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PubMed2005

Continuity of axes I and II: toward a unified model of personality, personality disorders, and clinical disorders.

In the current standard psychiatric nomenclature, the DSM-IV-TR (APA, 2000), mental disorders are divided into two groups: Clinical Disorders (CDs) and Personality Disorders (PDs), and CD and PD diagnoses are recorded on two separate axes (Axes I and II, respectively). This article considers evidence regarding putative bases for distinguishing between CDs and PDs, and finds that these constructs are more similar than distinct. Links between the domains may be better understood by focusing on how personality connects CDs and PDs. This perspective underlines the need to work toward a more unified model of personality, PDs, and CDs in research and in future editions of the DSM.

Adult↗
PubMed1996

Extensive RNA editing of U to C in addition to C to U substitution in the rbcL transcripts of hornwort chloroplasts and the origin of RNA editing in green plants.

We cloned and sequenced a portion of chloroplast DNA from the hornwort Anthoceros formosae. A nucleotide sequence of 7556 bp contained structures similar to those of ndhK, ndhC, trnV, trnM, atpE, atpB, rbcL, trnR and accD. The arrangement of these was the same as that of other chloroplast DNA. However, two nonsense codons were located within the putative coding region of rbcL, although they were used as putative termination codons of the genes. RNA was extensively edited in the transcripts of rbcL when cDNA sequences were analyzed. The unusual nonsense codons of TGA and TAA became CGA and CAA respectively. These are examples of U to C type RNA editing, which was never been found before in chloroplast mRNA. In general, 13 Cs of genomic DNA were found as Ts in the cDNA sequence and seven Ts were found as Cs. This is the first finding of RNA editing on the transcripts of rbcL and also in bryophytes. This event had been thought to arise in land plants after the split of bryophytes. The origin of RNA editing is discussed in relation to the landing of green plants.

Amino Acid Sequence↗
PubMed1998

T. brucei RNA editing: adenosine nucleotides inversely affect U-deletion and U-insertion reactions at mRNA cleavage.

In the currently envisioned mechanism of trypanosome mitochondrial RNA editing, U-insertion and U-deletion cycles begin with a common kind of gRNA-directed cleavage. However, natural, altered, and mutationally interconverted editing sites reveal that U-deletional cleavage is inefficient without and activated by ATP and ADP, while U-insertional cleavage shows completely reverse nucleotide effects. The adenosine nucleotides' effects appear to be allosteric and determined solely by sequences immediately adjacent to the anchor duplex. Both U-deletional and U-insertional cleavages are reasonably active at physiological mitochondrial ATP concentration. Notably, ATP and ADP markedly stimulate complete U-deletion and inhibit U-insertion reactions, reflecting their effects on cleavage. These plus previous results suggest that U deletion and U insertion are remarkably distinct.

Adenosine↗
PubMed2006

National Stroke Association guidelines for the management of transient ischemic attacks.

OBJECTIVE: Transient ischemic attacks are common and important harbingers of subsequent stroke. Management varies widely, and most published guidelines have not been updated in several years. We sought to create comprehensive, unbiased, evidence-based guidelines for the management of patients with transient ischemic attacks. METHODS: Fifteen expert panelists were selected based on objective criteria, using publication metrics that predicted nomination by practitioners in the field. Prior published guidelines were identified through systematic review, and recommendations derived from them were rated independently for quality by the experts. Highest quality recommendations were selected and subsequently edited by the panelists using a modified Delphi approach with multiple iterations of questionnaires to reach consensus on new changes. Experts were provided systematic reviews of recent clinical studies and were asked to justify wording changes based on new evidence and to rate the final recommendations based on level of evidence and quality. No expert was allowed to contribute to recommendations on a topic for which there could be any perception of a conflict of interest. RESULTS: Of 257 guidelines documents identified by systematic review, 13 documents containing 137 recommendations met all entry criteria. Six iterations of questionnaires were required to reach consensus on wording of 53 final recommendations. Final recommendations covered initial management, evaluation, medical treatment, surgical treatment, and risk factor management. INTERPRETATION: The final recommendations on the care of patients with transient ischemic attacks emphasize the importance of urgent evaluation and treatment. The novel approach used to develop these guidelines is feasible, allows for rapid updating, and may reduce bias.

Health Planning Guidelines↗
PubMed2004

[Cross-cultural adaptation of the Spanish version of the Child Health and Illness Profile, Child Edition (CHIP-CE)].

OBJECTIVES: To obtain a Spanish version of the CHIP-CE semantically and culturally equivalent to the original version. METHOD: The methodology used was based on the forward-backward method. Two translations into Spanish were performed. After the first reconciled version, 44 cognitive interviews were carried out with children aged 6-11 years old, selected from two schools in Barcelona. The interviews were recorded and transcribed. A qualitative content analysis of the textual data was carried out. A panel of experts developed the second reconciled version taking into account the children's comments. A back-translation into English was carried out and was compared with the original version. RESULTS: Of a total of 45 items induced in the first reconciled version, 21 were considered equivalent, 23 required changes and 1 was considered not equivalent. Comprehension of abstract concepts differed according to age. Older children differentiated among concepts and gave different examples of experiences related to these concepts, while younger children (6 to 7-year olds) provided similar examples for different concepts. The children's comments were used in the reformulation of the items. An illustrative figure reinforced understanding. Children aged 7 or more started to use an adequate recall period and used the response options correctly. CONCLUSIONS: The Spanish version of the CHIP-CE seems appropriate for children aged 6-11 in Spain. The present study shows that children from the age of 6 years onwards are able to describe the health concepts included in the CHIP-CE.

Child↗
PubMed1994

Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene, second edition.

A large number of different mutations in the factor VIII (F8) gene have been identified as a cause of haemophilia A. This compilation lists known single base-pair substitutions, deletions and insertions in the F8 gene and reviews the status of the inversional events which account for a substantial proportion of mutations causing severe haemophilia A.

Base Sequence↗
PubMed1994

Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene, second edition.

A large number of different mutations in the factor VIII (F8) gene have been identified as a cause of haemophilia A. This compilation lists known single base-pair substitutions, deletions and insertions in the F8 gene and reviews the status of the inversional events which account for a substantial proportion of mutations causing severe haemophilia A.

Base Sequence↗
PubMed1994

Broad factor scales of the 16 PF Fifth Edition and Millon personality disorder scales: a replication.

This study is a replication of the link between broad personality factors from the 16 PF and personality disorder scales based on Millon's typology of personality. The current study was done with the new version of the 16 PF during the final stages of norming. The sample consisted of 30 female and 2 male undergraduate and graduate students, ranging in age from about 21 to 60 years. The data from this replication are consistent with results of the earlier study in that 15 of the 18 expectations were in the expected direction. Of these 10 were significant.

Adult↗
PubMed2026

Cognitive Behavioral Therapy vs Media Literacy for Prevention of Gaming Disorder and Unspecified Internet Use Disorder: A Randomized Clinical Trial.

IMPORTANCE: Mitigating the harmful effects of digitalization on youth mental health is essential. OBJECTIVES: To evaluate the effectiveness of cognitive behavioral therapy (CBT) compared with a media literacy-based intervention for gaming disorder and unspecified internet use disorder and to determine whether universal or indicated prevention yields stronger benefits. DESIGN, SETTING, AND PARTICIPANTS: PROTECTconfirm was a randomized clinical trial conducted from July 1, 2020, to August 31, 2024, across 44 secondary schools in Baden-Württemberg, Germany, with 1-, 4-, and 12-month follow-up. All students were included in universal prevention analyses, whereas indicated prevention analyses included a subgroup of adolescents at high risk meeting 2 or more Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for gaming disorder or unspecified internet use disorder at baseline. INTERVENTIONS: Students were individually randomized within 90 classes to PROTECTtraining, a CBT-based program; or PROTECTinfo, a structurally parallel media literacy program. Both consisted of four 90-minute sessions delivered weekly during school hours by trained local prevention professionals under live supervision and adherence protocols. MAIN OUTCOMES AND MEASURES: The primary outcome was gaming disorder symptom severity and unspecified internet use disorder symptom severity, assessed at 12 months with a modified version of the Video Game Dependency Scale. Secondary outcomes included internalizing, externalizing, and transdiagnostic symptoms. Primary and secondary outcomes were analyzed according to the intention-to-treat principle. RESULTS: A total of 1793 students were randomized to PROTECTtraining (n = 896; mean [SD] age, 13.1 [1.5] years; 498 male students [56.1%]) or PROTECTinfo (n = 897; mean [SD] age, 13.1 [1.5] years; 484 male students [54.8%]). Participants in the subsample of 205 adolescents at high risk showed significantly lower 12-month severity of gaming disorder and unspecified internet use disorder symptoms with PROTECTtraining than with PROTECTinfo (mean [SD] Modified Video Game Dependency Scale score: 14.7 [9.7] vs 17.7 [10.3]; within-group Cohen d = -0.91 [95% CI, -1.10 to -0.72] vs Cohen d = -0.61 [95% CI, -0.80 to -0.42]; between-group Cohen d = -0.30 [95% CI, -0.55 to -0.05]), but not in the total sample (mean [SD] Modified Video Game Dependency Scale score: PROTECTtraining, 8.8 [8.3] vs PROTECTinfo, 9.4 [8.4]; within-group Cohen d = -0.11 [95% CI, -0.18 to -0.05] vs Cohen d = -0.04 [95% CI, -0.11 to 0.02]; between-group Cohen d = -0.07 [95% CI, -0.16 to 0.01]). Secondary outcomes did not differ significantly between groups. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of 1793 adolescents, the CBT-based intervention reduced gaming disorder symptoms and unspecified internet use disorder symptoms more effectively than the media literacy-based intervention among adolescents at high risk. These findings support the use of CBT-based approaches primarily within indicated, rather than universal, prevention. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) trial registration: DRKS00033989.

Humans↗
PubMed2003

ADAR2 A-->I editing: site selectivity and editing efficiency are separate events.

ADAR enzymes, adenosine deaminases that act on RNA, form a family of RNA editing enzymes that convert adenosine to inosine within RNA that is completely or largely double-stranded. Site-selective A-->I editing has been detected at specific sites within a few structured pre-mRNAs of metazoans. We have analyzed the editing selectivity of ADAR enzymes and have chosen to study the naturally edited R/G site in the pre-mRNA of the glutamate receptor subunit B (GluR-B). A comparison of editing by ADAR1 and ADAR2 revealed differences in the specificity of editing. Our results show that ADAR2 selectively edits the R/G site, while ADAR1 edits more promiscuously at several other adenosines in the double-stranded stem. To further understand the mechanism of selective ADAR2 editing we have investigated the importance of internal loops in the RNA substrate. We have found that the immediate structure surrounding the editing site is important. A purine opposite to the editing site has a negative effect on both selectivity and efficiency of editing. More distant internal loops in the substrate were found to have minor effects on site selectivity, while efficiency of editing was found to be influenced. Finally, changes in the RNA structure that affected editing did not alter the binding abilities of ADAR2. Overall these findings suggest that binding and catalysis are independent events.

Adenosine↗
PubMed2026

CRISPR-Cas9‑based lipid nanocarriers for advanced therapy of urinary bladder cancer.

Bladder cancer (BCa) exhibits significant genetic and phenotypic variability. This variability suggests that various tumor subtypes could be influenced by several biomarkers and signaling pathways, which presents a problem for monotherapy strategies. Despite the initial effectiveness of traditional therapies, BCa's high rates of progression and recurrence, and the eventual development of drug resistance in many patients, continue to be major concerns. Because of the potential to transform the genetic modifications linked to the disease, genome editing using CRISPR/Cas9 has become a transformative tool in medicine with noteworthy potential for BCa therapy. Although the CRISPR/Cas9 technology is incredibly effective at transforming the field of genome editing, its instability and cellular impermeability pose significant challenges to its delivery. To increase efficient delivery of CRISPR/Cas9, nanovectors may be investigated. Significant promise exists for improving the therapeutic potential of CRISPR-Cas9 technology and addressing complex cancer therapy difficulties because of the rapid development of nanotechnology-based delivery systems. Relevant articles were searched in Google Scholar, Scopus, and Web of Science covering studies published between 2007 and 2026. Along with the impact of lipid-based nanoparticles on their safe transport to cancer cells, this review emphasizes the significance of the CRISPR/Cas9 genome editing system in the treatment of BCa.

CRISPR–Cas9↗
PubMed1998

Two efficiency elements flanking the editing site of cytidine 6666 in the apolipoprotein B mRNA support mooring-dependent editing.

Normally, apolipoprotein B (apoB) mRNA editing deaminates a single cytidine (C6666) in apoB mRNA. However, when the catalytic subunit of the editing enzyme complex, APOBEC-1, was overexpressed in transgenic mice and rabbits, numerous cytidines in the apoB mRNA and in a novel mRNA, NAT1, were aberrantly hyperedited, and the animals developed liver dysplasia and hepatocellular carcinomas. To identify the RNA motifs in the apoB mRNA that support physiological editing and those that support aberrant hyperediting, we constructed rabbit apoB RNA substrates and tested them in vitro for physiological editing and hyperediting. Three previously unrecognized RNA elements that are critical for efficient physiological editing at C6666 were identified. In concert with the mooring sequence (6671-6681), the 5' efficiency element (6609-6628), an A-rich region (6629-6640), and the 3' efficiency element (6717-6747) increased editing at C6666. The 5' efficiency element was the most potent, elevating physiological editing to wild-type levels in combination with the mooring sequence. The 3' efficiency element was somewhat less important but increased physiological editing to levels approaching wild type. These elements encompass 139 nucleotides on the apoB RNA transcript and are sufficient for editing with the efficiency of full-length apoB mRNA. Furthermore, a distal downstream apoB region (6747-6824) may function as a recognition element in the apoB mRNA. Hyperediting at C6802 in the rabbit apoB mRNA is mediated by RNA elements similar to those required for normal physiological editing at C6666. Similarly sized upstream and downstream flanking regions of C6802 are necessary for hyperediting in combination with a degenerate mooring sequence.

APOBEC-1 Deaminase↗
PubMed2005

Novel mutation of the CYP17 gene in two unrelated patients with combined 17alpha-hydroxylase/17,20-lyase deficiency: demonstration of absent enzyme activity by expressing the mutant CYP17 gene and by three-dimensional modeling.

The CYP17 gene, located on chromosome 10q24-q25, encodes the cytochrome P450c17 enzyme. Mutations of this gene cause the 17alpha-hydroxylase/17,20-lyase deficiency, which is a rare, autosomal recessive form of congenital adrenal hyperplasia. Approximately 50 different mutations of the CYP17 gene have been described, of which some mutations have been identified in certain ethnic groups. In this study, we present the clinical history, hormonal findings and mutational analysis of two patients from unrelated families, who were evaluated for hypertension, hypokalemia and sexual infantilism. In the first patient, who was a 37-year-old female, additional studies showed a large myelolipoma in the left adrenal gland, and a smaller tumor in the right adrenal gland. In the second patient, who was a 31-year-old phenotypic female, clinical work-up revealed a 46,XY kariotype, absence of ovaries and presence of testes located in the inner opening of both inguinal canals. Analysis of the CYP17 gene by polymerase chain reaction amplification and direct sequencing demonstrated a novel homozygous mutation of codon 440 from CGC (Arg) to TGC (Cys) in both patients. The effect of this novel mutation on 17alpha-hydroxylase/17,20-lyase activity was assessed by in vitro studies on the mutant and wild-type P450c17 generated by site-directed mutagenesis and transfected in nonsteroidogenic COS-1 cells. These studies showed that the mutant P450c17 protein was produced in transfected COS-1 cells, but it had negligible 17alpha-hydroxylase and 17,20-lyase activities. In addition, three-dimensional computerized modeling of the heme-binding site of the P450c17 enzyme indicated that replacement of Arg by Cys at amino acid position 440 predicts a loss of the catalytic activity of the enzyme, as the mutant enzyme containing Cys440 fails to form a hydrogen bond with the propionate group of heme, which renders the mutant enzyme unable to stabilize the proper position of heme. Based on these findings we conclude that expressing the CYP17 gene with functional analysis, combined with three-dimensional computerized modeling of the heme-binding site of the protein provide feasible tools for molecular characterizing of functional consequences of the novel CYP17 mutation on enzyme function.

Adrenal Hyperplasia, Congenital↗
PubMed1994

RNA editing of transcripts of a chimeric mitochondrial gene associated with cytoplasmic male-sterility in Brassica.

The orf224 gene is a chimeric open reading frame associated with the Polima or pol cytoplasmic male sterility of Brassica napus. The first 58 codons and 5' upstream region of orf224 are derived from a conventional mitochondrial gene, orfB, while the origin of the remaining portion of the gene is unknown. Transcripts of the orf224 gene were found to be edited at a single site in the region of the gene that does not correspond to a known sequence. Oligonucleotides corresponding to the edited and unedited forms were shown to hybridize specifically to respective in vitro orf224 transcripts. Analysis of floral mtRNA by this method indicated that virtually all orf224 transcripts of both sterile and fertile, nuclear-restored pol cytoplasm plants are edited. Our results indicate that transcripts of novel, CMS-associated genes may be edited, but that, at least in this case, the degree of editing does not appear to be directly related to the male-sterile phenotype.

Amino Acid Sequence↗
PubMed1996

In vivo dissection of cis-acting determinants for plastid RNA editing.

Substitutional RNA editing changes single C nucleotides in higher plant chloroplast transcripts into U residues. To determine the cis-acting sequence elements involved in plastid RNA editing, we constructed a series of chloroplast transformation vectors harboring selected editing sites of the tobacco ndhB transcript in a chimeric context. The constructs were inserted into the tobacco plastid genome by biolistic transformation leading to the production of stable chimeric RNAs. Analysis of RNA editing revealed unexpected differences in the size of the essential cis elements or in their distance from the editing site. Flanking sequences of identical size direct virtually complete editing for one pair of editing sites, partial editing for a second and no editing at all for a third pair of sites. Serial 5' and 3' deletions allowed us to define the cis-acting elements more precisely and to identify a sequence element essential for editing site recognition. In addition, a single nucleotide substitution immediately upstream of an editing position was introduced. This mutation was found drastically and selectively to reduce the editing efficiency of the downstream editing site, demonstrating that position -1 is important for either site recognition or catalysis. Our results indicate that the editing of adjacent sites is likely to be mechanistically coupled. In no case did the presence in the plastome of the additional editing sites have any effect on the editing efficiency of the endogenous ndhB sites, indicating that the availability of site-specific trans-acting factors is not rate limiting.

Base Sequence↗
PubMed1996

The rpl5-rps14-cob gene arrangement in Solanum tuberosum: rps14 is a transcribed and unedited pseudogene.

The L5 ribosomal protein gene (rpl5) and a S14 ribosomal protein pseudogene were identified by sequence analysis in the potato mitochondrial genome. The two genes are separated by one nucleotide and are found upstream of the apocytochrome b gene (cob), an arrangement conserved also in Arabidopsis and Brassica. The rpl5 gene has an intact open reading frame while the rps14 locus is disrupted by a five nucleotide duplication that introduces a frameshift in the reading frame. Editing of rpl5 and pseudorps14 cotranscripts has been studied by cDNA sequence analysis. Eight C residues are edited into U in the rpl5 coding region, resulting in eight amino acid changes that increase the homology between potato and other RPL5 polypeptides. Interestingly, the rps14 pseudogene sequence is not edited at any nucleotide position.

Amino Acid Sequence↗
PubMed1993

Tissue- and stage-specific modulation of RNA editing of the psbF and psbL transcript from spinach plastids--a new regulatory mechanism?

The psbE operon of spinach chloroplasts, which includes the genes psbE, psbF, psbL and psbJ, encodes two RNA editing sites. One site corresponds to the initiation codon of the psbL transcript, as has been described earlier for the homologous transcript from tobacco, while at a second editing site, newly reported here, an internal phenylalanine codon of the psbF transcript is restored. Both these sites were investigated with respect to the extent of editing in spinach plastids at various developmental stages. The apparent existence of only completely edited transcripts in etioplasts and chloroplasts, indicates that light-induced processes are not acting as determinants in eliciting the editing process. Reduced editing is, however, observed in the psbF and psbL transcript from seeds and roots. This finding suggests that the RNA editing process is differentially down-regulated in leucoplasts and proplastids and that editing may, therefore, function as a regulatory device in plastid gene expression.

Amino Acid Sequence↗
PubMed1999

C to U editing of the anticodon of imported mitochondrial tRNA(Trp) allows decoding of the UGA stop codon in Leishmania tarentolae.

All mitochondrial tRNAs in kinetoplastid protists are encoded in the nucleus and imported into the organelle. The tRNA(Trp)(CCA) can decode the standard UGG tryptophan codon but can not decode the mitochondrial UGA tryptophan codon. We show that the mitochondrial tRNA(Trp) undergoes a specific C to U nucleotide modification in the first position of the anticodon, which allows decoding of mitochondrial UGA codons as tryptophan. Functional evidence for the absence of a UGA suppressor tRNA in the cytosol, using a reporter gene, was also obtained, which is consistent with a mitochondrial localization of this editing event. Leishmania cells have dealt with the problem of a lack of expression within the organelle of this non-universal tRNA by compartmentalizing an editing activity that modifies the anticodon of the imported tRNA.

Animals↗