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M Weir

Publications and source records attributed to M Weir.

51 records · Page 3Linked to original sources
PubMed1994

Renal adaptation to the failing heart. Understanding the cascade of responses.

Progressive systolic dysfunction of the heart results in a broad array of physiologic compensatory mechanisms within the kidney. These mechanisms are primarily stimulated by diminution of the effective arterial blood volume and resultant activation of a biochemical cascade of neurohormonal responses, including activation of the renin-angiotensin-aldosterone system and enhanced release of norepinephrine, arginine vasopressin, prostaglandins, endothelin, and atrial natriuretic peptide. The interaction of these neurohormonal systems within the kidney is complex. Vasoconstriction induced by angiotensin II, arginine vasopressin, and catecholamines may decrease renal perfusion by both endocrine and neural actions. In contrast, systemic pressures may rise, which may facilitate perfusion.

Adaptation, Physiological↗
PubMed1994

Renal adaptation to the failing heart. Avoiding a 'therapeutic misadventure'.

Systolic dysfunction of the heart represents a state of "prerenal" azotemia, in which the excess of total body salt and water is redistributed to venous and interstitial fluid compartments. This results in a diminished effective circulating blood volume and thereby decreases tissue perfusion. The kidneys perceive the ineffective circulating volume and employ a complex series of interconnected hemodynamic and neurohumoral effector mechanisms to restore "adequate" perfusion. This is done by reclaiming a greater fraction of filtered sodium and water and elevating systemic vascular resistance to keep perfusion pressure to vital organs constant despite diminished cardiac output. Knowledge of the physiologic compensatory responses that occur in the kidneys of heart failure patients allows clinicians to develop a logical treatment plan. This knowledge should also help avoid a therapeutic misadventure by making it possible to exclude drugs known to adversely affect renal function in patients with a failing heart and poorly compensating kidneys.

Adaptation, Physiological↗
PubMed1993

Egg ligation alters the Bcd protein gradient and segmentation gene expression in embryos of Drosophila.

A concentration gradient of the anterior morphogen Bicoid (Bcd) plays a key role in the specification of cell fates in the early Drosophila embryo. We found that introduction of a membrane barrier across the embryo results in increased levels of Bcd protein on the anterior side of the barrier and decreased levels on the posterior side, consistent with a blockage in the postulated anterior-to-posterior translocation of Bcd protein. The expression patterns of downstream segmentation genes were in large part consistent with their regulation by the Bcd morphogen. However, some aspects of the patterns did not correlate with the altered Bcd distribution, suggesting that other morphogens also regulate the anteroposterior pattern. Our results suggest that axial translocation of morphogens is critical for establishing a well-proportioned body plan.

Animals↗
PubMed1993

Synergistic activation of transcription is mediated by the N-terminal domain of Drosophila fushi tarazu homeoprotein and can occur without DNA binding by the protein.

Synergistic activation of transcription by Drosophila segmentation genes in tissue culture cells provides a model with which to study combinatorial regulation. We examined the synergistic activation of an engrailed-derived promoter by the pair-rule proteins paired (PRD) and fushi tarazu (FTZ). Synergistic activation by PRD requires regions of the homeodomain or adjacent sequences, and that by FTZ requires the first 171 residues. Surprisingly, deletion of the FTZ homeodomain does not reduce the capacity of the protein for synergistic activation, although this mutation abolishes any detectable DNA-binding activity. This finding suggests that FTZ can function through protein-protein interactions with PRD or other components of the homeoprotein transcription complex, adding a new layer of mechanisms that could underlie the functional specificities and combinatorial regulation of homeoproteins.

Animals↗
PubMed1991

Purification and characterization of the herpes simplex virus type 1 ribonucleotide reductase small subunit following expression in Escherichia coli.

The herpes simplex virus type 1 (HSV-1) gene encoding the ribonucleotide reductase (RR) small subunit (R2) was cloned as an unfused and intact open reading frame into a T7 RNA polymerase expression system in Escherichia coli. The expressed product was recovered from bacteria in soluble form and constituted 7% of the soluble protein. Protein purification yielded 3.5 mg of 95% pure R2 per litre of bacterial culture. The correct composition of the purified protein was verified by amino acid analysis and N-terminal sequencing. The isoelectric point of the protein was 5.3. Atomic emission spectroscopy indicated that the iron content of the E. coli-expressed R2 was 0.2 to 0.5 atoms of iron per R2 protomer as compared with a theoretical maximum value of 2. The E. coli-expressed HSV-1 R2 existed as a combination of a stable dimer and monomer. Combination of the E. coli-expressed R2 with the E. coli-expressed large subunit (R1) gave an active holoenzyme. Thus, the T7 expression system provides a rich source of enzymically active HSV-1 RR.

Amino Acids↗
PubMed1991

Functional dissection of the paired segmentation gene in Drosophila embryos.

An ectopic expression assay in Drosophila embryos was used to investigate the roles of pair-rule segmentation genes in the spatial regulation of the segment-polarity gene, engrailed (en). It is hypothesized that the regions of overlap in expression of two genes, paired (prd) and even-skipped (eve), define the odd-numbered en expression stripes. Consistent with this combinatorial model, ectopic expression of prd caused these en stripes to be expanded posteriorly. Surprisingly, however, ectopic expression of a prd gene with a deletion of the conserved paired box resulted in loss of these odd-numbered en stripes. This dominant negative effect is a phenocopy of en expression in prd embryos and suggests that the paired box is necessary for normal prd- function. A similar deletion of odd-numbered en stripes was also observed after ectopic expression of a chimeric fushi tarazu (ftz) gene containing a substituted prd gene homeo box; in addition, in these embryos, the even-numbered en stripes were expanded anteriorly, as observed when the unaltered ftz gene is ectopically expressed. These effects suggest that the chimeric protein may have DNA or protein targets of both the normal Ftz and Prd proteins.

Animals↗
PubMed1989

Identification of genes from pattern formation, tyrosine kinase, and potassium channel families by DNA amplification.

The study of gene family members has been aided by the isolation of related genes on the basis of DNA homology. We have adapted the polymerase chain reaction to screen animal genomes very rapidly and reliably for likely gene family members. Using conserved amino acid sequences to design degenerate oligonucleotide primers, we have shown that the genome of the nematode Caenorhabditis elegans contains sequences homologous to many Drosophila genes involved in pattern formation, including the segment polarity gene wingless (vertebrate int-1), and homeobox sequences characteristic of the Antennapedia, engrailed, and paired families. In addition, we have used this method to show that C. elegans contains at least five different sequences homologous to genes in the tyrosine kinase family. Lastly, we have isolated six potassium channel sequences from humans, a result that validates the utility of the method with large genomes and suggests that human potassium channel gene diversity may be extensive.

Amino Acid Sequence↗
PubMed1988

Posterior pattern formation in C. elegans involves position-specific expression of a gene containing a homeobox.

During postembryonic development in C. elegans, posterior-specific pattern formation requires the gene mab-5. Within the posterior body region, mab-5 activity controls epidermal, neuronal, and mesodermal cell differentiation, and also the direction of cell migration. Here, we show that mab-5 RNA is localized in the posterior body region, indicating that mab-5 activity is targeted to posterior cells, at least in part, by a mechanism that operates at the level of mab-5 RNA synthesis or stabilization. We also show that mab-5 contains a homeobox similar to that of the Drosophila Antennapedia gene. This suggests that mab-5 influences cell differentiation and cell migration by regulating gene expression, and clearly demonstrates that genes containing homeoboxes influence global aspects of pattern formation in organisms other than Drosophila.

Amino Acid Sequence↗
PubMed1988

Relationships between renal function and disposition of oral ciprofloxacin.

The relationships between creatinine clearance (CLCR) and the pharmacokinetics of oral ciprofloxacin were characterized. On the basis of these data, a dosage adjustment strategy, which incorporates the severity of infection and the size and renal function of the patient, was developed. An adaptive (feedback) control algorithm is proposed. A total of 32 subjects (8 normal, 8 anuric, and 16 with CLCR between 0.53 and 4.3 liters/h per 1.73 m2) were given a single 750-mg tablet of ciprofloxacin by mouth. Serial serum and urine samples were collected, assayed by high-pressure liquid chromatography, and comodeled. The population relationship between total apparent ciprofloxacin clearance (CL/f) and CLCR, both measured in liters per hour per 1.73 m2, was CL/f = 2.83 x CLCR + 21.8 (r = 0.69; P less than 0.001). The mean terminal half-life was not significantly related to CLCR but was much more variable in subjects with CLCR less than 3 liters/h per 1.73 m2 (F = 4.8; P less than 0.005). We conclude that patients with CLCR less than 1.2 liters/h per 1.73 m2 should receive two-thirds of the normal daily dose and that the dose interval should not be lengthened.

Administration, Oral↗
PubMed1987

Attitudes to adverse drug reactions and their reporting among medical practitioners.

The adverse drug reaction (ADR) reporting rate within the medical profession is exceptionally low, and doctors' approaches and attitudes to ADRs were explored through personal structured interviews. The total sample comprised 104 doctors in private practice, divided into three groups: 59 general practitioners, 26 medical specialists and 19 surgical specialists. Certain differences emerged between the groups. The surgical group observed far fewer ADRs than the other groups and not a single member had ever reported an ADR. A significantly larger number of medical specialists considered it necessary to report an ADR to an outside agency, while general practitioners tended to believe that only newly released medicines required ADR reporting. However, few doctors of any specialty regarded ADR reporting as part of the action they would take in their handling of ADRs in practice. The commonest explanation advanced for the marked underreporting of ADRs was that unusual or serious reactions were very infrequent and the common or trivial ones did not warrant reporting. Apathy and indifference were rated as the next most pertinent influence in non-compliance, while such factors as fear of personal consequences (e.g. criticism, medicolegal action) and uncertainty about what to report were deemed to be relatively unimportant.

Attitude of Health Personnel↗
PubMed1987

Pharmacokinetics of intravenously administered ciprofloxacin in patients with various degrees of renal function.

We examined the pharmacokinetic behavior of 200 mg of ciprofloxacin administered intravenously to 32 volunteers whose renal function as measured by creatinine clearance ranged from 0 to 8.99 liters/h per 1.73 m2. Serum clearances (mean +/- standard deviation) were 26.8 +/- 5.7 and 15.4 +/- 4.3 liters/h per 1.73 m2 in normal and anephric volunteers, respectively. The half-life (mean +/- standard deviation) increased from 4.3 +/- 0.8 h in normal volunteers to 8.6 +/- 3.3 h in anephric volunteers. There was good correlation between normalized creatinine clearance and both normalized serum and renal clearance. The regression equation for serum clearance (CLS) versus creatinine clearance (CLCR) was CLS = 1.97 X CLCR + 13.23, where r = 0.697; for renal clearance versus creatinine clearance, the equation was CLR = 2.26 X CLCR, where r = 0.845. On the basis of these data, we recommend a maximum 50% reduction in dose when ciprofloxacin is instituted at a renal function of 1.2 to 1.8 liters/h per 1.73 m2 (20 to 30 ml/min per 1.73 m2). Because of the observed variation in ciprofloxacin half-life in our anephric volunteers, we also recommend that a schedule of administration every 12 h be maintained, even for patients without urine output.

Adult↗
PubMed1982

MCF-specific murine monoclonal antibodies made against AKR-247 MCF virus recognize a unique determinant associated with the gp70-p-15(E) complex.

Hybridomas obtained from (NFS X AKR)F mice immunized with syngeneic cells infected with AKR-247 MCF virus produced antibodies specific for only AKR-247 or closely related MCF viruses which hare a previously defined MCF antigen (MCFA-3). These monoclonal antibodies recognized a new type of viral antigenic determinant which appeared to be a conformational determinant associated with the env precursor polyprotein (pr80env) or its disulfide-linked gp70-p15(E) complex (gp80) but not with free gp70 or p15(E) or any other virion or virus-induced protein.

AKR murine leukemia virus↗