Surgical strategies in very-low-birthweight neonates with necrotizing enterocolitis

Very-low-birthweight (VLBW) neonates are more prone to complications and death than term infants are. In a 15-year period, 19 neonates with VLBW were operated on for necrotizing enterocolitis (NEC). Indications for operation were pneumoperitoneum in 12 and deterioration of general condition in 7. Bowel resection and intestinal diversion was performed in 12, a lateral enterostomy at the site of perforation was created in 5, and 2 neonates with necrosis of the whole bowel underwent an exploratory laparotomy without any further surgical treatment. Surgical complications were found in one-third of the patients. The mortality rate was significantly higher when the ileum was affected. The survival rate was 68%. Prior to 1984 the survival rate was 37% (3/8); subsequently, it has improved to 91% (10/11) as a result of improved intensive therapy.     

Hormone replacement therapy and age-related brain shrinkage: regional effects

Neuroprotective properties of estrogen have been established in animal models, but clinical trials of hormone replacement therapy (HRT) produced contradictory results. We examined the impact of HRT on age-related regional changes in human brain volume. Six brain regions were measured twice, five years apart, in 12 healthy women who took HRT and in matched controls who did not. The controls showed a typical pattern of differential brain shrinkage in the association cortices and the hippocampus with no change in the primary visual cortex. In contrast, women who took HRT showed comparable shrinkage of the hippocampus but no significant shrinkage of the neocortex. Future large scale studies may benefit from applying regional rather than global measures in assessment of brain integrity.     

No facilitation of amphetamine- or cocaine-induced hyperactivity in adult rats after various 192 IgG-saporin lesions in the basal forebrain

Lesions of basal forebrain cholinergic neurons by intracerebroventricular (i.c.v.) injections of 192 IgG-saporin increased the locomotor response to 0.5 and 1.5 mg/kg of D-amphetamine in adult rats [A. Mattsson, S.O. Ogren, L. Olson, Facilitation of dopamine_mediated locomotor activity in adult rats following cholinergic denervation, Exp Neurol. 174 (2002) 96-108.]. In the present study, adult male rats were subjected to bilateral injections of 192 IgG-saporin either into the septum (Sp), the nucleus basalis magnocellularis (Nbm), both structures (SpNbm) or i.c.v. Locomotor activity was assessed in the home cage 23 days after surgery, and, subsequently, thrice after an intraperitoneal injection of D-amphetamine (1 mg/kg) and twice after an injection of cocaine (15 mg/kg). Analysis of AChE-stained material showed that Sp lesions induced preferentially hippocampal denervation, Nbm lesions induced preferentially cortical denervation, while both SpNbm and i.c.v. lesions deprived the hippocampus and the cortex of almost all AChE-positive reaction products. The spontaneous and drug-induced locomotor activity of all lesioned rats did not differ significantly from that of control rats, except in rats subjected to i.c.v. injections, in which the locomotor response was significantly increased after the second administration of cocaine. In addition, in Nbm and SpNbm rats, the locomotor reaction to cocaine was weaker right after the second injection. The present results do not confirm the report by Mattsson et al. on the potentiation of amphetamine-induced locomotion by i.c.v. injections of 192 IgG-saporin, but suggest that cocaine-induced locomotion can be increased by such lesions and, to some respect, attenuated by cholinergic damage in the Nbm.     

Relationship between eicosanoids and endothelin-1 in the pathogenesis of erythropoietin-induced hypertension in uremic rats

Recent studies suggest a possible link between recombinant human erythropoietin (rhEPO)-induced hypertension and endothelium-derived vasoconstrictor autocoids. The current study was designed to evaluate the role of eicosanoids such as thromboxane (TX) A and prostacyclin (PGI ) and of endothelin-1 (ET-1) and the relationship between these vasoactive substances in rhEPO-induced hypertension in uremic rats. Renal failure was induced by a two-stage 5/6 nephrectomy followed by a 6-week stabilization period. In protocol A, rats were divided into four groups: vehicle, rhEPO (100 u/kg, subcutaneously, three times per week), a selective ET receptor antagonist (ABT-627, 10 mg/kg/d), and rhEPO + ABT-627 for 5 weeks. In protocol B, uremic animals were divided into two groups: rhEPO and rhEPO + a TX receptor antagonist and synthesis inhibitor, ridogrel (25 mg/kg/d), for 5 weeks. At the end of the study, immunoreactive eicosanoid metabolites (TXB and 6-keto-PGF, stable metabolites of TXA and PGI ), and ET-1 were measured in either the thoracic aorta or in the mesenteric arterial bed. After 5/6 nephrectomy, the animals developed uremia, anemia, and hypertension. rhEPO corrected the anemia but aggravated the hypertension. Both drugs were effective in preventing the progression of hypertension in rhEPO-treated rats although ABT-627 was more potent than ridogrel. rhEPO increased the concentration of ET-1 and TXB in blood vessels and ABT-627 decreased tissue levels of both vasopressors. The concentration of 6-keto-PGF was not significantly changed. Ridogrel significantly decreased tissue TXB concentrations but had no effect on ET-1 levels. These results suggest that endothelium-derived vasoconstrictor autacoids (TXA and ET-1) are involved in the pathogenesis of rhEPO-induced hypertension in uremic rats. TXA probably serves as a mediator of the vascular effect of ET-1.     

Lead and stable lead isotope ratios in soil, earthworms, and bones of American woodcock (Scolopax minor) from eastern Canada

A study to discriminate among different possible sources of elevated Pb exposure for American woodcock (Scolopax minor) in eastern Canada is described. Undamaged wing bones excised from young-of-the-year woodcock collected from several locations in southern Ontario, southern Quebec, New Brunswick, and Nova Scotia, Canada, along with soil and earthworm (Aporrectodea tuberculata and Lumbricus rubellus) samples from the same sites, were analyzed for total Pb, and stable Pb isotopes. Ignoring six soil samples with high (> 60 microg/g) Pb concentration from the vicinity of Montreal (QC, Canada), the mean soil-Pb concentration for all sites combined was 19 microg/g (dry wt; n = 64), with a mean 206Pb:207Pb ratio of 1.19, values typical for uncontaminated rural soils in eastern North America. In earthworms, Pb concentrations ranged from 2.4 to 865 (microg/g [dry wt], mean = 24 microg/g). Concentrations of Pb in worms and soils were positively correlated (r = 0.71; p < 0.01), and 206Pb:207Pb ratios for worms and soils were also positively correlated (r = 0.54; p < 0.05). However, most young-of-the-year woodcock with high bone-Pb accumulation (> 20 microg/g) had 206Pb:207Pb ratios substantially different from worms and soils sampled from the same areas, even though woodcock feed extensively on soil invertebrates, especially earthworms. The range of 206Pb:207Pb ratios in wing bones of woodcock with elevated Pb exposure was not consistent with exposure to environmental Pb from past gasoline combustion nor Precambrian mining wastes but was consistent with ingestion of spent Pb shotgun pellets.     

Selective abrogation of the proinvasive activity of the trefoil peptides pS2 and spasmolytic polypeptide by disruption of the EGF receptor signaling pathways in kidney and colonic cancer cells

Trefoil peptides (TFFs) are now considered as scatter factors, proinvasive and angiogenic agents acting through cyclooxygenase-2 (COX-2)- and thromboxane A2 receptor (TXA2-R)-dependent signaling pathways. As expression and activation levels of the epidermal growth factor receptor (EGFR) predict the metastatic potential of human colorectal cancers, the purpose of this study was to establish whether the EGF receptor tyrosine kinase (EGFR-TK) contributes to cellular invasion induced by TFFs in kidney and colonic cancer cells. Both the dominant negative form of the EGFR (HER-CD533) and the EGFR-TK inhibitor ZD1839 (Iressa) abrogated cellular invasion induced by pS2, spasmolytic polypeptide (SP) and the src oncogene, but not by ITF and the TXA2-R. Similarly, EGFR-TK inhibition by ZD1839 reversed the invasive phenotype promoted by the constitutively activated form of the EGFR (EGFRvIII) and the EGFR agonists transforming growth factor alpha (TGFalpha), amphiregulin and EGF. We also provide evidence that TFFs, EGFRvIII, and TGFalpha trigger common proinvasive pathways using the PI3'-kinase and Rho/Rho- kinase cascades. These findings identify the EGFR-TK as a key signaling element for pS2- and SP-mediated cellular invasion. It is concluded that although pS2, SP and ITF belong to the same family of inflammation- and cancer-associated regulatory peptides, they do not control identical signaling networks.