Perinatal asphyxia in the rat has lifelong effects on morphology, cognitive functions, and behavior

Perinatal asphyxia (PA) is a major determinant of neurological morbidity and mortality in the neonatal period. Many studies have been investigating neurological deficits following PA, including seizures, cerebral palsy, mental retardation, as well as psychiatric deficits. Most research performed so far has been focusing on acute or subacute sequelae and has uncovered a variety of morphological, neurochemical, behavioral, and cognitive changes following PA. However, information on long-term sequelae of animals that underwent a period of PA is scanty. Perinatally asphyxiated rats at the end of their life span present with immunohistochemical and synaptic changes as well as changes in brain protein expression. Furthermore, deficits in cognitive function tested in the Morris water maze and changes in social behavior were described. In this review, we are summarizing and discussing reported effects of global PA on morphology, cognitive functions, and behavior in rats at the end of their life span.     

Clozapine in drug induced psychosis in Parkinson's disease: a randomised, placebo controlled study with open follow up

OBJECTIVE: To compare the efficacy and safety of clozapine in drug induced psychosis in Parkinson's disease (PD). METHODS: A four week, randomised, double blind, parallel comparison of clozapine and placebo, followed by a 12 week clozapine open period, plus a one month period after drug discontinuation, in 60 patients with PD. The primary efficacy outcome was the "clinical global impression scale" (CGI); the positive subscore of the "positive and negative syndrome scale" (PANSS) was used as the secondary efficacy parameter and the "unified Parkinson's disease rating scale" (UPDRS) and the "mini mental test examination" (MMSE) as safety outcomes. RESULTS: The mean (SD) dosage of clozapine was 35.8 (12.5-50) mg at the end of the double blind period. The mean (SD) scores on the CGI improved by 1.8 (1.5) for the clozapine group compared with 0.6 (1.1) for the placebo group (p = 0.001). The mean (SD) positive subscore of PANSS improved by 5.6 (3.9) for the clozapine group (0.8 (2.8) for the placebo group; p < 0.0001). At the end of the open period, 25 patients had completely recovered from delusions and hallucinations, and 19 experienced a relapse within one month after the clozapine washout period. The UPDRS motor and MMSE mean scores did not change significantly in either group. Somnolence was more frequent with clozapine than with placebo. CONCLUSIONS: Clozapine at a mean dose lower than 50 mg/day improves drug induced psychosis in PD without significant worsening of motor function, and the effect wears off once the treatment stops.     

Pharmacokinetics and pharmacodynamics of single-chain recombinant human follicle-stimulating hormone containing the human chorionic gonadotropin carboxyterminal peptide in the rhesus monkey

Objective: To compare the pharmacokinetics of a long-acting FSH analog containing the hCG-β carboxyterminal peptide (recombinant hFSH–CTP) with native recombinant hFSH and describe the pharmacodynamics of recombinant hFSH–CTP after SC injection in female rhesus monkeys.

Design: Rhesus monkey study.

Setting: Academic research environment.

Animal(s): Ten female rhesus monkeys.

Intervention(s): Recombinant hFSH and recombinant hFSH–CTP were administered via a single SC or IV dose to rhesus monkeys, and serial phlebotomy was performed (n = 2 and N = 4 for SC recombinant hFSH and recombinant hFSH–CTP, respectively; for IV dosing, N = 1 in each group). An additional two monkeys were pretreated with SC ganirelix and received SC recombinant hFSH–CTP after confirmation of pituitary suppression.

Main Outcome Measure(s): Plasma disappearance rate of recombinant hFSH and recombinant hFSH–CTP and serum estradiol levels.

Result(s): The elimination half-life of recombinant hFSH–CTP was twofold and fourfold longer than that for recombinant hFSH after SC and IV dosing, respectively. The absorption half-life was approximately threefold longer for recombinant hFSH–CTP than for recombinant hFSH after SC administration. Recombinant hFSH–CTP stimulates estradiol secretion for 5–7 days after an isolated SC dose.

Conclusion(s): Addition of the hCG-β carboxyterminal peptide to hFSH-β results in an FSH analog with longer absorption and elimination half-lives compared with native hormone. This analog is capable of prolonged ovarian stimulation in rhesus monkeys after an isolated SC injection.     

Inhibition of insulin-like growth factor-1 receptor signaling enhances growth-inhibitory and proapoptotic effects of gefitinib (Iressa) in human breast cancer cells

Introduction  

Gefitinib (Iressa, ZD 1839, AstraZeneca) blocks the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and inhibits proliferation of several human cancer cell types including breast cancer. Phase II clinical trials with gefitinib monotherapy showed an objective response of 9 to 19% in non-small-cell lung cancer patients and less than 10% for breast cancer, and phase III results have indicated no benefit of gefitinib in combination with chemotherapy over chemotherapy alone. In order to improve the antineoplastic activity of gefitinib, we investigated the effects of blocking the signalling of the insulin-like growth factor 1 receptor (IGF-1R), a tyrosine kinase with a crucial role in malignancy that is coexpressed with EGFR in most human primary breast carcinomas.     

The familial Mediterranean fever (MEVF) gene as a modifier of Crohn's disease

OBJECTIVES: Crohn's disease (CD) has been reported to be more frequent among non-Ashkenazi Jewish patients suffering from familial Mediterranean fever (FMF). Interestingly, functional similarities between the CD susceptibility gene (NOD2/CARD15) and the FMF gene (MEFV) have been described: both belong to the death domain containing protein family, important in the regulation of apoptosis, cytokine processing and inflammation. AIMS: To investigate the prevalence of MEFV mutations in Jewish non-Ashkenazi CD patients and its putative effect on CD presentation. METHODS: Germline DNA of 105 Israeli CD patients of non-Ashkenazi and mixed Ashkenazi-non-Ashkenazi ethnic background was analyzed for three most common MEFV mutations: M694V, V726A, and E148Q. Five patients (4.7%) with a clinical diagnosis of FMF were included. Data obtained from each patient included: age of onset, disease location, and behavior, the presence of extraintestinal manifestations of CD and therapeutic regimens. RESULTS: The overall prevalence of mutation carriers among non-FMF-CD patients was 13% (13/100). A stricturing disease pattern was observed in 56% (10/18) of all carriers, FMF-CD, and non-FMF-CD patients, and in 25% (22/87) of noncarriers (OR: 3.7, 95% CI: 1.3-10.5, p= 0.015). The prevalence of fistulas was comparable in both groups. Extraintestinal manifestations were significantly more frequent among carriers than noncarriers (65%vs 32%, OR 3.9, 95% CI = 1.3-11.5, p= 0.015). No differences were observed in disease location and disease severity. CONCLUSIONS: MEFV mutations are not associated with CD susceptibility, yet the presence of these mutations appears to be associated with a stricturing disease pattern and extraintestinal disease manifestations of CD.     

Mass spectrometrical analysis of human serine racemase in foetal brain

Summary. We analysed human serine racemase for the first time from human foetal brain by mass spectrometrical methods, MALDI MS and MS/MS. The detection of human serine racemase from a transient area of human foetal brain, the perireticular nucleus, that is suggested to be mainly involved in guidance of corticofugal and thalamocortical fibers, may be a clue for the important role of this enzyme in neuronal migration and brain development via regulation of NMDA receptor activity.     

Preterm infants with low immunoglobulin G levels have increased risk of neonatal sepsis but do not benefit from prophylactic immunoglobulin G

OBJECTIVE: In a prospective, randomized, placebo-controlled, multicenter study, we evaluated the prevention of neonatal infections with intravenous immunoglobulin G (IVIgG) prophylaxis for preterm infants (gestational age <33 weeks) with umbilical cord blood IgG levels < or =4 g/L. STUDY DESIGN: Intravenous IgG or placebo (albumin), 1 g/kg body weight, was given on days 0, 3, 7, 14, and 21 to 81 infants with umbilical cord blood IgG levels < or =4 g/L: (1) IVIgG group, n = 40, mean (SD) gestational age 27.5 (2.2) weeks and birth weight 1.06 (0.39) kg; (2) placebo group, n = 41, mean (SD) gestational age 27.7 (2.5) weeks and birth weight 1.13 (0.38) kg. Infants with umbilical cord blood IgG levels >4 g/L (n = 238) served as a separate comparison group. Neonatal infections according to European Society of Pediatric Infectious Disease criteria were monitored until 28 days of life. RESULTS: Infants with IgG levels < or =4 g/L at birth who received IVIgG had no significant reduction in infectious episodes or mortality rate when compared with those given placebo. However, infants with a serum concentration of IgG >4 g/L at birth had significantly fewer infectious episodes (culture-proven sepsis) than infants with low serum concentrations of IgG (< or =4 g/L) when compared at the same gestational ages (26 to 29 weeks, P <.003). CONCLUSIONS: Prophylactic immunotherapy with IVIgG did not improve the immune competence in preterm infants with low serum IgG concentrations at birth. We speculate that a spontaneously high serum IgG concentration at birth reflects placenta function and is an indicator of a more mature immune system capable of protecting the preterm infant against severe neonatal infections.     

Association of fetal and maternal carboxyhemoglobin levels in normal and Rh-alloimmune pregnancies

OBJECTIVE: To compare paired antepartum fetal/maternal COHb ratios in whole blood from control and alloimmunized pregnancies and to examine the relationships between fetal and maternal COHb. METHODS: COHb levels were measured in paired fetal and maternal blood samples obtained at cordocentesis in 47 control and 16 Rh-alloimmunized pregnancies. COHb was determined by gas chromatography. Results were analyzed by t-test, regression and analysis of covariance. RESULTS: Although fetal/maternal COHb ratios for control and alloimmunized pregnancies were not statistically significantly different, i.e. 1. 11+/-0.04 and 1.26+/-0.09, respectively (P=0.09), fetal COHb levels were higher in Rh-alloimmunized fetuses (P=0.0002). Fetal COHb levels were also higher than paired maternal levels among the alloimmunized group (P=0.011), but not among the control group (1. 04+/-0.04, P=ns). In univariate regression analysis, fetal and maternal COHb levels were significantly correlated with one another in both control (r=0.52, P=0.0002) and alloimmunized pregnancy groups (r=0.52, P=0.05). Comparison of the slopes of the fetal versus maternal COHb plots for the two groups showed a significant difference (P=0.02), with the alloimmunized group having the steeper slope. CONCLUSION: Differences in the antepartum fetal-maternal COHb relationships in control and alloimmunized groups likely reflect increased endogenous CO production among alloimmunized fetuses as a result of pathologic hemolysis.     

IGF1/insulin receptor kinase inhibition by BMS-536924 is better tolerated than alloxan-induced hypoinsulinemia and more effective than metformin in the treatment of experimental insulin-responsive breast cancer

Epidemiologic and experimental evidence suggest that a subset of breast cancer is insulin responsive, but it is unclear whether safe and effective therapies that target the insulin receptor (IR), which is homologous to oncogenes of the tyrosine kinase class, can be developed. We demonstrate that both pharmacologic inhibition of IR family tyrosine kinase activity and insulin deficiency have anti-neoplastic activity in a model of insulin-responsive breast cancer. Unexpectedly, in contrast to insulin deficiency, pharmacologic IR family inhibition does not lead to significant hyperglycemia and is well tolerated. We show that pharmacokinetic factors explain the tolerability of receptor inhibition relative to insulin deficiency, as the small molecule receptor kinase inhibitor BMS-536924 does not accumulate in muscle at levels sufficient to block insulin-stimulated glucose uptake. Metformin, which lowers insulin levels only in settings of hyperinsulinemia, had minimal activity in this normoinsulinemic model. These findings highlight the importance of tissue-specific drug accumulation as a determinant of efficacy and toxicity of tyrosine kinase inhibitors and suggest that therapeutic targeting of the IR family for cancer treatment is practical.     

Fetal MRI for prediction of neonatal mortality following preterm premature rupture of the fetal membranes

Background  

Lung MRI volumetrics may be valuable for fetal assessment following early preterm premature rupture of the foetal membranes (pPROM).