Paracetamol prevents hyperglycinemia in vervet monkeys treated with valproate

Valproate administration increases the level of the inhibitory transmitter, glycine, in the urine and plasma of patients and experimental animals. Nonketotic hyperglycinemia (NKH), an autosomal recessive disorder of glycine metabolism, causes increased glycine concentrations in blood, urine, and cerebrospinal fluid (CSF), most likely due to a defect in the glycine cleavage enzyme or possibly deficits in glycine transport across cell membranes. We investigated the relationship between the hyperglycinemic effect of valproate and induced pyroglutamic aciduria via paracetamol in the vervet monkey. Firstly it was determined if valproate could induce hyperglycinemia in the monkey. The second aim was to increase glutamic acid (oxoproline) urine excretion using paracetamol as a pre-treatment and to assess whether valproate has an influence on the γ-glutamyl cycle. Hyperglycinemia was induced in healthy vervet monkeys when treated with a single oral dose of 50 mg/kg valproate. An acute dose of 50 mg/kg paracetamol increased oxoproline in the urine. Pre-treatment with paracetamol opposed the hyperglycinemic effect of valproate. However, the CSF:serum glycine ratio in a nonketotic monkey increased markedly after paracetamol treatment and remained high following valproate treatment. These results indicate that the γ-glutamyl cycle does indeed play a role in the hyperglycinemic effect of valproate treatment, and that paracetamol may have value in preventing and/or treating valproate-induced NKH.     

Prenatal diagnosis of Non-ketotic hyperglycinaemia

Summary Non-ketotic hyperglycinaemia (NKH) is a devastating neurological disease for which there is no effective therapy. Consequently, most couples with a pregnancy known to be at risk for NKH request prenatal diagnosis. We have applied the combination of chorionic villus (CVS) assay for glycine cleavage enzyme activity and determination of amniotic fluid glycine concentration to increase the reliability of prenatal diagnosis for this disorder beyond that of each of these methods alone. All 15 of the at-risk pregnancies monitored had CVS glycine cleavage assay and five also had amniotic fluid glycine measurements. Two cases had no detectable cleavage activity in CVS and one gave uninterpretable enzyme results. Amniotic fluid glycine concentration was increased in all three and NKH was confirmed by abortus tissue assays for cleavage activity and amino acids. The remaining 12 case had activity in CVS (two also had normal amniotic fluid glycine levels) and delivered unaffected infants. Four of these 12 cases had cleavage activities below or at the low end of the normal range, perhaps indicating carrier status. We believe that the combination of CVS glycine cleavage assay and amniotic fluid glycine measurement is currently the best approach to the prenatal diagnosis of NKH.     

Formation of gamma-glutamycyst(e)ine in vivo is catalyzed by gamma-glutamyl transpeptidase.

These studies indicate that gamma-glutamylcyst(e)ine, found in the urine of a patient with gamma-glutamyl transpeptidase deficiency and also in the urine of experimental animals injected with glutathione or with inhibitors of gamma-glutamyl transpeptidase, is formed by the action of gamma-glutamyltranspeptidase. The evidence demonstrates that transpeptidation between glutathione and cystine occurs in vivo and also that this reaction constitutes a significant physiological function of the enzyme. The appearance of large amounts of gamma-glutamylcyst(e)ine in the urine seems to reflect an inhibitory effect of glutathione on the transport of gamma-glutamylcyst(e)ine into cells. The findings also indicate that conversion of glutathione to gamma-glutamylcysteine by hydrolytic cleavage of the COOH-terminal glycine moiety of glutathione (or analogous cleavage of glutathione disulfide) is not a quantitatively significant pathway. The results reported here show that gamma-glutamyl transpeptidase activity is not completely absent in a patient found to have a deficiency of this enzyme and that the activity of the enzyme is not abolished in experimental animals treated with potent gamma-glutamyl transpeptidase inhibitors.     

Urinary excretion of glycine in tropical sprue

Summary 1. Glycine accounts for a significantly greater portion of the total amino acid nitrogen in 24-hr. urine collections from patients with sprue than from normal persons on the same diet.2. Administration of a 15-gm. dose of glycine orally resulted in a urinary glycine excretion which was approximately three times as high in 5-hr. urine specimens from patients with sprue as in those from normal subjects.3. The data suggest that patients with sprue have either impaired utilization or abnormal renal excretion of glycine, or both.The authors express their appreciation for the technical assistance of Josefina Aviles, Yvonne Davila, Gloria Willet, Oren Babb, and Robert Lewis.     

One-methyl group metabolism in non-ketotic hyperglycinaemia: Mildly elevated cerebrospinal fluid homocysteine levels

Non-ketotic hyperglycinaemia (NKH) is a rare, severe brain disease caused by deficient glycine cleavage enzyme complex activity resulting in elevated glycine concentrations. Recent experience suggests that factors in addition to glycine kinetics are involved in its pathogenesis. The glycine cleavage reaction through the formation of methylenetetrahydrofolate is an important one-methyl group donor. A deficiency in one-methyl group metabolites, in particular of choline, has been hypothesized in NKH. We investigated metabolites involved in one-methyl group metabolism in plasma and CSF of 8 patients with NKH, and monitored the effect of treatment with choline in one patient. Plasma and CSF choline and phosphatidylcholine concentrations were normal, except for a low plasma choline in the single neonate studied. Choline treatment did not change brain choline content, and was not associated with clinical or radiological improvement. Methionine concentrations and, in one-patient, S-adenosylmethionine and 5-methyltetrahydrofolate concentrations were normal in CSF. Homocysteine concentrations in CSF, however, were slightly but consistently elevated in all four patients examined, but cysteine, cysteinylglycine and glutathione were normal. Serine is important in the transfer of one-methyl groups from mitochondria to cytosol. Serine concentrations were normal in plasma and CSF, but dropped to below normal in CSF in three patients on benzoate treatment. These observations add to our understanding of the complex metabolic disturbances in NKH.     

Non-ketotic hyperglycinaemia: Molecular lesion,diagnosis and pathophysiology

Summary Non-ketotic hyperglycinaemia (NKH) is a well-recognized metabolic cause of life-threatening illness in the neonate. The fundamental defect is in the glycine cleavage system, which consists of four protein components. Our study revealed that the majority of NKH patients had a specific defect in P-protein (glycine decarboxylase). The primary lesion of NKH at gene level was investigated, using cDNA encoding human glycine decarboxylase. A three-base deletion resulting in deletion of Phe⁷⁵⁶ was found in a Japanese patient with NKH. The majority of NKH patients in Finland, where there is a high incidence of NKH, were found to be due to a common mutation, a point mutation resulting in the amino acid substitution of Ile⁵⁶⁴ for Ser⁵⁶⁴. Prenatal diagnosis is feasible by determining the activity of the glycine cleavage system and is also possible by DNA analysis. Recent findings suggest that a high concentration of glycine in the brain may contribute to the pathophysiology of NKH by overactivatingN-methyl-d-aspartate receptors allosterically, which may result in intracellular calcium accumulation, DNA fragmentation and neuronal death. These provide the possibility that early treatment withN-methyl-d-aspartate receptor antagonist may prevent brain damage in NKH.     

Elevated glycine betaine excretion in diabetes mellitus patients is associated with proximal tubular dysfunction and hyperglycemia

In an ambulatory population of diabetic subjects (Type 1 and Type 2), the urine excretion of the renal osmolyte, glycine betaine, was compared to known markers of glycemic control, renal dysfunction and to the excretion of related betaines, including trigonelline, proline betaine, carnitine and acetyl-carnitine. Of the 85 subjects, 20 patients had urine glycine betaine concentrations above the reference range for normal subjects. Plasma glycine betaine concentrations were within reference ranges for normal subjects. Patients with elevated glycine betaine excretion tended to have lower plasma glycine betaine concentrations, but this did not reach statistical significance. One way analysis of variance found excretion is independent of treatment, duration of diagnosed diabetes, blood pressure and body mass index (BMI). An association between glycine betaine excretion and glycemic control was observed with statistically significant correlations occurring with both plasma glucose (r = 0.43, P < 0.001) and glycated haemoglobin (HbA1c) (r = 0.35, P < 0.005). The excretion of carnitine, acetyl-carnitine and proline betaine were related to glycine betaine excretion (r = 0.49, P < 0.001; r = 0.40, P < 0.001; r = 0.27, P < 0.05, respectively). Urine carnitine and acetyl-carnitine concentrations were also related to plasma glucose concentrations (r = 0.30, P < 0.01). Increased urine retinol binding protein concentrations (RBP), a marker of proximal tubular dysfunction, correlated with elevated urine glycine betaine excretion and plasma HbA1c (r = 0.28, P < 0.01). These results suggest poor glycemic control is associated with the increase in urine glycine betaine, carnitine, acetyl-carnitine and RBP excretion in diabetic patients. However, < 50% of the observed increase in glycine betaine excretion has been accounted for by the variables measured, suggesting other unidentified processes may also be involved.     

Glycine betaine excretion is not directly linked to plasma glucose concentrations in hyperglycaemia

Diabetes mellitus subjects, type 1 and type 2, have increased glycine betaine excretion compared to normal subjects that correlated with plasma glucose and HbA(1C) concentrations. The current study was undertaken to determine whether elevated glucose concentration directly increases glycine betaine excretion in an animal model. Non-pregnant female Coopworth sheep received an intravenous glucose load (12.5,25 and 50% w/v; rate 200 ml/h) for 6 h followed by a 12 h physiological saline washout (0.9% w/v). Plasma and urine samples were analyzed for glycine betaine and glucose. Urine volumes and osmolality were also measured. Using the non-parametric Kruskal Wallis analysis of variance test we found no difference in glycine betaine excretion between glucose loaded and saline infused control animals (P=0.861). However, a significant negative correlation (r=-0.28, P<0.001) was observed between urine osmolality and glycine betaine excretion independent of treatment. We conclude that acute elevations of plasma glucose concentrations did not result in increased glycine betaine excretion and is therefore unlikely to be directly responsible for elevated glycine betaine excretion observed in diabetes mellitus subjects.     

Levels of cardiovascular risk factors in type 2 diabetes mellitus are dependent on the stage of proteinuria.

Levels of cardiovascular risk factors were determined in 75 patients with Type 2 diabetes mellitus. The patients were divided into three groups according to their urinary protein excretion (UPE): (a) normal proteinuria (less than or equal to 70 mg d-1); (b) microproteinuria (70-500 mg d-1); and (c) macroproteinuria (greater than 500 mg d-1). A significant stepwise increase in mean systolic blood pressure, LDL-cholesterol and fibrinogen levels was observed from the first to the third investigated group of patients. Mean apoprotein B levels were significantly increased in the group with macroproteinuria compared to the other two groups. Significant linear correlations were found between UPE and LDL-cholesterol, total cholesterol, apoprotein B, creatinine, systolic blood pressure and diabetes duration. In summary, it is concluded that the levels of some cardiovascular risk factors increase with the stage of proteinuria in Type 2 diabetes mellitus.     

环孢素A对链脲佐菌素诱导的糖尿病大鼠肾脏基质金属蛋白酶-2和基质金属蛋白酶-9表达的影响

目的 观察免疫抑制剂环孢素A(CsA)对糖尿病大鼠肾脏基质金属蛋白酶(MMP)表达的影响.方法 健康雄性SD大鼠74只,平均体重250 g,采用数字表法随机分为正常对照组(n=10)、单纯糖尿病组(n=8)、胰岛素治疗组(n=9)、造模前低剂量CsA治疗组(n=9;造模前1周皮下注射1μg·g-1·d-1 CsA)、造模前中剂量CsA治疗组(n=8;造模前1周皮下注射4μg·g-1·d-1CsA)、造模前高剂量CsA治疗组(n=8;造模前1周皮下注射8μg·g-1·d-1CsA)、造模后低剂量CsA治疗组(n=8;造模后1周皮下注射1μg·g-1·d-1CsA)、造模后中剂量CsA治疗组(n=7;造模后1周皮下注射4μg·g-1·d-1 CsA)和造模后高剂量CsA治疗组(n=7;造模后1周皮下注射8μg·g-1·d-1 CsA).8周后处死动物,采用免疫组织化学法、逆转录-聚合酶链反应和Western blot检测肾脏MMP-2、MMP-9 mRNA和蛋白表达水平.采用单因素方差分析和直线相关分析进行统计学分析.结果 8周时,单纯糖尿病组24 h尿微量蛋白显著高于正常对照组[分别为(5.80±3.23)、(1.24±0.21)mg/24 h,F=4.229,P＜0.01];各CsA治疗组24 h尿微量蛋白不同程度降低,与正常对照组比较差异无统计学意义.单纯糖尿病组肾小管上皮细胞和肾小球系膜基质MMP-2、MMP-9mRNA(分别为2.22±0.08、2.55±1.10)和蛋白表达(分别为3.1±1.5、2.8±1.0)显著高于正常对照组(MMP-2 mRNA:0.70±0.26,F=6.031;MMP-9 mRNA:0.37±0.24,F=5.193;MMP-2蛋白:1.0±0.0,F=7.532;MMP-9蛋白:1.0±0.0,F=6.100;均P＜0.01).胰岛素治疗对其表达无影响,但CsA干预可下调MMP-2、MMP-9 mRNA和蛋白的异常表达.MMP-2 mRNA与蛋白表达呈显著正相关(r=0.618,P＜0.01),而MMP-9 mRNA与蛋白表达未见相关性(r=0.420,P＞0.05).结论 CsA可减少糖尿病大鼠肾脏MMP-2和MMP-9基因转录和蛋白表达,改善细胞外基质代谢紊乱,可能具有延缓糖尿病肾病发生的作用.     

Airway and cardiovascular responses to inhaled prostacyclin in normal and asthmatic subjects

Prostacyclin (PGI2) is one of several prostanoids released after antigen challenge of human lung fragments. To define its activity on human airways, we studied the effect of inhaled PGI2 in 10 normal and 8 asthmatic subjects. In random order, PGI2, 1 mg/ml, its hydrolysis product, 6-oxo-PGF1 alpha, 1 mg/ml, and glycine vehicle were given on separate occasions by nebulizer. Measurements of specific airway conductance (SGaw), blood pressure (BP), heart rate (HR), plasma 6-oxo-PGF1 alpha, and cyclic AMP levels were made at frequent intervals for as long as 45 min after nebulization. Prostacyclin and 6-oxo-PGF1 alpha caused cough and retrosternal discomfort. None of the drugs had any significant effect on SGaw in either the normal or asthmatic subjects, though 2 asthmatics showed consistent bronchodilatation with prostacyclin. Prostacyclin caused a marked fall in diastolic blood pressure (mean 20 +/- 3 mmHg) and increase in heart rate (29 +/- 3 beats X min-1) with a small late fall in systolic blood pressure (8 +/- 2 mmHg). This was associated with a 12- to 15-fold increase in plasma 6-oxo-PGF1 alpha levels maximal at 1 min, and in normal subjects only, a later twofold increase in plasma levels of cyclic AMP maximal at 5 min. Thus, inhaled PGI2 at concentrations that had pronounced cardiovascular activity produced no consistent effect on airway caliber in normal or asthmatic subjects.     

Milk: does it affect blood pressure? A controlled intervention study

In a double-blind trial, the effect on blood pressure of supplementation of normal milk (1180 mg Ca2+, 1650 mg K+ and 110 mg Mg2+ d-1) vs. 'mineral-poor' milk (95 mg Ca2+, 580 mg K+ and 10 mg Mg2+ d-1) was studied. Young healthy normotensive female students consumed one of the two supplements while on a low calcium diet (less than 500 mg Ca2+ d-1) for a period of 6 weeks. In both the normal milk- and 'mineral-poor' milk-supplemented groups systolic blood pressure decreased slightly. However, this decrease was persistently greater in the milk-supplemented group. The individual mean systolic blood pressure change during normal milk treatment (-4.1%) was significantly greater (P = 0.03) than that during 'mineral-poor' milk treatment (-1.3%). An effect of normal milk supplementation on diastolic blood pressure could not be demonstrated. The results of the present study indicate a small hypotensive effect of milk consumption, which is attributable to its content of essential minerals.     

Arterial hypertension in heart transplant patients treated with cyclosporin

Amongst 40 patients undergoing cardiac transplantation between 1981 and 1984 and treated with cyclosporin A, 23 had hypertension. Fifteen of these patients, aged 39 years (16-57 years), without cardiac failure, treated with 8 +/- 3 mg kg-1 d-1 of cyclosporin A and 0.27 +/- 0.1 mg kg-1 d-1 of prednisolone were studied on average 288 days after transplantation (63-788 days). Blood pressure in the out-patients department of these 15 patients was 164 +/- 14/112 +/- 13 mmHg, in the absence of any antihypertensive treatment for more than 15 days, with a urinary sodium of 104 +/- 48 mEq/d and a urinary potassium of 55 +/- 13 mEq/d (mean +/- standard deviation). Two abnormalities accompany the raised blood pressure: a reduced creatinine clearance of 63 +/- 30 ml min-1 and an increased plasma volume of 445 +/- 686 ml (p less than 0.05) with reference to Hurley's norms (1975). By contrast, urinary excretion of VMA and metanephrines were invariably normal. Plasma renin activity (PRA) was normal in a lying position (1.02 +/- 0.42 ng ml-1 h-1) and after orthostatic stimulation (2.55 +/- 1.31 ng ml-1 h-1). Renin release was not stimulated by acute inhibition of converting enzyme (1.11 +/- 0.70 ng ml-1 h-1). Plasma aldosterone (110 +/- 52 pg ml-1), plasma angiotensinogen (924 +/- 213 ng/ml) and converting enzyme activity (30 +/- 6 mU ml-1) were normal. In these patients with a denervated heart, the orthostatic position increased heart rate from 85 +/- 11 to 93 +/- 12 beats/min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cysteamine inhibition of [15N]-glycine turnover in cystinosis and of the glycine cleavage system in vitro

In order to clarify the hyperglycinemic effect of cysteamine treatment in children with nephropathic cystinosis, we measured [¹⁵N]-glycine turnover in three affected patients. Administration of cysteamine lowered the glycine flux and the glycine metabolic clearance rate but did not alter the glycine pool size. Formation of [¹⁵N]-serine from [¹⁵N]-glycine was lower in untreated patients than in control subjects and was reduced still further by cysteamine. Studies in vitro with isolated rat liver mitochondria and acetone extracts of mitochondria indicated that even low cysteamine concentrations (0.1 mM) inhibited the glycine cleavage system in both the direction of glycine oxidation and glycine synthesis. Cysteamine was a more potent inhibitor of the glycine cleavage system than any other sulfhydryl containing compound. Although no ill effects of cysteamine treatment were immediately apparent, patients receiving cysteamine should be monitored carefully for the appearance of any neurologic symptoms which might be referable to inhibition of the glycine cleavage system.     

Glycine andl-carnitine therapy in 3-methylcrotonyl-CoA carboxylase deficiency

Summary Genetic deficiency of 3-methylcrotonyl-CoA carboxylase (3-MCC) is a rare inborn error of leucine metabolism producing an organic acidaemia. With accumulation of 3-methylcrotonyl-CoA, there is increased production of 3-hydroxyisovaleric acid, the glycine conjugate (3-methylcrotonylglycine), and the carnitine conjugate (3-hydroxyisovalerylcarnitine). These conjugates represent endogenous detoxification products. We studied excretion rates of these conjugates at baseline and with glycine and carnitine therapy in an 8-year-old girl with 3-MCC deficiency. Her preadmission diet was continued. Plasma and urine samples were obtained after 24h of each of the following:l-carnitine 100mg/kg per day and glycine 100, 175 and 250mg/kg per day. Plasma and urinary carnitine levels were reduced by 80% and 50%, respectively with abnormal urinary excretion patterns. These normalized with carnitine therapy. Acylcarnitine excretion increased with carnitine therapy. The glycine conjugate, 3-methylcrotonylglycine (3-MCG), was the major metabolite excreted at all times and its excretion increased with glycine therapy. Clearly, in 3-MCC deficiency the available glycine and carnitine pools are not sufficient to meet the potential for conjugation of accumulated metabolites, suggesting a possible therapeutic role for glycine and carnitine therapy in this disorder.     

硝苯地平抑制核因子κB活性、改善鼠损伤血管炎症

目的 研究硝苯地平抑制损伤血管炎症反应的作用机制.方法 成年雄性C57BL/6J小鼠,10至12周龄,分为4组,即对照组(无手术无干预)、血管损伤组(只手术无干预)、硝苯地平1及5 mg·kg-1·d-1干预组(简称为硝苯地平1及5 mg干预组,手术+硝苯地平干预).另外,也检测了硝苯地平干预却未手术的小鼠的核因子κB(NF-κB)的表达,由于预测其结果与对照组相同,为免繁复,未单独设组.股动脉血管损伤手术后第5天采用Western blot检测NF-κB活性,第7天采用实时定量逆转录聚合酶链反应检测单核细胞趋化蛋白(MCP)-1 mRNA的表达、Western blot检测NF-κB的核转移.结果 术后第5天,血管损伤组、硝苯地平干预组NF-κB活性均显著高于对照组(P均＜0.05),硝苯地平5 mg干预组NF-κB活性显著低于血管损伤组(P＜0.05).术后第7天,血管损伤组、硝苯地平干预组MCP-1 mRNA表达显著上调[MCP-1 mRNA表达与GAPH的相对比率为:对照组0.0017±0.0001,血管损伤组0.0154±0.0002,硝苯地平1 mg干预组0.0120±0.0001,硝苯地平5 mg干预组0.0026±0.0001],血管损伤组、硝苯地平干预组MCP-1 mRNA表达均显著高于对照组(P均＜0.05),硝苯地平5 mg干预组MCP-1 mRNA表达显著低于血管损伤组(P＜0.05).术后第7天,血管损伤组、硝苯地平干预组细胞质中p50、IκBα及IκBβ蛋白水平显著下降[p50蛋白水平各组与对照组倍数比率为:对照组1.000±0.028,血管损伤组0.234±0.012,硝苯地平1 mg干预组0.303±0.014,硝苯地平5 mg干预组0.493±0.027.IκBot蛋白水平各组与对照组倍数比率为:对照组1.000±0.031,血管损伤组0.358±0.025,硝苯地平1 mg干预组0.373±0.029,硝苯地平5 mg干预组0.681±0.019.IκBβ蛋白水平各组与对照组倍数比率为:对照组1.000±0.022,血管损伤组0.483±0.047,硝苯地平1 mg干预组0.524±0.047,硝苯地平5 mg干预组0.723±0.031],血管损伤组、硝苯地平干预组细胞质中p50、IκBα及IκBβ蛋白水平均显著低于对照组(P均＜0.05),硝苯地平5 mg干预组细胞质中p50、IκBα及IκBβ蛋白水平均显著低于血管损伤组(P均＜0.05).血管损伤组、硝苯地平干预组细胞核内p50蛋白水平显著升高[p50蛋白水平各组与对照组倍数比率为:对照组1.000±0.031,血管损伤组24.608±1.078,硝苯地平1 mg干预组21.913±0.922,硝苯地平5 mg干预组6.522±0.504],血管损伤组、硝苯地平干预组细胞核内p50蛋白水平均显著高于对照组(P均＜0.05),硝苯地平5 mg干预组细胞核内p50蛋白水平显著低于血管损伤组(P＜0.05).结论 动脉血管损伤诱导血管炎症反应,硝苯地平抑制损伤动脉MCP-1表达,其可能是通过抑制NF-κB的DNA结合活性实现的,从而最终改善损伤血管的炎症反应.     

Mycophenolate mofetil and FK506 have different effects on kidney allograft fibrosis in rats that underwent chronic allograft nephropathy

ABSTRACT: BACKGROUND: Tacrolimus (FK506) is associated with renal fibrosis in long-term use. Mycophenolatemofetil (MMF) can also inhibit or attenuate the progression of renal fibrosis. This study aimed to determine the different effects of FK506 and MMF on fibrosis-associated genes in the kidney in rats that underwent chronic allograft nephropathy (CAN). METHODS: Fisher (F344) kidneys were orthotopically transplanted into Lewis rat recipients. All recipients were given Cyclosporin A (CsA) 10 mg/kg-1.d-1 x 10 day and were then randomly divided into three oral treatment groups (n = 9 in each group): (1) the vehicle group was given vehicle orally; (2) the FK506 group was given 0.15 mg/kg-1.d-1 FK506; and (3) the MMF group was given 20 mg/kg-1.d-1 MMF. At 4, 8, and 12 weeks post-transplantation, serum creatinine (SCr), collagen deposition, Connective tissue growth factor (CTGF), alpha smooth muscle actin (alpha-SMA) and E-cadherin expressions were determined and hematoxylin-eosin (HE) and Periodic acid-Schiff (PAS) stains were performed. RESULTS: Renal function progressively deteriorated and showed typical CAN morphology in the vehicle and FK506 groups, while SCr and inflammatory infiltration (Banff score) showed a significant decrease in the MMF group after 8 weeks post-transplantation compared with those in the other groups (p < 0.05). Furthermore, expression levels of CTGF and alpha-SMA in the MMF group were significantly reduced, and the down-regulated expression of E-cadherin was abated (p < 0.05). CONCLUSIONS: MMF showed favorable effects on renal interstitial fibrosis, thus efficiently retarding the progression of CAN.     

低分子肝素对子痫前期样大鼠肝脏保护作用研究

目的研究低分子肝素（Low Molecular Weight Heparin,LMWH）对子痫前期样大鼠肝脏组织的保护作用．并从抗细胞凋亡角度探讨其可能的作用机制。方法取10只正常非孕鼠为正常非孕组,另将30只孕鼠随机分为正常孕组、子痫前期组（preeclampsiagroup,PE组）及LMWH治疗组。PE组及LMWH治疗组孕鼠均于妊娠第13天开始给予左旋硝基精氨酸甲酯（L—NAME）200mg·kg-1·d-1皮下注射,共5d．建立子痫前期样孕鼠模型。PE组于妊娠第15～20天给予生理盐水0．5ml皮下注射,LMWH治疗组于妊娠第15～20天给予LMWH40μl·kg-1·d-1皮下注射。检测各组血压、尿蛋白及ALT、AST,对LMWH疗效进行评价;采用TUNEL法检测肝脏细胞凋亡率,荧光定量PCR及WesternBlot法检测分别检测肝脏组织中caspase-3、Bcl-2及BaxmRNA和蛋白表达。结果与PE组相比,LMWH组血压及尿蛋白显著降低（P〈0．05）,转氨酶J蝴及AST显著降低（P〈0．05）;LMWH组肝脏细胞凋亡率、Caspase-3mRNA及活化Caspase-3蛋白表达均显著低于PE组（P〈0．05）,Bcl-2mRNA及蛋白表达显著升高,而BaxmRNA及蛋白则显著降低（P〈0．05）。结论低分子肝素可以有效改善子痫前期样大鼠肝功能,减少肝脏细胞凋亡。对其肝脏具有保护作用,这一作用可能通过调节Bcl-2／Bax平衡抑制细胞凋亡。     

Nutritional iron requirements and food iron absorption

To prevent nutritional iron deficiency, sufficient iron must be absorbed from the diet to meet the normal physiological requirements. Daily iron losses in males are about 1 mg (14 micrograms kg-1), while the average additional requirements incurred in women include menstruation (0.6 mg), pregnancy (2.7 mg) and lactation (less than 0.3 mg). Requirements during pregnancy are not evenly distributed and increase to between 5-6 mg in the last trimester of pregnancy, which is more than can be absorbed from even an optimal diet. While the amounts absorbed are affected by the iron content of the diet, the composition of the latter is even more relevant. About one-quarter of the iron in haem proteins is absorbed regardless of the other components in the diet, while non-haem iron absorption is subject to the interplay of promoting and inhibiting substances in the diet. Thus diets rich in enhancers of non-haem iron absorption, chiefly meat and/or ascorbic acid, have high iron bioavailability (about 3 mg d-1) while diets in which inhibitors, such as polyphenols and phytates, predominate are poor sources of iron (less than 1 mg d-1). Examination of the relative proportions of promoters and inhibitors of iron absorption in individual foodstuffs and the measured iron absorption from them may be useful in predicting the overall iron bioavailability from mixed diets.     

The effect of hyperglycinemic treatment in captive-bred Vervet monkeys (Chlorocebus aethiops)

Metabolic Brain Disease - Nonketotic hyperglycinemia (NKH) is a neuro-metabolic disorder caused by a deficiency in the glycine cleavage system (GCS) and glycine transporter 1 (GlyT1). A case of...