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Biomedical subjects

D Mackey

Publications and source records attributed to D Mackey.

At least 19 recordsLinked to original sources
PubMed2000

Reproductive management of postpartum cows.

High reproductive efficiency in the dairy cow requires a disease-free transition period, high submission rates to AI and high pregnancy rates per service. A key risk factor that causes increased incidence of metabolic disease is low negative energy balance (NEB) in the periparturient and early postpartum periods. Low NEB decreases LH pulse frequency, growth rate and diameter of dominant follicle (DF), IGF-I, glucose, insulin concentrations and increases GH and certain blood metabolites; these effects result in greater loss of body condition score (BCS) and a higher percent of anoestrous cows in the herd. It is important to decrease the incidence of metabolic disease by achieving high dry matter intake (DMI) and minimising the period of NEB after calving. Thus, nutritional management of the cow in the transition period has a crucial role to play in improving reproductive efficiency, because acute nutritional deprivation of heifers has immediate deleterious effects on follicular growth and ovulation. To obtain high submission rates, it is necessary to decrease the incidence of anoestrus and to have good oestrous detection rates. Pregnancy rates per service are affected by a variety of factors. NEB can have deleterious effects on the follicle or the corpus luteum (CL) by decreasing IGF-I concentrations and steroidogenesis. High protein diets fed to postpartum cows leads to increased blood urea and lower fertility. Although the mechanism is not clear, the practical implication of feeding the appropriate level of crude protein in the diet is clear. Thus, a coordinated management approach involving herd managers, nutritionists and veterinarians is required to obtain high reproduction efficiency in dairy cows.

Animal Husbandry↗
PubMed1999

The linking regions of EBNA1 are essential for its support of replication and transcription.

The ability of distant cis-acting DNA elements to interact functionally has been proposed to be mediated by the interaction of proteins associated site specifically with those cis-acting elements. We have found that the DNA-linking regions of EBNA1 are essential for its contribution to both replication and transcription. The synthesis of plasmids containing the Epstein-Barr virus (EBV) origin of plasmid replication (oriP) can be mediated entirely by the cellular machinery; however, the replicated molecules are lost rapidly from proliferating cells. When EBNA1 is provided in trans, plasmids containing oriP (oriP plasmids) are synthesized during repeated S phases, and the newly formed daughter molecules are precisely segregated to the daughter cells. The contribution(s) of EBNA1 to the stable replication of oriP plasmids is therefore likely to be postsynthetic. In latently infected cells, EBNA1 also regulates the expression of multiple EBV promoters located as many as 10 kbp away. EBNA1 supports replication and transcription through binding to oriP; both the ability of EBNA1 to bind to DNA and the integrity of its binding sites in oriP are required. However, DNA binding by EBNA1 is not sufficient to support replication or transcription, indicating that an additional activity (or activities) is required. EBNA1 links DNAs to which it binds and can form a loop between the two subelements of oriP, the family of repeats and the region of dyad symmetry, each of which contains multiple binding sites for EBNA1. We have constructed a set of derivatives of EBNA1 which contain both, one, or neither of its linking regions in various contexts. Analyses of these derivatives demonstrate that the linking regions of EBNA1 are essential for its support of replication and transcription and that the ability of derivatives of EBNA1 to link DNAs correlates strongly with their support of these activities in cells. These findings indicate that protein-protein associations of the linking regions of EBNA1 underlie its long-range contributions to replication and transcription.

Cell Line↗
PubMed1997

Studies on the mechanism of DNA linking by Epstein-Barr virus nuclear antigen 1.

Epstein-Barr virus nuclear antigen 1 (EBNA1) can both bind to and link DNA. Dimers of EBNA1 bind specific sites, two clusters of which, the FR and DS, comprise the necessary cis-acting elements of the Epstein-Barr viral origin of plasmid replication. EBNA1-dimers can link FR and DS, looping out the intervening DNA. EBNA1 can also intermolecularly link DNAs to which it binds. Residues of EBNA1 that can mediate linking have been mapped to at least three, non-overlapping domains. These domains, when fused to the dimerization and DNA-binding domain of GAL4, can self-associate and thereby link DNAs bound site specifically by GAL4. Two disparate mechanisms could underlie self-association of linking domains: 1) linking domains could associate with other linking domains directly, or 2) linking domains could associate indirectly by binding to a common nucleic acid intermediate. We have found that EBNA1 can link DNA by each of these mechanisms, however, the linking domains associate directly with a greater apparent affinity than through a nonspecific nucleic acid intermediate.

Binding Sites↗
PubMed1995

Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees.

The nucleotide sequences of the mitochondrial genomes from patients with Leber hereditary optic neuropathy (LHON) were used for phylogenetic analysis to study the origin and population history of pathogenic mitochondrial mutations. Sequences of both the coding region (8300 bp) and the more rapidly evolving noncoding control region (1300 bp) were analyzed. Patients with the primary LHON mutations at nucleotides 3460, 11,778, and 14,484 were included in this study, as were LHON patients and non-LHON controls that lacked these primary mutations; some of the subjects also carried secondary LHON mutations. The phylogenetic analyses demonstrate that primary LHON mutations arose and were fixed multiple times within the population, even for the small set of LHON patients that was analyzed in these initial studies. In contrast, the secondary LHON mutations at nucleotides 4216, 4917, and 13,708 arose once: the mitochondrial genomes that carried these secondary mutations formed a well-supported phylogenetic cluster that apparently arose 60,000 to 100,000 years ago. Previous studies found secondary LHON mutations at a higher frequency among LHON patients than among control subjects. However, this finding does not prove a pathogenetic role of these mutations in LHON. Instead, the increased frequency is more likely to reflect the population genetic history of secondary mutations relative to that of primary LHON mutations.

Animals↗
PubMed1995

Multiple regions within EBNA1 can link DNAs.

Epstein-Barr virus nuclear antigen 1 (EBNA1) can bind specifically to two clusters of sites within the Epstein-Barr virus plasmid origin of DNA replication (oriP). EBNA1 activates DNA replication mediated by oriP and can also activate transcription and retain DNA in cells when bound site specifically. EBNA1 bound to oriP physically links the two clusters of EBNA1-binding sites, resulting in loop formation by the intervening DNA. To elucidate the contribution of DNA linking by EBNA1 to its biological activities, we identified regions within it that can independently link DNAs to which they are bound. An electrophoretic mobility shift assay was used to detect this activity. Proteins which link DNA aggregate that DNA into large lattices. Proteins which cannot link DNA but still bind to DNA retard the mobility of that DNA but do not cause it to form lattices. Amino-terminal truncations were used to map the amino-terminal limit of a minimal DNA-linking domain approximately to amino acid 372 of EBNA1. To map the carboxy-terminal limit of this minimal domain, fusion proteins containing the DNA-binding domain of GAL4 and fragments of EBNA1 were generated and studied. This approach identified the carboxy-terminal limit of this minimal domain to be approximately amino acid 391 and verified its amino-terminal limit. Internal deletions within a truncated EBNA1 derivative verified the importance of this region. Two additional fragments of EBNA1, each of which independently conferred DNA-linking activity on the domain of GAL4 which binds DNA, were identified within amino acids 54 to 89 and amino acids 331 to 361. Therefore, EBNA1 contains at least three regions that can act independently to link DNAs and that may act in concert within intact EBNA1.

Amino Acid Sequence↗
PubMed1994

Tobacco amblyopia.

Explore the source record for details and available documents.

Alcohol Drinking↗
PubMed1994

Exposure of emergency department personnel to tuberculosis: PPD testing during an epidemic in the community.

STUDY OBJECTIVE: The present epidemic of tuberculosis has increased the risk of transmission of tuberculosis to health care workers in general and emergency department staff in particular, who often treat patients with tuberculosis before their diagnosis. The purpose of this study was to determine the risk of tuberculosis exposure among the nursing and physician staff of an urban ED. DESIGN: Observational study of self-reported purified protein derivative (PPD) skin test results and tuberculosis exposure. SETTING: Urban, public ED. PARTICIPANTS: Attending physicians, resident physicians, and registered nurses. INTERVENTIONS: None. RESULTS: Questionnaires were sent to all attending physicians, resident physicians, and registered nurses in the ED at Harbor-UCLA Medical Center requesting information on the subject's present and prior PPD status, known exposure to tuberculosis, and duration of time and average number of hours worked in the ED. Ninety-six of 129 questionnaires (74%) were returned. Five of the respondents had been immunized with Bacillus of Calmette and Guerin vaccine (BCG) and 10 of the respondents were PPD positive before beginning work in the ED. Of the other 81 respondents, 31% (25 of 81) had become PPD positive while working in the ED. The majority of these conversions (15 of 25) occurred in the first 6 months of 1993. A Kaplan-Meier survival analysis revealed nearly a 40% risk of PPD conversion after 60 months of full-time work in the ED. CONCLUSION: As measured by self-reported PPD status, a high rate of exposure to tuberculosis has been observed among the ED staff at Harbor-UCLA Medical Center. The highest rate of PPD conversion has been noted most recently, suggesting that there has been a significant increase in staff exposure to tuberculosis during 1992 and the beginning of 1993. Systematic monitoring of PPD conversion rates among ED staff is necessary to determine the adequacy of ED respiratory isolation procedures during the current tuberculosis epidemic.

California↗
PubMed1994

Management of acute respiratory failure due to pulmonary edema with nasal positive pressure support.

The management of patients with respiratory failure from cardiogenic pulmonary edema may require intubation and mechanical ventilation. This provides both ventilatory assistance as well as the beneficial hemodynamic effects of positive intrathoracic pressure. As the need for ventilation is usually short term, noninvasive ventilatory support may be adequate. We report the use of biphasic positive airway pressure by nasal mask (BiPAP system) to successfully manage two patients with respiratory failure due to pulmonary edema.

Acute Disease↗
PubMed1993

Finger prick blood testing in Leber hereditary optic neuropathy.

Individuals from 33 unrelated Australian families with optic atrophy were screened for 10 different single base alterations in mitochondrial DNA (mtDNA) associated with Leber hereditary optic neuropathy (LHON) using direct polymerase chain reaction amplification of blood spots collected on Guthrie cards. This method using blood spots allows easily accessible screening for LHON mtDNA mutations with minimal biohazard risk and reduced expense in the storage and transport of specimens.

Base Sequence↗
PubMed1992

A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology.

The Tas2 and Vic2 Australian families are affected with a variant of Leber hereditary optic neuropathy (LHON). The risk of developing the optic neuropathy shows strict maternal inheritance, and the ophthalmological changes in affected family members are characteristic of LHON. However, in contrast to the common form of the disease, members of these two families show a high frequency of vision recovery. To ascertain the mitochondrial genetic etiology of the LHON in these families, both (a) the the nucleotide sequences of the seven mitochondrial genes encoding subunits of respiratory-chain complex I and (b) the mitochondrial cytochrome b gene were determined for representatives of both families. Neither family carries any of the previously identified primary mitochondrial LHON mutations: ND4/11778, ND1/3460, or ND1/4160. Instead, both LHON families carry multiple nucleotide changes in the mitochondrial complex I genes, which produce conservative amino acid changes. From the available sequence data, it is inferred that the Vic2 and Tas2 LHON families are phylogenetically related to each other and to a cluster of LHON families in which mutations in the mitochondrial cytochrome b gene have been hypothesized to play a primary etiological role. However, sequencing analysis establishes that the Vic2 and Tas2 LHON families do not carry these cytochrome b mutations. There are two hypotheses to account for the unusual mitochondrial genetic etiology of the LHON in the Tas2 and Vic2 LHON families. One possibility is that there is a primary LHON mutation within the mitochondrial genome but that it is at a site that was not included in the sequencing analyses. Alternatively, the disease in these families may result from the cumulative effects of multiple secondary LHON mutations that have less severe phenotypic consequences.

Adolescent↗