Serum bilirubin levels in breast- and formula-fed infants in the first 5 days of life.

A prospective study was conducted in a level II maternity unit to investigate the incidence of hyperbilirubinemia in healthy, term, breast-fed and formula-fed infants. Serum bilirubin levels were determined for 176 breast-red and 164 formula-fed infants in cord blood and on days 1, 2, 3 and 5 after birth. The mean total bilirubin levels were significantly higher on each postnatal day in the breast-fed infants, as was the proportion of infants with peak levels above 12 mg/dl (205 mumol/l; 28% v. 6%). The breast-fed infants also had significantly higher proportional weight losses on each postnatal day than the formula-fed infants. However, there was no correlation between the cumulative weight loss on day 3 and bilirubin levels on the same day with either feeding regimen. None of the infants required an exchange transfusion or prolonged care in hospital for hyperbilirubinemia.     

Sexual steroid levels and their clinical significance in the early neonatal age

Serum concentrations of progesterone (P) and estradiol (E2) in the umbilical cord blood were measured in healthy full term newborn infants and were related to the serum levels of indirect bilirubin at 72 hr postpartum in the same group of neonates. In those having higher concentration of bilirubin than 204 mumol/l at 72 hr after birth, cord P and E2 levels were significantly higher than in the rest of the group. Furthermore, strong correlation was found between serum levels of progesterone at 24 hr after birth and that of bilirubin at 72 hr postpartum in the same subjects. According to the authors' conclusion serum progesterone levels 24 hours after birth prognosticate the occurrence of neonatal hyperbilirubinaemia.     

Essential fatty acid status of neonates born to Inuit mothers: comparison with Caucasian neonates and effect of diet.

Fatty acid compositions were determined of phospholipids isolated from venous cord plasma and from the walls of umbilical arteries and veins, collected from healthy, a terme, Inuit and Caucasian (Dutch) neonates. The Inuit fatty acid profiles were characterized by a lower essential fatty acid (EFA) status, with higher levels of monounsaturated fatty acids, of Mead acid [20:3(n-9)] and its direct elongation product, and with lower amounts of the longer chain (greater than or equal to 20 carbon atoms), highly unsaturated (greater than or equal to 4 double bonds) fatty acids of both the (n-3) and (n-6) families. Levels of linoleic- and dihomo-gamma-linolenic acids were higher in Inuit as compared to Caucasian neonates, which suggests a low activity of the delta-5-desaturase in the Inuit. Within the Inuit group, a higher intake of marine food was associated with a better neonatal (n-3) status. Although the differences between Inuit and Caucasian neonates may be of genetic rather than of dietary origin, the results imply that dietary long-chain (n-3) or (n-6) fatty acids may be particularly important during pregnancy in Inuit mothers. Further studies are indicated with respect to the EFA content of the habitual Inuit diet and levels of delta-5-desaturase activity in the Inuit.     

Exertional heat stroke: the runner's nemesis.

Heat stroke in distance runners is increasing in frequency. A case is reported of a 41-year-old man who collapsed during a 10-km "fun run" held when the temperature was 31.6 degrees C and the humidity 80%. Acute renal failure (serum creatinine level 1530 mumol/l [17.3 mg/dl]), rhabdomyolysis, disseminated intravascular coagulation and hepatic damage complicated the clinical picture. Repeated peritoneal dialysis and one cycle of hemodialysis because of a very high serum level of uric acid (1.23 mmol/l [20.7 mg/dl]) were required. Although the illness was prolonged, recovery was almost complete, and 4 months after the man''s collapse the serum creatinine level had fallen to 133 mumol/l (1.5 mg/dl).     

Cryoprotective therapy for huge hepatocellular carcinoma: A study of 14 patients with a single lesion

Percutaneous cryoablation is a potential cure for hepatocellular carcinoma (HCC). This study reviewed retrospectively clinical data from 14 patients who underwent cryoablation of huge HCC (long diameter >7 cm). The side effects of cryosurgeries and liver function reverse were recorded and compared everyday. All the patients survived cryosurgery and none died before leaving hospital 2 weeks later. Despite liver-protective treatment before cryosurgery, alanine transaminase (ALT) and aspartate transaminase (AST) levels were increased significantly, but returned to preoperative levels 2 weeks post-cryosurgery. Before cryosurgery, mean total bilirubin (T.BIL) and direct bilirubin (D.BIL) levels were normal; 8–10 days after cryosurgery, they increased more than two-fold, but returned to the preoperative level 2 weeks post-cryosurgery. Serum transaminase and bilirubin levels were compared between hepatitis B positive and negative patients. The hepatitis B negative group’s AST level increased significantly 1 day post-cryosurgery (mean, 186 U/L) and decreased to the preoperative level at day 14. In the hepatitis B positive group, means transaminase and bilirubin reached peak values at different days post-cryosurgery. Overall, ALT and AST are valuable indicators of liver function impairment following cryosurgery. In patients with hepatitis B virus, close attention to the serum bilirubin level should be paid 8–10 days after cryosurgery. Liver-protective treatment may alleviate liver function impairment caused by cryosurgery of huge HCC.     

Neonatal serum bilirubin levels following the use of prostaglandin E2 in labour

A prospective study of 447 labours and the resulting neonates failed to reveal a significant difference between the mean serum bilirubin concentrations on the third and sixth day following spontaneous, accelerated or induced labour. A similar incidence of neonatal jaundice (bilirubin concentrations of 10 mg/100 or more) was found in the studied groups. However, there was a tendency for neonates born after accelerated or induced labour to have slightly higher bilirubin levels than those born after spontaneous labour. No strong dose dependent effect on the level of bilirubin concentration following Prostaglandin E₂ induced labour was demonstrated.     

Neonatal serum bilirubin levels following the use of prostaglandin E2 in labour.

A prospective study of 447 labours and the resulting neonates failed to reveal a significant difference between the mean serum bilirubin concentrations on the third and sixth day following spontaneous, accelerated or induced labour. A similar incidence of neonatal jaundice (bilirubin concentrations of 10 mg/100 or more) was found in the studied groups. However, there was a tendency for neonates born after accelerated or induced labour to have slightly higher bilirubin levels than those born after spontaneous labour. No strong dose dependent effect on the level of bilirubin concentration following Prostaglandin E2 induced labour was demonstrated.     

An integrated assessment of lead exposure in children: Correlation with biochemical and haematological indices

BackgroundLead (Pb) is a worldwide concern due to its persistent property in the environment. However, due to diminutive evidence and elusiveness, the impact of lead exposure on the biochemical and haematological parameter in school-age children is not well established.AimThis study primarily aimed to investigate blood lead (BL) in children and its association with haematological and biochemical parameter.MethodsA total of 43 children (4–12 years) were recruited in each control and study group. Furthermore, the study group were subdivided into two groups (group A (<10 μg/dl) and group B (>10 μg/dl)). BL level, haematological parameter including haemoglobin, packed cell volume, red blood cells, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, total leukocytes count, neutrophils, lymphocytes, monocytes, mean corpuscular volume, red cell distribution width, eosinophil’s, platelets in the whole blood and biochemical parameter such as liver function test (total bilirubin, alkaline phosphatase, serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, total protein, albumin) and kidney function test (sodium, potassium, blood urea nitrogen, creatinine) in serum were measured using anodic stripping voltammeter (ASV), Cell-Dyn Ruby Haematology analyser, Beckman coulter Unicel Dxc 800 Synchron Clinical analyser respectively.ResultsThe arithmetical mean of BL level was 19.93 ± 9.22 μg/dl (median: 17.5 μg/dl; range 9.1–37.4 μg/dl). Only 21 % children had BL levels <10 μg/dl and there were 79 % children with BL levels >10 μg/dl. Blood mean corpuscular haemoglobin concentration, Neutrophils, Monocytes were significantly higher between the control and study group. Additionally, haemoglobin, packed cell volume, red blood cells, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, Lymphocytes and mean corpuscular volume intensities were significantly lower in >10 μg/dl group whereas total leukocytes count, neutrophils, monocytes, red cell distribution width, eosinophil’s, platelets levels were statistically higher (p < 0.001).Serum alkaline phosphatase, serum glutamic-oxaloacetic transaminase, total protein, were higher (p < 0.05) and sodium, albumin were significantly lower in the study group. The mean value of sodium, potassium, total bilirubin, alkaline phosphatase, serum glutamic-pyruvic transaminase, total protein and blood urea nitrogen, creatinine in two groups (<10 μg/dl and >10 μg/dl) was not significantly different. Serum glutamic-oxaloacetic transaminase level was significantly higher (p = 0.015) while albumin levels were significantly lower (p = 0.034) in >10 μg/dl group. A statistically significant correlation of BL levels with all haematological parameters was also observed. Creatinine is positively and albumin was negatively correlated with BL levels.ConclusionThe outcomes specify that high BL levels were significantly associated with higher haematological and biochemical indices in exposed children. However, lead like noxious metals severely affected the haematological, kidney and liver health of children.     

Birth weight,length, head circumference and bilirubin level in Indian newborns in the Sioux Lookout Zone,northwestern Ontario.

The norms for birth weight, length, head circumference and bilirubin level for native newborns have not been available. To develop appropriate norms, data were obtained from the charts on all live births in the Sioux Lookout Zone, northwestern Ontario, in 1968-69 and 1974-77. These data were correlated to maternal age and parity as well as sex of the infant. Despite impoverished living conditions, the birth weights of the study population were significantly higher than the Canadian norms; length and head circumference, however, were not significantly different. Over one third of the infants had serum bilirubin levels greater than 12 mg/dL (205 mumol/L). Increased maternal age was associated with increased birth weight and length and a lower bilirubin level.     

Iron and copper concentrations in the maternal and fetal serum, placenta and amniotic fluid during the reproductive stadium as well as in the milk of rabbits

Serum concentrations of iron and copper from rabbits (New Zealand White hybrids; N = 12) were determined during the reproductive stadium (gestation and four weeks of lactation). Samples of serum from fetuses, placental tissue and amniotic fluid were also examined. Iron: a decrease of iron in the maternal serum during the second half of gestation was observed, whilst a significant rise occurred in the first week of lactation. The content of iron in the fetal serum dropped from day 21 to day 28 of gestation. The iron concentration in the placental tissue decreased during this time. A rise of the iron level in the amniotic fluid was determined from day 21 to day 28 of gestation. The iron content in the milk was about 33 mumol/l (first and second day of lactation). Copper: in the first half of pregnancy the copper level diminished slightly compared with the content of non-pregnant, non-lactating rabbits, while a rise was observed in the fourth week of this period. The copper concentration decreased in the first week of lactation and then reached the peak level in the second week of this phase. The copper level in the fetal serum declined from day 21 to day 28 of gestation, while the copper content in the amniotic fluid increased significantly on day 28, in comparison with day 21 of gestation. In contrast, a decline of the copper concentration in the placental tissue was noticed from day 21 to day 28 of this period. The copper content in the milk was nearly 25 mumol/l (first and second day of lactation).     

Cryoprotective therapy for hepatocellular carcinoma: Study of 51 patients with a single lesion

Percutaneous cryoablation is a potentially curative treatment for hepatocellular carcinoma (HCC). After liver cryosurgery, rapid elevations of transaminases and bilirubin are common, but are usually transient and normalize within a few days. This study retrospectively reviewed clinical data from 51 patients who underwent liver cryoablation in our hospital during the past 4.5 years. Sixty-six percutaneous cryoablations were performed in these patients and transaminase and bilirubin levels before and after the procedure were observed. Although most patients received liver-protective treatment before cryosurgery, transaminase levels were double (mean alanine transaminase (ALT) and aspartate transaminase (AST) were 71 U/L and 85 U/L, respectively) the normal ranges in our hospital. One day after cryosurgery, ALT and AST had increased 3.3-fold (peak mean was 241 U/L) and 5-fold (peak mean was 427 U/L), respectively, but were close to the preoperative level 5 days post-cryosurgery. No significant increase of serum bilirubin was observed. Serum transaminase and bilirubin levels were compared between hepatitis B positive and hepatitis B negative patients. Only in the hepatitis B positive group were total bilirubin (74 μmol/L/23 μmol/L = 3.2) and direct bilirubin (45 μmol/L/12 μmol/L = 3.8) more than 3 times the preoperative level 7–9 days after treatment. Overall, ALT and AST are valuable as indicators of liver function impairment following cryosurgery. In patients with hepatitis B virus, serum bilirubin was 3 times the preoperative level 7–9 days after cryosurgery. Liver-protective treatment may alleviate liver function impairment due to cryosurgery.     

Maternity blues and major endocrine changes: Cardiff puerperal mood and hormone study II.

OBJECTIVES--To define relation between mood and concentrations of progesterone and cortisol during perinatal period to test hypothesis that rapid physiological withdrawal of steroid hormones after delivery is associated with depression. DESIGN--Prospective study of primiparous women from two weeks before expected date of delivery to 35 days postpartum. SETTING--Antenatal clinic in university hospital, obstetric inpatient unit, patients'' homes. SUBJECTS--120 of 156 primiparous women interviewed. Remainder excluded because of major marital, socioeconomic, or medical problems or because caesarean section required. MAIN OUTCOME MEASURES--Concentrations of progesterone and cortisol in saliva samples; women''s moods assessed by various scores for depression. RESULTS--Changes in salivary progesterone and cortisol concentrations were similar to those already characterised for plasma. Peak mean score for maternity blues (5.3 on Stein scale) was on day five postpartum (P < 0.02 compared with mean scores on other postpartum days). High postpartum scores for maternity blues were associated with high antenatal progesterone concentrations on day before delivery (P < 0.05), with high rate of rise of antenatal progesterone concentrations (P < 0.05), with decreasing progesterone concentrations from day of delivery to day of peak blues score (P > or = 0.01), and with low progesterone concentrations on day of peak blues score (P < 0.01). Seventy eight women were designated as having maternity blues (peak score > or = 8 on Stein scale) while 39 had no blues. Women with blues had significantly higher antenatal progesterone concentrations and lower postnatal concentrations than women without blues (geometric mean progesterone concentrations: one day before delivery 3860 pmol/l v 3210 pmol/l respectively, P = 0.03; ten days postpartum 88 pmol/l v 114 pmol/l, P = 0.048). Cortisol concentrations were not significantly associated with mood. CONCLUSION--Maternal mood in the days immediately after delivery is related to withdrawal of naturally occurring progesterone.     

Cellular activities associated with the transition of chick embryo fibroblasts from stationary to proliferation state

Chick embryo fibroblasts on the 5th day of culture in proteinfree medium were stimulated to accelerated growth by supplementation of the medium with ATP (50 mumol/l, insulin (0.16 I.U./ml) or chick serum (5% v/v). Kinetics of the entry of cells into the S phase and later into the logarythmic phase of growth were found to be different in cultures treated with these three factors in spite that the final saturation densities reached after 30 days of culture were similar. No direct correlation between cell spreading and the cell transition from the stationary to the proliferation state was found. The proliferating cells showed the higher rate of locomotion than in stationary cultures. The initial protein-free medium, supporting the long survival of chick embryo fibroblasts and their susceptibility to growth accelerating factors, was further simplified by replacement of ADA buffer with EDTA (0.4 mmol/l).     

Formula feeding potentiates docosahexaenoic and arachidonic acid biosynthesis in term and preterm baboon neonates

Infant formulas supplemented with docosahexaenoic acid (DHA) and arachidonic acid (ARA) are now available in the United States; however, little is known about the factors that affect biosynthesis. Baboon neonates were assigned to one of four treatments: term, breast-fed; term, formula-fed; preterm (155 of 182 days gestation), formula-fed; and preterm, formula+DHA/ARA-fed. Standard formula had no DHA/ARA; supplemented formula had 0.61%wt DHA (0.3% of calories) and 1.21%wt ARA (0.6% of calories), and baboon breast milk contained 0.68 +/- 0.22%wt DHA and 0.62 +/- 0.12%wt ARA. At 14 days adjusted age, neonates received a combined oral dose of [U-13C]alpha-linolenic acid (LNA*) and [U-13C]linoleic acid (LA*), and tissues were analyzed 14 days after dose. Brain accretion of linolenic acid-derived DHA was approximately 3-fold greater for the formula groups than for the breast-fed group, and dietary DHA partially attenuated excess DHA synthesis among preterms. A similar, significant pattern was found in other organs. Brain linoleic acid-derived ARA accretion was significantly greater in the unsupplemented term group but not in the preterm groups compared with the breast-fed group. These data show that formula potentiates the biosynthesis/accretion of DHA/ARA in term and preterm neonates compared with breast-fed neonates and that the inclusion of DHA/ARA in preterm formula partially restores DHA/ARA biosynthesis to lower, breast-fed levels. Current formula DHA concentrations are inadequate to normalize long-chain polyunsaturated fatty acids synthesis to that of breast-fed levels.     

Effects of synthetic ovine corticotropin-releasing factor (CRF) on plasma ACTH and cortisol in 31 normal human males

Responses of plasma ACTH and cortisol to corticotropin-releasing factor (CRF) were evaluated in 31 normal human males. 1.0 micrograms/ks of sterilized synthetic ovine CRF was administered to the subjects, aged 19 to 53 yr and weighing 50 to 78 kg, at between 9:30 a.m. and 10:30 a.m. as an intravenous bolus injection after an overnight fast. Blood specimens were drawn before and 15, 30, 60, 90 and 120 min after injection for later determination of plasma ACTH and cortisol concentrations by radioimmunoassays. Plasma ACTH and cortisol levels for all subjects rose significantly (p less than 0.001) from the basal level (mean +/- SEM, 26.8 +/- 4.5 pg/ml and 12.6 +/- 0.9 micrograms/dl) to peak levels (58.4 +/- 5.5 pg/ml and 22.9 +/- 1.0 micrograms/dl) at 30 min and at 60 min, respectively. Although the plasma concentrations of ACTH and cortisol thereafter declined gradually, the levels at 120 min (43.4 +/- 5.2 pg/ml and 18.9 +/- 0.9 micrograms/ml, respectively) were still significantly higher than the basal levels (p less than 0.001). Significant inverse correlations were observed between the basal levels of each hormone and the ratio of the peak level to the basal level (p less than 0.01), and the increases in plasma ACTH and cortisol concentrations were either not significant or much smaller for the individuals in whom the basal levels were higher than 65 pg/ml and 17.0 micrograms/dl, respectively. No serious subjective symptom was observed during the experimental period in any of the subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rate of recalls in congenital hypothyroidism based upon a regional survey in Isfahan, Iran, using serum T4 and TSH analyses: comparison of two different recall methods

AIMS: To evaluate and compare the recall rate in congenital hypothyroidism screening project in Isfahan, first using an approach involving measures of both TSH and T4 and then using TSH alone. METHODS: From June 2002 to January 2005, serum TSH and T4 level of referred neonates were measured at 3rd to 7th day of birth through venous sampling. If neonates' serum TSH was >20 mIU/l or T4 was <6.5 microg/dl by the first protocol, or TSH was >20 mIU/l by the second protocol, they were recalled. TSH and T4 were measured using an immunoradiometric assay and radioimmunoassay, respectively. Neonates with TSH > 10 and T4 < 6.5 on their second measurement were considered as congenitally hypothyroid. RESULTS: Serum T4 and TSH of 29,425 neonates by first and 57,235 neonates by second recall approach were measured. Recall rate was higher in the first protocol (2.2% vs. 0.6%, p < 0.05). Most of the recalled neonates in the first protocol were recalled for low T4 level (p < 0.05). The prevalence of CH was 1 in 350 livebirths. CONCLUSION: Although the recall rate was in the acceptable range by either approach, the TSH alone protocol seems to be a more sensitive and practical approach with the least recall burden and considering the high prevalence of CH in our region merit adaptation of widespread screening for CH using TSH measurements from heel stab blood spotted on filter paper.     

Nitric oxide levels and antioxidant enzyme activities in jaundices of premature infants

Free radicals are effective in the genesis of several diseases in the neonatal period. This study aimed to show the relationship between serum bilirubin levels and plasma nitric oxide and the activity of enzymes in the erythrocyte such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in premature infants. In the study, 20 premature infants with newborn jaundice were included and the control group was formed by 15 premature infants without jaundice. Venous blood samples were taken from all neonates in the study and control groups on the first day of hospitalization. Plasma nitric oxide levels and activities of SOD, GSH-Px and CAT enzymes in the erythrocytes were investigated in these samples. Plasma nitric oxide and serum bilirubin levels were found to be significantly higher in the study group (47.4 +/- 7.25 micromol l(-1), 18.41 +/- 3.28 mg dl(-1), respectively) than those in the control group (33.46 +/- 6.43 micromol l(-1), 4.35 +/- 0.60 mg dl(-1), respectively; p < 0.001). In addition, erythrocyte SOD, GSH-Px and CAT enzyme activities (724 +/- 78.61, 673 +/- 90.5, 63 +/- 12.8 U g(-1) Hb, respectively) were found to be significantly lower in the study group than those in the control group (1208 +/- 129.04, 1097.6 +/- 75.8, 99.06 +/- 12.4 U g(-1) Hb, respectively, p < 0.001). It was concluded that in the aetiology of hyperbilirubinemia, neonatal erythrocytes and nitric oxide reactions are affected differently and that erythrocyte haemolysis caused as a result of these effects may play a role in the aetiopathogenesis of unconjugated hyperbilirubinemia. Haemolysis may also be seen because of the inadequacy of the protection by erythrocytes against the cytotoxic effects of free radicals resulting from the lack of antioxidant enzymes in these cells.     

Effect of pre-treatment with St John's Wort on nephrotoxicity of cisplatin in rats

An herbal health care supplement, St John's Wort (SJW, Hypericum perforatum) has become widely used in the treatment of depression, and is known to interact with therapeutic drugs. Here we report a preventive effect of SJW on cisplatin nephrotoxicity in rats. Rats were given SJW (400 mg/kg/day, p.o.) for 10 consecutive days, and were injected with cisplatin (5 mg/kg, i.v.) on the day after the final SJW treatment. Cisplatin treatment increased the serum creatinine level, which is an index of nephrotoxicity, to 1.51+/-0.22 mg/dl (mean+/-SE) from 0.28+/-0.05 mg/dl (control) on day 5 after the cisplatin injection. This increase fell significantly to 0.86+/-0.13 mg/dl by pre-treatment with SJW. Cisplatin-induced histological abnormality of the kidney was blocked by pre-treatment with SJW. When SJW was administered for 10 days, the amounts of renal metallothionein (MT) and hepatic multidrug resistance protein 2 (Mrp2) were increased to 164.8+/-13.0% and 220.8+/-39.3% (mean+/-SE) of controls, respectively. GSH levels in the kidney and liver were not changed. Total and free cisplatin concentration in serum was not influenced by SJW treatment. In conclusion, the results suggest that pre-treatment with SJW may diminish cisplatin nephrotoxicity.     

危重症新生儿肾上腺皮质功能状态的研究

目的:研究危重症新生儿肾上腺皮质功能状态、肾上腺皮质功能不全(AI)的发生率及其与患儿预后的关系。方法:选择我科收治的日龄2天的危重症新生儿52例(其中早产儿23例,足月儿29例),根据新生儿危重病例评分(NCIS)分为轻度危重组和重度危重组,分别检测其血清基础皮质醇和小剂量促肾上腺皮质激素(ACTH)刺激实验30分钟后的清皮质醇峰值。血清基础皮质醇15μg/dl为合并AI。结果:危重症早产儿基础皮质醇浓度及小剂量ACTH刺激实验前后皮质醇差值均较足月儿组低[(15.08±4.98)μg/dl vs(19.65±9.18)μg/dl,P=0.027;(12.06±3.71)μg/dl vs(19.09±4.75)μg/dl,P=0.000]。危重症新生儿合并AI的发生率为38.5%,其中早产儿组为47.8%,足月儿组为34.5%。AI组新生儿死亡2例,未发现AI与患儿的死亡率有关。结论:危重症早产儿肾上腺皮质功能较足月儿差。危重症新生儿合并AI的发生率较高,但与患儿的死亡率无关。     

Effect on Neonatal Jaundice of Oestrogens and Progestogens Taken before and after Conception

Study of 182 newborn babies has shown that among bottle-fed infants the mean plasma bilirubin concentration was slightly but significantly higher (P <0·01) in those whose mothers had previously used steroid contraceptives. A similar finding was not noted among breast-fed infants.A further 16 infants whose mothers had received progestogen therapy during their pregnancy had a mean plasma bilirubin concentration which was significantly higher than each of the four other groups of infants studied (P <0·01). Icterus occasionally reached clinically important levels in these babies.