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PubMed2005

Inverted terminal repeat sequences are important for intermolecular recombination and circularization of adeno-associated virus genomes.

The relatively small package capacity (less than 5 kb) of adeno-associated virus (AAV) vectors has been effectively doubled with the development of dual-vector heterodimerization approaches. However, the efficiency of such dual-vector systems is limited not only by the extent to which intermolecular recombination occurs between two independent vector genomes, but also by the directional bias required for successful transgene reconstitution following concatemerization. In the present study, we sought to evaluate the mechanisms by which inverted terminal repeat (ITR) sequences mediate intermolecular recombination of AAV genomes, with the goal of engineering more efficient vectors for dual-vector trans-splicing approaches. To this end, we generated a novel AAV hybrid-ITR vector characterized by an AAV-2 and an AAV-5 ITR at opposite ends of the viral genome. This hybrid genome was efficiently packaged into either AAV-2 or AAV-5 capsids to generate infectious virions. Hybrid AV2:5 ITR viruses had a significantly lower capacity to form circular intermediates in infected cells than homologous AV2:2 and AV5:5 ITR vectors despite their similar capacity to express an encoded enhanced green fluorescent protein (EGFP) transgene. To examine whether the divergent ITR sequences contained within hybrid AV2:5 ITR vectors could direct intermolecular recombination in a tail-to-head fashion, we generated two hybrid ITR trans-splicing vectors (AV5:2LacZdonor and AV2:5LacZacceptor). Each delivered one exon of a beta-galactosidase minigene flanked by donor or acceptor splice sequences. These hybrid trans-splicing vectors were compared to homologous AV5:5 and AV2:2 trans-splicing vector sets for their ability to reconstitute beta-galactosidase gene expression. Results from this comparison demonstrated that hybrid ITR dual-vector sets had a significantly enhanced trans-splicing efficiency (6- to 10-fold, depending on the capsid serotype) compared to homologous ITR vectors. Molecular studies of viral genome structures suggest that hybrid ITR vectors provide more efficient directional recombination due to an increased abundance of linear-form genomes. These studies provide direct evidence for the importance of ITR sequences in directing intermolecular and intramolecular homologous recombination of AAV genomes. The use of hybrid ITR AAV vector genomes provides new strategies to manipulate viral genome conversion products and to direct intermolecular recombination events required for efficient dual-AAV vector reconstitution of the transgene.

Animals↗
PubMed2002

Interstitial telomere-like repeats in the Arabidopsis thaliana genome.

Eukaryotic chromosomal ends are protected by telomeres, which are thought to play an important role in ensuring the complete replication of chromosomes. On the other hand, non-functional telomere-like repeats in the interchromosomal regions (interstitial telomeric repeats; ITRs) have been reported in several eukaryotes. In this study, we identified eight ITRs in the Arabidopsis thaliana genome, each consisting of complete and degenerate 300- to 1200-bp sequences. The ITRs were grouped into three classes (class IA-B, class II, and class IIIA-E) based on the degeneracy of the telomeric repeats in ITRs. The telomeric repeats of the two ITRs in class I were conserved for the most part, whereas the single ITR in class II, and the five ITRs in class III were relatively degenerated. In addition, degenerate ITRs were surrounded by common sequences that shared 70-100% homology to each other; these are named ITR-adjacent sequences (IAS). Although the genomic regions around ITRs in class I lacked IAS, those around ITRs in class II contained IAS (IASa), and those around five ITRs in class III had nine types of IAS (IASb, c, d, e, f, g, h, i, and j). Ten IAS types in classes II and III showed no significant homology to each other. The chromosomal locations of ITRs and IAS were not category-related, but most of them were adjacent to, or part of, a centromere. These results show that the A. thaliana genome has undergone chromosomal rearrangements, such as end-fusions and segmental duplications.

Arabidopsis↗
PubMedDate not supplied

Food interaction and steady-state pharmacokinetics of itraconazole oral solution in healthy volunteers.

STUDY OBJECTIVES: To evaluate the effect of food on the bioavailability of itraconazole (ITR) hydroxypropyl-beta-cyclodextrin (HP-beta-CD) solution under multiple-dose to steady-state conditions, and to determine the pharmacokinetics of ITR solution at steady state. DESIGN: Open-label, randomized, multiple-dose, crossover study SETTING: University-affiliated health center. PATIENTS: Thirty healthy men randomized to one of two treatment sequences (fasted-fed, fed-fasted). INTERVENTIONS: Subjects were either fasted or fed a standard breakfast before receiving ITR oral solution 200 mg once/day for 15 days. Crossover phases were separated by a 4-week washout period. MEASUREMENTS AND MAIN RESULTS: On day 1, blood samples were collected before the dose (time zero) and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours after the dose. Trough samples were obtained before the dose on days 4, 7, 12, 13, and 14. On day 15, samples were obtained at the same times as day 1, and at 36, 48, 72, 96, 168, 240, and 360 hours. Samples were analyzed by high-performance liquid chromatography for ITR and its major metabolite hydroxyitraconazole (OH-ITR). Urine was collected on days 1 and 15 before and 0-8 and 8-24 hours after the dose; HP-beta-CD was measured by size-exclusion chromatography. Mean bioavailabilities of ITR and OH-ITR were 43% and 38% higher, respectively, when ITR solution was taken as a single dose under fasted conditions. With multiple dosing, steady state was achieved by day 14. At steady state, mean bioavailabilities were 29% and 17% higher, respectively, in the fasted state; terminal half-life was similar under fasted and fed conditions (mean 39.8 and 37.5 hrs for ITR, respectively; 27.3 and 26.2 hrs for OH-ITR, respectively). HP-beta-CD was eliminated almost exclusively in urine. CONCLUSION: The bioavailability of ITR and OH-ITR is enhanced when ITR oral solution is given in the fasted state; this was true for both single and multiple dosing to steady state.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2004

Therapy of meningeal melanocytomas.

BACKGROUND: Meningeal melanocytomas are rare, benign central nervous system lesions with a high probability of recurrence. To the authors' knowledge, approximately 100 cases have been reported since 1972, when the entity first was described. In the current study, four therapies were compared with regard to local control and survival to identify which is best. METHODS: All reported cases were reviewed with regard to extent of resection, radiotherapy, local control, and survival. If published data were incomplete, the authors were contacted for additional data. Patients were categorized by therapy: complete resection (CTR), complete resection followed by radiotherapy (CTR-RT), incomplete resection (ITR), and incomplete resection followed by radiotherapy (ITR-RT). Local control and survival were calculated using the Kaplan-Meier method. A multivariate analysis was performed including age, gender, tumor location, confirmation of extent of resection, and treatment schedule. RESULTS: A total of 89 patients were included: 46 with CTR, 3 with CTR-RT, 23 with ITR, and 17 with ITR-RT. The 5-year local control rate was 80% after CTR, 100% after CTR-RT, and 72% after ITR-RT versus 18% after ITR (P < 0.001). The 5-year survival rate was 100% after CTR, CTR-RT, and ITR-RT, respectively, versus 46% after ITR (P < 0.001). Multivariate analysis demonstrated that therapy was the only variable that affected local control and survival significantly. In 14 patients treated with ITR-RT, RT was restricted to the tumor region. The radiation dose was 30-40 grays (Gy) in 6 patients, 45-55 Gy in 7 patients, and unknown in 1 patient. The 5-year local control rate was 86% after a dose of 45-55 Gy versus 27% after a dose of 30-40 Gy (P = 0.1). CONCLUSIONS: CTR was found to be significantly superior to ITR with regard to both local control and survival. Outcome was significantly improved by RT after ITR. Doses of 45-55 Gy appeared to be more beneficial than doses of < or = 40 Gy.

Adolescent↗
PubMed1984

Testicular infiltrates in children with acute lymphoblastic leukemia: a prospective study.

The incidence of testicular infiltrates in 68 boys with acute lymphoblastic leukemia in first remission (1974-81), was prospectively investigated through careful clinical examination and routine bilateral biopsies at 2-3 years of remission. All boys were under 14 years of age and they were treated with protocols D.74 and Pethema 7/78. Seven patients (10.3%) presented an isolated testicular relapse (ITR) during the chemotherapy period. In 13 of the 43 testicular biopsies (31%) leukemic infiltrates were found, and in another two findings were controversial. Three boys, two with previous negative biopsies, had an ITR 6 to 18 months after therapy was stopped. Finally, three others had simultaneous relapses in testes and bone marrow, one during chemotherapy and two after suppression. In all, 23 patients (33.8%) in first remission had overt or occult ITR. Overall estimated incidence rate of testes leukemia is 40% in all the groups. Incidence of early and occult ITR was higher in boys with initial WBC counts over 20 X 10(9)/1. Therapy in ITR generally consisted of local radiotherapy (20-25 Gy), a new induction treatment followed by 2-year maintenance treatment; in three patients with early ITR, orchidectomy was also performed and six were given a new CNS preventive treatment. Clinical course in the seven patients with early ITR was unfavourable in five, with subsequent hematological relapses and death; one had a long-term disease-free survival (80 + months) and the other was a recent case. Ten of the 13 patients with occult infiltrates continued in remission and four were off treatment with a follow-up of over 66 months. The three patients with late ITR were in 2nd remission at 8-18 months after a new cessation of therapy. It may be concluded from this study that prognosis in ITR is related to the phase of presentation: it is unfavourable in cases of early ITR, but in occult infiltrates, detected by routine biopsy, and in late ITR combined therapy is effective in most cases.

Adolescent↗
PubMed1984

[Clinical and occult testicular relapses in children with acute lymphoblastic leukemia. Treated with the D.74 and pethema 7/78 protocols].

The incidence of testicular infiltrates in 68 boys with acute lymphoblastic leukemia in first remission (1974-81), was prospectively investigated through careful clinical exams and routine bilateral biopsies at 2-3 years of remission. All boys were under 14 years of age and they were treated with protocols D.74 and pethema 7/78. Seven patients (10.3%) presented an isolated testicular relapse (ITR) during the chemotherapy period. In 13 out of the 43 testicular biopsies (31%) leukemic infiltrates were found and in other 2 findings were controversial. Three boys, two of them whose previous biopsy was negative, had an ITR, 6 to 18 months after stopping therapy. Finally, other 3 had simultaneous relapses in testes and bone-marrow: one during chemotherapy and two after suppression. In total, 23 patients (33.8%) in first remission had overt or occult ITR. Overall incidence of testes leukemia, is calculated to be 40% in all the group. Incidence of early and occult ITR was higher in boys with initial WBC counts over 20 X 10 9/l. Therapy in ITR generally consisted in local radiotherapy (20-25 Gy), a new induction treatment followed by 2 year maintenance treatment; in 3 patients with early ITR, orchidectomy was also performed and six were given a new preventive SNC treatment. Clinical course in the 7 patients with early ITR was unfavourable in 5 with subsequent hematological relapses and death; one had a long-term disease-free survival (78 + months) and the other was a recent case. 10 out of the 13 patients with occult infiltrates followed in remission and four were of treatment with a follow-up over 64 months. The 3 patients with late ITR were in second remission at 8-14 months after a new cessation of therapy. It may be concluded from this study that prognosis in ITR is related to the phase of presentation: It is unfavourable in cases of early ITR but in cases of occult infiltrates detected by routine biopsies and in late ITR the combined therapy is effective in most cases.

Adolescent↗
PubMed1987

Subdivisions and connections of inferior temporal cortex in owl monkeys.

Patterns of cortical connections and differences in architectonic appearance were used to subdivide inferior temporal cortex of owl monkeys into four main regions. These regions were named by location: ITC (the caudal subdivision of inferior temporal cortex), ITR (the rostral subdivision of inferior temporal cortex), ITP (the polar subdivision of inferior temporal cortex), and ITM (the medial subdivision of inferior temporal cortex). Two of these regions may contain further subdivisions--ITC, separate dorsal and ventral areas, and ITM, medial and lateral areas. The most caudal subdivision, ITC, was defined in an earlier report (Weller and Kaas: J. Comp. Neurol. 234:35-59, '85) as the projection zone of the dorsolateral visual area (DL). ITC occupies roughly the caudal half of the architectonic zone temporal area E (TE) (after von Bonin and Bailey: The Neocortex of Macaca mulatta. Urbana: University of Illinois Press, '47). TE is characterized by a dense, broad layer IV of granule cells and a dark inner band of myelination. Injections of 3H-proline in ITC demonstrated major projections to a more rostral division of the temporal lobe, ITR. Other projections were to the frontal eye field (FEF), a more ventral region of frontal cortex (FV), and a medial division of inferior temporal cortex, ITM, on the ventral surface of the temporal lobe. Feedback projections of ITC were to DL and adjoining temporal-parietal cortex (TP), while interhemispheric projections were to ITC and ITR. Connections between dorsal and ventral ITC, together with earlier evidence for two projection zones of DL in ITC (Weller and Kaas: ibid., '85), suggest that dorsal and ventral sectors of ITC are separate visual areas. The rostral division of inferior temporal cortex, ITR, was defined as the projection zone of ITC. ITR occupied the rostral half of the architectonic region TE. Slight differences in cortical architecture between ITC and ITR were noted, but an architectonic border between the two fields could not be reliably distinguished. Injections in ITR demonstrated projections to the rostral pole of temporal cortex, ITP, feedback projections to ITC, and inputs to FEF, FV, dorsomedial frontal cortex, and the rostroventral superior temporal gyrus. Interhemispheric projections were to ITR and ITP. The projections of ITR to the rostral pole defined ITP. ITP has broad, less distinct layers of cortex and appears to correspond to temporal area G (TG) of von Bonin and Bailey (ibid., '47). The only known input to ITP is from ITR, and its projections have not yet been determined.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids↗
PubMed2001

Enhanced expression and stable transmission of transgenes flanked by inverted terminal repeats from adeno-associated virus in zebrafish.

Mosaic expression of transgenes in the F0 generation severely hinders the study of transient expression in transgenic fish. To avoid mosaicism, enhanced green fluorescent protein (EGFP) gene cassettes were constructed and introduced into one-celled zebrafish embryos. These EGFP gene cassettes were flanked by inverted terminal repeats (ITRs) from adeno-associated virus (AAV) and driven by zebrafish alpha-actin (palpha-actin-EGFP-ITR) or medaka beta-actin promoters (pbeta-actin-EGFP-ITR). EGFP was expressed specifically and uniformly in the skeletal muscle of 56% +/- 8% of the palpha-actin-EGFP-ITR-injected survivors and in the entire body of 1.3% +/- 0.8% of the pbeta-actin-EGFP-ITR-injected survivors. Uniform transient expression never occurred in zebrafish embryos injected with EGFP genes that were not flanked by AAV-ITRs. In the F0 generation, uniformly distributed EGFP could mimic the stable expression in transgenic lines early in development. We established five transgenic lines derived from palpha-actin-EGFP-ITR-injected embryos crossed with wild-type fish and 11 transgenic lines derived from pbeta-actin-EGFP-ITR-injected embryos crossed with wild-type fish. None of these transgenic lines failed to express the transgene, a result confirmed by polymerase chain reaction analysis. Stable mendelian transmission of the transgenes was achieved in both alpha-actin and beta-actin transgenic lines without changing the patterns of expression and integration. Progeny inheritance test and Southern blot analysis results strongly suggest that transgenes flanked by AAV-ITRs were integrated randomly into the genome at a single locus with a concatamerized multiplier. Thus, incorporating AAV-ITRs into transgenes results in uniform gene expression in the F0 generation and stable transmission of transgenes in zebrafish.

Actins↗
PubMed1990

Treatment of isolated testicular relapse in childhood acute lymphoblastic leukemia: an Italian multicenter study. Associazione Italiana Ematologia ed Oncologia Pediatrica.

Between May 1980 and April 1987, 49 children with acute lymphoblastic leukemia (ALL) in isolated testicular and first leukemia relapse (ITR) were enrolled in the Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP) multicenter study REC80-ITR. According to the Rome Workshop criteria, 77% were at standard and 23% at high initial prognostic risk. In 33% of the cases, ITR occurred during first treatment. The REC80-ITR protocol consisted of an induction phase regimen of vincristine (VCR), cytarabine (ARA-C), methotrexate (MTX), and asparaginase (L-asp), and bilateral testicular irradiation, and CNS prophylaxis with intrathecal MTX and a maintenance phase with a multidrug rotating regimen. Total treatment duration was 30 months. The median time of observation after ITR was 51 months. The Kaplan-Meier estimates of survival and disease-free survival (DFS) at 4 years were 67.7% and 41%, respectively. Patients who had an ITR on therapy or within the first off-therapy year showed the poorest outcome. The DFS at 3 years was 20%, 47.6%, and 100%, respectively, for children who had an ITR on treatment (n = 16), within the first year of treatment withdrawal (n = 22), or later (n = 10) (P = .001). Patients with an asymptomatic occult testicular infiltrate at treatment discontinuation had a very unfavorable prognosis. Eighty-one percent of second relapses involved the bone marrow. In our experience, children presenting an early ITR (ie, within 6 months of treatment withdrawal) need a very aggressive treatment because of the high probability of an underlying systemic disease. On the other hand, patients with a late ITR seem to have a truly local recurrence and can apparently be cured by standard protocols, as shown in protocol REC80-ITR.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Defining the best available treatment for neurocytomas in children.

BACKGROUND: In children, neurocytomas are extremely rare tumors in the central nervous system. Since this entity was introduced in 1982, approximately 60 cases have been reported among patients age </= =18 years of age. The current analysis was performed to define the best available neurocytoma therapy in children. METHODS: All reported neurocytoma cases were reviewed for age, extent of resection, radiotherapy, radiotherapy dose, local control, and survival. Data were obtained from the literature and the authors. Statistical analysis was performed with the Kaplan-Meier method and log-rank test. RESULTS: Fifty-nine children were categorized by therapy: complete tumor resection (CTR; n = 20), complete tumor resection plus radiotherapy (CTR-RT; n = 11), incomplete tumor resection (ITR; n = 14), and incomplete tumor resection plus radiotherapy (ITR-RT; n = 14). Local control rates were better after CTR, CTR-RT, and ITR-RT than after ITR, at 5 years (86%, 100%, and 100% vs. 60%; P < 0.001) and at 10 years (86%, 100%, and 100% vs. 45%; P < 0.001). The 5-year and 10-year survival rates were 100% after CTR, 100% after CTR-RT, 100% after ITR-RT, and 93% after ITR (P = 0.4). In the ITR-RT group, no difference was observed between doses </= 50 gray (Gy) and >/= 54 Gy when compared for local control (P = 1.0) and survival rates (P = 1.0). Radiotherapy-related psychomotor retardation or secondary brain tumors were not reported. CONCLUSIONS: The prognosis of children with neurocytomas is extremely good. CTR was associated with better local control and survival rates than ITR. After ITR, radiotherapy improves local control, but not survival. If postoperative radiotherapy is considered, a dose of 50 Gy was appropriate for long-term local control in children, whereas higher doses were required in adults.

Adolescent↗
PubMed1992

Inhibition of isotretinoin teratogenicity by acetylsalicylic acid pretreatment in mice.

Although isotretinoin (ITR) has been suggested to cause malformations via cytopathic effects on embryonic cells, the molecular mechanisms of ITR cytotoxicity in teratogenesis are not clear. Since ITR undergoes metabolism by prostaglandin synthase to a potentially cytotoxic peroxyl free radical, the possible role of prostaglandin synthase metabolism as a modulator of ITR teratogenicity was evaluated. Craniofacial and limb abnormalities were noted in fetuses on day 18.5 of gestation following administration of ITR to pregnant CD-1 mice in a three dose regimen of 100 mg/kg at 4 hr intervals on day 10.5 of gestation (plug day = day 0.5 of gestation). Mice were also treated with acetylsalicylic acid (ASA), an irreversible inhibitor of the cyclooxygenase component of prostaglandin synthase, at doses of 20 and 60 mg/kg body weight 2 hr prior to each ITR dose. ASA pretreatment of mice receiving ITR treatment showed a dose-dependent decrease in the overall incidence of malformations, number of defects per fetus, and the incidence of specific craniofacial and limb defects. Equivalent doses of ASA given to control mice did not cause malformations or alter the incidence of resorptions. These results demonstrate that ASA is able to ameliorate the teratogenic effects of ITR observed in fetal mice near term and indicate that prostaglandin metabolism could play a mechanistic role in ITR teratogenicity.

Animals↗
PubMed2002

Distribution of interstitial telomere-like repeats and their adjacent sequences in a dioecious plant, Silene latifolia.

The dioecious plant Silene latifolia has large, heteromorphic X and Y sex chromosomes that are thought to be derived from rearrangements of autosomes. To reveal the origin of the sex chromosomes in S. latifolia, we isolated and characterized telomere-homologous sequences from intra-chromosomal regions (interstitial telomere-like repeats; ITRs) and ITR-adjacent sequences (IASs). Nine genomic DNA fragments with degenerate 84- to 175-bp ITRs were isolated from a genomic library and total genome of male plants. Comparing the nucleotide sequences, the IASs of the nine ITRs were classified into seven elements (IAS-a, IAS-b, IAS-c, IAS-d, IAS-e, IAS-f, and IAS-g) by sequence similarity. The ITRs were grouped into two classes (class-I and -II ITRs) according to the classification of IASs. The class-I ITRs were sub-grouped into three subclasses (subclasses-IA, -IB, and -IC ITRs) based on the arrangement of IAS elements. By contrast, the class-II ITR was located between two different IASs (IAS-f and IAS-g). Genomic Southern analyses showed that both the male and female genomes contained six (IAS-f) to 153 (IAS-d) copies of each IAS per haploid genome. Fluorescence in situ hybridization analyses showed that one IAS element, IAS-d, was distributed in the interstitial and proximal regions of the sex chromosomes of S. latifolia. The distribution of IAS-d is important evidence for past telomere-mediated chromosome rearrangements during the evolution of the sex chromosomes of S. latifolia.

Base Sequence↗
PubMed2004

Analyses of cis -acting elements that affect the transposition of Mos1 mariner transposons in vivo.

The left (5') inverted terminal repeat (ITR) of the Mos1 mariner transposable element was altered by site-directed mutagenesis so that it exactly matched the nucleotide sequence of the right (3') ITR. The effects on the transposition frequency resulting from the use of two 3' ITRs, as well as those caused by the deletion of internal portions of the Mos1 element, were evaluated using plasmid-based transposition assays in Escherichia coli and Aedes aegypti. Donor constructs that utilized two 3' ITRs transposed with greater frequency in E. coli than did donor constructs with the wild-type ITR configuration. The lack of all but 10 bp of the internal sequence of Mos1 did not significantly affect the transposition frequency of a wild-type ITR donor. However, the lack of these internal sequences in a donor construct that utilized two 3' ITRs resulted in a further increase in transposition frequency. Conversely, the use of a donor construct with two 3' ITRs did not result in a significant increase in transposition in Ae. aegypti. Furthermore, deletion of a large portion of the internal Mos1 sequence resulted in the loss of transposition activity in the mosquito. The results of this study indicate the possible presence of a negative regulator of transposition located within the internal sequence, and suggest that the putative negative regulatory element may act to inhibit binding of the transposase to the left ITR. The results also indicate that host factors which are absent in E. coli, influence Mos1 transposition in Ae. aegypti.

Aedes↗
PubMed1999

Adeno-associated virus (AAV) type 5 Rep protein cleaves a unique terminal resolution site compared with other AAV serotypes.

Adeno-associated virus (AAV) replication depends on two viral components for replication: the AAV nonstructural proteins (Rep) in trans, and inverted terminal repeat (ITR) sequences in cis. AAV type 5 (AAV5) is a distinct virus compared to the other cloned AAV serotypes. Whereas the Rep proteins and ITRs of other serotypes are interchangeable and can be used to produce recombinant viral particles of a different serotype, AAV5 Rep proteins cannot cross-complement in the packaging of a genome with an AAV2 ITR. In vitro replication assays indicated that the block occurs at the level of replication instead of at viral assembly. AAV2 and AAV5 Rep binding activities demonstrate similar affinities for either an AAV2 or AAV5 ITR; however, comparison of terminal resolution site (TRS) endonuclease activities showed a difference in specificity for the two DNA sequences. AAV2 Rep78 cleaved only a type 2 ITR DNA sequence, and AAV5 Rep78 cleaved only a type 5 probe efficiently. Mapping of the AAV5 ITR TRS identified a distinct cleavage site (AGTG TGGC) which is absent from the ITRs of other AAV serotypes. Comparison of the TRSs in the AAV2 ITR, the AAV5 ITR, and the AAV chromosome 19 integration locus identified some conserved nucleotides downstream of the cleavage site but little homology upstream.

Base Sequence↗
PubMed2005

Well-differentiated neurocytoma: what is the best available treatment?

Most neurocytomas are well differentiated, being associated with better long-term survival than the more aggressive atypical lesions. Atypical neurocytomas are characterized by an MIB-1 labeling index >3% or atypical histologic features. This analysis focuses on well differentiated neurocytomas in order to define the optimal treatment. A case with a follow-up of 132 months is presented. The patient developed two recurrences two and four years after first surgery, each showing an increasing proliferation activity. Furthermore, all published well-differentiated neurocytoma cases were reviewed for surgery, radiotherapy, and prognosis. Additional relevant data were obtained from the authors. Complete resection (CTR), complete resection plus radiotherapy (CTR + RT), incomplete resection (ITR), and incomplete resection plus radiotherapy (ITR + RT) were compared for outcome by using the Kaplan-Meier method and the log-rank test. Data were complete in 301 patients (CTR, 108; CTR + RT, 27; ITR, 81; ITR + RT, 85). Local control and survival were better after CTR than after ITR (P < 0.0001 and P = 0.0085, respectively). Radiotherapy improved local control after ITR (P < 0.0001) and after CTR (P = 0.0474), but not survival (P = 0.17 and P = 1.0, respectively). In the ITR + RT group, doses < or =54 Gy (n = 33) and >54 Gy (n = 32) were not significantly different for local control (P = 0.88) and survival (P = 0.95). The data demonstrated CTR to be superior to ITR for local control and survival. After CTR and ITR, radiotherapy improved local control, but not survival. A radiation dose of 54 Gy appeared sufficient. Application of postoperative radiotherapy should be decided individually, taking into account the risk of local failure, the need for another craniotomy, and potential radiation toxicity.

Adolescent↗
PubMedDate not supplied

Subcortical connections of subdivisions of inferior temporal cortex in squirrel monkeys.

On the basis of cortical connections and architectonics, inferior temporal (IT) cortex of squirrel monkeys consists of a caudal, prestriate-recipient region, ITC; a rostral region, ITR; and possibly an intermediate region along the border of ITC and ITR, "ITI" (Weller & Steele, 1992). ITC contains dorsal (ITCd) and ventral (ITCV) areas. The subcortical connections of these subdivisions of IT cortex were determined in the present study from the results of cortical injections of wheat-germ agglutinin conjugated to horseradish peroxidase, [3H]-amino acids and fast blue. ITC and ITR receive afferents from the locus coeruleus, dorsal raphe, nucleus annularis, central superior nucleus, pontine reticular formation, lateral hypothalamus, paracentral nucleus, and central medial nucleus; send efferents to the superior colliculus, reticular nucleus, and striatum; and have both afferent and efferent connections with the pretectum, pulvinar, claustrum, amygdala, and basal nucleus of Meynert. ITC and ITR have different patterns of connections with a number of subcortical structures, including the pulvinar and amygdala. Injections in ITC strongly label multiple nuclei of the inferior pulvinar and the medial division of the lateral pulvinar (PLM), and moderately label the medial pulvinar (PM), whereas injections in ITR strongly label PM and moderately label PLM. Injections in ITC label sparse projections to the lateral nucleus of the amygdala, in contrast to injections in ITR that label strong projections to the lateral and basal nuclei of the amygdala. Injections in "ITI" produce a pattern of subcortical label that has some features of that observed from injections in ITC and that observed from injections in ITR. Although most of the connections of ITCd and ITCv appear similar, only injections involving ITCd label the middle nucleus of the inferior pulvinar (PIM). Comparison of the subcortical connections of subdivisions of IT cortex in squirrel monkeys and what is presently known of the subcortical connections of subdivisions of IT cortex in macaque monkeys supports the previous suggestion that ITC of squirrel monkeys may be comparable to area TEO of macaques, ITI may be comparable to posterior area TE, and ITR may be comparable to anterior area TE (Weller & Steele, 1992).

Afferent Pathways↗
PubMed1980

An evaluation of the Illinois trauma registry: the completeness of case reporting.

The Illinois Trauma Registry (ITR) was developed as the principal evaluative tool for the comprehensive set of medical programs known as the Illinois Trauma System. In order to determine the completeness of case reporting to the ITR, a 10% sample of traumatic injuries was drawn at 33 hospitals designated as Trauma Centers. An attempt was then made to link the cases found at the Trauma Centers with those in the ITR; theoretically, all cases found in the Trauma Center should appear in the ITR. Analysis reveals that the ITR is drastically underreported; for all 33 Trauma Centers combined, only 36.9% of the cases appeared in the ITR. On an individual hospital basis, completeness ranged from 0.0% (eight hospitals) to 83.3%. Inclusion in the ITR is significantly associated with the categorization of hospital emergency capability, the method of patient transport to the hospital, the mechanism of injury and subsequent admittance to the intensive care unit. Of particular interest for evaluative studies is the marginally significant difference between the case fatality rate as reported in the ITR (5.0%) and that found in the hospital (2.8%). Guidelines are suggested to improve the development, management and data quality of future registries.

Humans↗
PubMed2003

Adeno-associated virus integrates site-specifically into human chromosome 19 in either orientation and with equal kinetics and frequency.

Adeno-associated virus type 2 (AAV-2) establishes latency by site-specific integration into a unique locus, AAVS1, on human chromosome 19 (chr19). To study the kinetics and frequency of chr19-specific integration, a rapid, sensitive and quantitative real-time PCR assay specific for AAV inverted terminal repeat (ITR)-chr19 junction sequences was developed. Since the assay only detected right-hand AAV ITR-specific integration events, the development of a complementary left-hand ITR-specific real-time PCR assay is described. The time-course of left-hand ITR-dependent AAV integration at AAVS1 of chr19 was determined in AAV-2-infected HeLa cells. Both the kinetics and frequencies of left-hand ITR-dependent integration were found to be similar to those of the right-hand ITR. In addition, left-hand ITR-specific fusion sequences and chromosomal breakpoints within AAVS1 were variable, yet were the same as those found in right-hand ITR-chr19 junction sequences. Thus, the AAV-2 genome integrates site-specifically into chr19 with similar efficiency in either orientation.

Chromosomes, Human, Pair 19↗