Biomedical subjects

N Martin

Publications and source records attributed to N Martin.

At least 19 recordsLinked to original sources

PubMed1999

CDKN2A variants in a population-based sample of Queensland families with melanoma.

BACKGROUND: Mutations in the CDKN2A gene confer susceptibility to cutaneous malignant melanoma (CMM); however, the population incidence of such mutations is unknown. Polymorphisms in CDKN2A have also been described, but it is not known whether they influence melanoma risk. We investigated the association of CDKN2A mutations and polymorphisms with melanoma risk in a population-based sample of families ascertained through probands with melanoma. METHODS: The 482 Queensland, Australia, families in our sample were characterized previously as having high, intermediate, or low family risk of CMM. Unrelated individuals (n = 200 families/individuals) drawn from the Australian Twin Registry served as control subjects. For individuals in the high-risk group, the entire CDKN2A gene coding region was screened for mutations by use of the polymerase chain reaction, agarose gel electrophoresis, allele-specific oligonucleotide (ASO) hybridization, and single-strand conformation polymorphism analysis. The intermediate- and low-risk families and control subjects were analyzed by ASO hybridization for a total of six recurring mutations as well as for polymorphisms at nucleotides (Nts) 442, 500, and 540. RESULTS: CDKN2A mutations were found only in the high-risk families (nine [10.3%] of 87). The prevalence of the Nt500G (guanosine) polymorphism increased linearly with increasing familial risk (two-sided P = .02) and was highest in the nine (primarily Celtic) families with CDKN2A mutations. After adjustment for ethnic origin, the relationship between risk group and the frequency of the Nt500G allele was weakened (P = .25); however, there was no relationship between ethnic origin and Nt500-polymorphism frequency among the control subjects. CONCLUSIONS: CDKN2A mutations are rare in this population (approximately 0.2% of all melanoma cases in Queensland) and appear to be associated with melanoma in only the most affected families. The Nt500G allele appears to be associated with familial risk, but this association probably reflects Celtic ancestry.

Autoradiography↗

PubMed1999

Cuspal deflection during polymerisation of composite lutes of ceramic inlays.

OBJECTIVE: The purpose of this study was to measure the cuspal deflection that occurs in teeth as a result of the dimensional changes of resin-based lutes during polymerisation. METHODS: Standardised MOD cavities were cut in 15 intact human premolar teeth using a custom paralleling device. A ceramic inlay was machined by the CEREC 2 system for each tooth ensuring an interface width of 50 microns (SD = 17.5) at the cavity margin. The 15 teeth were divided into three groups of five according to the cementation system employed: a microfilled hybrid posterior composite; a compomer restorative; a dual-cure luting composite. The inter-cuspal tooth dimension was recorded continuously with a laser micrometer assembly during a 2 min photoactivation period and a further 30 min post-activation period. RESULTS: A clear overall reduction in tooth dimension was detectable for the first 10 min of polymerisation. The mean changes ranged from -0.02% to -0.06% depending on the nature of the luting material. In addition, all samples exhibited a slight expansion of 0.03% during the time of light-activation. CONCLUSIONS: The dimensional changes that teeth experience during the polymerisation of resin-based lutes are clearly detectable. It can be postulated that an increase in the dimensions of the teeth during photoactivation occurs as a result of expansion of the lute due to the thermal energy delivered.

Analysis of Variance↗

PubMed1999

Supporting individuals with intellectual disability and challenging behaviour in integrated work settings: an overview and a model for service provision.

An overview of supported employment and its historical context is examined, and supported employment for individuals with both intellectual disability and challenging behaviour is discussed. A proposed model for working with such individuals is briefly outlined. This model is based on previous work in the field, and is characterized by a multi-component approach which addresses the issues of both support and behavioural intervention.

Behavior Therapy↗

PubMed1999

Volatile nitrosamines and tobacco-specific nitrosamines in the smoke of Thai cigarettes: a risk factor for lung cancer and a suspected risk factor for liver cancer in Thailand.

In Thailand, smoking of commercial cigarettes and of handmade cigarettes has drastically increased in recent decades. Cancer of the lung and of the upper aero-digestive tract have also increased in Thailand as they have in many other countries. It is our working hypothesis that the increase of primary cancer of the liver, especially of cholangiocarcinoma in the north-eastern provinces of Thailand is associated with the use of tobacco in men infested with the liver fluke Opisthorchis viverrini (OV). Bioassays have shown that volatile nitrosamines and tobacco-specific nitrosamines induce cholangiocarcinoma in laboratory animals and that the hepatocarcinogenic action of nitrosodimethylamine in hamsters is significantly increased by infestation with the liver fluke OV. The endogenous formation of nitrosamines is significantly increased by OV infestation. This report presents analytical data on the concentration of volatile nitrosamines and tobacco-specific nitrosamines in mainstream smoke of nine leading brands of commercially produced Thai cigarettes which represent approximately 85% of the market share in Thailand. Observed ranges (ng/cigarette) were 8.5-31.9 for nitrosodimethylamine, 8.8-49.6 for nitrosopyrrolidine and 4.2-18.9 for nitrosodi-n-butylamine. These values are exceptionally high compared with the smoke of light and blended cigarettes from North America and Western Europe. Among the tobacco-specific nitrosamines, the range was 28-730 for nitrosonornicotine and 16-370 for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. There was a correlation between volatile and tobacco-specific nitrosamines, and tar and nicotine deliveries in the mainstream smoke. The analytical data are in line with the rate for lung cancer and support our working hypothesis that nitrosamines, and especially the tobacco-specific nitrosamines, are associated with the increased risk for primary liver cancer among those Thai people who smoke cigarettes and also carry OV infestation.

Bile Duct Neoplasms↗

PubMed1998

Safety and immunogenicity of HIV recombinant envelope vaccines in HIV-infected infants and children. National Institutes of Health-sponsored Pediatric AIDS Clinical Trials Group (ACTG-218).

Study objectives were to evaluate the safety and immunogenicity of three HIV recombinant glycoproteins in HIV-infected infants and children between 1 month and 18 years of age with asymptomatic (P-1) infection. Using Chiron rgp 120 (SF-2) 15 or 50 microg; MicroGeneSys rgp 160 (IIIB) 40 or 320 microg; Genentech rgp120 (MN) 75 or 300 microg; or adjuvant control (Alum or MF-59), children were randomized to a double-blind, placebo-controlled, dose-escalating study of vaccine administered intramuscularly at entry and 1, 2, 3, 4, and 6 months later. No adverse events were attributed to study vaccines. Between 30% and 56% of volunteers exhibited a lymphoproliferative response as defined in terms of stimulation index (SI) to vaccine antigens; 65% of vaccinees but none of placebo recipients exhibited moderate or strong responses after enzyme immunoassay to HIV specific antigens. CD4 cell counts and quantitative HIV culture did not differ significantly among vaccine and control groups, nor were differences found among groups in HIV disease progression. The rgp160 and gp120 subunit vaccines were safe and immunogenic in this population.

AIDS Vaccines↗

PubMed1998

Assay of paclitaxel (Taxol) in plasma and urine by high-performance liquid chromatography.

A new, rapid and sensitive high-performance liquid chromatographic method for the analysis of paclitaxel (Taxol) in human plasma and urine was developed and validated. After addition of an internal standard, paclitaxel was extracted from plasma or urine by a liquid-liquid extraction using diethyl ether. Extraction efficiency averaged 90%. Chromatography was performed isocratically on a reversed-phase column monitored at 227 nm. Retention times were 7.7 and 6.7 min for paclitaxel and docetaxel, respectively, and the assay was linear in the range 25-1000 ng/ml. The limits of quantification for paclitaxel were 25 and 40 ng/ml in plasma and urine, respectively. The assay was shown to be suitable for pharmacokinetic studies of children involved in a phase I clinical trial.

Antineoplastic Agents, Phytogenic↗

PubMed1998

DNA binding by cut homeodomain proteins is down-modulated by casein kinase II.

The Drosophila and mammalian Cut homeodomain proteins contain, in addition to the homeodomain, three other DNA binding regions called Cut repeats. Cut-related proteins thus belong to a distinct class of homeodomain proteins with multiple DNA binding domains. Using nuclear extracts from mammalian cells, Cut-specific DNA binding was increased following phosphatase treatment, suggesting that endogenous Cut proteins are phosphorylated in vivo. Sequence analysis of Cut repeats revealed the presence of sequences that match the consensus phosphorylation site for casein kinase II (CKII). Therefore, we investigated whether CKII can modulate the activity of mammalian Cut proteins. In vitro, a purified preparation of CKII efficiently phosphorylated Cut repeats causing an inhibition of DNA binding. In vivo, overexpression of the CKII alpha and beta caused a decrease in DNA binding by Cut. The CKII phosphorylation sites within the murine Cut (mCut) protein were identified by in vitro mutagenesis as residues Ser400, Ser789, and Ser972 within Cut repeat 1, 2, and 3, respectively. Cut homeodomain proteins were previously shown to function as transcriptional repressors. Overexpression of CKII reduced transcriptional repression by mCut, whereas a mutant mCut protein containing alanine substitutions at these sites was not affected. Altogether our results indicate that the transcriptional activity of Cut proteins is modulated by CKII.

Amino Acid Sequence↗

PubMed1998

Structure and expression of Wnt13, a novel mouse Wnt2 related gene.

We have identified a novel mouse member of the Wnt family, Wnt13. Among mouse Wnt genes, Wnt13 is most closely related to Wnt2. Sequence comparisons and chromosomal localization strongly suggest that Wnt13, rather than Wnt2, is the mouse orthologue of both the human WNT13 and Xenopus XWnt2 genes. Wnt13 is expressed in the embryonic mesoderm during gastrulation. At later stages, transcripts are detected in the dorsal midline of the diencephalon and mesencephalon, the heart primordia, the periphery of the lung bud and the otic and optic vesicles. These data suggest that Wnt13 function might partially overlap with those of other Wnt genes in the cell signaling mechanisms controlling mesoderm specification during gastrulation and some aspects of brain, heart and lung formation.

Amino Acid Sequence↗

PubMed1998

Donor-derived Plasmodium vivax infection following volunteer unrelated bone marrow transplantation.

A 14-year-old girl from the UK underwent volunteer unrelated donor bone marrow transplant (VUD BMT) for accelerated phase chronic myeloid leukaemia. On day +40 she became febrile, and peripheral blood smears demonstrated a 1% Plasmodium vivax parasitaemia. Although she had never been outside the UK, her male donor had documented Plasmodium vivax infection during a vacation in Papua New Guinea. Following appropriate treatment, he had been asymptomatic for 11 months before marrow harvesting. This is the first case report of malarial transmission by VUD BMT, and illustrates the potential problem of recrudescence of latent, dormant forms of Plasmodium vivax infection following transplantation into an immuno-compromised recipient. Even after appropriate therapy, malarial infection should be included in the differential diagnosis for all post-transplant febrile episodes.

Adolescent↗

PubMed1998

Depression, cognition, and functional correlates of recovery outcome after traumatic brain injury.

The present study investigated the prevalence and magnitude of depressive symptomatology in a sample of patients who had sustained traumatic brain injury (TBI) six months earlier. Depression was examined as a function of recovery outcome status, and its association with neuropsychological functioning, personal competency, and employability was also explored. Subjects were 100 patients who had previously sustained moderate-to-severe TBI who were enrolled as research subjects in the UCLA Brain Injury Research Center, and 30 matched control subjects who had sustained traumatic injuries other than to the head six months prior to evaluation. The results showed a significant association between depression and recovery status as measured by the Glasgow Outcome Scale (GOS). A significant majority of depressed subjects were found in the poorer GOS outcome groups (severe and moderate disability), compared to TBI subjects who had good GOS outcomes, and control subjects. This association was also reflected in the magnitude of the mean depression scores on two self-report measures of depression. However, no association was found between depression status and performance on the neuropsychological measures. Effects of depression were found only on an examiner-rated Patient Competency scale, and a metacognition measure based on self-report. These results are discussed in terms of brain injury severity, recovery status, and metacognition issues in TBI and other disorders.

Activities of Daily Living↗

PubMed1998

Neuropsychological, psychosocial and vocational correlates of the Glasgow Outcome Scale at 6 months post-injury: a study of moderate to severe traumatic brain injury patients.

Traumatic brain injury (TBI) subjects at Glasgow Outcome Scale levels 3 (severe disability), 4 (moderate disability), 5 (good recovery), and an other-injury control group (OIC) were compared in terms of neuropsychological, psychosocial, and vocational functioning 6 months after injury. Subjects were a sample of 100 patients with a moderate to severe traumatic brain injury (TBI) and a matched sample of 30 other-injury control subjects (OIC) enrolled in the UCLA Brain Injury Research Center study of TBI outcome. Overall, the results showed a systematic decrease in mean neuropsychological test performance as a function of increasing GOS severity, as well as an increased prevalence of symptoms of depression and lower ratings on measures assessing employability and capacity for self care. TBI patients in the 'severe' and 'moderate disability' groups were distinctly inferior to the 'good recovery' and 'OIC' groups, who were quite similar to each other in terms of cognitive, psychosocial, and vocational outcomes. The results demonstrate overall support for the predictive and concurrent validity of the GOS 6 months post injury. Despite these results, which strengthen the utility and appeal of the GOS for multicentre studies, concerns still remain regarding GOS category 4 (moderate disability), which was shown to lack sufficient discriminability in this study.

Activities of Daily Living↗

PubMed1998

Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes.

The CCR5-Delta32 deletion obliterates the CCR5 chemokine and the human immunodeficiency virus (HIV)-1 coreceptor on lymphoid cells, leading to strong resistance against HIV-1 infection and AIDS. A genotype survey of 4,166 individuals revealed a cline of CCR5-Delta32 allele frequencies of 0%-14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and two microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, we estimate the origin of the CCR5-Delta32-containing ancestral haplotype to be approximately 700 years ago, with an estimated range of 275-1,875 years. The geographic cline of CCR5-Delta32 frequencies and its recent emergence are consistent with a historic strong selective event (e.g. , an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Multiple cerebral pseudoaneurysms and hemorrhages: the expanding spectrum of metastatic cerebral choriocarcinoma.

Cerebral metastases occur in 10-20% of patients with choriocarcinoma. Although single oncotic and pseudoaneurysms have been reported, multiple pseudoaneurysms and hemorrhages are rare. A 33-year-old woman developed 10 intracerebral hemorrhages over a 30-day period. Angiogram showed multiple focal areas of delayed contrast washout in distal vessels. Autopsy revealed intravascular choriocarcinoma without true aneurysm formation. A diagnosis of choriocarcinoma should be considered for women of childbearing age presenting with cerebrovascular syndromes, especially those found to have cerebral aneurysm pseudoaneurysm and/or hemorrhage.

Adult↗

PubMed1998

Desmosomes are regulated by protein kinase C in primary rat epithelial cells.

In the present study, we addressed the possible relevance of protein kinase C (PKC) in the regulation of intracytoplasmic desmosome assembly. Treatment of cultured rat lingual and epidermal keratinocytes with a potent and highly selective PKC inhibitor (GF109203X) induced an increase in granular labelling for major desmosomal proteins, desmoplakins, desmoglein and plakoglobin, both intracellularly and at the cell surface. This was associated with the formation of ultrastructurally recognizable desmosomes deep in the cytoplasm and increase in intercellular desmosome number. In contrast, PKC activation upon short exposure to 12-O-tetradecanoylphorbol 13-acetate (TPA) resulted in altered cell morphology, loss of intercellular contact and accumulation of desmosomal proteins in the juxtanuclear zone. On the other hand, PKC depletion by long term TPA treatment re-established cell-cell contact, where desmosomal markers were exclusively redistributed. Taken together, these results suggest that inhibition of PKC is required for intracytoplasmic as well as intercellular desmosome assembly, whereas its activation may regulate disassembly process.

Animals↗

PubMed1997

The origins of formal paraphasias in aphasics' picture naming.

Accounts of spoken word production differ on whether aphasics' formal paraphasias derive solely from segmental distortion or whether some derive instead from whole word substitution. Form-related paraphasias produced by nine aphasics during picture naming were examined for evidence of lexical effects (word, frequency, and grammatical class biases) and for the manner in which target phonemes and word shape were preserved. Preservation patterns were consistent with previous descriptions of aphasic and nonaphasic form-related speech errors. Evidence for word and frequency biases was found, as well as a grammatical class bias sensitive to the degree of target-response segmental overlap. In conjunction, the results indicate that formal paraphasias arise, at least in part, via word substitution. The findings are supportive of interactive models with phonological-to-lemma feedback and/or modular models with a grammatically organized lexeme level.

Adult↗

PubMed1997

Early detection of vasospasm after acute subarachnoid hemorrhage using continuous EEG ICU monitoring.

The neurologic morbidity of delayed ischemic deficits from vasospasm following aneurysmal subarachnoid hemorrhage (SAH) continues to be the most debilitating complication from this devastating illness. Neurologic critical care is focused on recognition and treatment of these secondary insults but often the treatment is withheld until an irreversible deficit becomes manifest. Continuous EEG (cEEG) monitoring provides a unique potential to recognize early secondary insults and offers an opportunity for early intervention. We studied 32 SAH patients using cEEG and trending of the quantitative measure, relative alpha (RA), to determine if reductions in RA variability occurred with documented vasospasm. In 19/19 patients with angiographically documented vasospasm, we found that RA variability was decreased by a mean of two grades and improved with resolution of vasospasm. In 10/19 this reduction in RA variability preceded the diagnosis of vasospasm by a mean of 2.9 days (SD 1.73). The positive predictive and negative predictive values are 76% and 100%, respectively. Non-diagnostic clinical signs at the time of RA variability reduction and vasospasm were present in 12/19 patients. Thus decreased RA variability is able to provide early detection of neurologic complications such as vasospasm in patients before clear clinical symptoms and signs occur.

Adult↗

PubMed1997

Influence of HLA alleles on the rate of progression of vertically transmitted HIV infection in children: association of several HLA-DR13 alleles with long-term survivorship and the potential association of HLA-A*2301 with rapid progression to AIDS. Long-Term Survivor Study.

The influence of host immunogenetics on the outcome of vertically transmitted HIV infection in children was examined in a multicenter cross sectional study of long term survivors and rapid progressors. Sequence-based typing was performed for the DRB1, DQB1 and HLA-A loci. 36.7% of 30 children surviving more than 8 years had one or more of the HLA-DR13 alleles, versus none of 14 rapidly progressing children who died within 2 years of age, p = 0.009, Haldane RR = 17.1. The alleles variably associated with this beneficial response to HIV were: DRB1*1301, DRB1*1302, DRB1*1303 and DRB1*1310, suggesting that the DR13 effect acted as a dominant trait. An additional 6 children were typed only by the SSOP method resulting in 44.4% of 36 long term surviving children with a DR13 allele and none of 14 rapid progressors, p = 0.002, Haldane RR = 23.3. No single DQB1 allele accounted for the HLA-DR13 allele association. In contrast, the presence of HLA A*2301 was associated with rapid progression to AIDS, 4% of long term survivors vs. 57.1% of 7 rapid progressors, p = 0.0006, RR = 0.031. Although the sample size is small, the marked differences in allele frequency along with differences between the peptide binding pockets of the HLA-A9 group of alleles including HLA A*2301 and the remainder of the HLA-A alleles suggest a structural basis for the dominant disadvantageous immune response to HIV conferred by A*2301.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Age changes in the causes of individual differences in conservatism.

Age-related changes are analyzed in the correlation of 3416 monozygotic and 3780 dizygotic U.S. twin pairs aged between 9 and 75+ years for conservatism scores derived from a 28-item social attitude inventory. The effects of the shared environment are overwhelming in twins aged 20 years or younger. In older twins, genetic effects appear to play a larger role. A more dynamic conception of the interaction between genes and environment in the development of complex human differences is needed.

Adolescent↗