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Biomedical subjects

D A Holt

Publications and source records attributed to D A Holt.

At least 19 recordsLinked to original sources
PubMed1995

Hepatitis B vaccination rates among staff at a district general hospital.

OBJECTIVE: To evaluate the uptake of hepatitis B vaccination by staff of a metropolitan district general hospital and associated community health service in order to determine if the existing vaccination program was adequate. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional survey of all 1464 staff of a 304-bed district general hospital and associated community health service, serving a population of approximately 240,000 people in a middle socioeconomic area of northern Sydney, by means of a self-reported anonymous questionnaire. RESULTS: The overall response rate was 56.4%, with 61.9% of high-risk and 48.7% of low-risk staff responding to the survey. The overall vaccination rate was 55.8%. Of high-risk respondents, 70.7% had been or were in the process of being vaccinated, compared with 29.4% of low-risk respondents. Of those already vaccinated, only 45.9% had subsequently been tested for antibody to hepatitis B surface antigen (anti-HBs); 12% of this group did not know whether their response to the vaccine had been adequate and 18% reported being advised to have another anti-HBs test later. Vaccination rates were higher in younger staff (68.7% of 20-29-year-olds) than in older staff (42.7% of 50-59-year-olds). There was no significant difference in vaccination rates between men (55.6%) and women (55.8%). Vaccination rates for doctors, dentists and nurses were 69%, 80% and 74.6%, respectively. CONCLUSION: The vaccination rate among high-risk staff is suboptimal: more than half did not know whether their vaccination had induced a suitable level of antibodies; more than 10% had been vaccinated more than five years previously; and 5% had not completed the full course of three injections. High-risk staff should be targeted in future vaccination programs.

Adult↗
PubMed1995

Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson's disease.

We performed fetal nigral transplantations in 4 Parkinson's disease (PD) patients. Solid grafts were bilaterally implanted into the postcommissural putamen using 3 to 4 donors per side aged 6 1/2 to 9 weeks postconception. Transplant deposits were separated by no more than 5 mm in three dimensions. Cyclosporine was employed for a total of 6 months. Patients were evaluated at baseline and at 1, 3, and 6 months postoperatively. Striatal 18-fluorodopa uptake was assessed by positron emission tomography at baseline and at 6 months postoperatively. The procedure was well tolerated in all patients. One patient had a clinically asymptomatic superficial cortical hemorrhage along the needle tract and a second had transient postoperative confusion and hallucinations. All patients experienced clinically meaningful benefit. Significant improvement (p < 0.05) was detected in total UPDRS score during the "off" state, Schwab-England disability score during the "off" state, percent "off" time, and percent "on" time with dyskinesia. Increased striatal fluorodopa uptake was observed bilaterally in each patient, with mean increases of 53% on the right (p = 0.01) and 33% on the left (p = 0.08). Our study demonstrated clear and consistent improvement in clinical features and striatal fluorodopa uptake following fetal tissue transplantation in patients with advanced PD whose condition was not improved preoperatively by drug manipulation. These preliminary results are encouraging and support further studies to evaluate grafting strategies as a therapy for PD.

Adult↗
PubMed1995

Cloning, expression and functional characterization of type 1 and type 2 steroid 5 alpha-reductases from Cynomolgus monkey: comparisons with human and rat isoenzymes.

The Cynomolgus monkey may provide an alternative pharmacological model in which to evaluate the efficacy of novel inhibitors of the two known human steroid 5 alpha-reductase (SR) isoenzymes. To evaluate the suitability of this species at the level of the molecular targets, a Cynomolgus monkey prostate cDNA library was prepared and screened using human SR type 1 and 2 cDNAs as hybridization probes. Two distinct cDNA sequences were isolated encoding the monkey type 1 and 2 SR isoenzymes. These sequences share 93 and 95% amino acid sequence identity with their human enzyme counterparts, respectively. Difference in monkey type 1 SR, however, was found within the contiguous four amino acids corresponding to the regions in the human and rat sequences that have been proposed previously to influence steroid and inhibitor affinities. Subsequently, both monkey cDNAs were individually expressed in a mammalian cell (CHO) line. Enzyme activities of both monkey SRs were localized to the membrane fractions of CHO cell extracts. Like the human and rat enzymes, the monkey type 1 and type 2 SRs were most active at neutral and low pH, respectively. The results of inhibition studies with over 30 known SR inhibitors, including epristeride, 4MA, and finasteride, indicate that the monkey SR isoenzymes are functionally more similar to the human than the rat homologues. The results from initial velocity and inhibition studies as functions of pH with the human and monkey type 2 SRs also compare favorably. These results, together, suggest that the monkey SR isoenzymes are structurally and functionally comparable on a molecular level to their respective human counterparts, supporting the relevance and use of the Cynomolgus monkey as a pharmacological model for in vivo evaluation of SR inhibitors.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1994

Epristeride is a selective and specific uncompetitive inhibitor of human steroid 5 alpha-reductase isoform 2.

Specificity of an enzyme inhibitor can have profound implications upon the compound's therapeutic potential, utility and safety profile. As potent inhibitors of human steroid 5 alpha-reductase (SR) the 3-androstene-3-carboxylic acids, or steroidal acrylates, may be useful in treatment of diseases such as benign prostatic hyperplasia for which 5 alpha-dihydrotestosterone (DHT) appears to be a causative agent. To determine its specificity profile, the interactions of a representative compound from this class, N-(t-butyl)androst-3,5-diene-17 beta-carboxamide-3-carboxylic acid (epristeride, SK&F 105657), have been studied with 7 other steroid processing enzymes and 5 steroid hormone receptors. The affinity of epristeride for each of these 12 potential targets was found to be at least 1000-fold weaker than that for SR, the intended target. In addition, using samples of the individually expressed two known forms of human SRs, epristeride has been shown to be a selective inhibitor of the recombinant human SR type 2, the predominant activity found in the prostate of man. Nonetheless, the mechanisms of SR inhibition for both isoenzymes involve formation of a ternary complex with epristeride, NADP+, and enzyme. Epristeride, consequently, has been shown to be an uncompetitive inhibitor versus steroid substrate of both human SR isoenzymes. These results suggest that this 3-androstene-3-carboxylic acid is a specific and selective inhibitor of the human type 2 SR, and that epristeride is an attractive compound for further investigation as a safe and effective therapeutic agent in the potential treatment of disease states associated with DHT-induced tissue growth.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1994

Immunisation practices of general practitioners in metropolitan Sydney.

An anonymous postal survey of all known general practitioners in the Northern Sydney Health Area (N = 987) examined the provision of immunisation services in general practice. Questions were asked about knowledge of storage of vaccines, the ages of patients administered measles-mumps-rubella vaccine, the use of reminder systems for subsequent vaccinations and whether maternal and family health was discussed at immunisation visits. There were 394 (40 per cent) respondents. Only 30 per cent used temperature monitors in their vaccine refrigerators, and 26 per cent correctly identified the period after opening that Sabin may be used (eight hours). Forty-one percent correctly injected infants in the anterolateral aspect of the thigh and 40 per cent administered measles-mumps-rubella vaccine by the recommended age of 12 months. Forty-one percent of respondents always used visits for immunisation to discuss other issues of maternal and child health and 16 per cent used reminder systems for follow-up. Sixty-six per cent of general practitioners stated that they were more likely to review the immunisation status of adolescents routinely, compared to 55 per cent who reviewed adults and 44 per cent who reviewed senior citizens. Routine review of all three groups was carried out by 43 per cent. These results must be interpreted with caution because of low response rates, and cannot necessarily be generalised to all general practitioners providing immunisation services. Nevertheless, important deficiencies in knowledge and practice of immunisation have been identified.

Adult↗
PubMed1992

BK virus.

BK virus is a human polyoma virus that infects the renal epithelium and remains latent until immunosuppression triggers reactivation. After reactivation, BK virus can be detected in the urine by methods currently available in the clinical laboratory. Correlations can be made between BK viruria and the occurrence of both renal and hepatic pathologies. BK virus is emerging as a significant pathogen in transplant patients. Additionally, the presence of BK virus DNA in primary brain and pancreatic tumors suggests that it may have oncogenic potential. Thus far, attempts to treat BK virus infection have been ineffective, though research has opened new avenues for treatment possibilities. Prevention of BK virus and other latent viral reactivation remains a challenge to viral research.

BK Virus↗
PubMed1992

Murine typhus: forgotten but not gone.

An occasional patient presents the classical symptoms of a disease that has become uncommon. Typhus is an example of such a disease, since it is now well contained through control of its rodent reservoir. It is readily treated with tetracycline or one of its long-acting analogues, doxycycline or minocycline. Because typhus is infrequently encountered, the physician may not initially include it in his differential diagnosis. Our case serves as a remainder that with the increasingly frequent movement of persons from one geographic area to another, the uncommon rickettsial infection, murine typhus, should continue to be in the differential of a febrile patient. Furthermore, our case underscores the importance of including typhus in the differential of typhoid fever.

Acute Disease↗
PubMed1991

Lyme borreliosis.

Lyme borreliosis is a complex infectious process that primarily involves the skin, heart, joints, and nervous systems. The infectious agent is the spirochete B burgdorferi, which is transmitted by the Ixodes genus of ticks. The clinical presentations of Lyme disease are protean because of the overlap of stages and varied organ system involvement. Furthermore, as previously mentioned, approximately one-third of Lyme patients are unable to recall a tick bite. Lyme borreliosis should be suspected in anyone with a tick bite. The findings of an EM lesion and flu-like symptoms strongly favor the diagnosis of stage 1 disease. Stage 2 evolves weeks to months after a tick bite, with cardiac and neurological findings as well as musculoskeletal pain. Stage 3 primarily manifests itself as arthritis associated with continuing or additional neurologic complications. Serologic studies are currently the most practical laboratory aid in diagnosis, because almost all infected individuals have a positive antibody response to the spirochete. Treatment with antibiotics usually proves successful, although longer courses of therapy may be needed in later stages of the disease, and some patients may not respond.

Anti-Bacterial Agents↗
PubMed1991

Postanginal sepsis with dysphagia.

We have described a 10-year-old girl who had dysphagia followed abruptly by arthritis. Streptococcus pyogenes was identified as the pathogen by fasciotomy with bone biopsy, and a tonsillar fluid collection confirmed the diagnosis of postanginal sepsis. The patient was cured by a 6-week course of parenteral antibiotics.

Anti-Bacterial Agents↗
PubMed1991

Use of antibiotics during pregnancy.

Pregnancy is occasionally complicated by infections that necessitate antibiotic therapy. When considering therapeutic options for pregnant women, both the physiologic changes of pregnancy and the prenatal effects of the drug must be weighed. Antibiotics should be selected with regard to the trimester of pregnancy. Some antibiotics are safe for use throughout pregnancy, while others are completely contraindicated. Choosing the proper antibiotic requires balancing the seriousness of the infection with the antibiotic's safety and antimicrobial activity.

Anti-Bacterial Agents↗
PubMed1990

Studies on the mechanism of steroid 5 alpha-reductase inhibition by 3-carboxy A-ring aryl steroids.

The mechanism of interaction between two 3-carboxy A-ring aryl steroids, 17 beta-(N,N-diisopropylcarboxamide)-estra-1,3,5(10)-triene-3-carboxy lic acid (1) and 17 beta-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid (2), with rat hepatic and human prostatic steroid 5 alpha-reductases has been investigated. Dead-end inhibition plots with 1 and 2 versus both substrates (testosterone and NADPH) were linear-uncompetitive using either enzyme, while double-inhibition analyses indicated cooperative binding to enzyme between NADP+ and 1 or 2. These results were interpreted within the ordered kinetic mechanism of steroid 5 alpha-reductase to result from the preferential association of 3-carboxy A-ring aryl steroids to the enzyme-NADP+ complex. The direct displacement by 2 of a radioligand known to associate to this same enzyme form provides further support for these conclusions.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1990

Inhibition of rat liver steroid 5 alpha-reductase by 3-androstene-3-carboxylic acids: mechanism of enzyme-inhibitor interaction.

The interactions of a series of newly discovered inhibitors of delta 4-3-oxo-steroid 5 alpha-reductase (SR; EC 1.3.1.30), the 3-androstene-3-carboxylic acids (steroidal acrylates), have been studied by using a solubilized rat liver enzyme preparation. As exemplified by one member of this series, 17 beta-[N,N-diisopropyl-carbamoyl)androst-3,5-diene-3-carboxylic acid (1a), the dead-end inhibition patterns of selected compounds in this class are best evaluated by a linear uncompetitive kinetic model versus either substrate, testosterone (T) or NADPH. These results were interpreted within the context of the preferentially ordered kinetic mechanism for rat liver SR to arise from the association of inhibitor to the binary complex of enzyme and NADP+. This proposed inhibition mechanism was supported by data from double-inhibition experiments implicating the synergistic binding of steroidal acrylate and NADP+ to SR. Further evidence for the preferential formation of this ternary complex was obtained from filtration binding assays with [3H]-1a, where radioligand association to protein was greatly enhanced in the presence of NADP+. The amount of [3H]-1a binding to protein was proportional to the specific activity of SR in the enzyme preparations, and the estimated dissociation constant from binding data by Scatchard analysis (Kd = 25 nM) was comparable to the inhibition constants estimated for SR activity (Ki = 12-26 nM). From the pH profile for inhibition of the solubilized liver SR with 1a, it is proposed that the anion of the steroidal acrylate (pK1 = 4.7 +/- 0.2) is the active inhibitory species, coordinating to a protonated active site functionality (pK2 = 7.5 +/- 0.1). On the basis of data from similar experiments with structural analogues of 1a, the determinants for binding recognition and inhibitory potency are compared to structural features of the putative enzyme-bound intermediate states. These compounds represent a potential therapeutic alternative in the treatment of 5 alpha-dihydrotestosterone specific androgen dependent disease states.

5-alpha Reductase Inhibitors↗
PubMed1990

Steroidal A ring aryl carboxylic acids: a new class of steroid 5 alpha-reductase inhibitors.

A series of 17 beta-carbamoyl-1,3,5(10)-estratriene-3-carboxylic acids has been prepared and evaluated in vitro as inhibitors of human and rat prostatic steroid 5 alpha-reductase (EC 1.3.1.30). Potent inhibition of the human enzyme, in particular, was observed and preliminary studies using rat enzyme suggest that the inhibition results from the formation of an enzyme-NADP(+)-inhibitor complex. The compounds were synthesized from estrone, generally employing a differentiated bis-triflate carbonylation strategy.

5-alpha Reductase Inhibitors↗
PubMed1990

Inhibition of steroid 5 alpha-reductase by unsaturated 3-carboxysteroids.

A series of unsaturated steroids bearing a 3-carboxy substituent has been prepared and assayed in vitro as inhibitors of human and rat prostatic steroid 5 alpha-reductase (EC 1.3.1.30). It is proposed that the observed tight binding of the 3-androstene-3-carboxylic acids is due to mimicry of a putative, high-energy, enzyme-bound enolate intermediate formed during the NADPH-dependent conjugate reduction of testosterone by steroid 5 alpha-reductase. These compounds were prepared through palladium(0)-catalyzed carbomethoxylations of enol (trifluoromethyl)sulfonates derived from 3-keto precursors. Modification of A and B ring unsaturation and substitution at C-3, -4, -6, and -11 was explored. Mono- and dialkylcarboxamides were employed as 17 beta side chains to enhance inhibitory activity with the human enzyme.

5-alpha Reductase Inhibitors↗
PubMed1990

Human T-cell lymphotropic virus-type I.

HTLV-I is a retrovirus now identified as the etiologic agent of two diverse disease processes: ATLL, an aggressive T-cell malignancy; and TSP/HAM, a chronic progressive myelopathy. Transmission can occur horizontally through blood transfusions, IV drug abuse and sexual intercourse. Vertical transmission may also occur. Available diagnostic modalities are serologic in nature and include the EIA and the more specific confirmatory assays WIB and RIPA. These studies are thus far suboptimal in terms of sensitivity and specificity, and await refinement. DNA amplification by the polymerase chain reaction seems to hold the most immediate diagnostic promise for the future. AZT apparently is not useful clinically, and current treatment is only palliative in nature. The diverse diseases caused by HTLV-I underscore the insidious nature of the Retroviridae family. These subtle cell-associated pathogens will undoubtedly be shown to play a significant role in other disease processes of uncertain etiology.

HTLV-I Infections↗