosphopeptide sequences that span a 1,000-fold range in binding affinity for the Lck SH2 domain have been identified. The Lck SH2 domain is highly selective for phosphotyrosyl-peptide binding; its specificity is dictated by the first and third residues C-terminal to the pTyr. The unexpected effects of some amino-acid substitutions indicate that the interactions seen between SH2 domains and ligand in the crystal structure may not be identical to those that occur in solution.


Workplace Gender Inequity Is Driven by Broader Societal Inequity: A Qualitative Study of Senior Japanese and American Radiation Oncologists.
Gender inequity in medicine harms society, and often originates in the context of broader societal discrimination. This study explores the experiences of older women in the radiation oncology specialty in Japan and the United States, with an emphasis on understanding how broader gender inequity affects career trajectory. Radiation oncology is an ideal setting to investigate cross-cultural physician gender equity issues, because few women enter the field despite fewer barriers (eg, frequent emergencies, evening/weekend hours, long procedures) that are commonly cited by women as deterrents in specialty selection. Between 2012 and 2016, the authors interviewed 14 older women in radiation oncology (department chairs or full professors), with 6 from Japan and 8 from the United States. Multiple analysts identified themes to explore the impact of societal gender inequity on female radiation oncologists' careers. Five themes were identified: (1) childhood gender constructs affect career aspirations, (2) persistent sexism and gender-based workplace challenges affect women's careers, (3) gender inequity in the home affects women's careers, (4) non-gender-related factors intersect to affect women's career satisfaction, and (5) attaining gender equity appears to be even more challenging in Japan compared with the United States. Female radiation oncologists in 2 of the most technologically advanced countries report that gender discrimination across their lifespans substantially affects career success. Because gender inequality reflects societal injustice and negatively affects scientific progress and patient outcomes, future research should focus on global approaches to address professional and domestic gender constructs that impede women's career progress.


Rapid flow cytometric method for viability determination of solventogenic clostridia.
We endeavored to develop a method for viability determination of solventogenic clostridia and to apply it for monitoring acetone-butanol-ethanol (ABE) fermentation. Six fluorescent probes (propidium iodide [PI], ethidium bromide, fluorescein diacetate, carboxyfluorescein diacetate [cFDA], rhodamine 123, bis-(1,3-dibutylbarbituric acid)trimethine oxonol [BOX]) were tested in order to distinguish two subpopulations of live and dead clostridial cells in suspension. Three of them were found to be appropriate (PI, BOX and cFDA) for this purpose. Developed fluorescent staining methods were applied to batch fermentation processes of Clostridium pasteurianum and C. beijerinckii carried out in a laboratory bioreactor under anaerobic conditions. Whereas PI was found to be applicable to both strains, BOX was convenient only for viability determination of C. pasteurianum. Although cFDA can distinguish two cell subpopulations in suspension, it was found to be unsuitable for viability determination under tested conditions, since it reflected more variable esterase activity during sporulation cell cycle than viability. Flow cytometry in combination with convenient fluorescent probe has been proved to be a valuable tool for viability determination. We assume this rapid and simple method can help to obtain more complex and precise information about ABE fermentation.


Differences in postprandial inflammatory responses to a 'modern' v. traditional meat meal: a preliminary study.
A low-grade inflammatory response ('metaflammation') has been found to be associated with certain chronic diseases. Proposed inducers of this have been aspects of the modern lifestyle, including newly introduced foods. Plasma TAG, and the inflammatory cytokines C-reactive protein (CRP), TNF-alpha and IL-6 were compared in a randomised, cross-over trial using ten healthy subjects before and after eating 100 g of kangaroo, or a 'new' form of hybridised beef (wagyu) separated by about 1 week. Postprandial levels for 1 and 2 h of TAG, IL-6 and TNF-alpha were significantly higher after eating wagyu compared with kangaroo (P = 0.002 for TAG at 1 h, P < 0.001 at 2 h; P < 0.001 for IL-6 and TNF-alpha at 1 and 2 h). CRP was significantly higher 1 h postprandially after wagyu (P = 0.011) and non-significantly higher 2 h postprandially (P = 0.090). We conclude that the metaflammatory reaction to ingestion of a 'new' form of hybridised beef (wagyu) is indicative of a low-grade, systemic, immune reaction when compared with lean game meat (kangaroo). Further studies using isoenergetic intake and isolating fatty acid components of meats are proposed.


Ab initio and DFT conformational study on N-nitrosodiethylamine, (C2H5)2N-N=O.
Ab initio (MP2) and DFT (B3LYP) calculations, using the cc-pVTZ and aug-cc-pVTZ basis sets, have been performed to characterize some stationary points on the ground state potential energy surface of the title molecules. Several properties as, for instance, relative energies, the barriers for NO rotation around the NN bond, NBO charges on O and amino N atoms, as well as the dipole moments, have been calculated and analyzed in the light of the structures found. Both computational levels here employed yield three minima, in which the C(2)NNO frame is 'planar' or 'quasi-planar'. Important correlations between NBO charges and geometric parameters, as well as between some structural features and dipole moments are also discussed. A total of 17 structures have been found for the (C(2)H(5))(2)N-N=O molecule. Two ranges of values have been obtained for the dipole moment, with the largest values occurring for the structures in which the nitrogen lone pair is parallel to the NO group π system. For instance, these two ranges are from ~4.1 to 4.5 D, and from ~1.6 to 2.1 D, at the MP2/cc-pVTZ level. These ranges are consistent with a larger and a smaller contribution of a dipolar resonance structure, respectively. As the method or basis set changes the values of the dipole moments change by at most ~0.23 D.


Effective compounds group of Mongolian prescriptions BAIMAI-SAN protect against peripheral neuropathy in lower limbs of rats through neuro protective effect.
BAIMAI-SAN prescription is a famous Chinese minority complex prescription used for curing neuropathy. The Effective Compounds Groups of BAIMAI-SAN (ECGBM) is determined by high through-put screening, and it includes picroside II, verbascose, taurine and ellagic acid and borneol. To research the potential protective effect of ECGBM on the function of peripheral neuropathy, diabetic rats with peripheral neuropathy were induced by streptozotocin and treated with ECGBM (0.1, 0.3, 0.9 mg/kg/day i.g.) for 75 days. Primary cortical neuronal cultures were subjected to high d-glucitol, and treated with ECGBM prophylactically. The administration resulted in reductions in speed of sciatic motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV) and response speed to pain in the sciatic nerve fiber. Data from primary cortical neuronal cultures experiments indicated that neuronal survival rates were increased, and LDH release was decreased and the loss of neurite length was alleviated in ECGBM group. It is first report that ECGBM could protect the peripheral neuron in diabetic rat in vivo and in vitro. This activity may be associated with the neuron protective effect.


Tackling the chronic disease burden: are there co-benefits from climate policy measures?
Each year, non-communicable diseases (NCDs) kill 40 million people worldwide and impose an estimated economic burden of $600 billion. Without effective policymaking, NCDs will continue to undermine health and economic systems globally. We propose that climate policy measures-such as carbon pricing-can yield significant health-related co-benefits aside from their intended greenhouse gas emission reduction. We simulate three carbon tax scenarios in the energy and food sector in Belgium and assess the resulting health-related co-benefits. These benefits originate from decreased exposure to two leading NCD risk factors: fine particulate matter and dietary regimes excessive in animal products. The carbon tax could prevent 42,300-78,800 Disability-Adjusted Life Years in Belgium, or save 0.6-1.1% of total health care expenditure and an additional 0.06-0.12% of Belgian GDP. We conclude that these health-related co-benefits should be included in the cost-benefit analysis of carbon pricing.


The N-terminal domain of TFIIB from Pyrococcus furiosus forms a zinc ribbon.
The three-dimensional structure of the N-terminal domain of an archaeal TFIIB, which has high sequence homology with eucaryal analogues, is strikingly similar to that of the C-terminal zinc ribbon of the eucaryal transcription elongation factor TFIIB.


Radioimmunoassays for aldosterone and deoxycorticosterone in plasma and urine.
Radioimmunoassays for aldosterone and deoxycorticosterone (DOC) are described in which a simple separation procedure using ammonium sulfate stabilization of bound steroid and extraction of free steroid into toluene scintillant allows an "in vial" assay without mechanical separation of the two phase system. Extraction and thin layer chromatographic methods for purification of aldosterone and DOC are free of solvent and plate blank effects. Normal values are given for unconjugated aldosterone and DOC in urine, for aldosterone and DOC in plasma and for aldosterone 18-glucuronide in urine.


Evaluation of intraocular lens fixation in pseudophakia.
I developed my own lens designs after analyzing the reasons for failure of previous designs. The iris clip lens and the capsular lens are supported by the iris and by the capsular membrane, respectively, the former having minimal and the latter having nearly no contact at all with intraocular tissues. A comparison between the iris and capsular membrane as support for an intraocular lens favor the capsular membrane.


Hormone concentrations before and after semen-induced ovulation in the bactrian camel (Camelus bactrianus).
During the follicular phase of bactrian camels, basal concentrations of LH were 2.7 +/- 1.2 ng/ml. By 4 h after insemination peak values of 6.9 +/- 1.0 ng/ml occurred. In addition, a smaller LH peak (5.4 +/- 2.5 ng/ml) appeared 1 day before regression of the follicle began in unmated camels. During the follicular phase peripheral plasma progesterone values were low (0.36 +/- 0.28 ng/ml), but values increased to reach 1.73 +/- 0.74 ng/ml at 3 days and 2.4 +/- 0.86 ng/ml at 7 days after ovulation. Plasma oestradiol-17 beta concentrations were 26.8 +/- 9.0 pg/ml during the follicular phase and 30.8 +/- 5.1 pg/ml when the follicle was maximum size. Values fell after ovulation but rose to 29.8 +/- 6.5 pg/ml 3 days later.


Neonatal line on fetus and infant teeth: An indicator of live birth and mode of delivery.
The neonatal line (NL) is an important issue in forensic odontology. It is the sign of a developmental birth defect, which is caused by the effect of metabolic stress on tooth structures when the fetus passes to extrauterine life. The aim of this research is to determine the existence and thickness of NL in teeth, as it is a legal necessity to indicate the signs of viability at birth in a forensic examination of a fetus or infant case. This research was conducted on 48 lower left and right lateral teeth, which were taken from 24 autopsy cases (46% female and 54% male). Left lateral teeth were sectioned in a vertical plane and right lateral teeth were sectioned in a horizontal plane. The NL thickness was measured with a scanning electron microscope (SEM). These cases comprised three conditions as: 70.3% normal birth, 16.7% caesarean sections, and 12.5% still birth cases under the legal and ethical permission. The mean NL thickness of normal birth cases was higher than caesarean cases as 7.7μm and 2.5μm, respectively. The results showed a statistical significance between all birth conditions. NL does not exist in still birth cases (p<0.001). Not only is the presence of NL a sign of live birth, but also its thickness is an indicator of the delivery mode where NL thickness of normal birth was found thicker than the caesarean cases.


Estrogen profile- and pharmacogenetics-based lamotrigine dosing regimen optimization: Recommendations for pregnant women with epilepsy.
During pregnancy, various physiological changes occur that can alter the pharmacokinetics of antiepileptic drugs, such as lamotrigine (LTG). Anticipating the change in LTG dose required to achieve a pre-pregnancy target concentration is challenging. This study aimed to develop a refined population pharmacokinetic (PopPK) model of LTG in pregnant women with epilepsy (WWE) to identify factors explaining the variability in pharmacokinetics and to establish a model-informed individualized dosing regimen. On that basis, a coarsened model containing only clinical variables was also developed to examine its predictive performance compared to the refined model. In total, 322 concentration-time points from 51 pregnant WWE treated with LTG were employed to establish a refined PopPK model that included endogenous estrogen profiles, variants of candidate genes encoding LTG-metabolizing enzymes and -transporter proteins, and other clinical variables and a coarsened model that included only clinical variables, respectively. Data from an additional 11 patients were used for external validation of these two models. A nonlinear mixed-effect modeling approach was used for PopPK analysis of LTG. The standard goodness-of-fit method, bootstrap, normalized prediction distribution errors and external evaluation were adopted to estimate the stability and predictive performance of the candidate models. Akaike information criterion (AIC) was used to compare the goodness of fit between these two models. A lower AIC indicates a better fit of the data and the preferred model. Recommended dosing regimens for pregnant WWE were selected using Monte Carlo simulation based on the established optimal model. In the refined PopPK model, the population mean of apparent LTG clearance (CL/F) in pregnant WWE was estimated to be 2.82 L/h, with an inter-individual variability of 23.6%. PopPK analysis indicated that changes in estrogen profile during pregnancy were the predominant reason for the significant variations in LTG-CL/F. Up to the 3rd trimester, the concentration accumulation effect of E2 increased LTG-CL/F by 5.109 L/h from baseline levels. Contrary to effect of E2, E3 as the main circulating estrogen in pregnancy with a peak value of 34.41 ng/mL is 1000-fold higher than that in non-pregnancy reduced LTG-CL/F by 1.413 L/h. In addition, the UGT2B7 rs4356975 C > T and ABCB1 rs1128503 A > G variants may contribute to a better understanding of the inter-individual variability in LTG-CL/F. LTG-CL/F was 1.66-fold higher in UGT2B7 rs4356975 CT or TT genotype carriers than in CC genotype carriers. In contrast, ABCB1 rs1128503 GG genotype carriers had only 71.9% of the LTG-CL/F of AA or AG genotype carriers. In the coarsened PopPK model, the gestational age was a promising predictor of changes in LTG-CL/F. When comparing these two models, the refined PopPK model was favored over the coarsened PopPK model (AIC = -30.899 vs. -20.017). Monte Carlo simulation based on optimal PopPK model revealed that the LTG dosage administered to carriers of the UGT2B7 rs4356975 CT or TT genotype required a 33-50% increase to reach the pre-pregnancy target concentration, and carriers of the ABCB1 rs1128503 GG genotype required a 33-66% lower dose of LTG than carriers of the ABCB1 rs1128503 AA or AG genotype. Changes in estrogen profile during pregnancy was a better predictor of variations in LTG-CL/F than gestational age. The developed model based on estrogen profile and pharmacogenetics can serve as a foundation for further optimization of dosing regimens of LTG in pregnant WWE.


A possible case of carbamazepine-induced renal phospholipidosis mimicking Fabry disease.
Fabry disease (FD) is a genetic disorder caused by a-galactosidase A gene mutation. Ultrastructural analysis revealing zebra bodies are the typical morphological characteristics. However, certain tricyclic antidepressants and some other medications could induce renal phospholipidosis mimicking FD. We report a 33-year-old man has been taking carbamazepine intermittently for around 10 years whenever he experiences pain and paresthesia in his fingers. He experienced mild edema on both lower limbs half a year ago. Laboratory tests revealed a fluctuating urine protein between + and ++. Electron microscopy revealed laminated "zebra body" in podocytes, which is typical of FD. However, the patient had no family history and the sequencing of the a-galactosidase gene revealed no mutations. The a-galactosidase A enzyme activity was normal at 6.03 μmol/mL/h (normal 2.40-17.65 μmol/mL/h), and low expression of globotriaosylceramide (Gb3) was detected in the renal tissue of this patient. Therefore, the diagnosis of Fabry disease was excluded. Considering the patient's long-term treatment with carbamazepine (blood level 1.8 μg/ml), we speculated whether the pathological features could be associated with renal phospholipidosis caused by carbamazepine. The follow-up data showed that proteinuria was improved (fluctuated at + ~ -) after discontinuing carbamazepine for six months, which further seemed to support the above diagnosis. Therefore, we concluded that a possible case of carbamazepine-induced renal phospholipidosis, mimicking that observed in FD, has been associated with its nephrotoxicity.


Delayed treatment with vitamin C and N-acetyl-L-cysteine protects Schwann cells without compromising the anti-myeloma activity of bortezomib.
Bortezomib-induced peripheral neuropathy (BIPN) emerges as a disabling adverse effect. As rat models for BIPN have demonstrated damage in nerve Schwann cells, we screened for cytoprotective agents to devise a method of rescuing Schwann cells from the cytotoxic effects of bortezomib without compromising its anti-myeloma effects. Schwann cells underwent macroautophagy along with cytoplasmic inclusion body and vacuole formation, and appeared much less susceptible to bortezomib-induced cytotoxicity than did myeloma cells. Vitamin C or N-acetyl-L-cysteine (NAC) achieved near-complete rescue of Schwann cells treated with bortezomib at 30 nM or less, and these agents in combination are able to cooperatively inhibit the morphological changes and the cytotoxicity in Schwann cells with higher doses of bortezomib. The delayed addition of vitamin C and/or NAC after the exposure to bortezomib alleviated the cytotoxicity in Schwann cells but not myeloma cells. These results suggest that delayed treatment with these agents may be instrumental in prophylaxis of BIPN.


Disruption in bone marrow fat may attenuate testosterone action on muscle size after spinal cord injury: a case report.
Mesenchymal stem cells can be differentiated into muscle satellite cells. Testosterone replacement therapy (TRT) promotes the differentiation of satellite cells into muscle cells. A 31-year-old male with a T4 complete chronic spinal cord injury (SCI) had fixation for a mid-shaft fracture of the left femur. The participant received transdermal testosterone patches (4 mg/day) daily for 16 weeks. Skeletal muscle and yellow bone marrow adiposity cross-sectional areas (CSAs) of both thighs were measured using magnetic resonance imaging. The yellow bone marrow CSA was 67-69% lower in the left femur compared to the right femur. Following intervention, a discrepancy was noted between the whole skeletal muscle CSAs of the right (+13%) and left (+6%) thighs. The right knee extensor CSA increased by 7% with no changes in the left CSA. Disruption in bone marrow fat may attenuate the systemic effects of TRT on muscle size.