Composition of PLGA and PEI/DNA nanoparticles improves ultrasound-mediated gene delivery in solid tumors in vivo

The goal of this study was to enhance gene delivery and tumor cell transfection in vivo by using a combination of ultrasonication with complex nanoparticles consisting of two types of nanoparticles: PEI/DNA β-gal plasmid with highly positive zeta-potential and air-filled poly (lactic-co-glycolic acid) (PLGA) particles (with negative zeta-potential) manufactured in our laboratory. The PLGA/PEI/DNA nanoparticles were a colloid with positive zeta-potential and injected i.v. in nude mice with DU145 human prostate tumors. We found that the combination of PLGA/PEI/DNA nanoparticles with ultrasonication substantially enhanced tumor cell transfection in vivo. The overexpression of β-gal gene was evaluated histochemically and by Western blot analysis. At least an 8-fold increase of the cell transfection efficacy was obtained in irradiated tumors compared to non-irradiated controls, while little to no cell death was produced by ultrasonication.     

Long-term effects of early kwashiorkor compared with marasmus. II. Intellectual performance

Intellectual performance including IQ (Wechsler Intelligence Scale for Children-Revised) and conservation was measured at ages 11-18 years in a follow-up study of Barbadian girls and boys who had histories of kwashiorkor (n = 53) or marasmus (n = 55) in their first year of life. They were compared with healthy neighborhood children matched by sex and age who had normal patterns of growth in early childhood (n = 58). On both IQ and conservation tests, children with previous kwashiorkor or marasmus had similar scores, which were significantly lower than scores of healthy comparison children. These findings were examined in relationship to current environmental conditions, which were similar in children with histories of kwashiorkor or marasmus and somewhat less advantaged than those of the comparison children. The effect of early malnutrition and related conditions at the time of episode still emerged as significant even when the current environmental factors were controlled for.     

Do blind persons have a better sense of smell than normal sighted people?

Functional disorders of sense organs may intensify the remaining senses. It is presumed that blind persons do not only hear better and have an intensified tactile sense but also have a stronger sense of smell. Better hearing ability was demonstrated by auditory evoked potentials. We investigated the sense of smell of blind persons by subjective tests (Sniffin' sticks: threshold, discrimination and identification) and for the first time also by objective tests (olfactory evoked potentials and trigeminal evoked potentials) and compared the results with the smelling ability of normal sighted persons by pair matching. Moreover, the investigated persons judged their performance via a questionnaire. The subjective test showed neither differences in the peripheral function nor in the central function between both groups. The amplitudes and latencies of the evoked potentials of vanillin, carbon dioxide and hydrogen sulfide were also not different. Blind persons tried unasked to identify the smell given in the discrimination test and thought themselves to be better in smelling. For the first time the smelling ability of blind people was compared with normal sighted people by objective test methods. Neither with subjective nor with objective methods differences were found.     

Chemical reactivity of the naproxen acyl glucuronide and the naproxen coenzyme A thioester towards bionucleophiles

Drugs may be metabolised to reactive electrophilic species that spontaneously react with proteins. The presence of such drug-protein adducts has been associated with drug toxicity. In this study, the reactivity of the major metabolite of naproxen--the 1-beta-O-glucuronide (Nap-GlcU)--was compared to the corresponding naproxen coenzyme A (Nap-CoA) thioester. The reactivity of the two metabolites was assessed in vitro in a phosphate buffer (pH 7.4; 0.1 M) at 37 degrees C towards the model bionucleophiles glutathione and human serum albumin (HSA). The reaction between the electrophilic species (Nap-GlcU and Nap-CoA) and glutathione forming the Nap-glutathione conjugate was monitored using LC-MS-MS and LC-UV, respectively. It was shown that Nap-CoA resulted in an approximate 100-fold higher formation of Nap-glutathione conjugate than Nap-GlcU. The presence of Nap-CoA also resulted in acylated HSA with a rate and a yield that was significantly higher than reported for Nap-GlcU. In summary, the data suggest that CoA metabolites may be more reactive species than acyl glucuronides that previously have been associated with severe drug related side effects in vivo.     

Plasma from patients undergoing major open surgery stimulates in vitro tumor growth: Lower insulin-like growth factor binding protein 3 levels may,in part,account for this change

BACKGROUND: Plasma from laparotomized mice has been shown to stimulate in vitro tumor growth when compared to results with preoperative plasma. This study assessed the effect of plasma from patients who underwent major open (OS) or laparoscopic surgery (LS) on in vitro tumor cell growth. METHODS: Eighty-four patients undergoing major abdominal surgery were studied (45 OS, 39 LS). Peripheral blood was collected preoperatively (PreOP) and on days 1 (POD1) and 3 (POD3) after operation. HT29 human colon cancer cells were plated with samples of the plasma. Proliferation was assessed by cell counts and the bromodeoxyuridine incorporation assay. Insulin-like growth factor binding protein 3 was detected in plasma by Western blot analysis. RESULTS: Increased mitogenic activity was noted in POD1 OS plasma when compared to PreOP OS plasma results (P <.005). This increase correlated with the length of incision (r = 0.58, P <.01). No differences were noted when the PreOP LS and POD1 LS results were compared or for any of the POD3 versus PreOP comparisons. CONCLUSIONS: Major OS is associated with alterations in plasma composition that promote HT29 tumor cell proliferation in vitro. As shown, this effect was due, at least in part, to surgery-related depletion of insulin-like growth factor binding protein 3 in peripheral blood.     

Early onset of cardiomyopathy in two brothers with X-linked Emery-Dreifuss muscular dystrophy

Two brothers are reported suffering from X-linked Emery-Dreifuss muscular dystrophy caused by a 59bp deletion eliminating nucleotides 329-388 of the STA gene. Besides the typical findings for Emery-Dreifuss muscular dystrophy, both patients showed an unusual early onset of cardiac symptoms at age 6 and 9 years, respectively, coinciding with unusual high creatine kinase. A cardiological follow up showed worsening of the cardiac condition in the beginning of the second decade. The two boys described here belong to the very few Emery-Dreifuss muscular dystrophy patients with early onset of cardiac involvement and contribute to the variability of cardiac symptoms in Emery-Dreifuss muscular dystrophy.     

Species differences in the projections from the entorhinal cortex to the hippocampus

Both differences and similarities exist between mammalian species in the projections from entorhinal cortex to the hippocampal formation. In most species, layer II cells of the entorhinal cortex project to the dentate gyrus, and they terminate in the outer two-thirds of the molecular layer of the dentate gyrus. The axons from layer III cells project bilaterally to areas CA(1) and CA(3) of the hippocampus, terminating in the stratum lacunosum moleculare. We have analyzed these projections in mice, and in general, the entorhinal cortex-to-hippocampus projections are similar to those in rats. Axons from layer II neurons terminate in the outer and middle thirds of the molecular layer of the dentate gyrus, and axons from layer III neurons terminate bilaterally in the stratum lacunosum moleculare of areas CA(1) and CA(3), and in the molecular layer of the subiculum. However, in contrast to rat, mouse entorhinal cortex neurons do not appreciably project to the contralateral dentate gyrus. Most species, including mice, show a similar topographical organization of the entorhinal-hippocampal projections, with neurons in the lateral part of both the lateral and medial entorhinal cortex projecting to the dorsal part or septal pole of the hippocampus, whereas the projection to the ventral hippocampus originates primarily from neurons in medial parts of the entorhinal cortex.     

Transgenic mice expressing the human presenilin 1 gene demonstrate enhanced hippocampal reorganization following entorhinal cortex lesions

We have examined the effects of the presence of the mutated human presenilin 1 gene (M146L; hps1*) on lesion-induced sprouting in the hippocampus of the mouse (C57/CBA). The entorhinal cortex was unilaterally lesioned with ibotenic acid in adult, male mice. Four weeks later the subsequent axonal sprouting in the dentate gyrus was analysed, by measuring the density of the synaptophysin immunocytochemical staining in the termination area of the entorhinal cortex axons. The data demonstrate that mice expressing either the human presenilin 1 gene (hps1) or the hps1* gene display a significantly increased density of immunocytochemical staining for synaptophysin, indicative of axonal sprouting, compared to the control mice. No (or a very small) sprouting response is observed in mice expressing the normal mouse ps1 gene. Taken together, these data indicate that the presence of a human ps1 gene, normal or with an Alzheimer's disease mutation, leads to enhanced plasticity in the mouse brain.