Fragment-based QSAR study to explore the structural requirements of DPP-4 inhibitors: a stepping stone towards better type 2 diabetes mellitus management.

Dipeptidyl peptidase-4 (DPP-4) inhibitors belong to a prominent group of pharmaceutical agents that are used in the governance of type 2 diabetes mellitus (T2DM). They exert their antidiabetic effects by inhibiting the incretin hormones like glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide which, play a pivotal role in the regulation of blood glucose homoeostasis in our body. DPP-4 inhibitors have emerged as an important class of oral antidiabetic drugs for the treatment of T2DM. Surprisingly, only a few 2D-QSAR studies have been reported on DPP-4 inhibitors. Here, fragment-based QSAR (Laplacian-modified Bayesian modelling and Recursive partitioning (RP) approaches have been utilized on a dataset of 108 DPP-4 inhibitors to achieve a deeper understanding of the association among their molecular structures. The Bayesian analysis demonstrated satisfactory ROC values for the training as well as the test sets. Meanwhile, the RP analysis resulted in decision tree 3 with 2 leaves (Tree 3: 2 leaves). This present study is an effort to get an insight into the pivotal fragments modulating DPP-4 inhibition.

Carnitine transport by organic cation transporters and systemic carnitine deficiency.

The intracellular homeostasis is controlled by different membrane transporters. Organic cation transporters function primarily in the elimination of cationic drugs, endogenous amines, and other xenobiotics in tissues such as the kidney, intestine, and liver. Among these molecules, carnitine is an endogenous amine which is an essential cofactor for mitochondrial beta-oxidation. Recently, a new family of transporters, named OCT (organic cation transporters) has been described. In this minireview, we present the recent knowledge about OCT and focus on carnitine transport, more particularly by the OCTN2. The importance of this sodium-dependent carnitine cotransporter, OCTN2, comes from various recently reported mutations in the gene which give rise to the primary systemic carnitine deficiency (SCD; OMIM 212140). The SCD is an autosomal recessive disorder of fatty acid oxidation characterized by skeletal myopathy, progressive cardiomyopathy, hypoglycemia and hyperammonemia. Most of the OCTN2 mutations identified in humans with SCD result in loss of carnitine transport function. Identifying these mutations will allow an easy targeting of the SCD syndrome. The characteristics of the juvenile visceral steatosis (jvs) mouse, an animal model of SCD showing similar symptoms as humans having this genetic disorder, are also described. These mice have a mutation in the gene encoding the mouse carnitine transporter octn2. Although various OCTN carnitine transporters have been identified and functionally characterized, their membrane localization and regulation are still unknown and must be investigated. This knowledge will also help in designing new drugs that regulate carnitine transport activity.

Hepatic mitochondrial proteins in congenitally hyperammonemic spf mice: effect of acetyl-L-carnitine.

The sparse-fur (spf) mutant mouse has an X-linked deficiency of hepatic ornithine transcarbamylase (OTC), and develops hyperammonemia immediately after weaning and maintains it throughout its life span. We have studied the effects of acetyl-L-carnitine (ALCAR) on the hepatic mitochondrial proteins of the chronically hyperammonemic spf mice. Two different age groups of mice were studied, the weanlings (3 weeks) and the adult mice (8 weeks). Our results indicate that in the mitochondrial matrix, the untreated chronic hyperammonemia induced a significant increase in the quantity of 54.4-kDa protein in spf adult mice. After ALCAR treatment, in spf adult mice, the quantities of the 54.4-kDa, 63.8-kDa, and 129-kDa matrix proteins were significantly increased. In the mitochondrial inner membrane fraction of the spf weanling mice, a 53.5-kDa protein was significantly increased by ALCAR treatment. Our results show that: (a) chronic hyperammonemia has altered the mitochondrial matrix protein profile in spf mice, that (b) ALCAR has a modulating effect on various matrix and inner membrane proteins, and that (c) there was no effect of hyperammonemia or ALCAR treatment on the outer membrane proteins.

Impaired cognitive performance in ornithine transcarbamylase-deficient mice on arginine-free diet.

Sparse-fur (spf) mice are a model for the congenital deficiency of ornithine transcarbamylase (OTC), the most common inborn error of urea synthesis in man. In this study, performance of clinically stable spf and control mice (8-10-weeks-old) on two learning tests was assessed under normal Arg(+) or arginine-free Arg(-) diet conditions. Used as an indicator of the metabolic status of the animals, plasma ammonia concentrations were significantly higher in spf than in controls on normal diet, and increased even more during the Arg(-) diet episode. Behaviourally, we found no difference in passive avoidance learning between control and spf mice on Arg(+) diet, whereas in spf mice receiving Arg(-) diet during training, retention performance was significantly reduced. In the hidden-platform water maze, spf mice on Arg(+) diet only showed decreased swimming velocity compared to controls. In mice on Arg(-) diet during the first week of acquisition training, performance on acquisition and retention (probe) trials showed that spf mice experienced more difficulties in actually locating the platform. Visible-platform control experiments only showed a reduction in swimming velocity in spf mice on either diet. We conclude that cognitive performance is impaired in spf mice as a consequence of Arg(-) diet-induced neurochemical alterations.

The ocular hypotensive effect of late pregnancy is higher in multigravidae than in primigravidae.

BACKGROUND: Systemic hypertension and degenerative vascular disease are more common in multigravidae than in primigravidae. The present study investigated whether the known ocular hypotensive effect of late pregnancy is influenced by the number of pregnancies. METHODS: Intraocular pressure (IOP) was measured in normotensive third-trimester primigravidae and multigravidae along with nulligravida controls by means of the Goldmann applanation tonometer. Depending upon the number of previous pregnancies, multigravidae were divided into four subgroups. RESULTS: The IOP of the pregnant group (primigravidae and multigravidae together) was (mean+/-SEM) 2. 1+/-0.07 mmHg (P<0.001) lower than in the nulligravida control group. The IOP of nulligravidae was 1.7+/-0.06 mmHg (P<0.001) and 2.5+/-0. 01 mmHg (P<0.001) higher than in third-trimester primigravidae and multigravidae, respectively. In all subgroups of multigravidae IOP was significantly lower (P<0.02) than in primigravidae. The differences among different subgroups of multigravidae were statistically insignificant. CONCLUSIONS: Gravidity influences IOP and should be taken into account in future research.

Hyperlipidemia of normal pregnancy in Karachi-Pakistan.

During pregnancy, changes in the levels of total cholesterol, triglyceride, low density lipoprotein-cholesterol, and high density lipoprotein-cholesterol have been described, but in the existing literature these effects remain controversial because of inconsistencies. Moreover, the degree of change varies from study to study. Therefore, the present study completely investigated changes in lipids and lipoproteins throughout the pregnancy and in the puerperium. We also investigated whether or not any relation between plasma lipids and other pregnancy related factors exist. Concentrations of cholesterol and triglyceride of total plasma, and lipoproteins were determined in 56 pregnant women throughout the pregnancy and in the puerperium along with 56 non-pregnant women. Compared to control group, concentrations of cholesterol and triglyceride of total plasma and lipoproteins increased significantly during second trimester and reached maximum in the third trimester. Both cholesterol and triglyceride concentrations decreased significantly within 24 hours of delivery and this was reflected in all lipoproteins. In the majority of subjects, cholesterol and triglycerides remained significantly high until 4 weeks of postpartum. The magnitude of the serum cholesterol increment appeared in part to be related to that of serum triglyceride, but these increments appeared to be independent of age, weight gain, numbers of previous pregnancies and sex of the fetus. This study concludes that hyperlipidemia is a common finding during pregnancy.

Seasonal and diurnal variations of ocular pressure in ocular hypertensive subjects in Pakistan.

BACKGROUND: Studies have been shown that intraocular pressure (IOP) shows a diurnal variation in ocular hypertensive subjects, but the amount of change differs from study to study. In recent years it has been noted that intraocular pressure is a dynamic function and is subjected to many influences both acutely and over the long term. The variability in the results may be due to negligence of factors that can affect IOP. Moreover, seasonal variations in the ocular hypertensive subjects have never been described. After placing control on those factors that can affect IOP, this study investigated seasonal and diurnal variations in IOP of ocular hypertensive subjects. PATIENTS AND METHODS: IOP was measured each month over the course of 12 months with the Goldmann applanation tonometer in 91 ocular hypertensive male subjects. To see the diurnal changes, subjects were asked to stay in the hospital for 24 hours. RESULTS: The average IOP in the winter months was higher than those in spring, summer, and autumn. The IOP difference between winter and summer was (mean +/- sem) 2.9 +/- 0.9 mmHg (p < 0.001). The peak of mean IOP in diurnal variation curve (25.7 +/- 1.2 mmHg) appeared in the morning when the subjects had just awaken. The mean diurnal variation was found to be 4.2 +/- 0.6 mmHg (p < 0.001). CONCLUSIONS: This study confirms that seasons influence IOP and it shows diurnal variations. As compared to other nations, diurnal variations in ocular hypertensive subjects seem to be somewhat less in Pakistan. Knowledge of the seasonal and diurnal variations in IOP may help glaucoma screeners.

Hyperlipidaemia during normal pregnancy, parturition and lactation.

Excessive accumulation of one or more of the major lipids in plasma can produce a marked increase in the risk of coronary heart diseases and other vascular complications. During and after pregnancy, changes in the levels of total cholesterol, triglyceride, low density lipoprotein-cholesterol, and high density lipoprotein-cholesterol have been described, but the amount of change varies from study to study. Therefore, the present study investigated changes in lipids and lipoproteins throughout the pregnancy and puerperium. We also investigated for the factors which may affect the plasma lipids during pregnancy. Concentrations of cholesterol and triglyceride of total plasma and lipoproteins were determined in 42 pregnant women throughout their pregnancy and puerperium together with a control group of 42 non-pregnant women. Compared to the control group, concentrations of cholesterol and triglyceride of total plasma and lipoproteins increased significantly during the second trimester and reached maximum in the third trimester. Concentrations of both, cholesterol and triglyceride, decreased significantly during post-partum. There was, however, a strikingly more rapid fall of plasma triglyceride and cholesterol in those mothers who breast-fed their infants compared with that in those in whom lactation was never established. In the majority of subjects, cholesterol and triglycerides remained significantly high until the fourth week of post-partum. The magnitude of the plasma cholesterol increment appeared in part to be related to that of plasma triglycerides, but these increments appeared to be independent of age, weight gain, numbers of previous pregnancies and sex of the foetus. This study concludes that hyperlipidaemia is a common finding during pregnancy and during post-partum. The concentrations of both cholesterol and triglycerides remain significantly higher in bottle-feeding than in breast-feeding mothers.

Effects of phosphatidylinositol 4,5-bisphosphate and neomycin on phospholipase D: kinetic studies.

The kinetics of phosphatidylcholine-specific phospholipase D activated by phosphatidylinositol 4,5-bisphosphate (PIP2) and inhibition by neomycin were studied in an enzyme preparation partially purified from human hepatocarcinoma cell line. It was found that phospholipase D was marginally activated by phosphatidyl-4-phosphate (PIP) and phosphatidylethanolamine (PE). In contrast, it was considerably activated by PIP2 in different concentration of phosphatidylcholine (PC). Sphingomyelin (SM), lysophosphatidylcholine (LPC) and phosphatidylserine (PS) were neither substrates nor inhibitors of the phospholipase D. PIP, induced an allosteric effect on phospholipase D and a negative cooperative effect with respect to phosphatidylcholine as indicated in the Lineweaver-Burk plot. In the absence of PIP2, a straight line was obtained, whereas a downward concave curve was observed in the presence of 25 microM of PIP2. The Hill coefficient and the apparent K(m) of phosphatidylcholine in the presence of 25 microM PIP, were calculated to be 0.631 and 10.79 mM, respectively. PIP2 also increased the maximal velocity (Vmax) of the phospholipase D reaction, suggesting that the affinity of substrate to enzyme was decreased, and the turnover number of the enzyme (kcat) was increased by PIP2. The activation of phospholipase D by PIP2 was dose dependent up to 50 microM of PIP2. The Ka of PIP2 was 15.8 mM. Neomycin, a polycationic glycoside, was shown to be an uncompetitive inhibitor of phospholipase D, and revealed the formation of a neomycin-PIP2 complex. The Ki of neomycin was estimated to be 8.7 mM.

Reduction in the MK-801 binding sites of the NMDA sub-type of glutamate receptor in a mouse model of congenital hyperammonemia: prevention by acetyl-L-carnitine.

Our earlier studies on the pharmacotherapeutic effects of acetyl-L-carnitine (ALCAR), in sparse-fur (spf) mutant mice with X linked ornithine transcarbamylase deficiency, have shown a restoration of cerebral ATP, depleted by congenital hyperammonemia and hyperglutaminemia. The reduced cortical glutamate and increased quinolinate may cause a down-regulation of the N-methyl-D-aspartate (NMDA) receptors, observed by us in adult spf mice. We have now studied the kinetics of [3H]-MK-801 binding to NMDA receptors in spf mice of different ages to see the effect of chronic hyperammonemia on the glutamate neurotransmission. We have also studied the Ca2+-dependent and independent (4-aminopyridine (AP) and veratridine-mediated) release of glutamate and the uptake of [3H]-glutamate in synaptosomes isolated from mutant spf mice and normal CD-1 controls. All these studies were done with and without ALCAR treatment (4 mmol/kg wt i.p. daily for 2 weeks), to see if its effect on ATP repletion could correct the glutamate neurotransmitter abnormalities. Our results indicate a normal MK-801 binding in 12-day-old spf mice but a significant reduction immediately after weaning (21 day), continuing into the adult stage. The Ca2+-independent release of endogenous glutamate from synaptosomes was significantly elevated at 35 days, while the uptake of glutamate into synaptosomes was significantly reduced in spf mice. ALCAR treatment significantly enhanced the MK-801 binding, neutralized the increased glutamate release and restored the glutamate uptake into synaptosomes of spf mice. These studies point out that: (a) the developmental abnormalities of the NMDA sub-type of glutamate receptor in spf mice could be due to the effect of sustained hyperammonemia, causing a persistent release of excess glutamate and inhibition of the ATP-dependent glutamate transport, (b) the modulatory effects of ALCAR on the NMDA binding sites could be through a repletion of ATP, required by the transporters to efficiently remove extracellular glutamate.

Restoration of hepatic cytochrome c oxidase activity and expression with acetyl-L-carnitine treatment in spf mice with an ornithine transcarbamylase deficiency.

The sparse fur (spf) mutant mouse, with an X-linked ornithine transcarbamylase deficiency, is a model of congenital hyperammonemia in children. Our earlier studies indicated a deficiency of hepatic carnitine, CoA-SH, acetyl CoA, and ATP in spf mice. We have now studied the effects of a 7-day treatment with acetyl-L-carnitine (ALCAR) in the spf/Y mice on the activity and expression of the respiratory chain enzyme cytochrome c oxidase (COX; EC 1.9.3.1). We found decreased hepatic activity and expression of COX in the untreated hyperammonemic spf/Y mice, which was restored upon ALCAR treatment. Because COX is a mitochondrial membrane protein, we also carried out studies to explain the mechanism of ALCAR through its effect on membrane stability. Our results indicate a decrease of the mitochondrial membrane cholesterol/phospholipid molar ratio (CHOL/PL ratio) with the activity and expression of COX in untreated spf/Y mice. While ALCAR treatment normalized the ratios, it also restored the hepatic ATP production to normal. To study further if there was any effect of ALCAR on the mitochondrial matrix urea cycle enzymes, we measured the activity and expression of mutant ornithine transcarbamylase (OTC; EC 2.1.3.3) and normal carbamyl phosphate synthase-I (CPS-I; EC 6.3.4.16) in spf/Y mice. There was no general effect on the specific activities of the matrix enzymes upon ALCAR treatment, although their mRNA levels were enhanced. Our studies point towards the feasibility of an ALCAR treatment in conjunction with other treatment modalities, e.g. sodium benzoate and/or arginine, to improve the availability of cellular ATP and to counteract the effects of hereditary hyperammonemic syndromes in children.

Neurabin is a synaptic protein linking p70 S6 kinase and the neuronal cytoskeleton.

p70 S6 kinase (p70(S6k)) is a mitogen-activated protein kinase that plays a central role in the control of mRNA translation. It physiologically phosphorylates the S6 protein of the 40s ribosomal subunit in response to mitogenic stimuli and is a downstream component of the rapamycin-sensitive pathway, which includes the 12-kDa FK506 binding protein and includes rapamycin and the 12-kDa FK506 binding protein target 1. Here, we report the identification of neurabin (neural tissue-specific F-actin binding protein), a neuronally enriched protein of 1,095 amino acids that contains a PDZ domain and binds p70(S6k). We demonstrate the neurabin-p70(S6k) interaction by yeast two-hybrid analysis and biochemical techniques. p70(S6k) and neurabin coimmunoprecipitate from transfected HEK293 cells. Site-directed mutagenesis of neurabin implicates its PDZ domain in the interaction with p70(S6k), and deletion of the carboxyl-terminal five amino acids of p70(S6k) abrogates the interaction. Cotransfection of neurabin in HEK293 cells activates p70(S6k) kinase activity. The mRNA of neurabin and p70(S6k) show striking colocalization in brain sections by in situ hybridization. Subcellular fractionation of rat brain demonstrates that neurabin and p70(S6k) both localize to the soluble fraction of synaptosomes. By way of its PDZ domain, the neuronal-specific neurabin may target p70(S6k) to nerve terminals.

Variations in ocular pressure during menstrual cycle.

The present study investigated whether a correlation between days of the menstrual cycle and variations in intraocular pressure exists or not. The number of days since the beginning of last menses was recorded along with intraocular pressure for 1,459 women. Measurements were taken by Goldmann applanation tonometer. The differences among various days of menstrual cycle were statistically insignificant. The highest mean IOP occurred between 20th and 22nd day and the second peak from 13th to 15th days of the cycle. The lowest mean IOP was found from 16th to 19th days of the cycle. This study concludes that intraocular pressure varies with the various days of the menstrual cycle, but fluctuations are statistically insignificant and cannot affect the diagnoses of glaucoma.

Differential inhibition by hyperammonemia of the electron transport chain enzymes in synaptosomes and non-synaptic mitochondria in ornithine transcarbamylase-deficient spf-mice: restoration by acetyl-L-carnitine.

Sparse-fur (spf) mouse is the ideal animal model to study the neuropathology of congenital ornithine transcarbamylase (OTC) deficiency. Our current hypothesis implies that an ammonia-induced depletion of energy metabolism in the spf mouse, could be due to a reduction in the activities of the enzymes of the electron transport chain and a treatment with acetyl-L-carnitine could normalize this abnormality. We also hypothesized that there might be a differential degree of inhibition in synaptosomal and non-synaptic mitochondria, for the enzymes of the electron transport chain, caused by congenital hyperammonemia. We have therefore measured the activities of NADH-cytochrome C oxidoreductase, succinate cytochrome C oxidoreductase and cytochrome C oxidase in synaptosomes and non-synaptic mitochondria, isolated from spf mice and CD-1 controls with and without acetyl-L-carnitine treatment. Our results indicate a significant reduction (19-34%) in the activities of these complexes in synaptosomes in untreated spf mice, whereas in non-synaptic mitochondria, there was a tendency for the activities to decrease. Acetyl-L-carnitine treatment enhanced these activities (15-64%) for all the three enzyme complexes and its effect was more prominent on succinate cytochrome C oxidoreductase activity (64%). These studies point out that: (a) ammonia-induced disturbances in the energy metabolism could be more pronounced in neuronal mitochondria, and (b) the effect of acetyl-L-carnitine on the restoration of cerebral ATP in hyperammonemia could be through an enhancement of the activities of various electron transport chain enzymes.

Monthly measurements of intraocular pressure in normal, ocular hypertensive, and glaucoma male subjects of same age group.

BACKGROUND: Recently it has been shown that environmental conditions have a significant influence on intraocular pressure (IOP). Due to differences in inherent constitution, diet and environmental conditions, there is a clear need for well collected IOP data in different countries and ethnic groups. The seasonal variation of IOP has never been described in Pakistani subjects. METHODS: IOP was measured each month over the course of 12 months with the Goldmann applanation tonometer in normal, ocular hypertensive, and glaucoma male subjects. RESULTS: In all groups, the average intraocular pressures in the winter months were highest, while lowest in summer months. The intraocular pressures of spring and autumn months were nearly the same. The intraocular pressure levels in these seasons were between the IOP levels in summer and winter seasons. The difference between highest and lowest IOP was 1.4 +/- 0.2, 3.1 +/- 1.4, and 2.3 +/- 1.1 mmHg, in normal, ocular hypertensive, and glaucoma subjects, respectively. The ups and downs of intraocular pressure were greater in the ocular hypertensive subjects than in the glaucoma patients. CONCLUSIONS: This study confirms that season influences IOP, and concludes that seasonal influence is highest in ocular hypertensive than in normal and glaucoma subjects. As compared to other nations, effect of seasons on IOP seems to be somewhat less pronounced in Pakistan.

Acquired carnitine abnormalities in critically ill children.

UNLABELLED: In order to characterize the role of carnitine during metabolic stress, we prospectively determined carnitine profiles in plasma and urine on admission, days 2, 5, 10 and 15, among 28 critically ill children free of any known conditions associated with secondary carnitine deficiency. More than 25% of plasma and 50% of urinary carnitine measurements were abnormal; 96% (27/28) of patients displayed on at least one occasion an abnormal [< -2 SD or > +2 SD] carnitine value in plasma. Three children had extremely low [< 10 micromol/l] free carnitine (FC) levels in plasma. Plasma esterified and FC levels on admission were not related to the risk of mortality [PRISM score], to muscle lysis [CK values], and to the caloric intake. Levels of FC and esterified carnitine in plasma were unrelated to those measured in urine. CONCLUSION: Abnormal plasma and urine carnitine measurements are frequently found in critically ill children; the biological significance of these perturbations remains unclear. Caution must be exercised before concluding that an abnormal carnitine value is indicative of an underlying hereditary metabolic disorder in this population.

Developmental study of hepatic glutamine synthetase in a mouse model of congenital hyperammonemia.

The development of hepatic glutamine synthetase (GS; EC 6.3.1.2) activity and expression was studied in 1 to 112 day old sparse-fur (spf) mutant mice, with X-linked ornithine transcarbamylase (OTC, EC 2.1.3.3.) deficiency. The spf/Y mutant mice were found to have a smaller body weight (p < 0.01) yet possessed a larger liver (p < 0.01-0.05) in comparison to normal male mice (+/Y). The neonatal hepatic GS activity was retarded in the spf/Y mice (p < 0.01) but reached normal values by the 28th day of age, after which it increased as compared to the control CD-I mice (p < 0.01). The spf GS activity remained constant from 28 to 56 days, whereas the CD-I GS activity decreased. A further significant increase in the spf GS activity was observed from 56 day to 112 day indicating its adaptation. The decrease of GS mRNA in the spf/Y mice from 28 to 112 days of age (3.72 +/- 0.25 vs 1.68 +/- 0.32, p < 0.01) suggests translational and post-translational modifications in the regulation of GS activity. The changes in the activity and expression patterns of GS could be due to an effect of the OTC mutation on the hepatic ammonia metabolism. This may be indicative of the adaptational processes in the spf mutant mice, which may play a specific role in this animal model to help it to survive with its hyperammonemia.

Intraocular pressure and pregnancy: a comparison between normal and ocular hypertensive subjects.

Decrease in intraocular pressure (IOP) during pregnancy has been reported by previous studies, but these studies have concentrated on the last trimester of pregnancy or one reading per trimester. Moreover, IOP changes during pregnancy in ocular hypertensive subjects have never been described. Therefore, the present study was planned to determine IOP throughout the pregnancy, in both normal and ocular hypertensive subjects. Intraocular pressure was measured at six-week intervals throughout the pregnancy in 44 normal and 32 ocular hypertensive women. Intraocular pressure was also measured in 44 normal and 32 ocular hypertensive non-pregnant controls of the same age group. IOP measurements were taken with the Goldmann applanation tonometer. In normal subjects, IOP decreased significantly at the 18th week (p < 0.05). The IOP differences between first and second (p < 0.05) and second and third (p < 0.01) trimesters of pregnancy were significant. In these subjects, pregnancy decreased IOP by 19.6%. About 35% of total decrease occurred between 12th and 18th weeks of pregnancy. In ocular hypertensive subjects, IOP decreased significantly at the 24th week (p < 0.05). The IOP differences between second and third (p < 0.001) trimesters of pregnancy were significant. In these subjects, pregnancy decreased IOP by 24.4%. About 61% of total decrease occurred between 24th and 30th weeks of pregnancy. In both groups, decreases in IOP were independent of systolic and diastolic blood pressures, body weight, height, and number of previous pregnancies. With advancing pregnancy, intraocular pressure decreases. The higher decrease in ocular hypertensive subjects may be due to their higher level of ocular pressure. In ocular hypertensive subjects, pregnancy can decrease intraocular pressure up to a level of normal limit.

Developmental profile of mitochondrial glycine N-acyltransferase in human liver.

OBJECTIVE: To study the developmental profile of glycine N-acyltransferase (GAT) in the livers of children of various ages and to compare the total and specific GAT activity with that of the adult control subjects. METHODS: We measured the specific and the total mitochondrial activity of GAT in liver samples taken from 13 children 4 hours to 11 years of age. The samples were compared with those of control adults aged 24 to 40 years. Samples, either from liver-transplant donors or from autopsy, from those who died of a disorder not related to the liver, were obtained between 6 and 36 hours after death. RESULTS: At 4 hours after birth, very low specific activity and the total liver mitochondrial activity were observed (0.19 mumol/min per milligram protein and 210 mumol/min), with a steady increase up to age 7 months (2.51 mumol/min per milligram protein and 812 mumol/min). The mean specific and total GAT activity in children (n = 5) aged 18 months to 11 years was 6.38 +/- 0.13 and 1389 +/- 43 and in control adults aged 24 to 40 years (n = 3) was 6.5 +/- 0.3 and 1461 +/- 71 mumol/min per milligram protein and mumol/min, respectively. These specific and total GAT activity values from children aged 18 months to 11 years were not statistically significant (by analysis of variance and Mann-Whitney test) in comparison with the corresponding activity values from the adult control subjects. CONCLUSIONS: Our results indicate that up to age 7 months, children have only 5% to 40% of liver GAT-specific activity, whereas the peak activity is achieved at 18 months and remains constant until age 40 years. The delayed development of GAT in children may thus compromise the detoxification of various drugs and xenobiotics.

The effect of exercise training on physical fitness and plasma lipids in young Chinese men and women.

BACKGROUND: The mortality from coronary heart disease (CHD) has been steadily increasing in many parts of the world. Measures to reduce the incidence of CHD were initially addressed mainly to middle aged and elderly population groups, but for effective prevention of CHD, measures addressed to younger age groups are also necessary. Moreover, differences between male and female plasma lipid changes after exercise training are not known exactly. METHODS: The concentrations of plasma lipids, before and after regular physical exercise training for 12 weeks, were analyzed in 25 male and 25 female medical students of the same age group. Physical fitness was evaluated by the measurement of maximum oxygen uptake. RESULTS: Results indicated that plasma tri-glyceride, HDL-cholesterol, LDL-cholesterol and VLDL-cholesterol differences between the before-and-after exercise were significant (p < 0.05) in males while the differences of plasma total cholesterol were found to be insignificant. In females there were no significant changes in the plasma lipids levels. In both males and females, the marked increase in maximal O2 uptake after exercise training indicated an improvement in physical fitness. CONCLUSIONS: This study concludes that a short-term exercise program can improve plasma lipid and lipoprotein patterns more in males than in females. It also suggests that daily physical exercise may be an important prevention for cardiovascular diseases in later life, so it is essential to establish a life style with optimum nutrition and physical activity in both the young and in adults of all ages.