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Biomedical subjects

R Young

Publications and source records attributed to R Young.

At least 127 records · Page 7Linked to original sources
PubMed1995

Relative androgenicity, blood pressure levels, and cardiovascular risk factors in young healthy women.

To test the hypothesis that androgens may play a role in the pathogenesis of atherosclerosis and hypertension, we investigated the association of delta 5 dehydroepiandrosterone sulfate [DHEAS]) and delta 4 (free testosterone [FT]) androgens with the resting, seated blood pressure (BP) levels and cardiovascular risk factors in 280 young, healthy women 18 to 24 years of age. After application of multiple regression analysis, systolic BP was positively and independently correlated with the ratio of dehydroepiandrosterone sulfate to free testosterone (DHEAS/FT), fasting insulin levels, and the diastolic BP with DHEAS/FT only. The DHEAS/FT ratio proved to be a stronger predictor of the BP levels than either hormone alone. Further, uric acid concentrations and HDL/total cholesterol ratio were independently correlated with both FT and body mass index in these young women. Serum triglycerides were independently correlated with FT and central body fat distribution. These data suggest that serum androgen concentrations are important independent predictors of cardiovascular risk factors and that the ratio of dehydroepiandrosterone sulfate to free testosterone ratio is an independent predictor of blood pressure levels in young women.

Acetone↗
PubMed1995

A phase I trial of bryostatin 1 in patients with advanced malignancy using a 24 hour intravenous infusion.

Bryostatin 1 is a macrocyclic lactone derived from the marine invertebrate Bugula neritina. In vitro, bryostatin 1 activates protein kinase C (PKC), induces the differentiation of a number of cancer cell lineages, exhibits anti-tumour activity and augments the response of haemopoietic cells to certain growth factors. In vivo, bryostatin 1 is also immunomodulatory, but the range of tumours which respond to bryostatin 1 in xenograft tumour models is mostly the same as the in vitro tumour types, suggesting a direct mode of action. Nineteen patients with advanced malignancy were entered into a phase I study in which bryostatin 1 was given as a 24 h intravenous infusion, weekly, for 8 weeks. Myalgia was the dose-limiting toxicity and the maximum tolerated dose was 25 micrograms m-2 per week. The myalgia was cumulative and dose related, and chiefly affected the thighs, calves and muscles of extraocular movement. The mechanism of the myalgia is unknown. CTC grade 1 phlebitis affected every patient for at least one cycle and was caused by the diluent, PET, which contains polyethylene glycol, ethanol and Tween 80. Most patients experienced a 1 g dl-1 decrease in haemoglobin within 1 h of commencing the infusion which was associated with a decrease in haematocrit. Radiolabelled red cell studies were performed in one patient to investigate the anaemia. The survival of radiolabelled red cells during the week following treatment was the same as that seen in the week before treatment. However, there was a temporary accumulation of radiolabelled red cells in the liver during the first hour of treatment, suggesting that pooling of erythrocytes in the liver might account for the decrease in haematocrit. Total or activated PKC concentrations were measured in the peripheral blood mononuclear cells (PBMCs) of three patients for the first 4 h of treatment and during the last hour of the infusion. This showed that PKC activity was significantly modulated during the infusion. Bryostatin 1 is immunomodulatory in vitro, and we have confirmed this activity in vivo. An investigation of the first three cycles of treatment in seven patients showed an increased IL-2-induced proliferative response in peripheral blood lymphocytes and enhanced lymphokine-activated killer (LAK) activity. A previously reported rise in serum levels of interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF 1) was not confirmed in our study; of nine patients in this study, including patients at all dose levels, none showed an increase in these cytokines.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1995

VAD chemotherapy as remission induction for multiple myeloma.

A total of 142 patients with multiple myeloma received VAD as remission induction therapy. Seventy-five were previously untreated and 67 had relapsed (31) or refractory disease (36). Vincristine (total dose 1.6 mg) was infused with doxorubicin 36 mg m-2 by continuous ambulatory pump over 4 days. In addition, oral dexamethasone 40 mg day-1 was given for 4 days. Intermittent dexamethasone was only given to 19 patients. Courses were repeated every 21 days. The overall response rate was 84% [27% complete response (CR)] in previously untreated patients and 61% (3% CR) in patients with relapsed and refractory disease. The median survival was 36 months for untreated patients and 10 months for those who had received prior therapy. VAD was well tolerated; however, despite prophylaxis, 54% patients received antibiotics at some time during therapy and 37% had dyspepsia. Twenty-three patients subsequently received a transplant (eight allografts, eight marrow autografts and seven peripheral blood stem cell transplants). Eight have died-four in the allogeneic group and four in the autologous group. The overall median survival of transplanted patients has not yet been reached. VAD is an effective, out-patient therapy for inducing remission in multiple myeloma. Post-remission therapy needs to be optimised, but it is likely that the needs of previously untreated patients may be different from those with relapsed and refractory disease.

Adult↗
PubMed1995

Fetal plasma insulin-like growth factor-binding protein-3 concentrations are elevated following bilateral nephrectomy in fetal sheep.

Insulin-like growth factors mediate many of the effects of growth hormone and are important in the regulation of growth, especially in the fetus where growth is less dependent on circulating growth hormone. In the ovine fetus, insulin-like growth factor-I (IGF-I) is bound mainly to the low molecular weight insulin-like growth factor-binding proteins (IGFBP), IGFBP-1 and IGFBP-2, with little binding to IGFBP-3 until near term at 147 days gestation. To determine if there was any difference in plasma IGF-I and IGFBP-3 concentrations in growth-retarded fetal sheep with altered renal status, concentrations were measured by specific radioimmunoassay from bilaterally nephrectomized fetal sheep between Days 113 and 135 gestation. Plasma IGFBP-3 concentrations were significantly (P < 0.001) increased in bilaterally nephrectomized fetuses (4.19 +/- 0.19 micrograms mL-1, n = 7) compared with control fetuses (2.33 +/- 0.10 micrograms mL-1, n = 7). There was no change in plasma IGFBP-3 concentration with gestational age in either experimental group. Maternal plasma IGFBP-3 concentrations did not differ between the bilateral nephrectomy group (3.11 +/- 0.09 micrograms mL-1, n = 7) and the control group (3.25 +/- 0.11 micrograms mL-1, n = 7) and showed no change within groups over the experimental period. Total plasma IGF-I concentrations in bilaterally nephrectomized fetuses and ewes were similar to those in control fetuses and ewes. The results indicate that the profile of IGF binding in fetal plasma is altered in the anephric fetal sheep. In nephrectomized fetal sheep, increased IGFBP-3 concentrations, and therefore increased IGF-binding capacity in fetal plasma, may have contributed to a decrease in free IGF in plasma and decreased IGF-I bioactivity. This would provide a possible mechanism for the growth retardation reported in bilaterally nephrectomized fetal sheep.

Animals↗
PubMed1995

Treatment of cyclic vomiting in childhood with erythromycin.

Cyclic vomiting syndrome (CVS) is an unusual cause of episodic emesis in children. It manifests as intermittent episodes of severe vomiting, similar in time of onset and duration, with no symptoms during the intervening period. Dehydration necessitating intravenous fluid therapy may occur. Most therapeutic maneuvers have proven unsuccessful. We report the use of erythromycin as a prokinetic agent in the treatment of cyclic vomiting in 24 children (10 boys, 14 girls). Many patients had mild associated abdominal pain with their vomiting. Fourteen patients had previously been given metoclopramide but none responded. Two patients were mildly developmentally delayed. Twenty-four patients were given oral erythromycin ethylsuccinate, approximately 20 mg/kg/day, in two to four divided doses for 7 days. This dose was repeated as needed when symptoms reappeared. Eighteen of 24 patients reported total resolution of symptoms when re-evaluated at 2 and 6 months. All males responded, eight of 18 responders were female, and all six with partial or no response to therapy were female. This uncontrolled trial suggests that erythromycin may be a useful prokinetic agent in the treatment of CVS in childhood. Because the study was uncontrolled, placebo effect cannot be excluded. Case-controlled, double-blinded prospective trials should be considered to evaluate the effectiveness of erythromycin in CVS.

Adolescent↗
PubMed1995

Effects of interleukin-6 on mobilization of primitive haemopoietic cells into the circulation.

Twenty-seven patients with advanced adenocarcinoma were studied. Groups of three patients received interleukin-6 (IL-6) in doses ranging from 0.5 to 20 micrograms/kg by daily subcutaneous injection on days 1-7 and 22-49. Four patients received IL-6 2.5 micrograms/kg/d with GM-CSF 5 micrograms/kg/d and three patients received IL-6 2.5 micrograms/kg/d with IL-3 5 micrograms/kg/d. Circulating platelet numbers increased 1.65-fold during IL-6 treatment, in a dose-dependent fashion (P = 0.01). This increase is inferior to that expected from laboratory studies. No significant change in total WBC was seen after IL-6 alone. After treatment with IL-6, significant increases in numbers of circulating mononuclear cells (2.2-fold, P = 0.006) and GM-CFC numbers (3.2-fold, P = 0.01) were seen, but there were no changes in circulating megakaryocyte-CFC numbers. In contrast, after treatment with IL-6 and GM-CSF, larger increases in both circulating GM-CFC (20-fold, P = 0.04) and megakaryocyte-CFC numbers (18-fold, P = 0.03) were seen. Increases in blood progenitors after treatment with IL-6 and IL-3 did not achieve statistical significance. The ability of peripheral blood mononuclear cells to generate and sustain long-term haemopoiesis in vitro was similar in IL-6-treated patients to that in untreated control subjects. No significant changes in the incidence of bone marrow progenitors or their cycling status (assessed by thymidine suicide) were seen. These data suggest that IL-6 alone will not be clinically useful to mobilize blood progenitor cells in cancer patients.

Adenocarcinoma↗
PubMed1995

Holins: form and function in bacteriophage lysis.

During the lytic cycle of most bacteriophages, a phage-encoded peptidoglycan-degrading activity is elaborated. At least four entirely distinct types of enzymes fulfill this role and are given the generic name 'endolysin'. Endolysins characterized to date are synthesized without a signal sequence and thus accumulate fully folded and active in the cytosol during the vegetative phase. Small membrane proteins are required in order for endolysins to gain access to the peptidoglycan. Because the available data suggest that the membrane lesion formed by these proteins is stable and non-specific, these proteins have been given the designation 'holins' ('hole'-formers). Analysis of the primary sequence suggests a simple membrane topology with two or more membrane-spanning helical domains and a highly charged, hydrophilic C-terminus. Comparison of the sequences of holins from phages of Gram-negative hosts suggests there are at least two major holin groups. Putative holin genes have also been found in bacteriophages of Gram-positive bacteria. Altogether, in phages of Eubacteria, 11 or more unrelated gene families which share the functional and structural characteristics of holins have been identified. Genetic and physiological analysis suggest that holins are primarily regulated at the level of function. Holin function is modulated in some cases by a second protein encoded by the holin gene. The primary regulation of holin function, however, appears to be intrinsic to the holin structure itself, since a missense allele of the S holin gene of phage lambda has been found which abolishes the normal delay that allows the vegetative phase to generate a useful number of progeny.

Amino Acid Sequence↗
PubMed1995

Phi X174 lysis requires slyD, a host gene which is related to the FKBP family of peptidyl-prolyl cis-trans isomerases.

Recessive mutations in the slyD (sensitivity to lysis) gene were isolated by selecting for survival after induction of the cloned lysis gene E of bacteriophage phi X174 [1]. The slyD- mutation, transduced into the normal phi X174 host, Escherichia coli C, confers an absolute block on the plaque-forming ability of the wild-type phage, indicating that slyD is required for E function. slyD encodes a protein with 196 residues. A segment corresponding to the first 142 residues of the predicted SlyD protein has significant similarity throughout its length to the FKBP family of peptidyl-prolyl cis-trans isomerases, or rotamases. The C-terminal 46 codons of slyD encode a remarkable histidine-rich peptide which is a metal-binding domain [2]. This sequence is dispensable for slyD function in E-mediated lysis. Although there is no obvious phenotype associated with the slyD- genotype other than the resistance to E-mediated lysis, overexpression of slyD causes cells to filament and to increase significantly in diameter. Mutations in phi X174 can restore the plaque-forming ability of the phage on a slyD- host. These pos (plates on slyD) mutants plate on E. coli C wild-type and slyD-. A model for SlyD involvement in E function and the role of SlyD in the cell is discussed.

Amino Acid Isomerases↗
PubMed1995

S gene expression and the timing of lysis by bacteriophage lambda.

The S gene of bacteriophage lambda encodes the holin required for release of the R endolysin at the onset of phage-induced host lysis. S is the promoter-proximal gene on the single lambda late transcript and spans 107 codons. S has a novel translational initiation region with dual start codons, resulting in the production of two protein products, S105 and S107. Although differing only by the Met-1-Lys-2... N-terminal extension present on S107, the two proteins are thought to have opposing functions, with the shorter polypeptide acting as the lysis effector and the longer one acting as an inhibitor. The expression of wild-type and mutant alleles of the holin gene has been assessed quantitatively with respect to the scheduling of lysis. S mRNA accumulates during the late gene expression period to a final level of about 170 molecules per cell and is maintained at that level for at least the last 15 min before lysis. Total S protein synthesis, partitioned at about 2:1 in favor of the S105 protein compared with the other product, S107, accumulates to a final level of approximately 4,600 molecules per cell. The kinetics of accumulation of S is consistent with a constant translational rate of less than one S protein per mRNA per minute. Mutant alleles with alterations in the translational initiation region were studied to determine how the translational initiation region of S achieves the proper partition of initiation events at the two S start codons and how the synthesis of S105 and S107 relates to lysis timing. The results are discussed in terms of a model for the pathway by which the 30S ribosome-fMet-tRNA complex binds to the translational initiation region of S. In addition, analysis of the relationship between lysis timing and the levels of the two S gene products suggests that S107 inhibits S105, the lethal lysis effector, by a stoichiometric titration.

Amino Acid Sequence↗
PubMed1995

Selected health-fitness rankings of low-income youth.

Two parameters, tricep skinfold and one-mile walk/run, from the American Alliance for Health, Physical Education, Recreation and Dance health-related fitness test were assessed in 226 low-income children, ages 10 through 14 years. Group means by age and sex were compared with state and national norms. As a whole, on both fitness parameters, this low-income sample fell in the bottom quartile for the state of Maine. The group's national ranking was even lower. Not only are low-income families burdened financially, it appears from this study that the children are also at health risk.

Adolescent↗
PubMed1994

A system for gene cloning and manipulation in the yeast Candida glabrata.

The opportunistic pathogenic yeast, Candida (Torulopsis) glabrata, is an asexual imperfect fungus that exists largely as a haploid. Besides being a clinically important pathogen, this yeast also provides a model system for understanding basic biological mechanisms such as metal-activated metallothionein-encoding gene transcription. To facilitate molecular genetic studies in C. glabrata, we isolated a strain auxotrophic for uracil biosynthesis. The ura- mutation could be functionally complemented by the URA3 gene of Saccharomyces cerevisiae, consistent with a defect in the C. glabrata URA3 gene in this strain. We also found that the centromere-based S. cerevisiae plasmid pRS316 could stably transform and replicate in multiple copies in C. glabrata. In contrast, high-copy-number S. cerevisiae plasmids containing the 2 mu circle autonomous replication sequence were not able to replicate productively in C. glabrata. We cloned the C. glabrata URA3 gene, encoding orotidine-5'-phosphate decarboxylase, by complementation of a ura3- strain of S. cerevisiae. The deduced amino-acid sequence is highly similar to that of the URA3 protein from S. cerevisiae. C. glabrata URA3 provides a genetic locus for targeted gene integration in C. glabrata. Integrative plasmids were constructed based on the cloned C. glabrata URA3 and are applicable for directed insertions of genes of interest at the ura3 locus through homologous recombination.

Amino Acid Sequence↗
PubMed1994

slyD, a host gene required for phi X174 lysis, is related to the FK506-binding protein family of peptidyl-prolyl cis-trans-isomerases.

Recessive mutations in the slyD gene were isolated by selecting for survival after induction of the cloned lysis gene E of bacteriophage phi X174 (Maratea, D., Young, K., and Young, R. (1985) Gene (Amst.) 40, 39-46). The slyD1 mutation, transduced into the normal phi X174 host, Escherichia coli C, confers an absolute block on the plaque-forming ability of the wild-type phage, indicating that slyD is required for E function rather than for expression from the plasmid vector. The cloning, sequencing, and deletion analysis of a 1-kilobase pair genomic fragment containing the slyD locus, mapping at 73.5', is reported. Three reading frames, orf72, orf159, and orf196, are contained within this fragment, with the latter two reading frames occupying the same DNA on opposite strands. Deletion analysis shows that the complementing activity is restricted to the orf159/orf196 DNA. Complementation of the SlyD phenotype was observed irrespective of the orientation of the orf159/orf196 DNA with respect to a vector promoter, indicating that a cryptic promoter serves slyD on this fragment. Using site-directed mutagenesis, nonsense mutations were created in each reading frame which were silent in the opposing frame. Both orf196 nonsense alleles failed to complement slyD1, whereas both orf159 nonsense alleles retained complementation, demonstrating rigorously that orf196 is slyD. A segment corresponding to the first 150 residues of the predicted SlyD protein has significant similarity throughout its length to the FKBP family of peptidyl-prolyl cis-trans-isomerases or rotamases. The COOH-terminal 46 codons of slyD encode a remarkable histidine-rich peptide sequence which is at least partly dispensable for slyD function in E-mediated lysis. Overexpression of slyD in E. coli is toxic. These findings are discussed in terms of a model for SlyD involvement in E function and in terms of a model for SlyD involvement of the ubiquitous FKBP rotamases.

Alleles↗
PubMed1994

Immune function of patients receiving recombinant human interleukin-6 (IL-6) in a phase I clinical study: induction of C-reactive protein and IgE and inhibition of natural killer and lymphokine-activated killer cell activity.

Interleukin-6 (IL-6) is a cytokine that acts on a variety of cell types, including myeloid progenitor cells and B and T lymphocytes. It has been found to activate cytotoxic T cells and natural killer (NK) cells and to induce T-cell-mediated antitumour effects in animal models. In a phase I clinical trial of recombinant human IL-6, 20 patients with advanced cancer were entered to receive daily subcutaneous injections of IL-6 over 7 days followed by a 2-week observation period and another 4 weeks of daily IL-6 injections. Doses varied between 0.5 microgram/kg and 20 micrograms/kg body weight and immune functions were monitored throughout. At all dose levels IL-6 administration led to a marked increase in serum levels of C-reactive protein and a moderate rise in complement factor C3. The proportions of CD4, CD8 or HLA-DR lymphocytes in peripheral blood did not alter with IL-6 treatment nor did the in vitro proliferation of peripheral blood mononuclear cells induced by either phytohaemagglutinin, pokeweed mitogen or fixed Staphylococcus aureus. By contrast, NK cell activity, lymphokine-activated killer (LAK) cell activity and proliferation induced by in vitro culture with interleukin-2 (IL-2) were suppressed at doses exceeding 2.5 micrograms/kg. Serum IgE levels were consistently elevated over the IL-6 dose range but IgM, IgG and IgA levels were unaffected. In summary there is a dose-dependent induction of acute-phase proteins by in vivo IL-6 treatment. At higher IL-6 doses there is a suppressive effect on NK and LAK activity measured in vitro. IL-6 may thus be useful in combination cytokine therapies that seek to suppress LAK and favour cytotoxic T lymphocyte responses. The rise in IgE levels in response to IL-6 was unexpected and suggests a more pivotal role than previously known for the control of IgE production; this could include IgE-related diseases.

Antibodies, Antinuclear↗
PubMed1994

Effect of preadmission brochures on surgical patients' behavioral outcomes.

This study tested the effects of preadmission teaching brochures on morning admission surgical patients' performance of specific postoperative exercises, teaching time, state anxiety, length of hospital stay, patient satisfaction, and return to functional status. The study participants were 38 women undergoing abdominal hysterectomies. Although the study results show no significant difference between those who received the preoperative teaching brochures and those who did not, the implications for further research are clearly defined. Preoperative nursing interventions that may help patients undergoing hysterectomies manage anxiety and return to function should be tested further.

Adult↗
PubMed1994

A dominant mutation in the bacteriophage lambda S gene causes premature lysis and an absolute defective plating phenotype.

The S and R genes of the bacteriophage lambda are required for lysis of the host. R encodes 'endolysin', a soluble transglycosylase which accumulates in the cytoplasm during late protein synthesis. S encodes a 'holin', a small membrane protein which, at a precisely scheduled time, terminates the vegetative cycle by forming a lethal lesion in the membrane through which gpR gains access to the peptidoglycan. A missense allele of S, Ala52Gly, causes lysis to occur prematurely at about 19-20 min after induction of a lysogen, compared to 45 min for the wild type. This allele has a severe plaque-forming defect which appears to be entirely a consequence of the early lysis and resultant severe reduction in particle burst size. The early-lysis phenotype is dominant and is aggravated, in terms of an even more reduced burst size, at both 30 degrees C and 42 degrees C. The mutation maps in the middle of a putative membrane-spanning helical domain of S, near the sites of other S- mutations with recessive non-lytic phenotypes. The mutation has no effect on S-protein accumulation or on the ratio of S107 and S105 products in the membrane. The mutation appears to affect the intrinsic timing function by which the S protein controls the lysis schedule.

Alleles↗