Ine Levels Research Articles

Lysosomal cyst(e)ine storage potentiates tolerance to oxidative stress in cancer cells

Cyst(e)ine is a key precursor for the synthesis of glutathione (GSH), which protects cancer cells from oxidative stress. Cyst(e)ine is stored in lysosomes, but its role in redox regulation is unclear. Here, we show that breast cancer cells upregulate major facilitator superfamily domain containing 12 (MFSD12) to increase lysosomal cyst(e)ine storage, which is released by cystinosin (CTNS) to maintain GSH levels and buffer oxidative stress. We find that mTORC1 regulates MFSD12 by directly phosphorylating residue T254, while mTORC1 inhibition enhances lysosome acidification that activates CTNS. This switch modulates lysosomal cyst(e)ine levels in response to oxidative stress, fine-tuning redox homeostasis to enhance cell fitness. MFSD12-T254A mutant inhibits MFSD12 function and suppresses tumor progression. Moreover, MFSD12 overexpression correlates with poor neoadjuvant chemotherapy response and prognosis in breast cancer patients. Our findings reveal the critical role of lysosomal cyst(e)ine storage in adaptive redox homeostasis and suggest that MFSD12 is a potential therapeutic target.

Incremental Frequent Mining Human Activity Patterns for Health Care Applications

Nowadays, there is a consistently expanding relocation of individuals to urban territories. Human services administrations is a Standout amongst the most difficult perspectives that is extraordinarily influenced by the immense deluge of individuals to downtown areas. In such change a great many homes are being with brilliant gadgets which create huge volume s of indexical information that can be dissected to help savvy city administrations. In this paper, we propose a model that uses savvy home huge information as a methods for learning and finding human movement designs for wellbeing applicati ons.for this we utilize visit design mining, bunch investigation and forecast to gauge and dissect vitality utilization changes the tenants behaviour. Since, individuals propensities are generally disti nguished by ordinary schedules, demonstrates in dividuals’ troubles in taking tend to themselves, for example, not planning nourishment or not utilizing shower/bath.our places of business the need to break down transient vitality utilization at mach ine level, which is straightforwardly identified with human exercises. This exploration utilizes the UK Domestic Appliance Level Electricity dataset(UK-Dale) time arrangement information of energy utilization gathered from 2012-2015 with time determ ination of six seconds for five houses with 109 app aratus from SouthernEngland.The information from shrewd meters are mined in the quantum/information cut of 24hrs, and the outcomes are kept up cro-sswise over progressive mining exercises.the after effect of distinguishing human movement desig-ns from machine use are displayed in points of interest.

The Role of Space in Remote Collaborations: An Exploration of Immersive Technology Attributes on Co-presence and Team Membership

GIScience 2016 Short Paper Proceedings Spatially situating remote users: An examination of immer- sive technology on presence and team participation D. Oprean 1 , M. B. Simpson 2 , A. Klippel 2 Stuckeman Center for Design Computing The Pennsylvania State University Email: dxo12@psu.edu Department of Geography The Pennsylvania State University Email: {marksimpson;klippel}@psu.edu Abstract As today’s workforce becomes more distributed, technology provides a means to communicate over long distances. This technology however offers limited forms of communication which can lead remote participants to not feel fully participant in collaborative efforts. With the re- newed interest in immersive virtual reality (iVR) technology, the promise of more affordable and better capabilities is better than ever. iVR technology can allow remote collaborators to become spatially situated in the content of a collaboration. For this work-in-progress we exam- ine levels of immersion to understand the role of co-presence for a remote participant on team membership and participation. Our experimental set up and preliminary results will be dis- cussed. Introduction In today’s workforce, technology has enabled communication and work to occur at a distance. Remote parties can easily join in meetings virtually through the use of various collaborative equipment. However, traditional audio and video technologies cannot create the full experience of being co-present in a meeting space with collaborators. With the increased capabilities, affordability, and renewed interest in immersive virtual reality (iVR) technology, the potential to spatially situate remote parties into a meeting is higher than ever. iVR technology has been a communication tool for several decades, but recent break- throughs make the hardware and software to create iVR experiences easier to use than ever before. Past research using iVR systems have examined their ability of spatially situating indi- viduals into task spaces with great success. However, these studies have examined such tech- nology through the limited scope of testing a single system. This ‘black-box’ approach to VR systems research is a limiting factor in the literature. We believe that comparing multiple iVR system aspects will allow for better connections to spatial experiences that will be generalizable to a broader scope of technology. We used our work-in-progress to address the question of how spatially present a remote collaborator feels when experiencing different levels of visual immersiveness. Specifically, this study seeks to examine the relative impact of different levels of immersive technology on spa- tial co-presence in a meeting with one remote participant. To do this, our study built on the theoretical framework and methodological approach of Balakrishnan, Oprean, Martin, and Smith (2012) to identify levels of immersiveness. Our methodological approach allowed us to address our question through examining technology affordances—the attributes of technology that allow for actions or perceptions of actions by the appropriate entity (Greeno 1994). 1.1 Presence and Immersion The nature of presence, the feeling of being ‘present’ within a given medium (Steuer 1992), in and of itself is highly subjective, making it hard to distinguish from concepts like immersion,

The Effects of Muscle Mass on Homocyst(e)ine Levels in Plasma and Urine

The present study was designed to examine the relationship between homocyst(e)ine (H[e]) lev-els and muscle mass. Two experimental groups each of 24 Caucasian males, one consisting of higher-muscle mass subjects (HMM) and the other of lower-muscle mass subjects (LMM) par-ticipated in this study. Muscle mass was estimated from 24-hour urine collections of creatinine (Crt). Muscle mass was 40.3 ± 15.9 kg in HMM and 37.2 ± 11.4 kg in LMM (P= 0.002). Mean plasma H(e) levels in HMM were 10.29 ± 2.9 nmol/mL, and in LMM were 10.02 ± 2.4 nmol/L (Not significant, [NS]). Urinary H(e) levels (UH[e]) were 9.95 ± 4.3 nmol/mL and 9.22 ± 2.9 nmol/mL for HMM and LMM, respectively (NS). Plasma H(e) levels correlated well with UH(e) (HMM: r= 0.58, P= 0.009; LMM: r= 0.66, P= 0.004). Muscle mass and was not correlated to either plasma H(e) or UH(e). However, in HMM trends were identified for body mass to be cor-related with UH(e) (r= 0.39, P= 0.10) and UCrt (r= 0.41, P= 0.08). Surprisingly, in HMM plasma and UCrt were only weakly correlated (r= 0.44, P= 0.06). Our results do not support a causal relationship between the amount of muscle mass and H(e) levels in plasma or urine.

Transient hypercapnic stress causes exaggerated and prolonged elevation of cardiac and renal interstitial norepinephrine levels in conscious hypertensive rats

The responses of sympathetic nerve activity to transient stress can be exaggerated in salt-sensitive (SS), hypertensive subjects. Cardiac and renal interstitial norepinephrine (iNE) levels during and after transient hypercapnia were investigated in conscious SS rats. Dahl SS and salt-resistant (SR) 6-wk-old rats were fed a high-salt diet, and at 12 wk iNE levels in the heart and kidney were determined using microdialysis with probes inserted in the left ventricular (LV) wall and kidney. A telemetry system determined blood pressure and heart rate (HR) in separate animals. After recovery from the operation, data were collected before, during, and after exposure to normoxic 10% CO(2) for 25 min under unanesthetized conditions. The plasma NE concentrations at baseline did not differ between the two strains. Both cardiac and renal iNE levels were much higher in SS rats than in SR rats at baseline as well as during hypercapnic stress. After stress, the markedly increased iNE levels of SS rats were prolonged in the LV as well as in the kidney. During hypercapnic stress, HR decreased in both SS and SR rats, while sudden increases in HR immediately after the withdrawal from stress were followed by its slower reduction in SS rats compared with SR rats. In conclusion, transient hypercapnic stress causes exaggerated and prolonged elevation of iNE levels in the heart as well as in kidneys of SS animals.

Emergence of Macrolide Resistance Gene mph (B) in Streptococcus uberis and Cooperative Effects with rdmC -Like Gene

Streptococcus uberis UCN60 was resistant to spiramycin (MIC = 8 microg/ml) but susceptible to erythromycin (MIC = 0.06 microg/ml), azithromycin (MIC = 0.12 microg/ml), josamycin (MIC = 0.25 microg/ml), and tylosin (MIC = 0.5 microg/ml). A 2.5-kb HindIII fragment was cloned from S. uberis UCN60 DNA on plasmid pUC18 and introduced into Escherichia coli AG100A, where it conferred resistance to spiramycin by inactivation. The sequence analysis of the fragment showed the presence of an rdmC-like gene that putatively encoded a protein belonging to the alpha/beta hydrolase family and of the first 196 nucleotides of the mph(B) gene putatively encoding a phosphotransferase known to inactivate 14-, 15-, and 16-membered macrolides in E. coli. The entire mph(B) gene was then identified in S. uberis UCN60. The two genes were expressed alone or in combination in E. coli, Staphylococcus aureus, and Enterococcus faecalis. Analysis of MICs revealed that rdmC-like alone did not confer resistance to erythromycin, tylosin, and josamycin in those three hosts. It conferred resistance to spiramycin in E. coli and E. faecalis but not in S. aureus. mph(B) conferred resistance in E. coli to erythromycin, tylosin, josamycin, and spiramycin but only low levels of resistance in E. faecalis and S. aureus to spiramycin (MIC = 8 microg/ml). The combination of mph(B) and rdmC-like genes resulted in a resistance to spiramycin and tylosin in the three hosts that significantly exceeded the mere addition of the resistance levels conferred by each resistance mechanism alone.

Acute multiple brain infarction in large-artery atherosclerosis is associated with hyperhomocyst(e)inemia

Although hyperhomocyst(e)inemia had been proven to be a potent risk factor for ischemic stroke, it is still controversial which subtype of stroke is associated with hyperhomocyst(e)inemia. The aim of this study was to clarify the association between plasma homocyst(e)ine (Hcy) levels and stroke subtypes according to TOAST classifications based on MRI findings. We prospectively recruited 124 consecutive first-ever ischemic stroke patients hospitalized in Toride Kyodo General Hospital. Each patient underwent brain MRI including diffusion-weighted imaging (DWI) and was evaluated for total plasma Hcy levels in addition to routine laboratory tests. Of the 93 patients enrolled in this study, 19 were subtyped with large-artery atherosclerosis with acute multiple brain infarction [LA-AMBI(+)], 13 with LA-AMBI(-). Patients with LA-AMBI(+) showed significantly higher plasma Hcy levels than those with LA-AMBI(-). Moreover, for LA-AMBI, the plasma Hcy level was associated with an OR of 1.3 (95% CI 1.06-1.71, P=0.017) per 1 mumol increase in concentration, and 1.4 (95% CI 1.04-1.77, P=0.025) after adjustment for age, sex and serum cholesterol levels. In the subset of patients with LA strokes, those with high Hcy levels are more likely to have AMBI than those without elevated Hcy levels possibly due to plaque instability.

Regional Differences in Cystine Accumulation Point to a Sutural Delivery Pathway to the Lens Core

To develop an imaging technique that maps the distribution of free cystine in the rat lens at subcellular resolution and enables cystine accumulation to be compared with the expression of the cystine-glutamate exchanger (Xc-). Whole lenses were fixed, cryoprotected, and then cryosectioned in either an equatorial or axial orientation. Sections were double labeled with either a cystine antibody designed to detect free cystine (the oxidized form of cysteine) or an antibody against the light chain of Xc-, and the membrane marker wheat germ agglutinin. Sections were imaged by confocal laser scanning microscopy. Cystine labeling was quantified using image analysis software and an intensity profile plotted as a function of distance from the lens periphery. High performance liquid chromatography (HPLC) was used to determine cyst(e)ine levels in the outer cortex, inner cortex, and core fractions and verify the cystine profiles derived from immunocytochemistry. Qualitative and quantitative imaging approaches both showed that cystine labeling at the lens equator was most intense in the outer cortex, but diminished in the inner cortex before increasing again in the core. HPLC from the outer cortex, inner cortex, and core fractions confirmed high levels of cyst(e)ine in the core relative to the inner cortex. The bimodal distribution of cystine labeling in the outer cortex and core correlated well with the expression of the cystine-glutamate exchanger in these regions, but this was not the case in the inner cortex. A similar bimodal distribution of cystine labeling was observed in axial sections. However, in these sections a track of high-intensity cystine labeling was observed that was associated with the sutures indicating that the sutures act as a delivery pathway to the core. These imaging approaches have revealed two distinct regions of cystine uptake in the outer cortex and core of the lens. Furthermore, this bimodal distribution of cystine has been shown to be the result of cystine delivery to the core via the sutures. This newly identified pathway opens an opportunity for the delivery of therapeutic antioxidants aimed at preventing age-related nuclear cataract.

Resistance Determinants of a Highly Arsenic-Resistant Strain of Leptospirillum ferriphilum Isolated from a Commercial Biooxidation Tank

Two sets of arsenic resistance genes were isolated from the highly arsenic-resistant Leptospirillum ferriphilum Fairview strain. One set is located on a transposon, TnLfArs, and is related to the previously identified TnAtcArs from Acidithiobacillus caldus isolated from the same arsenopyrite biooxidation tank as L. ferriphilum. TnLfArs conferred resistance to arsenite and arsenate and was transpositionally active in Escherichia coli. TnLfArs and TnAtcArs were sufficiently different for them not to have been transferred from one type of bacterium to the other in the biooxidation tank. The second set of arsenic resistance genes conferred very low levels of resistance in E. coli and appeared to be poorly expressed in both L. ferriphilum and E. coli.

High Plasma Cyst(e)ine Level May Indicate Poor Clinical Outcome in Patients With Acute Stroke: Possible Involvement of Hydrogen Sulfide

Cysteine is known to cause neuronal cell death and has been reported to be elevated in brain ischemia, but it has not been studied in clinical stroke. In this study, we correlated plasma levels of cyst(e)ine with long-term clinical outcome at 3 months in acute stroke. Patients were classified into 3 groups at 3 months as follows: good outcome (Rankin 0-1, n = 11), poor outcome (Rankin 2-5, n = 20), and dead (n = 5). Their plasma cyst(e)ine levels within 24 hours of stroke onset were 61 +/- 12, 67 +/- 9, and 82 +/- 14 micromol/L (standard deviation), respectively. The correlation between early plasma cyst(e)ine levels and long-term clinical outcome assessed at 3 months is significant with p < 0.001. None of the other 4 amino acids studied showed any significant correlation. Cyst(e)ine was also significantly elevated in patients who had early stroke deterioration (p < 0.02). Dose-dependent administration of cysteine increased the infarct volume by approximately 30% in a rat stroke model. This effect of cysteine was abolished by aminooxyacetic acid, an inhibitor of the enzyme cystathionine beta-synthase that converts cysteine to hydrogen sulfide (H2S), indicating that this novel neuromodulator may be acting as a mediator of ischemic brain damage. Raised plasma cyst(e)ine in patients with stroke may reflect increased production of H2S in the brain and thus predispose to poor outcome in clinical stroke. Inhibition of H2S formation may therefore be a novel approach in acute stroke therapy.

Brief Episode of Myocardial Ischemia Before Prolonged Ischemia Attenuates Cardiac Sympathetic Nerve Injury

The aim of this study was to investigate the effects of brief ischemia before prolonged ischemia on cardiac sympathetic neural function. Brief ischemia inhibits the sympathetic neural release of norepinephrine (NE) during subsequent sustained ischemia. However, whether it can attenuate the neural function after sustained ischemia remains unknown. Sympathetic neural function was assessed using 123I-metaiodobenzylguanidine (MIBG) in patients who with (Group I) or without angina (Group II) within 3 days prior to acute myocardial infarction. In the rat experiment, cardiac interstitial NE (iNE) with or without pretreatment of 5-min coronary ligation was determined during a 30-min occlusion. Differences between MIBG and Thallium-201 for the total defect score were significantly greater in Group II than in Group I (6.1 +/- 4.0 vs 0.4 +/- 4.4). Levels of iNE were less in rats with a 5-min pretreatment (7.3 +/- 2.3 vs 18.6 +/- 5.9 x 10(3) pg/ml, p < 0.01) and MIBG uptake of ischemic region was greater (0.061 +/- 0.029 vs 0.031 +/- 0.011 %kg dose/g, p < 0.05) compared with rats without the pretreatment. A brief episode of ischemia attenuates the sympathetic neural injury caused by subsequent prolonged ischemia and this protective effect is associated with attenuation of NE release during the prolonged ischemia.

Twin-Arginine Translocation of Active Human Tissue Plasminogen Activator in Escherichia coli

When eukaryotic proteins with multiple disulfide bonds are expressed at high levels in Escherichia coli, the efficiency of thiol oxidation and isomerization is typically not sufficient to yield soluble products with native structures. Even when such proteins are secreted into the oxidizing periplasm or expressed in the cytoplasm of cells carrying mutations in the major intracellular disulfide bond reduction systems (e.g., trxB gor mutants), correct folding can be problematic unless a folding modulator is simultaneously coexpressed. In the present study we explored whether the bacterial twin-arginine translocation (Tat) pathway could serve as an alternative expression system for obtaining appreciable levels of recombinant proteins which exhibit complex patterns of disulfide bond formation, such as full-length human tissue plasminogen activator (tPA) (17 disulfides) and a truncated but enzymatically active version of tPA containing nine disulfides (vtPA). Remarkably, targeting of both tPA and vtPA to the Tat pathway resulted in active protein in the periplasmic space. We show here that export by the Tat translocator is dependent upon oxidative protein folding in the cytoplasm of trxB gor cells prior to transport. Whereas previous efforts to produce high levels of active tPA or vtPA in E. coli required coexpression of the disulfide bond isomerase DsbC, we observed that Tat-targeted vtPA and tPA reach a native conformation without thiol-disulfide oxidoreductase coexpression. These results demonstrate that the Tat system may have inherent and unexpected benefits compared with existing expression strategies, making it a viable alternative for biotechnology applications that hinge on protein expression and secretion.

Is Hyperhomocyst(e)inemia A Humoral Predictor of Coronary Heart Disease?

Elevated plasma homocyst(e)ine levels have prothrombotic and proatherosclerotic effects. Data from prospective studies indicated that plasma homocyst(e)ine acts as a modest independent predictor of coronary heart disease. At present, no conclusive data are available on the possible interaction between hyperhomocyst(e)inemia and hypertension and the occurrence of cardiovascular events. Recent longitudinal studies in high risk patients indicated that hyperhomocyst(e)inemia is strongly associated with recurrent cardiovascular events. However, this finding is not in line with the few available data from prospective studies, which failed to observe a protective role of homocyst(e)ine-lowering therapy in secondary prevention of cardiovascular events. Future results from ongoing larger trials are expected to provide more definitive answers concerning the need to support the routine use of folic acid in patients with CHD. Since the definitive impact of mild hyperhomocyst(e)inemia on coronary heart disease is still to be established, widespread determination of homocyst(e)ine levels is not needed in a general population at the present time. In contrast, knowledge of homocyst(e)inemia may be important for specific groups of individuals, such as high risk patients, and for those patients in whom traditional risk factors do not appear to account for an increased incidence of cardiovascular events.

Hyperhomocyst(e)inemia impairs angiogenesis in a murine model of limb ischemia

Hyperhomocyst(e)inemia (HH) is an established independent risk factor for coronary, cerebral and peripheral vascular diseases. Recent studies have indicated that certain cardiovascular risk factors, including diabetes and hypercholesterolemia, impair expression of vascular endothelial growth factor (VEGF) and endogenous angiogenesis. In this study, we investigate the impact of moderate HH on angiogenesis and VEGF pathway in a mouse model of hindlimb ischemia. Upon induction of unilateral hindlimb ischemia, endogenous angiogenesis, expression of VEGF, and phosphorylation of the VEGF receptor Flk-1 were evaluated in mice heterozygous for a deletion of the cystathionine beta-synthase gene (CBS) and compared with those observed in CBS+/+ mice. CBS+/- mice exhibit moderate HH, as demonstrated by measuring plasma total homocyst(e)ine (tHcy) levels, which were significantly higher in these animals compared with CBS+/+ mice (4.77 +/- 0.82 vs 2.10 +/- 0.28, p < 0.01). Twenty-eight days after induction of ischemia, hindlimb blood flow was significantly reduced in CBS+/- mice compared with CBS+/+ animals (0.49 +/- 0.03, n = 12 vs 0.71 +/- 0.09, n = 10; p < 0.05). In addition, there was a significant negative correlation between plasma homocyst(e)ine levels and the laser Doppler perfusion ratio in CBS+/- mice (p = 0.0087, r = -0.7171). While VEGF expression and Flk-1 phosphorylation were not impaired in the ischemic muscles of CBS+/- mice, phosphorylation of the endothelial cell survival factor Akt was significantly inhibited by homocyst(e)ine in a dose-dependent manner in human umbilical vein endothelial cell (HUVECs) in vitro. In conclusion, our findings demonstrate that endogenous angiogenesis is inversely related to plasma levels of homocyst(e)ine in genetically engineered, heterozygous mice with moderate HH. This impairment, however, is not dependent on reduced expression of VEGF or impaired phosphorylation of its receptor Flk-1. In contrast, our data suggest that impaired Akt phosphorylation mediates the impairment of angiogenesis associated with HH.

Folic acid-based multivitamin therapy to prevent stroke: the jury is still out.

There is a large body of observational and laboratory evidence suggesting but not proving that increasing plasma concentrations of total homocysteine (tHcy) is a causal risk factor for atherothromboembolic ischemic stroke and other vascular events.1–9 Recent publication of the results of the landmark Vitamins in Stroke Prevention (VISP) Trial is the first evidence from a large randomized controlled trial (RCT) of the effect of lowering tHcy via folic acid–based multiple B vitamin supplementation on the incidence of “hard” clinical events, such as recurrent stroke, in patients with recent ischemic stroke.10,11 In contrast to what was expected from the epidemiological evidence, the VISP Trial did not identify a significant treatment effect of lowering tHcy by vitamin therapy on recurrent stroke, coronary events, or death, despite confirming a consistent and graded association between baseline tHcy and vascular risk (particularly the probability of stroke over time).11 Recruiting primarily from North America, VISP enrolled 3680 recent (3 to 120 days) survivors of nondisabling, noncardiogenic, ischemic stroke with baseline tHcy above the 25th percentile of the North American stroke population into a double-blind, randomized comparison of high versus low doses of a combination of 12 different vitamins, including folic acid, vitamin B12, vitamin B6, and riboflavin, which are cofactors for enzymes responsible for metabolizing homocysteine.11 After 2 years of follow-up, there was no significant difference in the cumulative incidence of the primary outcome event of recurrent cerebral infarction: 8.4% of 1814 patients who were allocated to high-dose multivitamins [including 2.5 mg of folic acid, 0.4 mg of vitamin B12, and 25 mg of vitamin B6] versus 8.1% of 1835 patients allocated to low-dose multivitamins [including 0.02 mg of folic acid, 0.006 mg of vitamin B12, 0.2 mg of vitamin B6 …

Methylenetetrahydrofolate reductase 677 C→T polymorphism and plasma folate in relation to pre-eclampsia risk among Peruvian women

Objectives: Pre-eclampsia is an important cause of maternal and fetal morbidity and mortality worldwide. Hyperhomocyst(e)inemia in pregnancy is associated with an increased risk of pre-eclampsia in most studies. Nutritional and genetic factors regulate homocyst(e)ine levels. A missense mutation 677 C→T in the gene for methylenetetrahydrofolate reductase (MTHFR) has been associated with an increased pre-eclampsia risk in some, although not most, previously studied populations.Methods: To further understand the role of this polymorphism in the etiology of pre-eclampsia, we genotyped a total of 125 pre-eclamptics and 179 normotensive pregnant Peruvian women.Results: The wild-type allele frequency among cases and controls was 54% and 58%, respectively. Twenty per cent of cases and 17% of controls were homozygous for the 677 C→T MTHFR genotype (T/T). After adjustment for confounding by covariates including maternal age, nulliparity, pre-pregnancy body mass index and use of prenatal vitamins, women homozygous for the 677 C→T MTHFR genotype (T/T) experienced a modest, statistically non-significant increased risk of pre-eclampsia (adjusted OR 1.6, 95% CI 0.7, 3.8). Maternal folate deficiency was associated with a statistically non-significant doubling in risk of pre-eclampsia in this population (adjusted OR 2.0, 95% CI 0.9, 4.3).Conclusions: There was no evidence to suggest that pre-eclampsia risk is positively associated with the T/T genotype overall, or in the context of folate deficiency.

Relation between the C677T transition in the methylentetrahydrofolate reductase gene, plasma homocyst(e)ine and folate levels, and coronary artery disease in the GENICA (Genetic and Environmental Factors in Coronary Atherosclerosis) study

treated cells, a number of differentially expressed transcripts were identified and cloned. Sequence homology search revealed and matched the identified clones to 1) a small subset of genes known to be involved in angiogenesis, e.g. platelet endothelial cell adhesion molecule 1 (PECAM-I), matrix metalloproteinase 2 (MMP2), endothelin converting enzyme 1 (ECE-I), and vascular endothelial growth factor receptor 2 (VEGFR-2); 2) a large subset of known genes with known function, but not involved in angiogenesis to date; and 3) about 5-10% of the clones were novel genes with unknown function, such as a putative G-protein coupled receptor. Thus there are clusters of related gene products, differentially regulated and involved with cholinergic, proliferative and apoptotic action. cDNA rmcroarray analysis (-48,000 elements) validated our findings Conclwon: Nicotme promotes angiogenesis through stimulation of angiogenic mechanisms partly through the cholinerglc pathway. Therapeutic modulation of nAChR may be useful in dlsorders of angiogenesis.

Association between homocyst(e)ine levels and risk of vascular events.

Homocyst(e)ine is a novel risk factor in vascular disease. First observations of vascular lesions in children with high blood homocyst(e)ine levels due to severe inborn enzyme deficiencies led to the hypothesis that elevated blood homocyst(e)ine levels might be a risk factor for vascular disease. A substantial body of evidence on the role of the homocyst(e)ine in the development of coronary and carotid artery disease, myocardial infarction, stroke, deep vein thrombosis and other disorders has been accumulated over the last 30 years. Cross-sectional and case-control studies provide initial and the strongest support for the hypothesis, followed by results from the prospective cohorts. Infrequent cases of homozygous mutations of the key enzymes in the homocyst(e)ine metabolism chain are able to produce extreme homocyst(e)inemia and early vascular lesions. More frequently, heterozygous enzyme mutations and deficiencies of folate and vitamins B6 and B12 cause mild to moderate homocyst(e)inemia, which is still strongly associated with the increased risk of vascular events. Elevated homocyst(e)ine levels may be effectively managed with adequate folate, B12 and B6 intake in doses comparable to or above FDA recommendations. Whether correction of elevated homocyst(e)ine levels with vitamins is helpful in prevention and treatment of vascular events remains unknown and is under investigation in ongoing clinical trials (VISP, VITATOPS). No consensus on homocyst(e)ine management is available at the present time.

Plasma homocyst(e)ine concentrations in eclamptic and preeclamptic African women postpartum

Objective: To examine the relationship between plasma homocyst(e)ine and risk of eclampsia and preeclampsia among sub-Saharan African women who delivered at Harare Maternity Hospital in Zimbabwe. Methods: We ran a hospital-based, case-control study at Harare Maternity Hospital, University of Zimbabwe, Harare, Zimbabwe comprising 33 pregnant women with eclampsia and 138 with preeclampsia. Controls were 185 normotensive pregnant women. Plasma was collected postpartum and homocyst(e)ine levels were measured by high-performance liquid chromatography and electrochemical detection. Results: Women with eclampsia or preeclampsia had significantly higher mean homocyst(e)ine levels than normotensive controls (12.54 or 12.77 μmol/L versus 9.93 μmol/L, respectively, P < .001). The odds ratio (OR) for eclampsia was 6.03 among women in the highest quartile of the control homocyst(e)ine distribution (median 13.9 μmol/L) compared with women in the lowest quartile (median 6.2 μmol/L). The corresponding OR for preeclampsia was 4.57. Nulliparas with elevated homocyst(e)ine had a 12.90 times higher risk of preeclampsia compared with multiparas without elevated homocyst(e)ine. Conclusion: Postpartum plasma homocyst(e)ine concentrations are higher among Zimbabwean women with eclampsia and preeclampsia compared with normotensive women.

Hyperhomocyst(e)inemia, but not methylenetetrahydrofolate reductase C677T mutation, as a risk factor in branch retinal vein occlusion

Objective To determine whether hyperhomocyst(e)inemia and methylenetetrahydrofolate reductase (MTHFR) C677T mutation are associated with branch retinal vein occlusion (BRVO). Design Retrospective, case-control study. Participants The study cohort consisted of 84 consecutive patients with branch retinal vein occlusion and 84 controls, matched for age and gender. Main outcome measures Fasting plasma homocyst(e)ine, folate, and vitamin B 12 levels, MTHFR C677T genotypes. Results Mean plasma homocyst(e)ine levels were significantly higher in patients than in controls (11.4 ± 4.3 μmol/l vs. 9.9 ± 2.8 μmol/l; P = 0.002). An increase of plasma homocyst(e)ine level by 1 μmol/l was associated with an odds ratio of 1.19 (95% confidence interval 1.06–1.34; P = 0.004). Mean plasma folate levels were significantly lower in patients than in the control group (4.5 ± 2.1 ng/ml vs. 5.6 ± 2.1 ng/ml; P = 0.007). The prevalence of the homozygous genotype of the MTHFR C677T mutation did not differ significantly between patients and controls. Conclusions Our results suggest that hyperhomocyst(e)inemia, but not homozygosity for the MTHFR C677T mutation, is associated with BRVO. Increased plasma homocyst(e)ine levels in our study are not the result of an increased prevalence of the homozygous genotype of MTHFR C677T mutation.