Structural correlates of cognitive deficits in a selected group of patients with Alzheimer''s disease

Mutated RAS oncoproteins and epidermal growth factor (EGF) are thought to contribute to the proliferative, invasive and metastatic properties of transformed cells. In the present study, we investigated the role of EGF in two H-ras transfected clones and compared it to that in the parental cell line, HaCaT and primary cultured keratinocytes. Our findings show that the motility on type I collagen, measured by the migration index, was similar for both the HaCaT cell line and normal human keratinocytes, whereas it was higher for the HaCaT-ras clones. These results suggest an involvement of the ras oncogene in the stimulation of cell migration. EGF in cell pretreatment or during the migration assay also caused an increase in migration of all the cells, but preserved the difference between HaCaT and HaCaT-ras. However, no significant difference in EGF-R expression was detected between normal cultured keratinocytes, HaCaT and HaCaT-ras cell lines with or without EGF pretreatment. Moreover, when the cells were stimulated with EGF, the MMP-9 activity was greatly increased in a dose-dependent manner in all the cells, and EGF stimulation particularly highlights the increased amount of MMP-9 in HaCaT-ras cells compared to HaCaT cells. In conclusion, EGF is able to enhance motility and to up-regulate MMP-9 activity in all cells, but with a higher impact in HaCaT-ras cells without an overexpression of EGF-R. As EGF acts in synergy with the H-ras mutation, they could be implicated in the local invasion by the HaCaT-ras clones.     

Trends in the incidence of myocardial infarction and in mortality due to coronary heart disease, 1987 to 1994

BACKGROUND AND METHODS: To clarify the determinants of contemporary trends in mortality from coronary heart disease (CHD), we conducted surveillance of hospital admissions for myocardial infarction and of in-hospital and out-of-hospital deaths due to CHD among 35-to-74-year-old residents of four communities of varying size in the United States (a total of 352,481 persons in 1994). Between 1987 and 1994, we estimate that there were 11,869 hospitalizations for myocardial infarction (on the basis of 8572 hospitalizations sampled) and 3407 fatal coronary events (3023 sampled). RESULTS: The largest average annual decrease in mortality due to CHD occurred among white men (change in mortality, -4.7 percent; 95 percent confidence interval, -2.2 to -7.1 percent), followed by white women (-4.5 percent; 95 percent confidence interval, -0.7 to -8.2 percent), black women (-4.1 percent; 95 percent confidence interval, -10.3 to +2.5 percent), and black men (-2.5 percent; 95 percent confidence interval, -6.9 to +2.2 percent). Overall, in-hospital mortality from CHD fell by 5.1 percent per year, whereas out-of-hospital mortality declined by 3.6 percent per year. There was no evidence of a decline in the incidence of hospitalization for a first myocardial infarction among either men or women; in fact, such hospital admissions increased by 7.4 percent per year (95 percent confidence interval for the change, +0.5 to +14.8 percent) among black women and 2.9 percent per year (95 percent confidence interval, -3.6 to +9.9 percent) among black men. Rates of recurrent myocardial infarction decreased, and survival after myocardial infarction improved. CONCLUSIONS: From 1987 to 1994, we observed a stable or slightly increasing incidence of hospitalization for myocardial infarction. Nevertheless, there were significant annual decreases in mortality from CHD. The decline in mortality in the four communities we studied may be due largely to improvements in the treatment and secondary prevention of myocardial infarction.     

Plasmin enzyme-assisted vitrectomy in traumatic pediatric macular holes

OBJECTIVE: This study aimed to evaluate the benefit of plasmin enzyme-assisted macular hole surgery on a consecutive series of pediatric patients with traumatic macular holes. DESIGN: Prospective noncomparative case series operated on at William Beaumont Hospital between July 13, 1996, and November 16, 1996, and observed for at least 6 months. PARTICIPANTS: During this interval, the authors operated on four eyes from four consecutive patients who were 14 years of age or younger with traumatic macular holes. INTERVENTION: The patients underwent plasmin enzyme-assisted pars plana vitrectomy with membrane peeling, fluid-gas exchange, and postoperative positioning. The enzyme used was 0.4 international unit (IU) of autologous plasmin enzyme. MAIN OUTCOME MEASURES: Snellen lines of improvement in visual acuity and rate of final visual acuity of 20/40 or greater, and incidence of complications and reoperations were measured. RESULTS: All four macular holes were closed successfully. Follow-up was from 6 to 12 months. There were no reoperations. Visual acuity improved from four to eight lines in all eyes. Three eyes (75%) achieved a postoperative visual acuity of 20/40 or better. Three eyes (75%) had transient, posterior, subcapsular cataracts develop: two of the eyes after surgery and one as a result of the initial injury. CONCLUSION: The treatment of pediatric traumatic macular holes with plasmin enzyme-assisted vitrectomy, membrane peeling, and gas-fluid exchange resulted in closure of the macular holes with significant visual improvement.     

Characterization of electric-pulse-induced permeabilization of porcine skin using surface electrodes

We measured the transient and long-term changes of permeability of full-thickness porcine skin after the application of a single or a train of electric pulses, as the basis for optimization of the electrical parameters for enhancing transdermal drug or gene delivery by electroporation. Two electrodes were attached to the stratum corneum of excised skin for transdermal electric pulse delivery and impedance measurement. Both transient and long-term permeabilization were found to be dependent on the electrical exposure dose, i.e., the product of pulse voltage and cumulative pulsing (exposure) time. Skin resistance dropped to about 20% of its prepulsing value when pulsed beyond a critical dosage of 0.4 V-s (with 20-40 V across each skin path), but recovered rapidly within seconds after the pulse. Long-term permeabilization of the skin required repeated pulsing with a minimum potential of 160 V (80 V across each skin path). The maximum long-term resistance drop, to 35% of the initial value, required a dose greater than 200 V-s, recovering slowly and seldom completely in tens of minutes to hours. The decrease and recovery of the resistance were dependent on the frequency and pulse length only for low-dose electrical exposure.     

Relationship between gonadal steroids and corticosterone during blood sampling in saker falcons

Blood sampling in manually restrained or ketamine (15 mg/kg given intramuscularly) treated saker falcons (Falco cherrug) induced an increased concentration in plasma corticosterone. Elevated plasma progesterone, oestradiol 17 beta, and testosterone concentrations also were observed in some of these birds. An inverse relationship was demonstrated between levels of corticosterone and progesterone, but not with the levels of other hormones. It is suggested that progesterone measurement should be taken into consideration when studying the influence of stressors in falcons.     

An assessment of the developmental toxicity of inorganic arsenic

A critical analysis of the literature base regarding the reproductive and developmental toxicity of arsenic compounds, with emphasis on inorganic arsenicals, was conducted. The analysis was stimulated by the great number of papers that have purported to have shown an association between exposure of pregnant laboratory animals to arsenic compounds and the occurrence of offspring with cranial neural tube defects, particularly exencephaly. For the most part, the literature reports of arsenic developmental toxicity in experimental animals are inadequate for human risk assessment purposes. Despite the shortcomings of the experimental database, several conclusions are readily apparent when the animal studies are viewed collectively. First, cranial neural tube defects are induced in rodents only when arsenic exposure has occurred early in gestation (on Days 7 [hamster, mouse], 8 [mouse], or 9 [rat]). Second, arsenic exposures that cause cranial neural tube defects are single doses that are so high as to be lethal (or nearly so) to the pregnant animal. Third, the effective routes of exposure are by injection directly into the venous system or the peritoneal cavity; even massive oral exposures do not cause increases in the incidence of total gross malformations. Fourth, repetition of similar study designs employing exaggerated parenteral doses is the source of the large number of papers reporting neural tube defects associated with prenatal arsenic exposure. Fifth, in five repeated dose studies carried out following EPA Guidelines for assessing developmental toxicity, arsenic was not teratogenic in rats (AsIII, 101 micromol/kg/d, oral gavage; 101 micromol/m3, inhalation), mice (AsV, 338 micromol/kg/d, oral gavage; est. 402 micromol/kg/d, diet), or rabbits (AsV, 21 micromol/kg/d, oral gavage). Data regarding arsenic exposure and adverse outcomes of pregnancy in humans are limited to several ecologic epidemiology studies of drinking water, airborne dusts, and smelter environs. These studies failed to (1) obtain accurate measurements of maternal exposure during the critical period of organogenesis and (2) control for recognized confounders. The lone study that examined maternal arsenic exposure during pregnancy and the presence of neural tube defects in progeny failed to confirm a relationship between the two. It is concluded that under environmentally relevant exposure scenarios (e.g., 100 ppm in soil), inorganic arsenic is unlikely to pose a risk to pregnant women and their offspring.     

Structural information on a cecropin-like synthetic peptide, Shiva-3 toxic to the sporogonic development of Plasmodium berghei

This study is a contribution towards the understanding of the mode of action of Shiva-3 and more generally that of cecropin-like peptides. Structural information on Shiva-3 (a cecropin-like synthetic peptide) in water and in a membrane-mimicking environment (trifluoroethanol alcohol, SDS) were obtained using analytical centrifugation, CD and NMR spectroscopies. A total of 20 converged structures were retained on the basis of 197 non-redundant experimental constraints, including 166 distance constraints from the nuclear Overhauser effect measurements and 31 dihedral angle restraints derived from the purged COSY experiments. Some results obtained in presence of SDS are also presented. The toxic effects of the peptides obtained by cleavage (trypsin and lysine-C hydrolysis) of Shiva-3 on Escherichia coli and on Plasmodium berghei sporogonic stages are reported. Biological effects are discussed in relation to the calculated structure. The antiparasite activity and the low mosquito toxicity of Shiva-3 make this peptide a good candidate for genetic transformation of mosquito vectors which warrants further studies aimed at the improvement of the molecule.     

Evolution of a full-thickness macular hole

Autosomal recessive polycystic kidney disease (ARPCD) is a congenital kidney disease with severe prognosis. We present a male infant who was diagnosed prenatally by ultrasonography. He died at two months of age in a septic stage. The genetic defect for ARPCD has been mapped to chromosomal region of 6p21-cen. This represents the first study from this region of the world. The linkage studies up to this date fall to show genetic heterogeneity.     

Doppler-derived left ventricular rate of pressure rise and inotropic requirements during mitral valve surgery

OBJECTIVE: Inherited resistance to activated protein C (APC resistance), which is caused by a single point mutation in the factor V gene, is a frequent risk factor for venous thromboembolism. The aim of this study was to determine the prevalence of APC resistance and other coagulation disorders in fertile women with venous thromboembolism and also the risk factors these women had been exposed to in connection with thromboembolic events. DESIGN: A retrospective, case-control study of 36 month duration. SETTING: The study was carried out at Blekinge Hospital, Karlskrona, Sweden. SUBJECTS: The study population comprised 27 fertile women age 16-47 years with thromboembolic complications, referred to the department of Internal Medicine at Blekinge Hospital in Karlskrona during a 36-month period. RESULTS: APC resistance was found in 10 out of 27 women. APC resistance was associated with treatment with oral contraceptives in five out of six women and with pregnancy in one of seven women. All women with resistance to APC developed venous thrombosis in association with a predisposing situation (risk situation) such as surgery, trauma, immobilization, pregnancy, inflammatory state or the use of oral contraceptives. Amongst women not resistant to APC, all but one developed thrombosis in connection with a risk situation. CONCLUSION: APC resistance was found to be highly prevalent amongst fertile women with a history of thromboembolic complication occurring during their use of oral contraceptives.     

One-stage reconstruction of post-electrical burn forearm and hand defects using microsurgical transfer of an ulnar neuromyotendinocutaneous unit

Epirubicin is known to be metabolized in the liver. Therefore, drugs such as cimetidine, which inhibit the cytochrome P-450 enzyme system or reduce liver blood flow, may reduce the plasma clearance of epirubicin. In a small study, epirubicin 100 mg/m2 every 3 weeks was administered intravenously to eight patients, who also received oral cimetidine (400 mg b.d. for 7 days starting 5 days before chemotherapy) with either the first or second cycles. Epirubicin pharmacokinetics and liver blood flow (idocyanine green clearance) were assessed at each course. The areas under the plasma concentration time curves (AUCs) were used to compare the systemic exposure to epirubicin and its metabolites with each course. The estimated median percentage increase (95% confidence interval CI) in the AUC with cimetidine were: epirubicin 50% (95% CI -18 to 193, epirubicinol 41% (95% CI 1 to 92). Despite the small numbers studied, the increase in the active metabolite epirubicinol was significant (P < 0.05). These changes in exposure were not explained by reduced cytochrome P-450 activity as the 7-deoxy-doxorubicinol aglycone AUC was not reduced (357% increase: 95% CI 17 to 719) or by a decrease in liver blood flow (17% increase: 95% CI -39 to 104). Cimetidine is likely to be coprescribed or self-administered with epirubicin and therefore clinicians should be aware of this potential interaction.