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Biomedical subjects

M MacDonald

Publications and source records attributed to M MacDonald.

At least 37 records · Page 2Linked to original sources
PubMed1998

Substance-dependent, conduct-disordered adolescent males: severity of diagnosis predicts 2-year outcome.

Most delinquent youths have conduct disorder (CD), often with comorbid substance use disorder (SUD), attention-deficit/hyperactivity disorder (ADHD) and depression. Some youths' conduct problems later abate, while those of others persist into adult antisocial personality disorder. Earlier CD onset and ADHD reportedly predict persisting antisocial problems, but predictors of persisting SUD are poorly understood. Males aged 13-19 years (n = 89), most referred by criminal justice and social service agencies, received residential treatment for comorbid CD and SUD. They had diagnostic assessments for SUD at intake and for CD, ADHD, and depression (as well as drug-use assessments) at intake and 6, 12 and 24 months later. At intake nearly all had DSM-III-R substance dependence (usually on alcohol and marijuana) and CD with considerable violence and criminality. The 2-year follow-ups revealed improvements in criminality, CD, depression and ADHD, but substance use remained largely unchanged. Various aspects of conduct, crime and substance outcomes at 2 years were predicted by intake measures of intensity of substance involvement, and by CD severity and onset age, but not by severity of either ADHD or depression, nor by treatment duration. Earlier CD onset, more severe CD and more drug dependence predicted worse outcomes, supporting the validity of these diagnoses in adolescents.

Adolescent↗
PubMed1998

HIV and HCV prevalence among trawler crew.

A survey of 51 people who work on trawlers was carried out to describe injecting and sexual behaviour and the prevalence of HIV and HCV antibody. All crew members who were departing from an Australian port during the last week of February 1996 to work on trawlers were asked to complete a brief, self-administered questionnaire and provide a finger prick blood sample. Questionnaires were received from 51 (77%) and blood samples from 45 (68%) of the 66 crew from 15 vessels. Almost half the respondents reported ever injecting illicit drugs. No respondents had HIV antibody while 27% had HCV antibody detected. Among 20 injecting drug user (IDU) respondents, the prevalence of HCV was 55% (95% CI 32%-77%). Twelve respondents reported new sex partners in the past month of whom half reported no condom use with these sex partners. The survey emphasises the diversity of the IDU population in Australia. Yet it would appear that regardless of the sub-population surveyed that HCV is endemic among IDUs in Australia. Effective HCV prevention programs targeted specifically for these (and other) sub-populations of IDUs should be devised.

Adolescent↗
PubMed1998

1H NMR spectroscopy studies of Huntington's disease: correlations with CAG repeat numbers.

Huntington's disease (HD) is the result of an expanded (CAG) repeat in a gene on chromosome 4. A consequence of the gene defect may be progressive impairment of energy metabolism. We previously showed increased occipital cortex lactate in HD using localized 1H spectroscopy. We have now extended these studies to show an almost threefold elevation in occipital cortex lactate in 31 HD patients as compared with 17 normal control subjects (p < 10(-11)). The spectra in three presymptomatic gene-positive patients were identical to normal control subjects in cortical regions, but three in eight showed elevated lactate in the striatum. Similar to recently reported increases in task-related activation of the striatum in the dominant hemisphere, we found that striatal lactate levels in HD patients were markedly asymmetric (higher on the left side). Markers of neuronal degeneration, decreased N-acetylaspartate (NAA)/creatine and increased choline/creatine levels, were symmetric. Both decreased NAA and increased lactate in the striatum significantly correlated with duration of symptoms. When divided by his or her age, an individual's striatal NAA loss and lactate increase were found to directly correlate with the subject's CAG repeat number, with correlation coefficients of 0.8 and 0.7, respectively. Similar correlations were noted between postmortem cell loss and age versus CAG repeat length. Together, these data provide further evidence for an interaction between neuronal activation and a defect in energy metabolism in HD that may extend to presymptomatic subjects.

Adult↗
PubMed1997

High resolution characterization of an interstitial deletion of less than 1.9 Mb at 4p16.3 associated with Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome (WHS) caused by 4p16.3 deletions comprises growth and mental retardation, distinct facial appearance and seizures. This study characterized a subtle interstitial deletion of 4p16.3 in a girl with mild retardation and possessing facial traits characteristic of WHS. The patient had generalized seizures in conjunction with fever at 3 and 5 years of age. Fluorescence in situ hybridization (FISH) with a series of markers in the 4p16.3 region showed that the interstitial deletion in this patient was between the probes D4S96 and D4S182, enabling the size of the deletion to be estimated as less than 1.9 Mb. This is the smallest interstitial deletion of 4p16.3 which has been reported. The patient contributes to a refinement of the phenotypic map of the WHS region in 4p16.3. The critical region for the characteristic facial changes of WHS, failure to thrive and developmental delay is now localized to a region of less than 700 kb. The mental retardation of this patient was mild suggesting that small interstitial deletion may have less severe phenotypic consequences.

Child, Preschool↗
PubMed1997

HIV prevalence and risk behaviour in needle exchange attenders: a national study. The Collaboration of Australian Needle Exchanges.

OBJECTIVE: To determine whether needle and syringe exchange programs represent feasible sites to describe the prevalence of HIV and related risk behaviour among injecting drug users. DESIGN: Cross-sectional survey. SETTING: 21 needle and syringe exchange programs in all Australian jurisdictions. PARTICIPANTS: All persons attending the needle and syringe exchange programs over one week in March 1995 were eligible to participate in the study once. INTERVENTION: Needle and syringe exchange attenders were asked to complete a brief, self-administered questionnaire and provide a finger-prick blood sample. MAIN OUTCOME MEASURES: Prevalence of HIV antibody, drug injecting and sexual behaviour, and survey cost. RESULTS: Completed questionnaires with blood samples suitable for testing were provided by 1005 (42%) of 2373 individuals who attended the needle and syringe exchange programs during the survey week. Women were more likely than men to participate in the survey but there was no difference in the response rate by age group. The HIV prevalence was 2.1% and was significantly higher in men who described themselves as homosexual, compared to men who described themselves as heterosexual (22.5% v. 0.7%; P < 0.001). Thirty-one per cent of respondents reported using a syringe after someone else in the preceding month. CONCLUSION: Cross-sectional surveys of needle exchange clients offer a practical method for monitoring risk behaviour and seroprevalence of bloodborne viral infections.

Adolescent↗
PubMed1997

Huntingtin immunoreactivity in the rat neostriatum: differential accumulation in projection and interneurons.

Huntington's disease is caused by a mutation of the gene encoding the protein huntingtin. Features of the human disease, characterized by selective loss of neurons from the neostriatum, can be replicated in rodents by administration of excitotoxins. In both affected individuals and the rodent model, there is massive loss of striatal projection neurons with selective sparing of interneurons. Furthermore, in the human disease the earliest evidence of striatal injury is found in striosomal regions of the striatum. The mRNA encoding huntingtin is known to be expressed by neurons throughout the brain, a distribution which does not account for the selective patterns of neuronal death which are observed. Using fluorescence immunocytochemistry and confocal microscopy with an antibody to huntingtin, we have observed that in rats a subset of striatal projection neurons contains dense accumulations of huntingtin immunoreactivity (HT-ir), while most neurons in the striatum contain much smaller amounts. The intensely stained neurons are concentrated within the striatal striosomes, as defined by calbindin-D28K staining. In the matrix regions, relatively few neurons contain dense accumulations of HT-ir, and these cells always lack perikaryal staining for calbindin-D28K. Striatal interneurons, identified by the presence of immunoreactivity for choline acetyltransferase, parvalbumin, calretinin, or neuronal nitric oxide synthase, exhibit little or no HT-ir. The paucity of HT-ir in striatal interneurons, as well as the prominence of staining in a subset of striosomal neurons, mirrors the selective vulnerability of these different types of cells in early stages of human Huntington's disease and in rodent excitotoxic models of the disorder. Our observations suggest that mechanisms which modulate the accumulation of huntingtin may play a central role in the neuronal degeneration of Huntington's disease.

Animals↗
PubMed1997

Phase I trial of etoposide, carboplatin, and GM-CSF in extensive small-cell lung cancer: a Cancer and Leukemia Group B study (CALGB 8832).

The maximum tolerated dose (MTD) of etoposide and carboplatin without growth factor support was previously defined by Cancer and Leukemia Group B (CALGB) as 200 and 125 mg/m2/day x 3, respectively, given every 28 days to previously untreated patients who have extensive, small-cell lung cancer (SCLC). Myelosuppression was dose-limiting. The purpose of this phase I trial was to determine if granulocyte macrophage colony-stimulating factor (GM-CSF) support allows the dosage of the combination of etoposide and carboplatin to be increased above the previously determined MTD. In this CALGB study of 44 evaluable patients with performance status 0-2, cohorts were treated with etoposide and carboplatin given intravenously on days 1-3 followed by GM-CSF (molgramostim) given subcutaneously on days 4-18. Four dose levels of bacteria-derived recombinant GM-CSF (5, 10, 20 microg/kg/day and 5 microg/kg every 12 h), three dose levels of etoposide (200, 250, and 300 mg/m2/day x 3), and two dose levels of carboplatin (125 and 150 mg/m2/day x 3) were evaluated. There was no chemotherapy dose escalation in individual patients. With 5 microg/kg/d GM-CSF, the first etoposide and carboplatin cycle of 300 and 150 mg/m2/day x 3, respectively, could be administered with acceptable toxicity. However, GM-CSF did not allow repeated administration of this dose-escalated regimen every 21 days, since delayed platelet and/or neutrophil recovery was dose limiting in later cycles. These results demonstrate that GM-CSF alone has limited capability to support the repeated administration of high doses of etoposide and carboplatin. CALGB currently is testing the ability of interleukin (IL)-6 given with GM-CSF to ameliorate the cumulative myelosuppression of this intense regimen.

Adult↗
PubMed1997

Production of monoclonal antibodies against excretory-secretory products of adult male Onchocerca gibsoni.

Nine monoclonal antibodies (mabs) have been produced against excretory-secretory products (ES) of adult male Onchocerca gibsoni. These mabs fail to interact with the highly cross-reactive phosphorylcholine (PC) group and with ES of the related rodent filarial parasites Acanthocheilonema viteae and Litomosoides carinii. Eight of the mabs are of the IgG isotype: 1 is an IgM. Three of the mabs, OGMES 4, 9, and 10, were each found by immunoprecipitation/SDS-PAGE analysis of [3H] leucine-labeled ES, to recognize a triplet of polypeptides of molecular weight 120, approximately 210, and approximately 260 kDa. No recognition was observed by any mab when [3H] glucosamine was employed as the radiolabel for ES. Western blotting employing [125I] as indicator system demonstrated that OGMES 7 recognized a molecule of 27 kDa, and OGMES 1, a molecule of approximately 210 kDa, albeit faintly. These mabs may be of value to researchers working on the isolation, characterization, and detection in the bloodstream of Onchocerca volvulus ES.

Animals↗
PubMed1996

Do excretory-secretory products of Onchocerca gibsoni contain phosphorylcholine attached to O-type glycans?

Excretory-secretory products (ES) of adult male Onchocerca gibsoni contain phosphorylcholine (PC). PC-ES are detected as a smear of M(r) approximately 60- approximately 200 kDa by western blotting employing a monoclonal antibody (mAb) against PC, suggesting that they are glycoproteins. Exposure of PC-ES to N-glycosidase F results in weak and inconsistent loss of binding of the mAb, indicating that unlike the situation with respect to ES of Acanthocheilonema viteae, PC is highly unlikely to be solely attached to N-type glycans. Conversely, treatment of O. gibsoni PC-ES with mild alkali, a strategy for removing O-type glycans, abolishes mAb binding. These results suggest that PC may be attached to O. gibsoni proteins mainly via O-type glycans, and raise the possibility that filarial parasites may vary with respect to their mode of attachment of PC. The implications of this with respect to the design of inhibitors of PC attachment for use as anti-filarial drugs, are discussed.

Amidohydrolases↗
PubMed1995

An improved approach to prepare human brains for research.

We describe two protocols for preparing human brains collected for research and diagnosis. In both protocols, one half brain is processed for research and the other for neuropathological evaluation. Clinical, neuropathological and tissue mRNA retention data are used for sample categorization. In protocol 1, coronal, whole hemisphere slices cut at standardized landmarks are frozen with a cooling device at -90 degrees C, which yields discrete anatomical structures. In selected instances, small blocks of brain are frozen at -160 degrees C in liquid nitrogen vapor. Cooling device or liquid nitrogen vapor frozen samples are suitable for in situ hybridization, protein blotting or immunohistochemistry. Morphological freezing artifacts are minimal. In protocol 2, one half brain is frozen en bloc on dry ice; this tissue is suitable for regional evaluation of gene expression or neurochemistry. Morphological freezing artifacts are severe. In both protocols, the other half brain is fixed in formalin prior to sectioning and diagnostic evaluation. The standardized selection of paraffin blocks from each brain allows precise diagnoses to be established, including identification of dangerous infectious processes; moreover, it makes it possible to produce a set of uniformly selected blocks and slides for comparative studies. These protocols lead to standardized tissue preparation for research and reduce variables impairing interpretation and comparison of data.

Brain↗
PubMed1994

Mutation analysis for cystic fibrosis to determine carrier status in 167 sperm donors from the Nebraska Genetic Semen Bank.

Cystic fibrosis is the most common autosomal recessive disorder in Caucasian populations, with an approximate frequency of 1/2500 live births and a carrier frequency of 1/25. Due to the high rate of predicted carriers (> 63,000) in the Nebraska population (1990 U.S. Census = 1,578,358), we analyzed sperm DNA obtained from semen donors at the University of Nebraska Genetic Semen Bank for eight of the more common mutations to determine the frequency and diversity in our population. The subjects included 167 semen donors (31 normal healthy donors, 56 infertility patients, 21 prevasectomy patients, and 59 prechemotherapy or preradiation cancer patients). The mutations analyzed included delta F508, R117H, G542X, S549R/N, G551D, R553X, R560T, and W1282X. Analyses were performed using PCR amplified products that were analyzed using polyacrylamide gel electrophoresis, slot blot, and restriction endonuclease digestion. These results were correlated with results from the clinical semen analyses and selected clinical parameters. Results for the total donor population studied showed that the delta F508 mutation was present in 8/167 (4.8%) donors, the R117H mutation was present in 4/167 (2.4%) donors and the G542X mutation was present in 1/167 (0.6%) donors. The observed number of carriers from this population, 13/167 (7.8%), was significantly greater (P = 0.02) than that expected assuming a carrier frequency of 1/25. The excess of carriers was restricted to the subgroup of infertility patients. This suggests that CF carriers may be at higher risk for infertility than the general population.

Cystic Fibrosis↗
PubMed1994

High resolution localization of recombination hot spots using sperm typing.

We have applied sperm DNA typing to determine the distribution of crossover events within a one megabase region of the short arm of human chromosome 4 near the locus for Huntington disease. A total of 29 recombinants were detected among 602 sperm typed after whole genome amplification. These recombinants were typed for seven polymorphic markers. The 280 kilobase D4S10-D4S126 interval was found to undergo recombination at a 6-9-fold greater rate per unit of physical distance than the adjacent 720 kb D4S126-D4S127 interval. Sperm typing has the potential to dissect mammalian recombination hot spots to the point where DNA sequence analysis may reveal the molecular basis for hyperrecombination.

Base Sequence↗
PubMed1994

Some preliminary data on the nature/structure of the PC-glycan of the major excretory-secretory product of Acanthocheilonema viteae (ES-62).

The structure of the PC-glycan of the major excretory-secretory product (ES-62) of Acanthocheilonema viteae has been investigated using endoglycosidases and lectins. Results obtained raise the possibility that it may be of the high mannose type. This, and the insensitivity of the PC-glycan to treatments which remove PC or choline from bacterial PC-glycans, suggests that it may be more analogous to fungal, than to bacterial PC-containing glycans.

Animals↗
PubMed1994

The origin of 47,XXY and 47,XXX aneuploidy: heterogeneous mechanisms and role of aberrant recombination.

We investigated the parent and cell division of origin of the additional sex chromosome in 142 males with a 47,XXY constitution and 50 females with a 47,XXX constitution. In 66 of the 47,XXY males the additional chromosome was paternal in origin and in 76 it was maternal in origin, while among the 47,XXX females only 5 had an additional paternal X chromosome, the remaining 45 having an additional maternal chromosome. Among the 107 maternally derived aneuploids for whom it was possible to determine the cell division of origin, 73 were the result of a mat MI error, 24 the result of a mat MII error and 10 the result of a post zygotic mitotic (PZM) error involving the maternal X chromosome. Among those in which the non-disjunction was attributable to an error at the first meiotic division (MI) we observed three different mechanisms of origin. Approximately 30% were associated with complete absence of recombination (nullichiasmate); approximately 24% were associated with a normal number of recombinant events but an abnormal distribution of exchanges (perturbed recombination), while approximately 45% were associated with a normal number and distribution of recombinant events (normochiasmate). Nondisjunction due to an error at the second meiotic division (MII) was associated with a slight reduction in the total number of recombinant events and an abnormal distribution of exchanges. Thus of the four different meiotic mechanisms of origin, three were associated with an abnormal number and/or distribution of exchange events. There was no evidence of an increased paternal age in the aneuploids of paternal origin.(ABSTRACT TRUNCATED AT 250 WORDS)

Aneuploidy↗
PubMed1994

Trinucleotide repeat length and progression of illness in Huntington's disease.

The genetic defect causing Huntington's disease (HD) has been identified as an unstable expansion of a trinucleotide (CAG) repeat sequence within the coding region of the IT15 gene on chromosome 4. In 50 patients with manifest HD who were evaluated prospectively and uniformly, we examined the relationship between the extent of the DNA expansion and the rate of illness progression. Although the length of CAG repeats showed a strong inverse correlation with the age at onset of HD, there was no such relationship between the number of CAG repeats and the rate of clinical decline. These findings suggest that the CAG repeat length may influence or trigger the onset of HD, but other genetic, neurobiological, or environmental factors contribute to the progression of illness and the underlying pace of neuronal degeneration.

Adolescent↗