Biomedical subjects
Publications and source records attributed to J Lamb.
The event related outdating(ERO) theory is based on the assumption that items that are properly cleaned, wrapped, sterilized, stored and handled will remain sterile indefinitely unless the integrity of the package becomes compromised. The authors describe how one Surgical Suite (performing approximately 600 cases/month) implemented an ERO program with estimated annual savings of almost $10,000/year.
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This case report identifies a temporal relationship between the diagnosis of localized granuloma annulare and the subsequent development of primary hypothyroidism in a previously healthy 10-year-old girl. We suspect these disorders are associated, but any association between them requires further study.
The RAD6 gene of Saccharomyces cerevisiae encodes a ubiquitin-conjugating enzyme that is required for postreplication repair of UV-damaged DNA, DNA damage induced mutagenesis, sporulation, and amino-end rule protein degradation. RAD6 interacts physically with the UBR1 gene product in carrying out the multiubiquitination of amino-end rule proteolytic substrates. In mediating postreplication repair, it has remained unclear whether RAD6 acts in a pleiotropic manner distal from the site of DNA damage or is targeted to the damage site via interaction with another repair component. Here, we show that RAD6 forms a specific complex with the product of the DNA repair gene RAD18. The biological significance of this interaction is attested by the observation that overproduction of the rad6 Ala-88 mutant protein, which lacks ubiquitin-conjugating activity but retains the ability to interact with RAD18 protein, confers a high level of UV sensitivity on wild-type RAD+ cells that can be corrected by the concomitant overexpression of RAD18. We demonstrate that whereas RAD6 has no affinity for DNA, RAD18 binds single-stranded DNA. Thus, association of RAD6 with RAD18 could provide a means for targeting RAD6 to damage-containing DNA regions, where the RAD6 ubiquitin-conjugating function could modulate the activity of a stalled DNA replication machinery. We also show that RAD6 forms separate complexes with RAD18 and with UBR1, and the extremely conserved amino terminus of RAD6 that is required for complex formation with UBR1 is dispensable for complex formation with RAD18.
Activation of allergen-reactive human T helper (Th)2 cells in the absence of professional antigen-presenting cells, induces non-responsiveness or anergy in these cells in vitro. This induction of anergy is accompanied by phenotypic modulation and altered cytokine production. Furthermore, peptide-treated Th2 cells fail to provide B-cell help for IgE synthesis. Recent studies indicate that impaired signal transduction via the T-cell receptor may account for the lack of responsiveness to antigenic stimulation. Here, we review present knowledge on the cell biology of non-responsive or anergic Th2 cells.
Fine needle aspirates (FNA) from 31 invasive carcinomas of tubular type and 22 radial scar/complex sclerosing lesions (RS/CSL), diagnosed in Edinburgh between 1986 and 1991, were reviewed. The lesions in this study varied in size and palpability at presentation, but are of increasing interest in the differential diagnosis of non-palpable areas of increased mammographic density. In agreement with previously published information, it was found that the tubular cancers were usually selected for biopsy following aspiration, but less often definitively diagnosed as malignant. Nearly 50% of the RS/CSL group were correctly reported benign on cytology, but in 40%, biopsy was recommended to exclude malignancy. In addition, cytological features helpful in suggesting malignancy in aspirates from tubular cancers, also raised suspicion in aspirates from the RS/CSL group, with a risk of overdiagnosis of cancer.
1. The effects of agents that elevate either cyclic AMP (the phosphodiesterase (PDE) III inhibitor siguazodan, salbutamol) or cyclic GMP (sodium nitroprusside (SNP)) on the relaxant activity of the PDE IV inhibitor, rolipram, were investigated in carbachol (0.1 microM) precontracted guinea-pig tracheal sheets. 2. Rolipram, siguazodan and SNP caused concentration-related reductions in tone of tissues precontracted with 0.1 microM carbachol (EC50 values 12.5; 2.73 and 0.35 microM respectively). Whilst the concentration-response relationship for the PDE III inhibitor, siguazodan, was monophasic that of the PDE IV inhibitor, rolipram, was biphasic. 3. The relaxant activity of rolipram was markedly enhanced in the presence of 10 microM siguazodan (EC50 < 0.01 microM), 0.1 microM salbutamol (EC50 0.03 microM) and 0.3 microM SNP (EC50 0.03 microM). In contrast, the relaxant activity of siguazodan was unaffected by SNP and only modestly enhanced by rolipram (10 microM) and salbutamol (0.1 microM). 4. The relaxant activity of SNP was enhanced by the PDE V inhibitor SK&F 96231 (30 microM: EC50 0.06 microM) and rolipram (30 microM, EC50 0.08 microM) but was unaffected by 30 microM siguazodan. 5. At concentrations up to 10 microM, neither siguazodan nor rolipram elevated tracheal cyclic AMP levels. However, the combination of 10 microM rolipram and siguazodan caused a two fold increase in the cyclic AMP content (from 2.19 to 4.36 pmol cyclic AMP mg-1 protein). SNP (0.1-10 microM) failed to produce a significant increase in tracheal cyclic AMP levels. At 0.1 microM the effect of SNP on tracheal cyclic AMP levels was significantly (P < 0.05) increased in the presence of rolipram but not siguadozan. 6. The results indicate that the relaxant effects of rolipram are markedly enhanced by agents that inhibit PDE III activity or elevate cyclic GMP. They support the hypothesis that SNP potentiates the effects of rolipram via the inhibitory action of cyclic GMP on hydrolysis of cyclic AMP by PDE III. The findings also suggest that whilst PDE III may be more significant in regulating basal smooth muscle tone in the absence of any exogenous stimulus to cyclic AMP accumulation, PDE IV activity may be more tightly coupled to the pool of adenylyl cyclase stimulated by beta2-adrenoceptor agonists.
1. We have investigated the bronchodilator potential of type V phosphodiesterase (PDE V) inhibitors in anaesthetized ventilated guinea-pigs using the potent and selective PDE V inhibitor, SK&F 96231. We have compared its activity to that of salbutamol, the PDE III inhibitors, siguazodan and SK&F 95654 and to the PDE IV inhibitor rolipram. 2. Administered as an i.v. infusion SK&F 96231 (0.6 and 1 mg kg-1 min-1, i.v.) caused a slowly developing inhibition of histamine (100 nmol kg-1, i.v.)-induced bronchoconstriction and elevated tracheal cyclic GMP levels in the anaesthetized guinea-pig. SK&F 96231 (0.1 and 0.3 mg kg-1 min-1, i.v.) was without effect on histamine-induced bronchoconstriction. In the presence of a sub-threshold infusion of SNP (0.1 mumol kg-1 min-1, i.v.) there was a marked enhancement of SK&F 96231-induced inhibition of histamine responses such that at infusion rates that were ineffective alone, SK&F 96231 caused a > 50% inhibition of histamine responses. The stimulation of tracheal cyclic GMP accumulation by SK&F 96231 was also potentiated. 3. Administered directly into the airway, SK&F 96231 (300 micrograms in 5 mg lactose carrier) was largely without effect on histamine-induced bronchoconstriction (4.9 +/- 1.9% inhibition). In the presence of SNP (0.1 mumol kg-1 min-1, i.v.) or isosorbide dinitrate (200 micrograms administered by insufflation into the trachea) there was a marked potentiation of the inhibitory activity of SK&F 96231 (40 +/- 4% and 62 +/- 1.8% respectively). 4. Salbutamol and rolipram (3-300 microg by insufflation) caused a dose-related inhibition of histamine responses with a maximum of 91 +/- 2% and 59 +/- 10% respectively. The PDE III inhibitor, siguazodan,was without effect on histamine responses but they were reduced (27.7 +/- 4.8% at 300 microg) by SK&F95654. There was a marked enhancement of the inhibitory activity of rolipram in the presence of SK&F 95654.5. We conclude that SK&F 96231 has weak anti-spasmogenic activity in the guinea-pig in vivo, we suggest that this is primarily a consequence of a low endogenous guanylate cyclase activity in the airway. The potentiation of the anti-spasmogenic activity of SK&F 96231 by SNP suggests that a combination of PDE V inhibitor and guanylate cyclase agonist might provide significant bronchodilator activity.6. We have established that PDE IV inhibitors are bronchodilators when administered directly into the airway of anaesthetized guinea-pigs but that PDE III inhibitors are only weakly active. The marked enhancement of the inhibitory activity of rolipram by the PDE III inhibitor, SK&F 95654, indicates that inhibitors of both PDE III and PDE IV might offer greater potential as bronchodilators than inhibitors of either isoenzyme alone.
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Human T cells, when activated, express small but detectable levels of MHC class II on their surface and as a result have the potential to present antigens in the context of MHC class II molecules. There are reports demonstrating MHC class II restricted antigen presentation by human T-cell clones. In this report, we show evidence for one such clone that can present peptide antigen to itself. This clone, HA1.7 ml, is clearly different in its accessory signaling requirements from the parental clone HA1.7, and shows a decrease in the surface level of CD54. We have analyzed the accessory signaling abilities of T cells by using HA1.7 ml as a responder population, and demonstrate that the accessory signaling potential of T-cell clones is sufficient to bring about activation of HA1.7 ml but not of HA1.7. This accessory signaling ability is, however, different from that of B cells in providing bystander accessory signals. T-cell APCs cannot provide bystander accessory signals for the proliferative response of HA1.7 ml, nor can they block the induction of tolerance in this subline, whereas bystander B cells can mediate both events to a limited extent. Thus, there are significant differences in the accessory signaling abilities of T cells as APCs as compared with classic APCs such as B cells, independent of their ability to generate peptide-MHC complexes. It also appears that although HA1.7 ml can be activated by self-presentation of antigen, it is still susceptible to the induction of tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)
In this report we describe a PCR-based method for the diagnosis of the most common form of alpha thalassaemia, the -alpha 3.7 deletion which occurs throughout all tropical and subtropical regions of the world. The same procedure also identifies the reciprocal recombinant chromosome (alpha alpha alpha anti 3.7). Restriction mapping of the PCR products has enabled us to distinguish between the type I (-alpha 3.7 I), type II (-alpha 3.7 II) and type III (-alpha 3.7 III) deletions. This strategy will be very useful in screening programmes of alpha thalassaemia occurring on its own or in association with beta thalassaemia and sickle cell disease.
This study was designed to determine the feasibility of improving gifted girls' attitudes toward mathematics. This study was conducted in three school districts in an isolated rural setting. Subjects were 24 gifted girls in Grades 4-7. A control group also contained 24 gifted girls at the same grade levels. On pretest, using the Mathematics Attitude Inventory (MAI), no significant differences were found between groups in their attitudes toward math. The intervention program included problem-solving activities, math-related career options, and self-esteem issues. MAI posttest scores after the 18-week program indicated that the program was effective in changing attitudes toward mathematics of gifted girls in a rural environment.
We have previously described a series of patients in whom the deletion of 1-2 megabases (Mb) of DNA from the tip of the short arm of chromosome 16 (band 16p13.3) is associated with alpha-thalassemia/mental retardation syndrome (ATR-16). We now show that one of these patients has a de novo truncation of the terminal 2 Mb of chromosome 16p and that telomeric sequence (TTAGGG)n has been added at the site of breakage. This suggests that the chromosomal break, which is paternal in origin and which probably arose at meiosis, has been stabilized in vivo by the direct addition of the telomeric sequence. Sequence comparisons of this breakpoint with that of a previously described chromosomal truncation (alpha alpha)TI do not reveal extensive sequence homology. However, both breakpoints show minimal complementarity (3-4 bp) to the proposed RNA template of human telomerase at the site at which telomere repeats have been added. Unlike previously characterized individuals with ATR-16, the clinical features of this patient appear to be solely due to monosomy for the terminal portion of 16p13.3. The identification of further patients with "pure" monosomy for the tip of chromosome 16p will be important for defining the loci contributing to the phenotype of this syndrome.
We have assessed the effect of screening for cystic fibrosis (CF) carrier status on anxiety levels, attitudes, knowledge and actions of participants in a pilot programme conducted through primary health care services. Over 3000 individuals were screened and 100 carriers with no previous family history were identified. Varying degrees of anxiety were found to be associated initially with a positive result, but most of this was allayed by genetic counselling, and we find no adverse long-term psychological consequences in carriers. Most discussed carrier status with their partner (89%), parents, other relatives and also with friends; 87% of partners to whom testing was suggested have been screened. Those testing positive indicated that knowledge of carrier status would be considered in future reproductive decisions, and after 6 months carriers retained a reasonable level of knowledge about CF and its inheritance. Carriers and non-carriers uniformly approve of screening and are glad to have been tested. Knowledge of CF in the sample of non-carriers has also increased after testing, suggesting screening may improve understanding of CF among the entire target population. Fears of possible social costs of screening may be ill-founded.
The polyphosphoinositides phosphatidylinositol 4-monophosphate (PIP) and phosphatidylinositol 4,5-bisphosphate (PIP2) inactivate the actin filament-severing proteins villin and gelsolin and dissociate them from monomeric and polymeric actin. A potential polyphosphoinositide- (PPI) binding site of human plasma gelsolin regulating filament severing has been localized to the region between residues 150-169 and to the corresponding region in villin which occurs in the second of six homologous domains present in both proteins. Synthetic peptides based on these sequences bind tightly to both PIP and PIP2, in either micelles or bilayer vesicles, compete with gelsolin for binding to PPIs, and dissociate gelsolin-PIP2 complexes, restoring severing activity to the protein. These peptides also bind with moderate affinity to F-actin, suggesting that inactivation of the severing function of the intact proteins by PPIs results from competition between actin and PPIs for a critical binding site on gelsolin-villin. The PPI-binding peptides contain numerous basic amino acids, but their effects on PPIs are far greater than those of Arg or Lys oligomers, a highly basic peptide derived from the calmodulin-binding site of myristoylated, alanine-rich kinase C substrate protein, or the 5-kDa actin-binding protein thymosin beta-4, suggesting that specific aspects of the primary and secondary structure of these basic peptides are important for their interaction with the acidic headgroups of PPIs. In addition to elucidating the structure of PIP2-binding sites in gelsolin, the results describe a sensitive assay for phosphoinositide-binding molecules based on their ability to prevent inhibition of gelsolin function.
We report a case of sacrococcygeal chordoma initially diagnosed by fine-needle aspiration cytology. The value of awareness by cytopathologists of the histology of soft tissue tumours is emphasized.
A series of experiments were conducted to evaluate the effects of Win 49,596, a novel steroidal androgen receptor antagonist, in animal models of prostate cancer. In the first experiment, oral administration of Win 49,596 at doses of 30, 100, or 300 mg/kg/day for 28 days inhibited (P less than 0.05) the growth of the androgen-sensitive PAP variant of the Dunning R-3327 prostatic carcinoma in intact male rats relative to intact controls. The degree of inhibition at 100 and 300 mg/kg/day Win 49,596 was similar (P greater than 0.10) to that observed in castrate controls as well as in intact rats administered the nonsteroidal androgen receptor antagonist flutamide orally at 15 mg/kg/day. Castration as well as treatment with either Win 49,596 or flutamide also decreased (P less than 0.05) the weight of the prostate in tumor-bearing animals. Additional studies were conducted to determine the effect of Win 49,596 on the growth of the androgen-dependent PC-82 human prostatic carcinoma xenografted into athymic nude male mice. Oral administration of Win 49,596 at 30, 100, or 300 mg/kg/day for 35 days inhibited (P less than 0.05) tumor growth relative to intact controls. The degree of tumor inhibition was similar to that observed in intact male mice administered the nonsteroidal androgen receptor antagonist flutamide orally at 30 mg/kg/day but was less than that observed following castration. Ventral prostate weights were also reduced (P less than 0.05) in castrate mice as well as in intact mice administered either Win 49,596 or flutamide. In the last experiment, at equivalent total daily dosages of either 150 or 300 mg/kg/day Win 49,596, twice a day (BID) dosing was more effective than once a day (SID) dosing in inhibiting tumor growth. The inhibitory effects of Win 49,596 at 150 mg/kg BID on tumor growth were similar to those observed following castration. Although Win 49,596 treatment reduced (P less than 0.05) ventral prostate weights relative to intact controls, there was no difference (P greater than 0.10) between SID vs. BID dosing. Based on the results of these studies and subject to further testing, Win 49,596 may have utility in the treatment of hormonally dependent metastatic prostate cancer in humans.
As survival and quality of life continue to improve for cardiac transplant recipients, there is an ever-increasing possibility that these patients will present for elective and/or emergency surgery outside of a transplantation center. Cyclosporine therapy has been a major factor in extending homograft survival, but recent studies have suggested that cyclosporine administration increases the duration of action of some anesthetics. The authors evaluated the influence on anesthetic management of cardiac transplantation and chronic cyclosporine therapy in a retrospective review of all postcardiac transplant patients who presented for noncardiac surgery at the study institution. The data suggest that a number of commonly used anesthetic techniques can be administered safely to these patients when no evidence of graft rejection is present. No clinically significant prolongation of anesthetic effect was encountered following the doses of anesthetics described.