Biomedical subjects
Publications and source records attributed to L McDonald.
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Thiamine-responsive megaloblastic anaemia (TRMA), also known as Rogers syndrome, is an early onset, autosomal recessive disorder defined by the occurrence of megaloblastic anaemia, diabetes mellitus and sensorineural deafness, responding in varying degrees to thiamine treatment (MIM 249270). We have previously narrowed the TRMA locus from a 16-cM to a 4-cM interval on chromosomal region 1q23.3 (refs 3,4) and this region has been further refined to a 1.4-cM interval. Previous studies have suggested that deficiency in a high-affinity thiamine transporter may cause this disorder. Here we identify the TRMA gene by positional cloning. We assembled a P1-derived artificial chromosome (PAC) contig spanning the TRMA candidate region. This clarified the order of genetic markers across the TRMA locus, provided 9 new polymorphic markers and narrowed the locus to an approximately 400-kb region. Mutations in a new gene, SLC19A2, encoding a putative transmembrane protein homologous to the reduced folate carrier proteins, were found in all affected individuals in six TRMA families, suggesting that a defective thiamine transporter protein (THTR-1) may underlie the TRMA syndrome.
Sensitivity to oestrogens and apoptosis are critical determinants of the development and progression of breast cancer and reflect closely linked pathways in breast epithelial cells. For example, induction of BCL-2 oncoprotein expression by oestrogen contributes to suppression of apoptosis and BCL-2 and oestrogen receptor (ER) are frequently co-expressed in tumours. BAG-1/HAP is a multifunctional protein which complexes with BCL-2 and steroid hormone receptors (including the ER), and can suppress apoptosis and influence steroid hormone-dependent transcription. Therefore, analysis of expression of BAG-1 in human breast cancer is of considerable interest. BAG-1 was readily detected by immunostaining in normal breast epithelial cells and most ER-positive tumours, but was undetectable or weakly expressed in ER-negative tumours. BAG-1 positive cells showed a predominantly cytoplasmic or cytoplasmic plus nuclear distribution of staining. A correlation between ER and BAG-1 was also evident in breast cancer derived cell lines, as all lines examined with functional ER expression also expressed high levels of BAG-1. In addition to the prototypical 36 kDa BAG-1 isoform, breast cancer cells expressed higher molecular weight isoforms and, in contrast to BCL-2, BAG-1 expression was independent of oestrogens. BAG-1 isoforms were differentially localized to the nucleus or cytoplasm and this was also independent of oestrogens. These results demonstrate a close association between BAG-1 and functional ER expression and suggest BAG-1 may be useful as a therapeutic target or prognostic marker in breast cancer.
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The complete genome sequence of Treponema pallidum was determined and shown to be 1,138,006 base pairs containing 1041 predicted coding sequences (open reading frames). Systems for DNA replication, transcription, translation, and repair are intact, but catabolic and biosynthetic activities are minimized. The number of identifiable transporters is small, and no phosphoenolpyruvate:phosphotransferase carbohydrate transporters were found. Potential virulence factors include a family of 12 potential membrane proteins and several putative hemolysins. Comparison of the T. pallidum genome sequence with that of another pathogenic spirochete, Borrelia burgdorferi, the agent of Lyme disease, identified unique and common genes and substantiates the considerable diversity observed among pathogenic spirochetes.
Employees in healthcare are exposed to numerous and varied risks that pose the threat of injury. Management of those exposures by the organization will ultimately help create a safe environment for staff, patients and the public. Incorporating workers' compensation into the risk management program is the first step toward managing and reducing these exposures. This article presents a suggested outline for a written risk management plan for workers' compensation exposures.
A peritoneal dialysis (PD) solution containing 1.1% amino acids as the osmotic agent was evaluated in a 3-month randomized, prospective, open-label study in malnourished PD patients. Patients in the treatment group (DAA) received one or two exchanges daily with the amino acid solution, depending on tolerance, in place of glucose solutions. Controls (DD) received their usual therapy with glucose dialysate. Fifty-four DAA and 51 DD patients completed the study. In DAA, but not in DD patients, there was a significant increase at month 3 in serum insulin-like growth factor-1 (IGF-1) levels and significant decreases in serum potassium (all 3 months) and inorganic phosphorus levels (months 1 and 3), indicating a general anabolic response. Prealbumin and transferrin levels were significantly increased in DAA but not in DD patients at month 1, but the groups did not differ at months 2 and 3. In patients with baseline albumin levels less than 3.5 g/dL (bromcresol green [BCG] method), DAA patients showed increases in albumin, transferrin (months 1 and 2), and prealbumin levels (all 3 months) relative to baseline values, whereas these serum protein levels were unchanged in DD patients, although the changes from baseline did not differ between groups. In this subgroup, midarm muscle circumference (MAMC) did not change in DD or DAA patients. In patients with baseline albumin levels of 3.5 g/dL or greater, DD patients had decreases in albumin and total protein levels at all 3 months and in prealbumin levels at months 1 and 2, relative to baseline. In DAA patients, there were fewer changes in serum proteins. MAMC increased significantly from baseline in DAA but not in DD patients, although changes from baseline did not differ between DAA and DD groups. DAA patients showed no changes in peritoneal membrane transport characteristics. The results indicate that treatment with one or two exchanges daily of this amino acid-based PD solution is safe and provides nutritional benefit for malnourished PD patients.
Nightingale's passionate commitment to statistics was based on her faith in a god of order, who created a world that ran by law. God's laws could be known through research, as a result of which suitable interventions to better the world could be applied. Statistics were a vital component in her holistic approach to health care as a system. They served both to indicate serious problems and to assist in policy making, and then again to monitor the effects of the new policies. She pioneered the use of evaluative statistics and saw reforms achieved as a result of her advocacy. This article explores three key aspects selected from Nightingale's more than 40 years of applied statistical work: her adaptation of Quetelet's methodological foundations, the use of statistics in monitoring public health care systems, and her pioneering study of maternal mortality in childbirth.
The genome of the bacterium Borrelia burgdorferi B31, the aetiologic agent of Lyme disease, contains a linear chromosome of 910,725 base pairs and at least 17 linear and circular plasmids with a combined size of more than 533,000 base pairs. The chromosome contains 853 genes encoding a basic set of proteins for DNA replication, transcription, translation, solute transport and energy metabolism, but, like Mycoplasma genitalium, it contains no genes for cellular biosynthetic reactions. Because B. burgdorferi and M. genitalium are distantly related eubacteria, we suggest that their limited metabolic capacities reflect convergent evolution by gene loss from more metabolically competent progenitors. Of 430 genes on 11 plasmids, most have no known biological function; 39% of plasmid genes are paralogues that form 47 gene families. The biological significance of the multiple plasmid-encoded genes is not clear, although they may be involved in antigenic variation or immune evasion.
Archaeoglobus fulgidus is the first sulphur-metabolizing organism to have its genome sequence determined. Its genome of 2,178,400 base pairs contains 2,436 open reading frames (ORFs). The information processing systems and the biosynthetic pathways for essential components (nucleotides, amino acids and cofactors) have extensive correlation with their counterparts in the archaeon Methanococcus jannaschii. The genomes of these two Archaea indicate dramatic differences in the way these organisms sense their environment, perform regulatory and transport functions, and gain energy. In contrast to M. jannaschii, A. fulgidus has fewer restriction-modification systems, and none of its genes appears to contain inteins. A quarter (651 ORFs) of the A. fulgidus genome encodes functionally uncharacterized yet conserved proteins, two-thirds of which are shared with M. jannaschii (428 ORFs). Another quarter of the genome encodes new proteins indicating substantial archaeal gene diversity.
A 75-year-old man suffered a cardiac arrest and severe anoxic encephalopathy. A serial study of electroencephalograms during 4 days showed sequential changes from periodic approximately 2 Hz spike activity to absence-like status (ALS) and then into a suppression-burst pattern. Intravenous administration of phenytoin had no effect on ALS. A small dose of intravenous diazepam reduced a suppression-burst pattern. We speculate that the ALS originates in the midline structures, spreading bilaterally and synchronously to the "dysfunctional" cortex; the sustained discharges were a manifestation of associated reticular lesions, and we believe that intravenous diazepam suppressed the spread of ALS to the "dysfunctional cortex," leading to the appearance of the suppression-burst pattern. The only limitation for definitive conclusions may be a lack of postmortem verification. Autopsy findings, however, could not have confirmed the dynamic changes that occurred during the 5 days before the patients death.
Agreement was examined between the answers to an employment survey administered to discharged patients with spinal cord injury on two occasions 6 mo. apart. Analysis suggested reasonable test-retest reliability, with kappas ranging from .65 to .87 for the categorical data, e.g., current employment information and amount of time before respondents achieved any return to work.
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Using a polymerase chain reaction strategy we identified a serine proteinase inhibitor (serpin) in human bone marrow that is related to the cellular serpin proteinase inhibitor 6 (PI-6) and the viral serpin cytokine response modifier A (CrmA). This serpin, proteinase inhibitor 9 (PI-9), has an unusual reactive center P1(Glu)-P1'(Cys), which suggests that it inhibits serine proteinases that cleave after acidic residues. The only known serine proteinase with this specificity is granzyme B, a granule cytotoxin produced by cytotoxic lymphocytes. To test the interaction of PI-9 with granzyme B we prepared recombinant hexa-histidine tagged PI-9 in a yeast expression system. Addition of the recombinant protein to native granzyme B resulted in an SDS-resistant complex typical of serpin-serine proteinase interactions. Further analysis showed that complex formation followed bimolecular kinetics with a second order rate constant of 1.7 +/- 0.3 x 10(6) M-1 s-1, which is in the range for a physiologically significant serpin-proteinase interaction. Recombinant PI-9 also completely abrogated granzyme B and perforin-mediated cytotoxicity in vitro. Examination of PI-9 mRNA distribution demonstrated that it is expressed in immune tissue, primarily in lymphocytes. The highest levels of PI-9 mRNA and protein were observed in natural killer cell leukemia cell lines and in interleukin-2 stimulated peripheral blood mononuclear cells, which also produce granzyme B. Like PI-6, PI-9 was shown to be a cytosolic protein that is not secreted. Fractionation of natural killer cells and stimulated peripheral blood mononuclear cells demonstrated that PI-9 is in a separate subcellular compartment to granzyme B. These results suggest that PI-9 serves to inactivate misdirected granzyme B following cytotoxic cell degranulation. This may explain why cytotoxic cells are not damaged by their own granzyme B during destruction of abnormal cells.
PURPOSE: To determine the adequacy of documenting the preoperative evaluation for cataract surgery using criteria derived from published practice guidelines. METHODS: In 1990, 1139 surgeries that were performed on 1139 patients at ten institutions of the Academic Medical Center Consortium were reviewed for completeness of documentation of the preoperative evaluation. Criteria for completeness were derived from the American Academy of Ophthalmology Preferred Practice Pattern on cataract evaluation and the Agency for Health Care Policy and Research-sponsored guidelines. RESULTS: Twenty-six percent of charts lacked documentation of at least one of four basic elements of the preoperative evaluation. These four elements are (1) vision in the surgical eye; (2) vision in the fellow eye; (3) evaluation of the fundus, macula, or visual potential in the surgical eye: and (4) presence of some form (general or specific) of functional visual impairment. If, as stated in the guideline, a specific deficit in visual functioning should be identified, then 40% of charts fail to meet criteria. CONCLUSION: Documentation of the ocular preoperative assessment for cataract surgery is inadequate in more than one quarter of cases. The relation between lack of documentation and incompleteness of the examination is unknown. Improved documentation is needed to better measure and enhance the quality of care.
Three age groups (teenage; 50-65 and 65+) completed a written version of Piaget's moral reasoning tasks to determine the general level of moral reasoning and performance on eight separate categories. Significant age effects were found. Though the nature of the age group difference was mixed, younger subjects consistently achieved lower levels of performance. Results indicate that Piaget overestimated all subjects' level of performance on his tasks and that, although there are differences in different areas of moral reasoning, the relationship with age is not uniform in its direction.
A 58-year-old diabetic woman with necrobiosis lipoidica diabeticorum demonstrated lesions with raised, prominent borders. These areas were found on biopsy to have transepidermal elimination of elastic fibers. We present this case as a unique finding and review the characteristics and possible mechanisms of transepidermal elimination.