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Biomedical subjects

R Love

Publications and source records attributed to R Love.

At least 37 records · Page 2Linked to original sources
PubMed1995

Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation.

Mutations in the BRCA1 gene, discovered in 1994, are associated with an 80-90% lifetime risk of breast cancer. We have analysed 60 families with a history of breast and/or ovarian cancer for germline mutations in BRCA1. Twenty-two different mutations were detected in 32 families (53%), of which 14 are previously unreported. We observed a significant correlation between the location of the mutation in the gene and the ratio of breast to ovarian cancer incidence within each family. Our data suggest a transition in risk such that mutations in the 3' third of the gene are associated with a lower proportion of ovarian cancer. Haplotype analysis supports previous data which suggest some BRCA1 mutation carriers have common ancestors; however, we have found at least two examples where recurrent mutations appear to have arisen independently.

BRCA1 Protein↗
PubMed1995

Positive end-expiratory pressure decreases mesenteric blood flow despite normalization of cardiac output.

Positive end-expiratory pressure (PEEP) is a commonly used adjunct to mechanical ventilation and is known to have deleterious effects on cardiac output (CO). Its effects on regional blood flow are not well known. We evaluated the effect of PEEP on the mesenteric microcirculation and CO. Sprague-Dawley rats were treated with mechanical ventilation and either no PEEP (Control) or increasing levels of PEEP (PEEP). Using in vivo video-microscopy, mesenteric A1 arteriolar optical Doppler velocities and A1 and A3 (the first- and third-order arterioles branching off the feeding mesenteric arcade) intraluminal diameters were measured (n = 6/group). In a separate set of experimental animals, CO was determined by thermodilution technique (n = 5/group). Additionally, after the PEEP group attained a PEEP level of 20-cm H2O PEEP, two boluses of 2 mL 0.9 normal saline (NS) were given intravenously. The Control groups had the same determinations performed over the same time course as the PEEP group but were not exposed to any PEEP. Mesenteric blood flow (MBF) was calculated from vessel diameter and red blood cell velocity. The MBF and CO fell progressively as PEEP was increased from 10- to 15- to 20-cm H2O pressure. MBF was reduced 75% (p < 0.05) and the CO was reduced 31% (p < 0.05) from baseline at 20-cm H2O pressure PEEP. After 4 mL normal saline, the MBF was still 45% below baseline (p < 0.05) while the CO had returned to baseline. In conclusion, both MBF and CO are decreased significantly with increasing PEEP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Safety and pharmacologic activity of a new nitrate ester, ITF 296, after intravenous administration in healthy volunteers.

To evaluate the safety and pharmacologic activity of ITF 296 in humans, three groups of healthy male normotensive subjects were studied. The first two groups (six subjects each) received, in ascending order, three dose levels of ITF 296 by 30-min intravenous infusion (group I, 0.1, 0.5, 1.0 microgram/kg/min; group II, 2.0, 4.0, 6.0 micrograms/kg/min). The third group of eight subjects received, in ascending order, four dose levels of ITF 296 (10, 20, 40, 80 micrograms/kg) by 1-min i.v. injection. The study was double-blind, and placebo-controlled according to a within-patient, incomplete, unbalanced block design, such that each subject received the placebo once. Hemodynamics were assessed by means of Dynamap and BOMED. The following parameters were evaluated at different times before and after ITF 296 administration: systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), stroke volume index (SVI), cardiac index (CI), and systemic vascular resistance index (SVRI). Blood samples for kinetic assessment of ITF 296 were taken before and at different times after ITF 296 administration. The drug was well tolerated. Only a few mild (except for one, moderate) side effects (mainly headache and dizziness) were reported, usually at the higher dose levels. All safety clinical chemistry and hematologic parameters were unaffected. After i.v. infusion of ITF 296, blood pressure started to fall at the dose of 2 micrograms/kg/min, DBP being significantly reduced at doses above 1 microgram/kg/min. The effect lasted for up to 60 min after the end of the infusion. The increase in heart rate was only modest, although apparently dose-dependent. SVI was only slightly reduced, and the other hemodynamic parameters did not change. After bolus administration of ITF 296, SBP was significantly reduced starting at a dose of 20 micrograms/kg with higher doses producing a more marked effect (up to -15 mm Hg). DBP was significantly reduced only at the higher dose level of 80 micrograms/kg. The effect lasted for up to 60 min after bolus administration. HR was slightly increased after doses of 40 and 80 micrograms/kg. SVI was slightly reduced and a small transient decrease in CI was observed, whereas SVRI did not change. Satisfactory, linear kinetic correlation was found between total doses administered and AUCs measured. ITF 296 in healthy male normotensive volunteers was effective and well tolerated. The results of this study justify the planning of further studies in patients in order to test the anti-ischemic activity of the compound.

Adolescent↗
PubMed1993

The effect of reduced eyedrop size and eyelid closure on the therapeutic index of phenylephrine.

In this study we examined the relative effects of reducing eyedrop size (from 30 microliters to 10 microliters) and eyelid closure on the ocular efficacy and systemic absorption of 10% phenylephrine. Thirteen subjects participated in a quadruple crossover study that involved dilation with a 10-microliters and a 30-microliters drop of phenylephrine with and without eyelid closure. The 10-microliters drop was just as effective for pupillary dilation as the 30-microliters drop. Eyelid closure improved dilation for both drop sizes. Both eyelid closure and reducing the drug volume decreased systemic absorption of phenylephrine as measured by plasma concentration. When used together, eyelid closure and the smaller drop size reduced plasma concentration by 45%. The therapeutic index for 10% phenylephrine appears to be improved by using a 10-microliters drop followed by eyelid closure.

Absorption↗
PubMed1993

Important deficits of lung function in three modern colliery populations. Relations with dust exposure.

To determine whether dust-related "clinically important" deficits of lung function still occur in British coal miners we have analyzed the relationship between lifetime cumulative exposure to respirable dust and risk of defined functional deficits in a population of miners who were examined between 1981 and 1986. The study group consisted of a sample of men who had worked at any one of three collieries (South Wales, Yorkshire, and North East England) between 1970, when new dust standards were introduced, and date of medical survey. There were 1,671 men studied, including men who had left the collieries. "Clinically important" deficits of FEV1 from predicted values derived in this population were defined by comparisons with questionnaire data on exercise tolerance limited by breathlessness. The mean FEV1 of men in the South Wales colliery, for example, who said they had to stop for breath when walking at their own pace on level ground was 942 ml less than the predicted value for nonsmokers after taking age and stature into account. Individual cumulative exposures to respirable dust were calculated from a long-term program of measurements of dust concentrations and occupational records commencing in 1953. In the three colliery populations, 24, 24, and 12% in South Wales, Yorkshire, and the North East, respectively, had FEV1 deficits that were at least as severe as the average deficit associated with the severe grade of exertional dyspnea described above. In all collieries deficits were more common in smokers than in nonsmokers, and more common in men who had left the industry than in men still within it.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Reactive sites of an anticarcinogenic Bowman-Birk proteinase inhibitor are similar to other trypsin inhibitors.

The three-dimensional structure of the Bowman-Birk type proteinase inhibitor (PI-II) has been determined by x-ray crystallography and refined at 2.5-A resolution. This protein is a specific inhibitor of trypsin. Two reactive site loops, one at each end of the PI-II molecule, are structurally similar to each other and to reactive-site loops of pancreatic secretory trypsin inhibitor (Bolognesi, M., Gatti, G., Menegatti, E., Guarneri, M., Marquart, M., Papamokos, E., and Huber, R. (1982) J. Mol. Biol. 162, 839-869) and bovine pancreatic trypsin inhibitor (Deisenhofer, J., and Steigemann, W. (1975) Acta Crystallogr. B31, 238-250). PI-II is the first reported Bowman-Birk type inhibitor structure to be refined at high resolution, providing further insight into inhibitor mechanisms.

Amino Acid Sequence↗
PubMed1992

No evidence for germline mutations in exons 5-9 of the p53 gene in 25 breast cancer families.

Recent studies have demonstrated that families with the Li-Fraumeni syndrome carry inherited point mutations of the p53 gene. In the present study 25 families with strong histories of breast cancer were screened for the presence of such mutations. Polymerase chain reaction products of exons 5-9 of the p53 gene were examined by single-stranded conformational polymorphism analysis and, in addition, exon 7 was further screened by direct sequencing. No mutations were detected in constitutive DNA by either method. These results indicate that familial breast cancer does not usually result from germline point mutations in the p53 gene.

Breast Neoplasms↗
PubMed1990

Does rapid wound closure improve survival in older patients with burns?

Seventy-five patients more than fifty years of age were admitted for treatment of burns from January 1, 1986, to December 31, 1987, to two community-hospital-based burn units. Patients were managed by a team of burn surgeons at each unit and early excision and grafting was used whenever possible in deep partial-thickness and full-thickness burns. The extent of burn was charted weekly during hospitalization and rate of wound healing was calculated using linear regression analysis. The mean total percent burn was 26.2 per cent (range, 4-85%). The overall mortality rate was 40 per cent. Mortality rate increased sharply by decade from 17.4 per cent for those aged 50-59 years to 100 per cent for the five patients age 90 and more. Excision and grafting were performed in 40 patients; 35 patients were not operated upon. Although hospitalization was somewhat longer in patients treated surgically, survival was better. Excision and grafting should be used when needed to achieve rapid wound closure in patients more than fifty years of age.

Accidents, Home↗
PubMed1989

Determinants of EcoRI endonuclease sequence discrimination.

The arginine at position 200 of EcoRI endonuclease is thought to make two hydrogen bonds to the guanine of the sequence GAATTC and thus be an important determinant of sequence discrimination. Arg-200 was replaced by each of the other 19 naturally occurring amino acids, and the mutant endonucleases were assessed for activities in vivo and in vitro. The mutant endonuclease with lysine at position 200 exhibits the most in vivo activity of all the position 200 mutants, although the in vitro activity is less than 1/100th of wild-type activity. Five other mutants show more drastically reduced levels of in vivo activity (Cys, Pro, Val, Ser, and Trp). The Cys, Val, and Ser mutant enzymes appear to have in vivo activity which is specific for the wild-type canonical site despite the loss of hydrogen bonding potential at position 200. The Pro and Trp mutants retain in vivo activity which is independent of the presence of the EcoRI methylase. In crude cell lysates, only the Cys mutant shows a very low level of in vitro activity. None of the mutant enzymes show a preference for alternative sites in assays in vitro. The implications of these results are discussed.

Arginine↗
PubMed1987

Clustering of null mutations in the EcoRI endonuclease.

EcoRI endonuclease mutants were isolated in a methylase-deficient background following in vitro hydroxylamine mutagenesis of plasmid pKG2 (Kuhn et al.: Gene 44:253-263, 1986). Mutants which survived high-level endonuclease expression (IPTG induction) were termed null mutants. Sixty-two of 121 null mutants tested by Western blot contained normal levels of endonuclease cross-reacting protein. The complete endonuclease gene was sequenced for 27 null mutants. This group was found to consist of 20 single base-change missense mutations, 6 double mutations, and 1 triple mutation. Ten of the 20 single mutations were clustered between residues 139 and 144. When examined with respect to the structure of the EcoRI-DNA complex (McClarin et al.: Science 234:1526-1541, 1986), these alterations were found to fall predominantly into two classes: substitutions at the protein-DNA interface or substitutions at the protein-protein (dimer) interface. Protein from several of the mutants was purified and sized by using HPLC. Wild-type EcoRI endonuclease and protein from three of the DNA interface mutations (Ala139----Thr, Gly140----Ser, Arg203----Gln) appeared to be dimeric, while protein from subunit interface mutations (Glu144----Lys, Glu152----Lys, Gly210----Arg) migrated as monomers.

Amino Acid Sequence↗
PubMed1987

72-hour preservation of the canine pancreas.

A new flushout solution for preservation of the pancreas was tested in the dog model of segmental pancreas autotransplantation. The solution osmolality was 320 mOsm/L, K+ = 120 mM, Na+ = 30 mM, and it contained the anion, lactobionate, and raffinose as impermeants to the cell. Preservation times studied were 48 and 72 hr. The pancreas was flushed out with about 250 ml of the new solution and stored at 0 degrees C. Dogs were monitored postoperatively for blood glucose and intravenous glucose tolerance (IVGTT). Results were compared with control (no preservation) segmental pancreas autotransplants. Dogs receiving pancreases stored for 48 or 72 hr were normoglycemic on day one and remained normoglycemic for at least 28 days, or until time of sacrifice. Two of four dogs with pancreases stored for 48 hr were sacrificed on day 14 with normal IVGTT for histology. The remaining two dogs had normal pancreatic function for 28 days. Two of eight dogs receiving pancreas grafts after 72-hr cold storage died of causes unrelated to the pancreas graft, which was still functioning at the time of death. Six dogs remained normoglycemic and had a normal IVGTT at least for 28 days. This study demonstrates the feasibility of preserving the pancreas for three days for transplantation.

Animals↗
PubMed1984

Individualist and structuralist perspectives on nutrition education for Canadian children.

The controversy over the most efficacious approach to health education is presented as a debate between the individualist perspective which stresses lifestyle change and the structuralist perspective which emphasizes change in socio-political conditions. Within the context of nutrition education for Canadian children as a case study, the two perspectives are compared and contrasted with respect to their definitions of (1) the root causes of poor health, (2) the most appropriate strategies for health education programs and (3) the training and subsequent role of the health educator in health promotion. The authors discuss the conflict between the two perspectives and suggest that synthesis is needed for progressive health promotion for Canadian children to occur.

Attitude to Health↗
PubMed1983

Hyponatremia secondary to olfactory neuroblastoma.

A patient with a four-year history of unexplained hyponatremia was seen with recurrent nasal discharge and was found to have a typical olfactory neuroblastoma. The clinical laboratory diagnostic studies suggested that the patient's sodium deficiency was secondary to the syndrome of inappropriate antidiuretic hormone. Subsequent resection of the neoplasm led to resolution of the hyponatremia, suggesting that a (tumor-associated) humoral factor, such as vasopressin or a vasopressinlike substance, was responsible for the electrolyte disturbance. A search of the literature disclosed one previous case of vasopressin-secreting nasal neuroblastoma.

Adult↗