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BackgroundThe mechanisms linking UV radiation and vitamin D exposure to the risk of acquiring the latitude and critical period-dependent autoimmune disease, multiple sclerosis, is unclear. We examined the effect of vitamin D on DNA methylation and DNA methylation at vitamin D receptor binding sites in adult and paediatric myeloid cells. This was accomplished through differentiating CD34+ haematopoietic progenitors into CD14+ mononuclear phagocytes, in the presence and absence of calcitriol.ResultsFew DNA methylation changes occurred in cells treated with calcitriol. However, several VDR-binding sites demonstrated increased DNA methylation in cells of adult origin when compared to cells of paediatric origin. This phenomenon was not observed at other transcription factor binding sites. Genes associated with these sites were enriched for intracellular signalling and cell activation pathways involved in myeloid cell differentiation and adaptive immune system regulation.ConclusionThese results suggest vitamin D exposure at critical periods during development may contribute to latitude-related differences in autoimmune disease incidence.

Epstein–Barr Virus (EBV) infection appears to be necessary for the development of Multiple Sclerosis (MS), although the specific mechanisms are unknown. More than 200 single-nucleotide polymorphisms (SNPs) are known to be associated with the risk of developing MS. About a quarter of these are also highly associated with proximal gene expression in B cells infected with EBV (lymphoblastoid cell lines—LCLs). The DNA of LCLs is hypomethylated compared with both uninfected and activated B cells. Since methylation can affect gene expression, and so cell differentiation and immune evasion, we hypothesised that EBV-driven hypomethylation may affect the interaction between EBV infection and MS. We interrogated an existing dataset comprising three individuals with whole-genome bisulfite sequencing data from EBV transformed B cells and CD40L-activated B cells. DNA methylation surrounding MS risk SNPs associated with gene expression in LCLs (LCLeQTL) was less likely to be hypomethylated than randomly selected chromosomal regions. Differential methylation was independent of genomic features such as promoter regions, but genes preferentially expressed in EBV-infected B cells, including the LCLeQTL genes, were underrepresented in the hypomethylated regions. Our data does not indicate MS genetic risk is affected by EBV hypomethylation.

Retrotransposons are genetic elements capable of their own propagation and insertion into the human genome. Because of their mutagenic potential, retrotransposons are heavily suppressed by mechanisms including DNA methylation. Increased age is associated with decreasing DNA methylation of the LINE-1 retrotransposon and may partially explain the predisposition towards malignancy with advancing age. Vitamin D has been investigated for its effects on DNA methylation at LINE-1 elements with mixed results. This study hypothesised that LINE-1 DNA methylation is altered by vitamin D exposure and age. Using whole genome bisulfite sequencing of adult and newborn haematopoietic progenitors, DNA methylation at LINE-1 elements was not found to vary between cells cultured with or without calcitriol, both in adults and newborns. In contrast, several LINE-1 regions were found to be differentially methylated between adults and children, but these were not uniformly hypermethylated in paediatric cells. The results of this study suggest that at least in haematopoietic cells, vitamin D does not appear to affect LINE-1 methylation.

Multiple lines of evidence indicate Multiple Sclerosis (MS) is affected by vitamin D. This effect may be mediated by methylation in immune cell progenitors. We aimed to determine (1) if haematopoietic stem cell methylation constrains methylation in daughter cells and is variable between individuals, and (2) the interaction of methylation with the vitamin D receptor binding sites. We interrogated genomic methylation levels from matching purified CD34+ haematopoietic stem cells and progeny CD14+ monocytes and CD56+ NK cells from 11 individuals using modified reduced representation bisulfite sequencing. Differential methylation of Vitamin D Receptor binding sites and MS risk genes was assessed from this and using pyrosequencing for the vitamin D regulated MS risk gene ZMIZ1. Although DNA methylation states at CpG islands and other sites are almost entirely recapitulated between progenitor and progeny immune cells, significant variation was detected at some regions between cell subsets and individuals; including around the MS risk genes HLA DRB1 and the vitamin D repressor NCOR2. Methylation of the vitamin D responsive MS risk gene ZMIZ1 was associated with risk SNP and disease. We conclude that DNA methylation settings in adult haematopoietic stem cells may contribute to individual variation in vitamin D responses in immune cells.

DNA methylation is increasingly being recognised as a mechanism through which environmental exposures confer disease risk. Several studies have examined the association between vitamin D and changes in DNA methylation in areas as diverse as human and animal development, genomic stability, chronic disease risk and malignancy. In many cases, they have demonstrated clear associations between vitamin D and DNA methylation in candidate disease pathways. Despite this, a clear understanding of the mechanisms by which these factors interact is unclear. This paper reviews our current understanding of the effects of vitamin D on DNA methylation. In light of current knowledge in the field, the potential mechanisms mediating vitamin D effects on DNA methylation are discussed, as are the limiting factors and future avenues for research into this exciting area. This article is protected by copyright. All rights reserved.

Immune Thrombocytopenia Purpura (ITP) secondary to vaccinations is rare, especially after autologous hematopoietic stem cell transplantation (HSCT). A 31-yearold female received autologous HSCT for relapsed Hodgkin Disease, with platelet engraftment at Day+14. One week after receiving second scheduled vaccinations, she developed severe thrombocytopenia (3x10

Solid-state NMR is an information-rich spectroscopic technique for the study of chemical species on catalytic surfaces. In this article, we provide an overview of NMR methods that are useful to the investigation of structures and dynamics of chemical species on surfaces including 2D correlation experiments and applications using quadrupolar nuclei. Particular focus is given to dynamic nuclear polarization surface-enhanced NMR spectroscopy (DNP-SENS), which allows amplification of NMR signals by up to two orders of magnitude. Successful application of DNP-SENS significantly reduces the signal averaging time for NMR experiments of low-concentration surface species. The reader is encouraged to learn more about DNP-SENS and NMR of surface science from the articles listed under “Further Reading.”

This paper reports a metal-oxide RRAM with novel Defect Engineering Technology (DET) that achieves forming-free, multi-level capable, self-rectifying, large 2×104 resistance window, ultra-low 0.24nW reset power and good endurance of 10p6 cycles at the same time. Besides, by the same DET with additional forming process, we demonstrate a complementary resistive switching (CRS) on single-stack metal-oxide with large 15X resistance window, good endurance of 105 cycles and stable high-temperature disturbance.

Drain current (Id) degradation due to Fowler-Nordheim (FN) stress and Vg=Vd stress were investigated in 0.15 µm n-channel metal-oxide-semiconductor field-effect transistors (nMOSFETs) and p-channel metal-oxide-semiconductor field-effect transistors (pMOSFETs). When pMOSFETs reach the lifetime under Vg=Vd stress, the damage resulting from gate-to- source tunneling current is not negligible in comparison with the damage caused by channel hot carriers. Id degradation models of pMOSFETs under FN stress and Vg=Vd stress were established. According to the Id degradation models, the impact of gate-to-source tunneling current on the result of hot-carrier reliability testing is discussed.

This study aims to assess and compare the aerobic fitness (max VO2) of 210 healthy adult men in sedentary occupations in Singapore. All the subjects studied were in codes 0 to 2 of the Singapore Standard Occupational Classification, comprising professional, technical, administrative and related workers. Their max VO2 were determined from direct analyses of their expired respiratory gases during an all-out run on a treadmill. Of these 210 men, 71 (33.8 per cent) were recreation-related regular exercisers and their mean max VO2 of 40.9 ml/kg per min STPD (at standard temperature and pressure, dry) and 95 per cent confidence interval of 39.2-42.6 ml/kg per min was significantly higher (p less than 0.001) than that of the remaining 139 men (34.3 ml/kg per min STPD) with 95 per cent confidence intervals of 33.2-35.4 ml/kg per min who were not regular exercisers. The regular exercisers also met the max VO2 requirements for heavy physical work capacity and compared favourably with the recommended standards for aerobic fitness in the National Physical Fitness Award of Singapore as well as Cooper's Standards based on North American men while the non-regular exercisers did not. The study has shown that the recreation-related regular exercise of the study-defined type, intensity, duration and frequency can significantly improve the physical work capacity of healthy adult men in sedentary occupations in Singapore.

There have been several unconfirmed case reports of dermatitis caused by Collembola (springtails). We recently investigated two nurses with dermatitis suspected to be caused by Drepanura Schött (Collembola: Entomobryidae). IgE antibodies to Collembola proteins were not detected in sera from the nurses and skin tests with the Collembola extract and crushed whole Collembola were negative in both the nurses and volunteers. This study suggests that the springtail Drepanura may not cause human dermatitis and that other organisms and organic matter that are also found in the moist environment inhabited by Collembola might instead be responsible.

Treatment option of Haematological malignancies has expanded over the last decade. The outcome of treatment is expected to be better compare to previously. However, study of treatment outcome for haematological malignancies has not been carried out in Malaysia. The goal of this study is to measure the treatment outcome in patients with haematological malignancy.

The channel field and substrate current models developed for n-MOSFETs are applicable to p-MOSFETs. The impact ionization rate extracted for holes is found to be 8*10/sup 6/ exp (-3.7*10/sup 6//E), where E is the electric field. The lucky electron approach was used to model the gate current of surface-channel (SC) p-MOSFETs successfully. Device degradation in p-MOSFETs is due to trapped electrons in the oxide. p-MOSFET lifetime has good correlation with gate current in SC p-MOSFETs. The correlation is better than with substrate current. I/sub G/ can be larger in a buried-channel (BC) p-MOSFET than in a comparable SC n-MOSFET. This makes the SC MOSFET a much more reliable device. Device lifetime of a p-MOSFET under pulse stress can be predicted from DC stress data for inverterlike waveforms. For other waveforms, there is an extra degradation probably caused by the excess hot carriers generated during the gate turn-off transient. >

Psychiatrists in non-gazetted treatment settings, like psychiatric wards in restructured general hospitals and private hospitals, face a major problem when psychiatric patients who require admission are either not competent or refuse to consent to admission and treatment, although they are clearly in need of such inpatient management. Admission to the state mental hospital is often refused by their relatives for a number of reasons, like the stigma attached to admission to such a hospital, and the fear that future employment prospects might be affected.Mr X, a manic, violent patient, had no insight into his disorder and refused admission and treatment for his manic episode. He was the head of a large corporation, and his relatives were apprehensive he would make decisions that could jeopardize the company.He refused oral medication, could not tolerate parenteral haloperidol and had lithium nephrotoxicity. Inpatient electroconvulsive therapy had to be administered, after which he responded satisfactorily.The legal implications in this case, like consent for treatment and admission, and ethical issues, are discussed.

Enhanced hot-carrier induced drain current degradation under high gate voltage stress is observed in pMOSFETs. Electron tunneling from the gate plus Auger recombination assisted hot-hole energy gain process is responsible for this phenomenon. This enhancement in drain current degradation is more severe for devices with thinner gate oxide, or devices operated under higher temperature or lower drain voltage.

Hot-carrier-limited device lifetime of surface-channel p-MOSFETs (p-channel metal-oxide-semiconductor field-effect transistors) is found to correlate well with gate current over a wide range of bias. The same result is not observed for buried-channel p-MOSFETs. A gate current model for surface-channel p-MOSFETs is presented. Using this gate current model, reasonable estimates of AC (pulse) stress lifetime can be made based on DC stress data. >

We propose a novel process whereby Antimony Assisted Arsenic Source/Drain Extension (A/sup 3/ SDE) is employed to realize a steep and retrograde indium pocket profile for sub-0.1 /spl mu/m nMOSFETs. By engineering the defect distributions in the amorphous layer created by an indium implant, this new process improves by 8% the current drive while maintaining the same I/sub off/. It reduces nMOS diode leakage by two orders of magnitude and sidewall junction capacitance near the gate by 14%. Reliability assessment of devices fabricated by the A/sup 3/ SDE process reveals significant improvement in hot carrier effects and no observable degradation of gate oxide integrity.

A 90-year-old man presented to the emergency department with multiple symptoms including double vision, reduced mobility, dysphagia, recent rapid weight loss, ear discharge and deafness. He had diabetes and other chronic medical problems, including otitis media with mastoiditis. This case highlights the difficulty of investigating weight loss in older people, who may not show the usual clinical features of infection, and of distinguishing between infection and malignancy when radiological findings are inconclusive. His eventual diagnosis was osteomyelitis of the skull base with cranial nerve involvement.

Enhanced hot-carrier-induced drain current degradation is observed in ultra-thin gate oxide pMOSFETs stressed under high gate voltage. Electron tunnelling from the gate plus an Auger-recombination-assisted hot hole energy gain process is responsible for this phenomenon. This enhancement in drain current degradation is more severe for devices with thinner gate oxide or devices stressed under lower drain voltage.

While hot-carrier-induced degradation is aggravated at cryogenic temperature, a very thin gate-oxide (52-A) device can still tolerate a 3-V power-supply voltage at 77 K. Hot-carrier-induced degradation may not be the limiting factor in choosing the power-supply voltage and special drain structures may be necessary for very thin gate MOSFET's even at 77 K. However, mobility reduction at high V G is more severe both at lower temperatures and for thinner oxides. Electron mobility appears to be oxide-thickness-dependent at 77 K. The dependence of the electron mobility on the normal field is so strong that it results in unusual I-V characteristics such as negative transconductance at 77 K for an oxide field above 3 MV/cm. The I--V characteristics have been modeled with a mobility dependence on V GS of the form µn ∞ (1 + η(V GS - V t /T ox )2+ (E/E c ))-1for 52-A devices.

The recovery of threshold voltage due to high drain or gate voltage and the effects of hot-carrier stressing on the drain breakdown voltage of MOSFETs have been studied. A high oxide field causes slow recovery through tunneling detrapping of electrons in both p- and n-MOSFETs. For n-MOSFETs the mechanism of fast recovery is low-level hole injection at high V/sub D/. Hot-carrier stressing at high V/sub G/ causes the drain breakdown voltage to decrease (walk-in). This results in enhanced hold injection, thus increasing the rate of subsequent recovery of V/sub t/. The breakdown voltage increases and then decreases when stressed at low gate voltages. >

Width dependence of hot-electron currents in MOSFET's fabricated with LOCOS, non-LOCOS, and a modified LOCOS processes are studied. The experimental results show that the substrate and gate currents are apparently enhanced in narrow width devices. The enhancement, however, is due to different voltage drops across the source-drain series resistance. The voltage drops are usually larger in wider devices. After correcting for the resistance effect, the substrate and gate currents scale with the device width. With this typical LOCOS process, the bird's beak and in-diffusion of field implant dopants do not cause excess hot-electron activities along the channel/field edges as has been suspected. Some other LOCOS process could, of course, produce a different result. Studies using wide test devices must consider the series resistance effect. With this precaution taken, models derived from wide-channel data will be applicable to narrow-channel devices, at least for some processes.

Under the same gate and drain bias, the substrate current in a depletion-mode MOSFET is smaller than in an enhancement-mode MOSFET. The difference, however, is gate bias dependent, being larger at low gate voltages and smaller at high gate bias. The phenomenon can be understood in terms of an effective gate-oxide thickness concept. Other hot-carrier effects in the depletion-mode MOSFET, such as gate current and hot-carrier-induced breakdown, can also be understood on the same basis. On the other hand, hole injection into the oxide at very low V G is larger in a depletion-mode device. Such large hole injection leads to a more negative V t after stressing. The maximum shift in V t (negative ΔV t ) is comparable to that in an enhancement-mode device.

This study describes the relation between types and frequency of exercises and cardiopulmonary fitness. Of the 255 subjects studied, 69 (27·1%) were non-exercisers, 66 (25·9%) exercised 1 to 2 times/week, 82 (32·1%) exercised 3 to 4 times/week and 38 (14·9%) exercised 5 to 7 times/week. Of the exercisers, 131 (51·3%) subjects were engaged in aerobic exercises and 55 (21·7%) in non-aerobic activities for at least 6 months prior to this study. The 2·4–km run test and the maximum oxygen consumption (V˙O2 max) determination were used as indicators of aerobic performance or cardiopulmonary fitness. The V˙O2 max was measured by direct analyses of the expired gases of subjects using a Beckman Metabolic Cart during an all-out run on a treadmill. Regular exercisers who exercised three or more times/week were aerobically fitter than non-exercisers (p< 0·001) and those who exercised less frequently than three times/week (p

It is shown that the substrate current characterization method and modeling approach used for n-MOSFET's is also applicable to p-MOSFET's. The impact ionization rate extracted for holes is found to be 8 × 106exp (-3.7 × 106/E), where E is the electric field. Based on our measurement and modeling result, roughly twice the channel electric field is required for p-MOSFET's to generate the same amount of substrate current as n-MOSFET's. The hot-carrier-induced breakdown voltage is therefore also about two times larger.

Photons are generated by forward biasing a silicon p-n junction at 10-5∼ 10-4quantum efficiency through radiative recombination. At large distances from the forward-biased junction, leakage currents of magnitudes significant for some VLSI circuits can appear due to the substrate minority carriers generated by the photons. The effective decay length of the measured leakage current is about several hundred to one thousand micrometers. The effects of forward biasing an input node or a parasitic lateral bipolar transistor are, therefore, longer ranged than commonly assumed.

Lifetimes under AC stress are calculated with a quasistatic model using parameters extracted from DC stress data. For inverter-like waveforms, the measurement data show reasonable agreement with the simulation results. For waveforms with turnoff transient occurring in the presence of high drain voltage, more degradation than the model predicts is found if the transient is short ( >

An epidemiological survey of 3216 primary school children living in the industrial, urban and rural areas of Singapore revealed a high prevalence of various respiratory symptoms and illnesses, with 13.1% cough, 8.2% wheezy chest, 25.9% blocked/running nose, 4.3% sinusitis, 7.8% asthmatic attacks and 4.1% bronchitis/pneumonia. Differences in the prevalence of respiratory illnesses and lung function tests were observed among children in the three areas, but this could not be accounted for by the varying air pollution levels which have been maintained below the long-term standards set up by WHO. It was probably responsible for the differences noted.

The purpose of this study was to determine histologically the distribution of microspheres (MSs) (14 micron), and hence the relative distribution of blood flow, in rat plantaris muscle relative to the fiber types (fast-twitch-oxidative-glycolytic [FOG], fast-twitch-glycolytic [FG], and slow-twitch-oxidative [SO]). Three conditions were investigated: 1) preexercise standing; 2) treadmill locomotion at 15 m/min (fast walking); and 3) treadmill locomotion at 60 m/min (moderate galloping). The MS suspension (containing 1 x 10(6) MSs) was infused into the ascending aorta via a catheter in the carotid artery under each of the 3 conditions so that MSs were distributed to the tissues in proportion to their respective blood flows. Sections (20 micron) of the plantaris muscle were cut and assayed for reduced nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR) and myofibrillar adenosine triphosphatase (ATPase) activities so the fibers could be typed as SO, FOG, or FG. MSs were located in the NADH-TR sections, and the fibers next to the MSs were classified and counted. The observed numbers of fibers of each type in each condition that were adjacent to MSs were compared to the predicted number of adjacent fibers based on the assumption the MSs were randomly distributed in the tissue. This analysis demonstrated that MSs (and blood flows) were preferentially distributed to SO fibers during preexercise, to SO and FOG fibers during slow locomotion, and to FOG fibers during fast locomotion. The data support the contention that blood flow is distributed in muscles of conscious animals as functions of fiber type and exercise intensity.

This paper reviews several recent studies on the possible benefits and dangers of non-aerobic exercises in cardiac rehabilitation programmes. It presents the case for including in such programmes, exercises which specifically improve components of overall physical fitness other than aerobic or cardiorespiratory endurance fitness. This is because many of these other components of overall physical fitness are required in the daily lives of patients in cardiac rehabilitation programmes and can best be acquired through non-aerobic exercises. These non-aerobic exercises include judicious callisthenic and isometric exercises to specifically improve on joint flexibility, agility, muscular strength, muscular endurance and coordination.

Nonvolatile storage, electrical programming, and erasing of analog signals are shown to be possible for EEPROMs. Analog signals are sampled, then stored in a commercial 2 K*8 EEPROM and read out in a manner simulating speech recording. Modification of peripheral circuitry can make EEPROMs potential analog memory devices. >

While hot-carrier-induced degradation is aggravated at cryogenic temperature, a very thin gate-oxide (52-A) device can still tolerate a 3-V power-supply voltage at 77 K. Hot-carrier-induced degradation may not be the limiting factor in choosing the power-supply voltage and special drain structures may be necessary for very thin gate MOSFET's even at 77 K. However, mobility reduction at high V G is more severe both at lower temperatures and for thinner oxides. Electron mobility appears to be oxide-thickness-dependent at 77 K. The dependence of the electron mobility on the normal field is so strong that it results in unusual I-V characteristics such as negative transconductance at 77 K for an oxide field above 3 MV/cm. The I--V characteristics have been modeled with a mobility dependence on V GS of the form µn ∞ (1 + η(V GS - V t /T ox )2+ (E/E c ))-1for 52-A devices.