Adina Bar-Haim

Changes in serum hepcidin levels in acute iron intoxication in a rat model

Hepcidin is an important and recently discovered regulator of iron homeostasis. Acute iron intoxication is one of the leading causes of overdose mortality in children. It is difficult to estimate the degree of iron intoxication since iron serum levels do not correlate with the actual clinical severity. In the current study we aimed to investigate whether serum hepcidin levels are elevated in acute iron intoxication. Rats were divided into two iron dose groups and one control group. Each group was further subdivided into four time groups following the administration of iron. Levels of hepcidin, iron and liver enzymes were measured, and animals were followed for signs of toxicity. Serum hepcidin levels were significantly higher in the group treated with toxic doses of iron (p=0.005). No significant difference in serum iron levels was found between the groups. In acute iron intoxication serum hepcidin levels increase significantly and remain elevated for at least 6h. We postulate that beyond the first hour after iron administration, serum hepcidin levels provide a better estimate of the amount of iron intake than do serum iron levels.

The proliferation arrest of primary tumor cells out-of-niche is associated with widespread downregulation of mitotic and transcriptional genes

Abstract In recording the changes acquired in gene expression profile during culture of fresh bone marrow samples from patients with multiple myeloma or acute myeloid leukemia, the most remarkable finding in both instances was widespread downregulation of mitotic and transcriptional genes (e.g. MKI67, CCNB1, ASPM, SGOL1, DLGAP5, CENPF, BUB1, KIF23, KIF18a, KIF11, KIF14, KIF4, NUF2, KIF1, AE2FB, TOP2A, NCAPG, TTK, CDC20, and AURKB), which could account for the ensuing proliferation arrest. Many of these genes were also underexpressed in leukemic cells from the blood or myeloma cells from an extramedullary site compared with their expression in the aspirates. Taken together, our results exhibited mitotic and transcriptional gene subsets where their expression appears to be coordinated and niche dependent. In addition, the genes induced during culture specified a variety of angiogenic factors (e.g. interleukin-8 and CXCL-5) and extracellular matrix proteins (e.g. osteopontin and fibronectin) probably released by the tumor cells while generating their favored microenvironment.

Oral N-acetylcysteine has a deleterious effect in acute iron intoxication in rats.

Acute iron intoxication is associated with depletion of reduced glutathione in hepatocytes and changes in the glutathione system enzymes. We hypothesized that treatment with N-acetylcysteine (NAC), a glutathione reducing agent and an antioxidant, would reduce mortality in acute iron intoxication. We used a rat model to test this hypothesis. Male rats were assigned to 4 groups. Group 1 received 400 mg/kg elemental iron by oral gavage, group 2 received the same dose of iron followed by NAC, group 3 received NAC only, whereas group 4 received distilled water. Iron and liver transaminases in the blood, and glutathione system enzymes in the liver and erythrocytes were measured. Mortality in group 2 was significantly higher after 2, 6, and 24 hours compared with group 1 (P < .001). No deaths were observed in groups 3 and 4. Serum iron levels were significantly higher in group 2 rats compared to group 1 rats (P < .001). Hepatic and erythrocyte glutathione system enzymes were significantly lower among rats in group 2 compared to rats in group 1. The administration of NAC probably increased the absorption of iron through the gastrointestinal tract, causing higher serum iron levels with significant hepatic damage. These results indicate that in a rat model of acute iron intoxication, orally administered NAC may increase mortality.

Hepcidin in acute iron toxicity

BACKGROUND Hepcidin regulates extracellular iron concentration by inhibiting iron release from macrophages and preventing iron absorption in the intestine. Our objective was to evaluate the expression of hepcidin in the liver in acute iron poisoning in a rat model. METHODS Male Wistar rats were assigned to group 1, who received 750 mg/kg elemental iron (LD(50)) by gavage, and group 2 (control), who received distilled water. Iron concentrations and liver transaminases were measured in the serum. Hepcidin messenger RNA levels were measured in the liver. RESULTS Mean serum iron levels, aspartate aminotransferase, alanine aminotransferase, and uric acid were significantly higher in group 1 compared to group 2 (P < .0001, P = .01, P < .0001, and P = 0.0001, respectively). Hepcidin messenger RNA levels in the liver were significantly higher in the study group (P = .005). CONCLUSIONS In acute iron intoxication, hepcidin expression in the liver significantly increased. Further studies are needed to determine whether hepcidin levels correlate with the severity of the intoxication.

GPRC5D is a promising marker for monitoring the tumor load and to target multiple myeloma cells

Abstract In a comparison of gene expression profile in unsorted bone marrow (BM) samples from patients with multiple myeloma (MM), acute leukemia, and diffuse large B-cell lymphoma infiltrating the BM, the leading myeloma distinguishing gene was GPRC5D. This gene was highly expressed in BM samples from the 10 MM cases examined as opposed to minimal expression in samples from the eight cases with other hematological malignancies. Moreover, following antimyeloma treatment the expression of GPRC5D decreased several folds. The strong and selective expression of GPRC5D in MM cells makes this gene and its encoded surface protein as promising markers for monitoring the tumor load and hopefully also as targets for antimyeloma antibodies.

Depletion of glutathione system enzymes of the liver and erythrocytes in a rat model of acute iron poisoning.

ABSTRACT The proposed mechanism of iron-induced hepatotoxicity is free radical formation. It was hypothesized that the glutathione system of the liver and erythrocytes will be affected by acute iron poisoning. Male Wistar rats, 6–8 weeks of age, were assigned to one of three groups. Group I received distilled water, group II received 400 mg/kg elemental iron, and group III received 750 mg/kg elemental iron. All groups were gavage fed. Iron concentration, glutathione, and glutathione system enzymes were then measured in the liver and erythrocytes. The hepatic level of reduced glutathione (GSH) was significantly lower in groups II (3.1 ± 4.6 μmol/mg protein) and III (4.7 ± 4.6 μmol/mg protein) in comparison with group I (11.5 ± 6.2 μmol/mg protein) (p < 0.001). Hepatic levels of glutathione S-transferase (GST) were higher and glutathione peroxidase (GPX) levels were lower in group III compared to groups II and I (p < 0.001 and p < 0.001). Compared to group I, glutathione reductase (GR) was lower in groups II and III (p < 0.001). There was no correlation between GSH, oxidized glutathione (GSSG), GST, GR, and GPX levels in the erythrocytes and in the liver (p = 0.41, p = 0.48, p = 0.49, p = 0.53, p = 01.4, and p = 0.84, respectively). In conclusion, acute iron intoxication in rats is associated with depletion of reduced glutathione in the liver.

Lamotrigine Serum Concentration in Children With Epilepsy

The correlation between lamotrigine serum concentration, efficacy, and toxicity in children is controversial. The database of the Clinical Pharmacology Laboratory at Assaf Harofeh Medical Center was retrospectively searched to identify lamotrigine serum concentrations in children aged 2-19 years with refractory epilepsy who received lamotrigine as monotherapy or polytherapy from 2007-2010. Data collected included age at epilepsy onset, additional antiepileptic drugs, lamotrigine dose, monthly seizure frequency before and after lamotrigine treatment, and side effects. Sixty blood samples were collected from 42 children aged 10.1 ± 4.9 years (range, 2-20 years). Seizure types included complex partial (n = 28), simple partial (n = 7), absence (n = 2), and generalized tonic-clonic (n = 23). Decreased seizure frequency was observed in 38 (63.3%) patients. No correlation with lamotrigine serum concentration was evident, but seizure frequency was significantly influenced by age and lamotrigine dose. Side effects were reported in 21 (35%) patients. Only diplopia was significantly correlated with lamotrigine serum concentration. Lamotrigine was more effective at lower doses and in older children. Lamotrigine serum concentration correlated significantly with diplopia, but not with other side effects or with clinical efficacy. Overall, lamotrigine is effective and safe in children with refractory epilepsy.

Hyperbaric Oxygen Treatment Reduces Mortality in Acute Iron Intoxication in Rats

Acute iron intoxication is one of the leading causes of overdose morbidity and mortality in children. The toxicity of iron has been postulated to be related to free radical formation and subsequent lipid peroxidation. Hyperbaric oxygen treatment can result in a number of beneficial biochemical, cellular and physiological effects, and has recently been shown to induce cellular protection against ischaemia, and in some cases against free radical formation. In the current study, we aimed to investigate the effects of hyperbaric oxygen treatment on mortality in acute iron intoxication in rats. After iron administration, 57 animals were divided into two groups: a treatment group receiving hyperbaric oxygen treatment (n = 30) and a control group (n = 27), and followed for 48 hr for signs of severe intoxication. In the second part of the study, 21 animals were divided into a treatment group receiving hyperbaric oxygen treatment (n = 10) and a control group (n = 11), and markers of oxidative stress were evaluated. We showed a significant reduction in mortality in hyperbaric oxygen-treated animals from 17 of 27 (62.9%) among untreated rats to 6 of 30 (20%). Surprisingly, in the treatment group, levels of oxidative stress markers were higher. We postulate that hyperbaric oxygen has a potentially beneficial effect in acute iron intoxication.

Effect of a 24+ hour fast on breast milk composition.

In this preliminary prospective study, breast milk is sampled surrounding 4 religious fast days to determine the effect of a more than 24-hour fast on breast milk composition. The participants are 48 healthy women nursing healthy babies between 1 and 6 months of age. Samples are collected within 2 days before the fast (baseline), immediately after the fast, and 24 hours after fast completion. Samples are tested for sodium, calcium, phosphorus, triglycerides, total protein, and lactose. From baseline to immediately after fast, mean sodium, calcium, and protein levels increase (P = .013, P < .0001, and P < .0001, respectively) and mean phosphorus and lactose levels decrease (P < .0001 and P = .003, respectively). Mean triglycerides are unchanged. Twenty-four hours after fast, parameters are no longer significantly different from baseline except for elevated mean protein levels (P = .022) and lactose that is still reduced (P = .017). A fast of this nature is statistically associated with certain biochemical changes in breast milk. J Hum Lact. 25(2):194-198

Valganciclovir Dosing for Cytomegalovirus Prophylaxis in Pediatric Solid-organ Transplant Recipients: A Prospective Pharmacokinetic Study

Background: Valganciclovir is extensively used for prophylaxis and treatment of cytomegalovirus (CMV) infection in solid-organ transplant recipients. However, pharmacokinetic data in children are scarce, and the pediatric dosing regimen is uncertain. This study sought to prospectively evaluate the pharmacokinetic profile, the clinical efficacy and safety of oral valganciclovir in pediatric transplant recipients and compare different dosing regimens. Methods: The cohort included solid-organ transplant recipients treated with valganciclovir for CMV prophylaxis in 2014–2015 at a tertiary pediatric medical center. All received a weight-based once-daily oral dose of 17 mg/kg. Ganciclovir concentrations were measured and the area under the curve (AUC0–24) was calculated. Results: Thirteen children of median age 7.3 years (interquartile range, 2.2–11.6) were included. Median ganciclovir AUC0–24 was 21.0 mcg·h/mL (interquartile range, 17.1–39.8); 10 patients (77%) attained AUC0–24 <40 mcg·h/mL. Exposure to ganciclovir was about 2-fold lower in young children (<9 years old; P = 0.01) and children with low body surface area (BSA; <0.7 m2; P = 0.006) than in their counterparts. Significantly lower doses were recommended with our weight-based protocol than with the manufacturer-recommended BSA- and glomerular filtration rate-based protocol (P = 0.002), reaching a 3-fold difference in infants. No evidence of CMV viremia or disease was observed while prophylaxis was given. Conclusions: The weight-based regimen of 17 mg/kg/dose oral valganciclovir results in relatively low ganciclovir exposure, especially in young children with low BSA, yet showed satisfactory clinical efficacy for CMV prophylaxis. The manufacturer’s dosing recommendation appears to result in supratherapeutic ganciclovir concentrations. Further studies are needed to establish target AUCs and valganciclovir dosing for CMV prophylaxis in pediatric transplant recipients.