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Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.
Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.
Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.
This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.
In this paper, the melting of stainless steel 316L using Computational Fluid Dynamics to observe the melt pool characteristics is studied. The simulation model allows the observation of the molten pool flow during the selective laser melting process due to Marangoni's effect and recoil pressure. Furthermore, different parameters are tested to show their effects on the melt pool and track formation. Different laser powers, as well as scanning speeds, were used to study the effects they have on the melt pool characteristics. The results were used to determine the relationships between these factors and the melt pool characteristics.
The response of soil microbial communities to soil quality changes is a sensitive indicator of soil ecosystem health. The current work investigated soil microbial communities under different fertilization treatments in a 31-year experiment using the phospholipid fatty acid (PLFA) profile method. The experiment consisted of five fertilization treatments: without fertilizer input (CK), chemical fertilizer alone (MF), rice (Oryza sativa L.) straw residue and chemical fertilizer (RF), low manure rate and chemical fertilizer (LOM), and high manure rate and chemical fertilizer (HOM). Soil samples were collected from the plough layer and results indicated that the content of PLFAs were increased in all fertilization treatments compared with the control. The iC15:0 fatty acids increased significantly in MF treatment but decreased in RF, LOM and HOM, while aC15:0 fatty acids increased in these three treatments. Principal component (PC) analysis was conducted to determine factors defining soil microbial community structure using the 21 PLFAs detected in all treatments: the first and second PCs explained 89.8% of the total variance. All unsaturated and cyclopropyl PLFAs except C12:0 and C15:0 were highly weighted on the first PC. The first and second PC also explained 87.1% of the total variance among all fertilization treatments. There was no difference in the first and second PC between RF and HOM treatments. The results indicated that long-term combined application of straw residue or organic manure with chemical fertilizer practices improved soil microbial community structure more than the mineral fertilizer treatment in double-cropped paddy fields in Southern China.
The gastrointestinal tract (GIT) of animals is capable of sensing various kinds of nutrients via G-protein coupled receptor-mediated signaling transduction pathways, and the process is known as ‘gut nutrient chemosensing’. GPR40, GPR41, GPR43 and GPR119 are chemoreceptors for free fatty acids (FFAs) and lipid derivatives, but they are not well studied in small ruminants. The objective of this study is to determine the expression of GPR40, GPR41, GPR43 and GPR119 along the GIT of kid goats under supplemental feeding (S) v. grazing (G) during early development. In total, 44 kid goats (initial weight 1.35±0.12 kg) were slaughtered for sampling (rumen, abomasum, duodenum, jejunum, ileum, cecum, colon and rectum) between days 0 and 70. The expression of GPR41 and GPR43 were measured at both mRNA and protein levels, whereas GPR40 and GPR119 were assayed at protein level only. The effects of age and feeding system on their expression were variable depending upon GIT segments, chemoreceptors and expression level (mRNA or protein), and sometimes feeding system × age interactions (P<0.05) were observed. Supplemental feeding enhanced expression of GPR40, GPR41 and GPR43 in most segments of the GIT of goats, whereas G enhanced expression of GPR119. GPR41 and GPR43 were mainly expressed in rumen, abomasum and cecum, with different responses to age and feeding system. GPR41 and GPR43 expression in abomasum at mRNA level was greatly (P<0.01) affected by both age and feeding system; whereas their expression in rumen and abomasum at protein level were different, feeding system greatly (P<0.05) affected GPR41 expression, but had no effect (P>0.05) on GPR43 expression; and there were no feeding system×age interactions (P>0.05) on GPR41 and GPR43 protein expression. The expression of GPR41 and GPR43 in rumen and abomasum linearly (P<0.01) increased with increasing age (from days 0 to 70). Meanwhile, age was the main factor affecting GPR40 expression throughout the GIT. These outcomes indicate that age and feeding system are the two factors affecting chemoreceptors for FFAs and lipid derivatives expression in the GIT of kids goats, and S enhanced the expression of chemoreceptors for FFAs, whereas G gave rise to greater expression of chemoreceptors for lipid derivatives. Our results suggest that enhanced expression of chemoreceptors for FFAs might be one of the benefits of early supplemental feeding offered to young ruminants during early development.
Coinfection with human immunodeficiency virus (HIV) and viral hepatitis is associated with high morbidity and mortality in the absence of clinical management, making identification of these cases crucial. We examined characteristics of HIV and viral hepatitis coinfections by using surveillance data from 15 US states and two cities. Each jurisdiction used an automated deterministic matching method to link surveillance data for persons with reported acute and chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections, to persons reported with HIV infection. Of the 504 398 persons living with diagnosed HIV infection at the end of 2014, 2.0% were coinfected with HBV and 6.7% were coinfected with HCV. Of the 269 884 persons ever reported with HBV, 5.2% were reported with HIV. Of the 1 093 050 persons ever reported with HCV, 4.3% were reported with HIV. A greater proportion of persons coinfected with HIV and HBV were males and blacks/African Americans, compared with those with HIV monoinfection. Persons who inject drugs represented a greater proportion of those coinfected with HIV and HCV, compared with those with HIV monoinfection. Matching HIV and viral hepatitis surveillance data highlights epidemiological characteristics of persons coinfected and can be used to routinely monitor health status and guide state and national public health interventions.
The mammalian target of rapamycin (mTOR) has been shown to be involved in lipopolysaccharide (LPS)-induced immune responses in many mammal cells. Here, we suggest that the mTOR pathway is involved in the intestinal inflammatory responses evoked by LPS treatment in chicken embryos. The intestinal tissue from Specific pathogen free chick embryos was cultured in the presence of LPS for 2 h. Secretory immunoglobulin A (sIgA) concentrations, messenger RNA (mRNA) expression of cytokines, and protein levels of nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), mTOR and p70 ribosomal S6 kinase (p70S6K) were determined. The results showed that LPS treatment increased sIgA concentrations in a dose-dependent manner. The mRNA levels of interleukine (IL)-6, IL-8, IL-10, tumor necrosis factor-α and Toll-like receptor (TLR) 4 were upregulated by LPS treatment (P<0.05). Lipopolysaccharide increased the phosphorylation of Jun N-terminal kinase (JNK), p38 MAPK and NF-κB (P<0.05) while decreasing the phosphorylation level of mTOR (P<0.05). Supplementation of leucine at doses of 10, 20 and 40 mM dose-dependently decreased sIgA production. Leucine supplementation at 40 mM restored the phosphorylation level of mTOR and p70S6K while suppressing the phosphorylation levels of NF-κB (P<0.05) and partially down-regulating the phosphorylation of p38 MAPK and JNK. The transcription of IL-6 was significantly decreased by leucine supplementation. These results suggested that leucine could alleviate LPS-induced inflammatory responses by down-regulating NF-κB signaling pathway and evoking mTOR/p70S6K signaling pathway, which may involve in the regulation of the intestinal immune system in chicken embryos.
Placental transport of vitamin D and other nutrients (e.g. amino acids, fats and glucose) to the fetus is sensitive to maternal and fetal nutritional cues. We studied the effect of maternal calorific restriction on fetal vitamin D status and the placental expression of genes for nutrient transport [aromatic T-type amino acid transporter-1 (TAT-1); triglyceride hydrolase/lipoprotein uptake facilitator lipoprotein lipase (LPL)] and vitamin D homeostasis [CYP27B1; vitamin D receptor (VDR)], and their association with markers of fetal cardiovascular function and skeletal muscle growth. Pregnant sheep received 100% total metabolizable energy (ME) requirements (control), 40% total ME requirements peri-implantation [PI40, 1–31 days of gestation (dGA)] or 50% total ME requirements in late gestation (L, 104–127 dGA). Fetal, but not maternal, plasma 25-hydroxy-vitamin D (25OHD) concentration was lower in PI40 and L maternal undernutrition groups (P<0.01) compared with the control group at 0.86 gestation. PI40 group placental CYP27B1 messenger RNA (mRNA) levels were increased (P<0.05) compared with the control group. Across all groups, higher fetal plasma 25OHD concentration was associated with higher skeletal muscle myofibre and capillary density (P<0.05). In the placenta, higher VDR mRNA levels were associated with higher TAT-1 (P<0.05) and LPL (P<0.01) mRNA levels. In the PI40 maternal undernutrition group only, reduced fetal plasma 25OHD concentration may be mediated in part by altered placental CYP27B1. The association between placental mRNA levels of VDR and nutrient transport genes suggests a way in which the placenta may integrate nutritional cues in the face of maternal dietary challenges and alter fetal physiology.
Studies from low- and middle-income countries (LMIC) indicate that the use of audio computer-assisted self-interviewing (ACASI) is associated with more accurate reporting of sensitive behaviors (e.g. substance use and sexual risk behaviors) compared with interviewer-administered questionnaires. There is a lack of published information on the process of designing, developing, and implementing ACASI in LMIC. In this paper we describe our experience implementing an ACASI system for use with a population of orphans and vulnerable children in Zambia.
A questionnaire of mental health, substance use, and HIV risk behaviors was converted into an ACASI system, tested in pilot and validity studies, and implemented for use in a randomized controlled trial. Successes, barriers, and challenges associated with each stage in the development and implementation of ACASI are described.
We were able to convert a lengthy and complex survey into an ACASI system that was feasible for use in Zambia. Lessons learned include the importance of: (1) piloting the written and electronic versions; (2) proper and extensive training for study assessors to use ACASI and for those doing voice recordings; and (3) attention to logistics such as appropriate space, internet, and power.
We found that ACASI was feasible and acceptable in Zambia with proper planning, training, and supervision. Given mounting evidence indicating that ACASI provides more accurate self-report data and immediate data download compared with interview-administered measures, it may be an effective and economical alternative for behavioral health research studies in LMIC.
We consider single-server queueing systems that are modulated by a discrete-time Markov chain on a countable state space. The underlying stochastic process is a Markov random walk (MRW) whose increments can be expressed as differences between service times and interarrival times. We derive the joint distributions of the waiting and idle times in the presence of the modulating Markov chain. Our approach is based on properties of the ladder sets associated with this MRW and its time-reversed counterpart. The special case of a Markov-modulated M/M/1 queueing system is then analysed and results analogous to the classical case are obtained.
Chinese psychiatrists have gradually started to focus on those who are deemed to be at ‘clinical high-risk (CHR)’ for psychosis; however, it is still unknown how often those individuals identified as CHR from a different country background than previously studied would transition to psychosis. The objectives of this study are to examine baseline characteristics and the timing of symptom onset, help-seeking, or transition to psychosis over a 2-year period in China.
The presence of CHR was determined with the Structured Interview for Prodromal Syndromes (SIPS) at the participants' first visit to the mental health services. A total of 86 (of 117) CHR participants completed the clinical follow-up of at least 2 years (73.5%). Conversion was determined using the criteria of presence of psychotic symptoms (in SIPS). Analyses examined baseline demographic and clinical predictors of psychosis and trajectory of symptoms over time. Survival analysis (Kaplan–Meier) methods along with Log-rank tests were performed to illustrate the relationship of baseline data to either conversion or non-conversion over time. Cox regression was performed to identify baseline predictors of conversion by the 2-year follow-up.
In total 25 (29.1%) of 86 completers transitioned to a psychotic disorder over the course of follow-up. Among the CHR sample, the mean time between attenuated symptom onset and professional help-seeking was about 4 months on average, and converters developed fully psychotic symptoms about 12 months after symptom onset. Compared with those CHR participants whose risk syndromes remitted over the course of the study, converters had significantly longer delays (p = 0.029) for their first visit to a professional in search of help. At baseline assessment, the conversion subgroup was younger, had poorer functioning, higher total SIPS positive symptom scores, longer duration of untreated prodromal symptoms, and were more often given psychosis-related diagnoses and subsequently prescribed antipsychotics in the clinic.
Chinese CHR identified primarily by a novel clinical screening approach had a 2-year transition rate comparable with those of specialised help-seeking samples world-wide. Early clinical intervention with this functionally deteriorating clinical population who are suffering from attenuated psychotic symptoms, is a next step in applying the CHR construct in China.
The objective of this study was to investigate the effects of maternal protein or energy restriction on hormonal and metabolic status of pregnant goats during late gestation and their postnatal male kids. Forty-five pregnant goats were fed a control (CON), 40% protein-restricted (PR) or 40% energy-restricted (ER) diet from 90 days of gestation until parturition. Plasma of mothers (90, 125 and 145 days of gestation) and kids (6 weeks of age) were sampled to determine metabolites and hormones. Glucose concentration for pregnant goats subjected to PR or ER was less (P<0.001) than that of CON goats at 125 and 145 days of gestation. However, plasma nonesterified fatty acids concentration was greater (P<0.01) at 125 and 145 days for PR and ER than CON. Protein restriction increased (P<0.01) maternal cortisol concentration by 145 days of gestation, and ER decreased (P<0.01) maternal insulin concentration at 125 days of gestation. Moreover, maternal amino acid (AA) concentrations were affected by nutritional restriction, with greater (P<0.05) total AA (TAA) and nonessential AA (NEAA) for PR goats but less (P<0.05) TAA and NEAA for ER goats at 125 days of gestation. After 6 weeks of nutritional recovery, plasma concentrations of most metabolic and hormonal parameters in restricted kids were similar to CON kids, except for reduced (P<0.05) insulin concentration in ER, and reduced (P<0.05) Asp concentration in PR and ER kids. These results provide information on potential metabolic mechanisms responsible for fetal programming.
Reconstruction with a vascularised flap provides the most reliable outcome, with post-operative cerebrospinal fluid leak rates of less than 5 per cent. This article aims to review and summarise the critical technical aspects of the vascularised flaps most commonly used for skull base reconstruction.
Vascularised flaps are classified as intranasal or extranasal. The intranasal group includes the Hadad–Bassagaisteguy nasoseptal flap, the Caicedo reverse nasoseptal flap, the nasoseptal rescue flap, the posteriorly or anteriorly based lateral wall flaps, and the middle turbinate flap. Extranasal flaps include the transfrontal pericranial and transpterygoid temporoparietal flaps.
The Hadad–Bassagaisteguy nasoseptal flap is overwhelmingly favoured for reconstructing extensive defects of anterior, middle and posterior cranial base. Its pertinent technical features are described. However, it is essential to master the skills required for the various extranasal or regional vascularised flaps because each can offer a reconstructive alternative for specific patients, especially when open approaches are needed and/or intranasal vascularised flaps are not feasible.
A method of diamond heteroepitaxial lateral overgrowth is demonstrated which utilizes a photolithographic metal mask to pattern a thin (001) epitaxial diamond surface. Significant structural improvement was found, with a threading dislocation density reduced by two orders of magnitude at the top surface of a thick overgrown diamond layer. In the initial stage of overgrowth, a reduction of diamond Raman linewidth in the overgrown area was also realized. Thermally-induced stress and internal stress were determined by Raman spectroscopy of adhering and delaminated diamond films. The internal stress is found to decrease as sample thickness increases.
Batch cultures of mixed rumen micro-organisms were used to evaluate varying enzyme products with high xylanase activity (EPX), four of which were recombinant single xylanase activity developmental enzyme products (EPX1–EPX4, products of xylanase genes derived from Trichoderma harzianum, Trichoderma reesei, Orpinomyces and Aspergillus oryzae, respectively), for their potential to improve in vitro ruminal fermentation of three forages [maize (Zea mays) stover (MS), rice (Oryza sativa) straw (RS) and Guimu No. 1 grass (Pennisetum americanum×Pennisetum purpureum, GM)]. The enzyme product EPX5, derived from Trichoderma longibrachiatum, was used as a positive control that could improve in vitro fermentation of forages. Enzymes were supplied at dose rates of 0 (control), 20 (low), 50 (medium) and 80 (high) enzymic units of xylanase/g of dry matter (DM). There were no interactions between EPX and dose for the fermentation characteristics evaluated. Increasing EPX dose linearly increased gas production (GP) kinetic characters [i.e. asymptotic GP (VF), half time when GP is half of the theoretical maximum GP (t0·5), and initial fractional rate of degradation (FRD0)] and methane (CH4) production from RS and GM at 24 h, and increased degradability of DM at 24 h for MS and RS. A linear increase in degradability of neutral detergent fibre (NDF) of the three forages at 24 h was observed with increasing dose of EPX, but at 48 h only NDF degradability of RS was increased. There were differences in the effects of EPX on degradability of DM and NDF from RS at 24 h, with EPX4 having the highest and EPX1 having the lowest. In addition, increasing EPX dose linearly increased acetate proportion at 24 h and total volatile fatty acids (TVFA) at 48 h in MS. Increasing EPX dose linearly increased TVFA at 24 h, and ammonia-nitrogen (NH3-N) concentration at 48 h in RS. For GM, linear or quadratic effects of dose on acetate and butyrate concentration were observed at 24 and 48 h. The present study indicates that applying EPX to low-quality forages has the potential to improve rumen degradability and utilization. Furthermore, EPX from different sources differed in their effects when applied at the same dose rate, with the responses being forage-specific. For RS, the EPX derived from A. oryzae showed the greatest positive effects on forage degradation; whereas for MS and GM, the source of micro-organism where EPX gene was derived did not affect the degradation, with little difference among the EPX evaluated.
This study aimed to investigate the validity and feasibility of cervical oesophagostomy as a treatment for patients with severe dysphagia after radiotherapy for nasopharyngeal carcinoma.
The study retrospectively analysed the clinical data, symptoms, physical signs, treatment and outcomes of 12 patients treated with cervical oesophagostomy for severe dysphagia after radiotherapy for nasopharyngeal carcinoma, from 2006 to 2010.
In all 12 cases, the oesophageal stoma remained stable, without any complications such as pharyngeal fistula or inflammation. No oesophageal stricture or granuloma growth was observed. All patients reported significant improvement in their nutritional status and quality of life after the oesophagostomy surgery.
Cervical oesophagostomy is a valid and feasible method of treating severe dysphagia following radiotherapy for nasopharyngeal carcinoma. Oesophagostomy shows specific advantages over nasogastric tubing, gastrostomy and jejunostomy. Patients' nutrition and quality of life can be improved significantly if cervical oesophagostomy is executed in a timely fashion, especially in cases with severe trismus and multiple radiation-induced cranial nerve palsies unresponsive to rehabilitation.
Cognitive impairment is a core feature of schizophrenia. Its relationship with duration of untreated psychosis (DUP), a potentially malleable prognostic factor, has been less studied, with inconsistent findings being observed in the literature. Previous research investigating such a relationship was mostly cross-sectional and none of those prospective studies had a follow-up duration beyond 2 years.
A total of 93 Hong Kong Chinese aged 18 to 55 years presenting with first-episode schizophrenia-spectrum disorder were studied. DUP and pre-morbid adjustment were measured using a structured interview incorporating multiple sources of information. Psychopathological evaluation was administered at intake, after clinical stabilization of the first psychotic episode, and at 12, 24 and 36 months. Cognitive functions were measured at clinical stabilization, and at 12, 24 and 36 months.
DUP exerted differential effects on various cognitive domains, with memory deficits being the most related to DUP even when potential confounders including pre-morbid adjustment and sex were adjusted. Prolonged DUP was associated with more severe impairment in visual memory at clinical stabilization and verbal memory at 24 and 36 months. Further, patients with a long DUP were found to have worse outcomes on negative symptoms at 36 months. The effects of DUP on verbal memory remained significant even when negative symptoms were taken into consideration.
Our findings provided further supportive evidence that delayed treatment to first-episode psychosis is associated with poorer cognitive and clinical outcomes. In addition, DUP may specifically affect memory function and its adverse impact on verbal memory may only become evident at a later stage of the recovery process.
Non-typhoidal Salmonella are an important but poorly characterized cause of paediatric diarrhoea in developing countries. We conducted a hospital-based case-control study in children aged <5 years in Ho Chi Minh City to define the epidemiology and examine risk factors associated with Salmonella diarrhoeal infections. From 1419 diarrhoea cases and 571 controls enrolled between 2009 and 2010, 77 (5·4%) diarrhoea cases were stool culture-positive for non-typhoidal Salmonella. Salmonella patients were more likely to be younger than controls (median age 10 and 12 months, respectively) [odds ratio (OR) 0·97; 95% confidence interval (CI) 0·94–0·99], to report a recent diarrhoeal contact (8·1% cases, 1·8% controls; OR 5·98, 95% CI 1·8–20·4) and to live in a household with >2 children (cases 20·8%, controls 10·2%; OR 2·32, 95% CI 1·2–4·7). Our findings indicate that Salmonella are an important cause of paediatric gastroenteritis in this setting and we suggest that transmission may occur through direct human contact in the home.