Protein topology of presenilin 1

Mutations in a gene encoding a multitransmembrane protein, termed presenilin 1 (PS1), are causative in the majority of early-onset cases of AD. To determine the topology of PS1, we utilized two strategies: first, we tested whether putative transmembranes are sufficient to export a protease-sensitive substrate across a lipid bilayer; and second, we examined the binding of antibodies to specific PS1 epitopes in cultured cells selectively permeabilized with the pore-forming toxin, streptolysin-O. We document that the "loop," N-terminal, and C-terminal domains of PS1 are oriented toward the cytoplasm.     

Drugs and homicide by women

In this paper we use data derived from interviews with 215 female homicide offenders incarcerated or on parole in New York to examine their drug use prior to and at the time of the homicide, their victims' drug use, and their perceptions as to the drug-relatedness of the homicides. We found that about 7 out of 10 respondents had been regular users of some drug at some point in their lives prior to their incarceration, while over half had been addicted to a substance. Over one-third of the respondents who were present at the scene were "high" on a drug at the time, while about half of the victims of these homicides used drugs before the homicide. Almost two-thirds of the homicides committed by respondents who were present at the scene were perceived to be drug-related. Alcohol, crack, and powdered cocaine were the drugs most likely to be related to these homicides. The implications of our findings are discussed.     

Treatment of schizophrenic psychoses with Lyorodin

Forty-four patients suffering from acute and chronic schizophrenic psychoses were used to obtain, by using Lorr's scale (IMPS) and taking the changes in disease state observed within three months as a base, suggestions or pointers as to the proper treatment of disease with fluphenazine (lyorodin) which is a neuroleptically highly potent phenothiazine derivative. Megalomania, grandiose delusions apathetic and depressive syndromes showed marked tendencies toward major improvement. An "antiautistic" effect was observed in chronic patients. The effective dose was between 6 and 12 mg a day. The drug was well tolerated. In the majority of cases it was also necessary for antiparkinsonian drugs to be administered to patients. After twelve months of treatment, slight to major improvements or even freedom from symptoms could be observed in 28 cases (or 64%).     

Metabolic mapping of the effects of oral alcohol self-administration in rats

A method for the quantitation of protein carbonyls, which have been widely employed as markers of protein oxidative damage, is described. Protein carbonyls were derivatized with tritiated sodium borohydride and the tritiated proteins were separated on SDS-PAGE. Protein bands, visualized by Coomassie blue staining, were then excised and incubated in 30% H2O2 at 60 degrees C for 48 h. Tritium, incorporated into the proteins, was quantitated by liquid scintillation counting after gel solubilization by H2O2. This method can be applied to the measurement of carbonylation of specific proteins as it employs SDS-PAGE and has the advantage that unreacted NaB3H4 in the labeling reaction mixture need not be removed. The present method, when combined with immunochemical detection of protein carbonyls, should be very useful in the quantitation of oxidative damage to individual proteins.     

Thermodynamische Berechnungen für CO<Subscript>2</Subscript>-Kältemaschinenprozesse mit ein- oder zweistufiger Verdichtung in Klimaanlagen

For the design of an (automotive) air-conditioning system which employs R744 (carbon dioxide, CO₂) as a refrigerant, thermodynamic calculations are performed for vapour compression refrigeration processes with single-stage or double-stage compression and throttle-valve expansion. The process parameters are varied systematically for an evaporation temperature of 0?°C and a CO₂-cooler exit-temperature (lowest CO₂ temperature in heat transfer to the ambient) between 15?°C and 55?°C. Their influence upon the coefficient of performance, the specific and the volumetric refrigeration capacities is described. For the double-stage compression cycle, the ratio of the high-pressure and low-pressure mass flows is determined, too. The double-stage compression with interstage cooling and internal heat exchanger in the low- or high-pressure cycle shows the potential for a substantial increase in coefficient of performance relative to the single-stage compression cycle. Thermodynamically optimized intermediate pressure, high pressure and temperature change in the internal heat exchangers are presented for CO₂-cooler exit-temperatures of 25 and 40?°C. The increase in energy efficiency is paid for by additional invest and the more complex operation of the CO₂ refrigeration unit.The results are not only valid for air conditioning systems but can also be applied in the design and operation for other applications of CO₂ refrigeration systems with an evaporation temperature of 0?°C.     

Aspirin-triggered 15-epi-lipoxin A4 (ATL) generation by human leukocytes and murine peritonitis exudates: development of a specific 15-epi-LXA4 ELISA

Aspirin (ASA) triggers the formation of 15-epi-lipoxins (15-epi-LXs or ATL [ASA-triggered LX]), which are potent bioactive eicosanoids that may contribute to the therapeutic impact of ASA. To elucidate the role of these new compounds in vivo, it is essential to establish quick and sensitive detection methods. To this end, we prepared an enzyme-linked immunosorbent assay specific for 15-epi-LXA4 that proved to be highly sensitive (IC50 approximately 50 pg, minimum detection approximately 3.5 pg) and stereoselective. The amounts of 15-epi-LXA4 generated by human neutrophils from peripheral blood of healthy volunteers using this enzyme-linked immunosorbent assay were in agreement with those values obtained by liquid chromatography. Formation of 15-epi-LXA4 was cell ratio-dependent during THP-1 (a monocytic leukemia cell line)-neutrophil interactions with ASA-treated cells, and 15-epi-LXA4 was not detected with either cell type alone. Generation of 15-epi-LXA4 was also examined in murine peritonitis with ASA administration. Exudates from ASA-treated mice showed increased production of 15-epi-LXA4 that was diminished by indomethacin, a blocker of ASA-dependent acetylation of prostaglandin G/H synthase. A cytochrome P450 inhibitor administered in the presence of ASA did not prevent 15-epi-LXA4 formation, which suggests that P450 does not significantly contribute to formation of 15-epi-LXA4 in this murine model. These results indicate that the new enzyme-linked immunosorbent assay is both sensitive and selective for 15-epi-LXA4 and that 15-epi-LXA4 is produced by human leukocyte-leukocyte interactions. In addition, 15-epi-LXA4 is generated by inflammatory exudates when ASA is administered during murine peritonitis and when prostaglandin G/H synthase is upregulated and acetylated. This assay should provide rapid means to investigate 15-epi-LXA4 generation in both cellular and animal models.     

The antitumour activity of the prodrug N-L-leucyl-doxorubicin and its parent compound doxorubicin in human tumour xenografts

The antitumour activity of the investigational agent N-L-leucyl-doxorubicin (Leu-DOX) was compared with that of doxorubicin (DOX) in human tumour xenografts growing subcutaneously in athymic nude mice. Leu-DOX was developed as a prodrug of DOX, and may be converted into the clinically active parent compound by hydrolytic enzymes present in or on tumour cells. It has been suggested that a better therapeutic index with a reduced cardiac toxicity and higher efficacy might be obtained. Both compounds were administered intravenously weekly for 2 weeks, each at maximum tolerated doses of 8 mg/kg and 28 mg/kg for DOX and Leu-DOX, respectively. The panel of xenografts represented three different tumour types. Leu-DOX showed antitumour activity, defined as tumour growth inhibition > 50% and specific growth delay > 1.0, in 10 of the 16 tumours, including two of five breast, five of seven small cell and three of four non-small cell lung carcinomas. In comparison, DOX was active in one breast, four small cell lung and two lung adenocarcinoma xenografts. In all the DOX sensitive lung tumours, Leu-DOX showed higher efficacy than the parent compound. Based on the results of the present study, and since phase I clinical trials with Leu-DOX have already been performed, phase II clinical evaluation of Leu-DOX in patients with breast and lung cancer is recommended.     

Arthroscopic-assisted reduction of distal radius fractures

The outcomes of seven patients with severe comminuted intraarticular fractures of the distal radius treated by arthroscopic reduction and percutaneous external fixation (ARPEF) were retrospectively reviewed. All of the fractures were classified as C3 types using the AO classification scheme. Outcomes were evaluated using the Gartland and Werley functional criteria, an objective wrist examination, a radiographic analysis, and a self-assessment outcome form at an average follow-up of 27 months (range, 12 to 45 months). All patients were free of pain and had returned to their prior occupations. No patient had articular incongruency of greater than 1 mm, and there was no evidence of radiocarpal degenerative change. Active range of motion and maximal grip strength averaged 92% and 98%, respectively, of the uninjured wrist. The technique of arthroscope-assisted reduction and percutaneous external fixation yielded excellent results in a small group of patients, with minimal complications.