Verbal Representation and Therapeutic Change in Anaclitic and Introjective Inpatients.

This study examined the relation between changes in clinical functioning and changes in verbal expression in 81 seriously disturbed and treatment-resistant young adults seen in a comprehensive, psychoanalytically oriented inpatient treatment. Clinical functioning was evaluated with a battery of clinical and social measures. Verbal representations were assessed using computer-assisted scoring of Thematic Apperception Test responses. Changes in the frequency of verbal content and style in the narratives of these patients covaried with changes in clinical functioning. Significantly different covariations of verbal and clinical change, particularly differences in covariates of referential activity, were found for patients with anaclitic versus introjective personality configurations. The implications of these findings for understanding and treating severe psychopathology are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Antisense oligonucleotide inhibition of hepatitis C virus gene expression in transformed hepatocytes

Genetic and biochemical studies have provided convincing evidence that the 5' noncoding region (5' NCR) of hepatitis C virus (HCV) is highly conserved among viral isolates worldwide and that translation of HCV is directed by an internal ribosome entry site (IRES) located within the 5' NCR. We have investigated inhibition of HCV gene expression using antisense oligonucleotides complementary to the 5' NCR, translation initiation codon, and core protein coding sequences. Oligonucleotides were evaluated for activity after treatment of a human hepatocyte cell line expressing the HCV 5' NCR, core protein coding sequences, and the majority of the envelope gene (E1). More than 50 oligonucleotides were evaluated for inhibition of HCV RNA and protein expression. Two oligonucleotides, ISIS 6095, targeted to a stem-loop structure within the 5' NCR known to be important for IRES function, and ISIS 6547, targeted to sequences spanning the AUG used for initiation of HCV polyprotein translation, were found to be the most effective at inhibiting HCV gene expression. ISIS 6095 and 6547 caused concentration-dependent reductions in HCV RNA and protein levels, with 50% inhibitory concentrations of 0.1 to 0.2 microM. Reduction of RNA levels, and subsequently protein levels, by these phosphorothioate oligonucleotides was consistent with RNase H cleavage of RNA at the site of oligonucleotide hybridization. Chemically modified HCV antisense phosphodiester oligonucleotides were designed and evaluated for inhibition of core protein expression to identify oligonucleotides and HCV target sequences that do not require RNase H activity to inhibit expression. A uniformly modified 2'-methoxyethoxy phosphodiester antisense oligonucleotide complementary to the initiator AUG reduced HCV core protein levels as effectively as phosphorothioate oligonucleotide ISIS 6095 but without reducing HCV RNA levels. Results of our studies show that HCV gene expression is reduced by antisense oligonucleotides and demonstrate that it is feasible to design antisense oligonucleotide inhibitors of translation that do not require RNase H activation. The data demonstrate that chemically modified antisense oligonucleotides can be used as tools to identify important regulatory sequences and/or structures important for efficient translation of HCV.     

Mixed anaclitic-introjective psychopathology in treatment-resistant inpatients undergoing psychoanalytic psychotherapy.

Utilizing data from the Riggs-Yale Project, 45 male and 45 female 18-29-year-old treatment-resistant inpatients undergoing intensive psychoanalytically oriented treatment were studied. Twenty-seven mixed-type anaclitic-introjective inpatients were compared with 29 "pure" anaclitic and 34 "pure" introjective inpatients. At intake, mixed-type inpatients were more clinically impaired (i.e., were more symptomatic, cognitively impaired, and thought disordered) and more vulnerable (i.e., less accurate object representations and more frequently used maladaptive defense mechanisms) in comparison with clearly defined anaclitic and introjective patients. Mixed-type patients, however, improved significantly more in the course of psychoanalytically oriented treatment, in terms of clinical functioning (i.e., symptoms, cognitive functioning) and psychological vulnerability (i.e., utilization of more adaptive defense mechanisms). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Multichannel Security Protocols

Multichannel security protocols transmit messages over multiple communication channels, taking into account each channel's security properties. Our first intentional use of these protocols goes back to a 1999 article that proposed physical contact for imprinting as opposed to the wireless channel used in subsequent operations. Only later did we understand three key points. First, explicit use of multiple channels in the same protocol can offer significant advantages for both security and usability. Second, explicitly stating the properties of the channel on which each protocol message is transmitted is useful for understanding one's own protocol in greater depth and therefore for addressing subtle vulnerabilities early on. Third, multichannel protocols existed long before we recognized them as such - think of the courier handcuffed to the briefcase carrying the code book that will later protect postal or telegraphic traffic. The paper presents a security protocol that exploit additional transmissions over lower-capacity channels, typically found in ubicomp environments, that offer a different combination of security properties.     

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as a substrate of cytochrome P450 2D6: allosteric effects of NADPH-cytochrome P450 reductase

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that produces Parkinsonism symptoms in man, has been examined as a substrate of recombinant human cytochrome P450 2D6. When cumene hydroperoxide is used as an oxygen and electron donor, a single product is formed, identified as 4-phenyl-1,2,3,6-tetrahydropyridine. The K(m) for formation of this product (130 microM) is in agreement with the dissociation constants for MPTP binding to the enzyme determined by optical and nuclear magnetic resonance (NMR) spectroscopy. When the reaction is carried out with nicotinamide adenine dinucleotide phosphate (reduced) (NADPH) and recombinant human NADPH-cytochrome P450 reductase, a second product, identified as 1-methyl-4-(4'-hydroxyphenyl)-1,2,3,6-tetrahydropyridine, is formed in addition to 4-phenyl-1,2,3,6-tetrahydropyridine. The K(m) values for formation of these two products are 19 microM and 120 microM, respectively. Paramagnetic relaxation experiments have been used to measure distances between the protons of bound MPTP and the heme iron, and these have been used to construct models for the position and orientation of MPTP in the active site. For the cytochrome alone, a single mode of binding was observed, with the N-methyl close to the heme iron in a position appropriate for the observed N-demethylation reaction. In the presence of the reductase, the data were not consistent with a single mode of binding but could be explained by the existence of two alternative orientations of MPTP in the active site. One of these, characterized by a dissociation constant of 150 microM, is essentially identical to that observed in the absence of the reductase. In the second, which has a K(d) of 25 microM, the MPTP is oriented so that the aromatic ring is close to the heme iron, in a position appropriate for p-hydroxylation leading to the formation of the product seen only in the presence of the reductase. In the case of codeine, another substrate for cytochrome P450 2D6, the addition of reductase had no effect on the nature of the product formed, the dissociation constant, or the orientation in the binding site. These observations show that NADPH-cytochrome P450 reductase has an allosteric effect on the active site of cytochrome P450 2D6 that affects the binding of some substrates but not others.