PTEN inhibits cell proliferation and induces apoptosis by downregulating cell surface IGF-IR expression in prostate cancer cells

PTEN is a tumor suppressor gene that is frequently mutated in human tumors. It functions primarily as a lipid phosphatase and plays a key role in the regulation of phosphatidylinositol-3'-kinase. PTEN appears to play a crucial role in modulating apoptosis by reducing the levels of PtdIns(3,4,5)P3, a phospholipid that activates AKT, a central regulator of apoptosis. To understand the role of PTEN in regulating cell proliferation and apoptosis, we stably overexpressed PTEN in PC3 cells, which are prostate cancer cells that lack PTEN. Overexpression of PTEN in two different clones inhibited cell proliferation and increased serum starvation-induced apoptosis, as compared to control cells. Interestingly, PTEN overexpression resulted in a 44-60% reduction in total insulin-like growth factor-I receptor (IGF-IR) protein levels and a 49-64% reduction in cell surface IGF-IR expression. [35S]methionine pulse experiments in PC3 cells overexpressing PTEN demonstrated that these cells synthesize significantly lower levels of the IGF-IR precursor, whereas PTEN overexpression had no effect on IGF-IR degradation. Taken together, our results show that PTEN can regulate cell proliferation and apoptosis through inhibition of IGF-IR synthesis. These results have important implications for understanding the roles of PTEN and the IGF-IR in prostate cancer cell tumorigenesis.     

NBQX or topiramate treatment after perinatal hypoxia-induced seizures prevents later increases in seizure-induced neuronal injury

PURPOSE: To evaluate the efficacy of NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f) quinoxaline-2,3-dione) and topiramate (TPM) given after hypoxia-induced seizures in preventing the delayed effect of hypoxia on subsequent susceptibility to seizures and neuronal injury. METHODS: We used "two-hit" rodent seizure model to study the long-term effect of perinatal hypoxia on later kainate (KA) seizure-induced neuronal damage and investigated the therapeutic efficacy of a postseizure treatment protocol in reversing the conditioning effect of early-life seizures. RESULTS: Hypoxia at P10 induces seizures without cell death but causes an increase in susceptibility to second seizures induced by KA as early as 96 h after hypoxia, and this lowered seizure threshold persists to adulthood. Furthermore, perinatal hypoxia increases KA-induced neuronal injury at postnatal day (P)21 and 28/30. Repeated doses of NBQX (20 mg/kg) or TPM (30 mg/kg) given for 48 h after hypoxia-induced seizures prevent the increase in susceptibility to KA seizure-induced hippocampal neuronal injury at P28/30. CONCLUSIONS: Our results suggest that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor blockade after hypoxia prevents the priming effect of perinatal hypoxia-induced seizures and that this protection occurs independent of its anticonvulsant action.     

Renal effects of parenteral fish oil administered to heart-beating organ donors and renal-transplant recipients: a tolerance study

BACKGROUND & AIMS: Nutrition can interfere with organ function during the different stages of transplantation. Oral fish oil supplementation to kidney transplant recipients has been found to improve renal function. The aim of the present study was to determine the safety and tolerance of intravenous administration of fish-oil emulsion to heart-beating brain-dead donors and, subsequently, to the kidney recipients, and to assess its effects on renal function. METHODS: A lipid emulsion enriched with omega-3 fatty acids (MLF 541) was given intravenously to 8 heart-beating, brain-dead organ donors for up to 4 h before organ harvesting and to the kidney recipients for 5 days postoperatively. Hemodynamic, biochemistry and hematological parameters were measured before and at the end of lipid administration in the donors and on posttransplantation days 1, 5, 30 and 180 in the recipients. Findings in the recipients were compared with a concurrent control group. RESULTS: There were no significant changes in hemodynamic or laboratory parameters during the MLF infusion in the donors or the 5 days of MLF administration in the recipients. Blood urea nitrogen and serum creatinine levels decreased over time in both the study and control recipients (P < 0.05 for both), with no significant between-group difference at any of the time points studied. CONCLUSIONS: Administration of MLF 541 is safe in organ donors and in kidney recipients. Further studies involving nutrients as pharmacological agents in organ transplantation are warranted.     

Efficient priming of antigen-specific cytotoxic T lymphocytes by human cord blood dendritic cells

Previous studies have suggested that defective immune responses in early life may be related to the immaturity of neonatal antigen-presenting cells. To test this hypothesis, we assessed the capacity of neonatal dendritic cells (DC) to prime and polarize in vitro human naive antigen-specific T cells. We report that mature cord blood DC efficiently prime an oligoclonal population of antigen-specific CD8 T cells, capable of cytolytic activity and IFN-gamma secretion. In contrast, cells primed by immature cord blood DC do not acquire cytolytic activity and secrete lower amounts of IFN-gamma. Upon priming by either immature or mature DC, neonatal T cells acquire markers of activation and differentiation towards effector-memory cells. Our results demonstrate that, if appropriately activated, neonatal DC can prime efficient cytotoxic T lymphocyte (CTL) responses. Furthermore, these findings have important implications for the development of vaccine strategies in early life and for the reconstitution of a functional CTL repertoire after bone marrow transplantation.     

Perinatal management and outcome of prenatally diagnosed congenital diaphragmatic hernia: a 1995-2000 series in Rennes University Hospital

OBJECTIVES: To assess the prognosis of prenatally diagnosed congenital diaphragmatic hernia (CDH) during the years 1995-2000 in order to improve prenatal counselling. METHODS: Retrospective study of all 31 cases of women with prenatally diagnosed CDH. RESULTS: Nine pregnancies (29%) were terminated and two fetuses (6%) were stillborn. Ten fetuses (32%) had associated anomalies (four Fryns' syndrome) and four (13%) had underlying chromosomal anomalies. Twenty pregnancies were continued. Seven babies died before surgery either immediately in the delivery room (five between 1 and 45 min), or during the 'stabilisation period' (two babies, 7 and 21 h). Three babies presented with trisomy 18, Fryns' syndrome or transposition of the great arteries with microdeletion 22q11. Thirteen babies had the defect repaired (median 18 h, range 4-72 h) and 12 survived. Mechanical ventilation was required for a median of 12 days. One survivor has cerebral palsy. CONCLUSION: Of 31 prenatally diagnosed CDH cases 38% are alive, of 20 ongoing pregnancies 60% are alive, and of 13 babies who underwent surgery 92% are alive. No baby with associated malformations survived. These numbers need to be known by each member of the counselling team in order to give parents adequate information to make their decision.     

European multicentre evaluation of the Du Pont Dimension 380 under the auspices of the European Group for the Evaluation of Analytical Systems in Laboratory Medicine (EGE-Lab)

The Clinical Chemistry Analyzer Dimension 380 manufactured by Du Pont de Nemours was tested in a multicentre evaluation according to the guide-lines of the European Committee for Clinical Laboratory Standards (ECCLS) and in part to the protocol of the Société Fran?aise de Biologie Clinique (SFBC). The instrument and the reagents were evaluated as a system, since both reagents and reagent cartridges are specifically designed for the instrument. Fourteen analytes including electrolytes, substrates and enzymes were tested. The evaluators summarized their experience as follows: 1. All parameters tested yield results comparable to established procedures. 2. Very good performance of the ion-selective-electrode unit. 3. The imprecision data of the system are, for most parameters, between 1 and 4% CV and thus equal to or better than those of the instruments compared. 4. No reagent or sample carry-over was detected after a minor modification of the instrument. 5. The linearity of Dimension test methods in general covers the range stated by the manufacturer. 6. Very good stability of the calibration curves (up to 2 months). 7. Good practicability of the whole system, including handling of reagents and a very user-friendly software.     

The influence of bright background flicker during different saccade periods on saccadic performance

We investigated saccades from central fixation to targets at 5 degrees to the left or right. These targets were red laser points of light with an intensity unmodulated in time (referred to as steady), while a bright background (76 cd/m(2)) was illuminated by a special fluorescent lamp, the output of which were series of light pulses (at frequencies of 50 or 100 Hz) that were presented only during certain periods, in synchrony with the saccade: e.g. during fixation of the central target, or during the latency (i.e. the period from target onset to saccade onset), or during the execution of the saccade; otherwise, the background luminance was steady. We observed a mean increase in latency of about 23 ms when 50 Hz flicker pulses occurred during the latency alone. This result is interpreted in terms of saccadic inhibition [Reingold & Stampe, (2000) In: Kennedy, Radach, Heller, & Pynte (Eds.) Reading as a perceptual process. Elsevier, Amsterdam]: our bright background flicker during the latency may have produced longer latencies, similar to the remote distractors in the model of Findlay and Walker [Behav. Brain Sci. 22 (1999) 661].     

Progression rate of Chinese herb nephropathy: impact of Aristolochia fangchi ingested dose

Sir, Muniz Martinez et al. [1] report, in 71 patients with Chineseherbs nephropathy (CHN), an interesting relationship betweenthe total amount of ingested Stephania tetrandra/Aristolochiafangchi herbs and the progression rate of renal failure. Fiveyears ago we reached a similar conclusion in an analysis of15 patients: we demonstrated a striking relationship betweenthe duration of Chinese herbs     

Pharmacokinetics of a low molecular weight heparin (Fraxiparine) in various stages of chronic renal failure.

This study investigates the pharmacokinetics of a low molecular weight heparin (Fraxiparine) after a single bolus intravenous injection of 100 antifactor Xa IC U.kg-1 in 3 groups of patients affected by chronic renal insufficiency of various severity: group A (n = 7) was composed of hemodialyzed patients; groups; B (n = 7) had a creatinine clearance ranging from 10 to 20 ml.min-1 and group C (n = 5) from 30 to 50 ml.min-1. There was no significant difference between the pharmacokinetic parameters determined in the 3 groups of patients and no correlation between these parameters and the creatinine clearance. However, when compared to the values established in a group of 12 healthy volunteers, the half-life of disappearance of the antifactor Xa activity was significantly prolonged. Therefore it is advised to monitor antifactor Xa activity in patients affected by chronic renal insufficiency of any severity to avoid a possible accumulation phenomenon.     

Loss of function IFT27 variants associated with an unclassified lethal fetal ciliopathy with renal agenesis

Ciliopathies comprise a group of clinically heterogeneous and overlapping disorders with a wide spectrum of phenotypes ranging from prenatal lethality to adult‐onset disorders. Pathogenic variants in more than 100 ciliary protein‐encoding genes have been described, most notably those involved in intraflagellar transport (IFT) which comprises two protein complexes, responsible for retrograde (IFT‐A) and anterograde transport (IFT‐B). Here we describe a fetus with an unclassified severe ciliopathy phenotype including short ribs, polydactyly, bilateral renal agenesis, and imperforate anus, with compound heterozygosity for c.118_125del, p.(Thr40Glyfs*11) and a c.352 +1G > T in IFT27, which encodes a small GTPase component of the IFT‐B complex. We conclude that bilateral renal agenesis is a rare feature of this severe ciliopathy and this report highlights the phenotypic overlap of Pallister–Hall syndrome and ciliopathies. The phenotype in patients with IFT27 gene variants is wide ranging from Bardet–Biedl syndrome to a lethal phenotype.