***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    ***EXAMPLES*** 
    Input: Recent meta-analyses have created uncertainties regarding the appropriate clinical role of colloid resuscitation fluids in critically ill patients and prompted changes in fluid management practice . Such changes may not be justified in view of method ological limitations inherent in the meta-analyses . Further research is nevertheless needed to resolve the questions raised concerning the relationship between choice of resuscitation fluid and patient outcome . Animal studies can play an important part by reliably indicating whether particular fluids are likely to prove effective and safe in clinical trials . It is important to avoid costly large-scale clinical trials that fail to demonstrate the clinical utility of the tested therapy , as re sources expended in failed trials raise overall development costs and thereby restrict the range of therapies meeting criteria of commercial feasibility . Promising therapies may thus not be pursued , even though an urgent clinical need may exist . An alternative pathway of pre clinical research may be of value in avoiding some of the major clinical trial failures of recent years , particularly in the area of sepsis . This alternative pathway commences with the formulation of hypotheses by therapeutics developers . Independent pre clinical investigators are challenged , by means of a competitive request for proposals , to test the hypotheses in rigorous r and omized studies employing clinical ly relevant animal models . Promising proposals would then be selected for further development with the aid of peer review . The results of the r and omized animal studies , along with other pre clinical data , could also be evaluated using accepted principles of ' critical appraisal ' commonly applied to clinical trial results . This critical appraisal might , where appropriate , include meta- analysis of animal study findings . This alternative pre clinical pathway to new product evaluation should be completed before the commencement of large-scale clinical trials OBJECTIVE The purpose of this study was to determine whether second-trimester plasma homocysteine levels are elevated among women whose pregnancies are subsequently complicated by pregnancy-induced hypertension , preeclampsia , or intrauterine growth restriction . STUDY DESIGN Women with normal but relatively low plasma zinc levels were r and omly assigned to receive zinc supplementation or placebo from 19 weeks ' gestation until delivery . Plasma homocysteine concentration and plasma and erythrocyte folate levels were determined for all available stored sample s ( zinc group , 231/294 ; placebo group , 206/286 ) at 26 and 37 weeks ' gestation . Among all women with available sample s , pregnancy-induced hypertension ( n = 12 ) or preeclampsia ( n = 4 ) developed in 16 women , and 22 pregnancies were complicated by intrauterine growth restriction . RESULTS Mean homocysteine levels in women with pregnancy-induced hypertension and preeclampsia  were similar to those of control subjects at 26 weeks ' gestation but were significantly higher at 37 weeks ' gestation . Homocysteine levels were similar between women with pregnancies complicated by intrauterine growth restriction and control subjects at both time points . CONCLUSION Second-trimester plasma homocysteine concentrations do not predict the subsequent development of pregnancy-induced hypertension , preeclampsia , and intrauterine growth restriction OBJECTIVE Our purpose was to assess the incidence of hyperhomocysteinemia in patients with a history of preeclampsia or fetal growth restriction , to evaluate the effects of vitamin supplementation on the methionine loading test , and to study the course of subsequent pregnancies in women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction . STUDY DESIGN A total of 207 consecutive patients with a history of preeclampsia or fetal growth restriction was tested for hyperhomocysteinemia . Thirty-seven were found to be positive and were treated with folic acid and vitamin B6 , and 27 had a second methionine loading test after vitamin supplementation . Fourteen patients became pregnant again while receiving vitamins and aspirin . RESULTS All patients who underwent a methionine loading test after vitamin supplementation had a completely normalized methionine loading test . Of the 14 pregnancies in women receiving vitamins and aspirin , 7 were complicated by preeclampsia . Birth weights were 2867 + /- 648 g compared with 1088 + /- 570 g in the previous pregnancies . CONCLUSIONS Vitamin B6 and folic acid correct the methionine loading test in patients with hyperhomocysteinemia . Perinatal outcome in patients with a history of preeclampsia or fetal growth restriction and hyperhomocysteinemia appears to be favorable We hypothesized that physiological increments in plasma homocysteine after low-dose oral methionine or dietary animal protein induce vascular endothelial dysfunction and that there is a grade d , inverse relationship between homocysteine concentration and endothelial function . We studied 18 healthy volunteers aged 18 to 59 years .  Brachial artery flow-mediated and glyceryltrinitrate-induced dilatation were measured after 1 ) oral L-methionine ( 10 , 25 , and 100 mg/kg ) , 2 ) dietary animal protein ( lean chicken 551+/-30 g , comprising 3.2+/-0.2 g methionine ) , and 3 ) methionine-free amino acid mix ( 100 mg/kg ) . Methionine ( 10 , 25 , and 100 mg/kg ) induced a dose-related increase in homocysteine ( 9.4+/-1.3 to 12.2+/-2.1 , 17 . 6+/-2.6 , and 26.1+/-4.2 micromol/L , respectively ; P<0.001 ) and a reduction in flow-mediated dilatation ( 4.1+/-0.8 to 2.1+/-0.8 , 0 . 3+/-0.8 , and -0.7+/-0.8 % , respectively ; P<0.001 ) at 4 hours . Compared with usual meal , animal protein increased plasma homocysteine ( 9.6+/-0.8 to 11.2+/-0.9 micromol/L , P=0.005 ) and reduced flow-mediated dilatation ( 4.5+/-0.7 % to 0.9+/-0.6 % , P=0.003 ) . Methionine-free amino acid mix did not induce any changes . Glyceryltrinitrate-induced dilatation was unchanged throughout . In this study , small physiological increments in plasma homocysteine after low-dose methionine and dietary animal protein induced vascular endothelial dysfunction . We propose that protein intake-induced increments in plasma homocysteine may have deleterious effects on vascular function and contribute to the development and progression of atherosclerosis Objective : Elevated plasma homocyst(e)ine is a risk factor for endothelial dysfunction and vascular disease . In late gestation , levels of homocyst(e)ine are higher in preeclamptics , as compared with normotensive pregnant women . Our objective was to determine whether homocyst(e)ine elevations precede the development of preeclampsia . Study Design : We used a prospect i ve nested case-control study design to compare second trimester maternal serum homocyst(e)ine concentrations in 52 patients who developed preeclampsia ( pregnancy-induced hypertension with proteinuria ) compared with 56 women who remained normotensive throughout pregnancy . Study subjects were selected from a base population of 3,042 women who provided blood sample s at an average gestational age of 16 weeks and later delivered at our center .  Serum homocyst(e)ine  was measured by high-performance liquid chromatography and electrochemical detection . Results : Approximately 29 % of preeclamptics , as compared to 13 % of controls had homocyst(e)ine levels ≥5.5 μmol/l ( upper decile of distribution of control values ) . Adjusted for maternal age , parity , and body mass-index , a second trimester elevation of homocyst(e)ine was associated with a 3.2-fold increased risk of preeclampsia ( adjusted OR = 3.2 ; 95 % CI 1.1–9.2 ; p = 0.030 ) . There was evidence of a interaction between maternal adiposity ( as indicated by her prepregnancy body mass index ) and parity with second trimester elevations in serum homocyst(e)ine . Nulliparous women with elevated homocyst(e)ine levels experienced a 9.7-fold increased risk of preeclampsia as compared with multiparous women without homocyst(e)ine elevations ( 95 % CI 2.1–14.1 ; p = 0.003 ) . Women with a higher prepregnancy body mass index ( ≥21.4 kg/m2 , or upper 50th percentile ) and who also had elevated homocyst(e)ine levels , as compared with leaner women without homocyst(e)ine elevations were 6.9 times more likely to later develop preeclampsia ( 95 % CI 1.4–32.1 ; p = 0.016 ) . Conclusion : Our findings are consistent with other indications of vascular endothelial dysfunction predating clinical preeclampsia . Studies design ed to examine the effect of dietary and /or pharmacological mediators of homocyst(e)ine metabolism in preeclampsia are warranted UNLABELLED Preeclampsia and eclampsia are the primary causes of maternal mortality . In the state of Nuevo León , from 1990 to 1998 , these conditions represented 44.1 % of maternal deaths . The presence of thrombogenic substances ( homocysteine , C protein , and anticardiolipin antibodies ) in the mother 's blood has been related to this problem . The C677 T polymorphism of the enzyme methylene tetrahydrofolate reductase ( MTHFR ) favors the increase of homocysteine levels , while folic acid ( FA ) supplementation decreases its levels . OBJECTIVE To establish the role of FA in the physiopathology of preeclampsia in our environment . KIND OF STUDY : Longitudinal , prospect i ve and comparative . MATERIAL AND METHODS CASES Women with severe preeclampsia and /or eclampsia ( n-13 ) . CONTROLS Women in the third trimester of a normal pregnancy ( n + 15 ) . 20 mL Blood sample s were taken during the first 24 hours of puerperium , and their AF , homocysteine and MTHFR polymorphism  were measured . The t Student test and the Exact Fisher test were used to compare between both groups . RESULTS The values obtained for homocysteine were ( x + SD ) : CASES 9.85 micromoles/L + 2.88 , and controls : 7.61 micromoles/L + 1.32 ( p < 0.04 ) . The frequency ( % ) of the genetic polymorphism for MTHFR was : positive homozygotes ( T/T ) : 38.46 vs. 20 , heterozygotes ( C/T ) : 38.46 vs. 26.6 , negative homozygotes ( C/C ) : 23 vs 53 , for cases and controls , respectively . CONCLUSIONS According to our study , the frequency of the homozygote state ( T/T ) of MTHFR and increased blood levels of homocysteine is greater in women suffering from preeclampsia OBJECTIVE The purpose of this study was to evaluate prospect ively midtrimester homocysteine concentration levels for the prediction of superimposed preeclampsia in women with chronic hypertension . STUDY DESIGN Between March 1 , 2000 , and February 1 , 2002 , pregnancies that were complicated by chronic hypertension that required medication had homocysteine , vitamin B(12 ) , and folate concentrations measured between 16 and 20 weeks of gestation . All women received folate supplementation . An upper limit threshold for increased homocysteine was defined as the mean value plus 2 SDs . RESULTS Fifty-seven women were enrolled .  Mean homocysteine concentration levels were 5.1+/-1.7 micromo/L for the 16 women who had preeclampsia compared with 4.7+/-1.3 micromo/L for the 41 women without preeclampsia ( P=.56 ) . Two of 16 women with preeclampsia ( 13 % ) had concentration levels that exceeded the 95th percentile ( 6.9 micromo/L ) compared with 2 of 41 women ( 5 % ) without preeclampsia ( P=.31 ) . The sensitivity and specificity were 13 % ( 95 % CI , 1.6 - 38.3 ) and 95.1 % ( 95 % CI , 83.5 - 99.4 ) , respectively . CONCLUSION Second-trimester homocysteine concentration levels were not helpful in the prediction of preeclampsia in chronically hypertensive women It is well established that folic acid supplementation in early pregnancy significantly reduces the incidence of neural tube defects ( NTDs ) [ 1 ] . Consistent with national guidelines [ 2 ] , it is current practice in the UK to advise pregnant women to take folic acid supplementation until 12 weeks gestation . A recent report , however , suggests that supplementation with folic acid throughout pregnancy may effect a reduction in adverse pregnancy outcomes [ 3 ] , although this is not yet confirmed . If folic acid supplementation throughout pregnancy led to a reduction in such outcomes , it would be a safe , simple , 
    Output:
    
There was no dose-response relationship between homocysteine concentration and severity of preeclampsia .
: Homocysteine concentrations are slightly increased in normotensive pregnancies that later develop preeclampsia and are considerably increased once preeclampsia is established .