Biomedical subjects

C Reid

Publications and source records attributed to C Reid.

At least 73 records · Page 4Linked to original sources

PubMed1998

Hypoechoic plaque at US of the carotid artery: an independent risk factor for incident stroke in adults aged 65 years or older. Cardiovascular Health Study.

PURPOSE: To investigate the association between incident (first) stroke and the echogenicity of internal carotid arterial plaque at ultrasonography (US). MATERIALS AND METHODS: A cohort of 4, 886 individuals who, at baseline, were 65 years of age or older and without symptoms of cerebrovascular disease was followed up for an average of 3.3 years. Baseline clinical findings were from color Doppler and duplex US studies of the carotid arteries and a record of traditional risk factors: age, sex, presence of diabetes mellitus, pack-years of cigarette smoking, presence of hypertension, elevated systolic and diastolic blood pressure, elevated low-density lipoprotein cholesterol level. RESULTS: Incident strokes, excluding hemorrhagic strokes and strokes of cardiac origin, were seen in 104 individuals (2.1%) at risk. Age- and sex-adjusted odds ratios for incident stroke were significant for hypoechoic plaque (odds ratio, 2.53; 95% CI, 1,42,4.53). After controlling for risk factors in a Cox proportional hazards model, the relative risk (RR) of incident stroke was 1.72 (p = .015) for hypoechoic plaque and 2.32 (P = .004) for internal carotid arterial narrowing of at least 50%. In addition, hypoechoic plaque (RR, 2.78; CI, 1.36,5.69) and 50%-100% stenosis (RR, 3.08; CI, 1.28, 7.41) were associated with ipsilateral, nonfatal stroke. CONCLUSION: In asymptomatic adults aged 65 years or older, that risk of incident stroke was associated with two US features: hypoechoic internal carotid arterial plaque and an estimated internal carotid arterial stenosis of 50%-100%.

Aged↗

PubMed1998

Anaesthetic management of the morbidly obese patient.

Morbidly obese patients are prone to many clinical conditions that can effect anaesthesia. Of major concern to the anaesthetist are difficulties with airway management and abnormalities of cardiorespiratory function. Safe anaesthesia requires an appreciation of potential problems and a thorough understanding of the pathophysiological changes that accompany morbid obesity.

Anesthesia↗

PubMed1997

Improved P1/P1' substituents for cyclic urea based HIV-1 protease inhibitors: synthesis, structure-activity relationship, and X-ray crystal structure analysis.

We present several novel P1/P1' substituents that can replace the characteristic benzyl P1/P1' moiety of the cyclic urea based HIV protease inhibitor series. These substituents typically provide 5-10-fold improvements in binding affinity compared to the unsubstituted benzyl analogs. The best substituent was the 3,4-(ethylenedioxy)benzyl group. Proper balancing of the molecule's lipophilicity facilitated the transfer of this improved binding affinity into a superior cellular antiviral activity profile. Several analogs were evaluated further for protein binding and resistance liabilities. Compound 18 (IC90 = 8.7 nM) was chosen for oral bioavailability studies based on its log P and solubility profile. A 10 mg/kg dose in dogs provided modest bioavailability with Cmax = 0.22 microg/mL. X-ray crystallographic analysis of two analogs revealed several interesting features responsible for the 3,4-(ethylenedioxy)benzyl-substituted analog's potency: (1) Comparing the two complexes revealed two distinct binding modes for each P1/P1' substituent; (2) The ethylenedioxy moieties are within 3.6 A of Pro 81 providing additional van der Waals contacts missing from the parent structure; (3) The enzyme's Arg 8 side chain moves away from the P1 substituent to accommodate the increased steric volume while maintaining a favorable hydrogen bond distance between the para oxygen substituent and the guanidine NH.

Animals↗

PubMed1997

Probing protein hydration and conformational states in solution.

The addition of polyethylene glycol (PEG), of various molecular weights, to solutions bathing yeast hexokinase increases the affinity of the enzyme for its substrate glucose. The results can be interpreted on the basis that PEG acts directly on the protein or indirectly through water activity. The nature of the effects suggests to us that PEG's action is indirect. Interpretation of the results as an osmotic effect yields a decrease in the number of water molecules, delta Nw, associated with the glucose binding reaction. delta Nw is the difference in the number of PEG-inaccessible water molecules between the glucose-bound and glucose-free conformations of hexokinase. At low PEG concentrations, delta Nw increases from 50 to 326 with increasing MW of the PEG from 300 to 1000, and then remains constant for MW-PEG up to 10,000. This suggests that up to MW 1000, solutes of increasing size are excluded from ever larger aqueous compartments around the protein. Three hundred and twenty-six waters is larger than is estimated from modeling solvent volumes around the crystal structures of the two hexokinase conformations. For PEGs of MW > 1000, delta Nw falls from 326 to about 25 waters with increasing PEG concentration, i.e., PEG alone appears to "dehydrate" the unbound conformation of hexokinase in solution. Remarkably, the osmotic work of this dehydration would be on the order of only one k T per hexokinase molecule. We conclude that under thermal fluctuations, hexokinase in solution has a conformational flexibility that explores a wide range of hydration states not seen in the crystal structure.

Crystallography, X-Ray↗

PubMed1997

A self-administered questionnaire for detection of unrecognised coronary heart disease.

On an individual and a population basis, an increased incidence of coronary heart disease is associated with classical cardiovascular risk factors, but many cases occur in people not identified as at high risk. Conversely, many people at high statistical risk do not develop coronary disease. We used a questionnaire to identify unrecognised coronary heart disease in people attending large-scale health survey centres. Participants were required to report the presence and characteristics of any chest pain. Those returning responses consistent with myocardial ischaemia were offered treadmill exercise ECG tests. Over 18 months, 4070 questionnaires were returned. Of 475 respondents offered testing, 229 (198 male, 131 female) accepted. Thirty-two subjects (15 male, 17 female: a detection rate of 13.9 per cent of those assessed as likely on questionnaire, or 0.8 per cent of all respondents) had results consistent with significant coronary heart disease. Follow-up was available in 30 cases. There was no difference in classical risk-factor distribution (including multivariate risk percentiles: 42.4 (male) and 46.7 (female)) between those newly diagnosed with coronary heart disease and their community counterparts. More women than men were identified as suffering from unrecognised coronary heart disease, with a preponderance of younger women. Cost per case identified was A$1220. Screening by self-administered questionnaire is a useful and relatively cost-effective means of identifying unrecognised coronary heart disease.

Aged↗

PubMed1997

Neonatal presentation of Caroli's disease.

A neonatal presentation of Caroli's disease with severe cardiac and progressive renal pathology is described. The availability of small paediatric endoscopes ensured early diagnosis. Despite aggressive medical management, the baby died with severe bleeding complications before potentially life saving multiple organ transplantation could take place.

Arterial Occlusive Diseases↗

PubMed1997

Submicroscopic deletions at 16p13.3 in Rubinstein-Taybi syndrome: frequency and clinical manifestations in a North American population.

Rubinstein-Taybi syndrome (RTS) is a well delineated multiple congenital anomaly syndrome characterised by mental retardation, broad thumbs and toes, short stature, and specific facial features. The recent localisation of the disorder to 16p13.3 and subsequent identification of a submicroscopic deletion of this region in RTS patients led us to screen a large cohort of affected subjects using the RT1 probe. Among 64 patients with clinical evidence of RTS, seven (11%) had a deletion. Another patient had a translocation of the region without evidence of a deletion. The features of coloboma, growth retardation, naevus flammeus, and hypotonia have a positive predictive value for the presence of an RT1 deletion. Because of the relatively low frequency of deletions in RTS, the RT1 probe is useful in diagnostic confirmation, but has limited use as a screening tool.

Adolescent↗

PubMed1997

Universal radiographic screening for tuberculosis among inmates upon admission to jail.

OBJECTIVES: This study evaluated the efficacy of radiographic screening for tuberculosis in correctional facilities. METHODS: Inmates at an admission facility in New York, NY, were screened for tuberculosis by registry cross-match, symptom interviews, tuberculin testing, and chest radiography. RESULTS: Thirty-two cases of tuberculosis were detected among 4172 inmate admissions (767 cases per 100,000). Twenty-five inmates (78%) were previously diagnosed but incompletely treated; all were identified by registry cross-match. Seven inmates (22%) were newly diagnosed, of whom four (57%) were asymptomatic, had negative skin tests, and were detected only by their abnormal radiographs. CONCLUSIONS: Screening strategies that limit radiographic testing to inmates with either positive skin tests or symptoms may result in missed opportunities for diagnosing active tuberculosis.

Adolescent↗

PubMed1996

Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450.

BACKGROUND: Effective HIV protease inhibitors must combine potency towards wild-type and mutant variants of HIV with oral bioavailability such that drug levels in relevant tissues continuously exceed that required for inhibition of virus replication. Computer-aided design led to the discovery of cyclic urea inhibitors of the HIV protease. We set out to improve the physical properties and oral bioavailability of these compounds. RESULTS: We have synthesized DMP 450 (bis-methanesulfonic acid salt), a water-soluble cyclic urea compound and a potent inhibitor of HIV replication in cell culture that also inhibits variants of HIV with single amino acid substitutions in the protease. DMP 450 is highly selective for HIV protease, consistent with displacement of the retrovirus-specific structural water molecule. Single doses of 10 mg kg-1 DMP 450 result in plasma levels in man in excess of that required to inhibit wild-type and several mutant HIVs. A plasmid-based, in vivo assay model suggests that maintenance of plasma levels of DMP 450 near the antiviral IC90 suppresses HIV protease activity in the animal. We did identify mutants that are resistant to DMP 450, however; multiple mutations within the protease gene caused a significant reduction in the antiviral response. CONCLUSIONS: DMP 450 is a significant advance within the cyclic urea class of HIV protease inhibitors due to its exceptional oral bioavailability. The data presented here suggest that an optimal cyclic urea will provide clinical benefit in treating AIDS if it combines favorable pharmacokinetics with potent activity against not only single mutants of HIV, but also multiply-mutant variants.

Administration, Oral↗

PubMed1996

Selection conditions affect the evolution of specific mutations in the reverse transcriptase gene associated with resistance to DMP 266.

OBJECTIVE: To monitor the appearance of HIV-1 variants resistant to inhibition by DMP 266, a benzoxazinone non-nucleoside reverse transcriptase inhibitor using two different protocols for applying drug selective pressure in tissue culture. To compare the phenotype and genotype of viral isolates selected by each method. METHODS: MT-2 cells and fresh donor peripheral blood mononuclear cells (PBMC) were infected with HIV-1 strain RF. The MT-2 cells were infected in the presence of a 50% inhibitory concentration (IC50) of DMP 266 and the concentration was slowly increased during the selection period. The PBMC were infected for 1 week in the absence of inhibitor and then a single concentration was maintained throughout the selection period. Both cultures were passaged for approximately 4 months. Virus and cell pellets were harvested over this in vitro selection period, the RT genes amplified by polymerase chain reaction from the cell pellets, and the proviral DNAs sequenced. Isolated virus was tested for DMP 266 susceptibility in either the AIDS Clinical Trials Group/Department of Defense consensus assay or MT-2 yield reduction assay. RESULTS: Passage in MT-2 cells resulted in accumulation of three substitutions in RT (V179D, L1001, Y181C) after 24 passages associated with 1000-fold reduced susceptibility to DMP 266. In PBMC cultures treated with 0.96 microM DMP 266, virus replication was completely suppressed after 2 weeks; no regrowth occurred in the presence of compound after 10 weeks or in the absence of compound for 3 additional weeks. The 0.096 microM treated cultures had an initial 2.5-log reduction in infectious virus titre followed by rapid regrowth. Virus obtained at week 6 displayed a 28-fold reduction in susceptibility with an L1001 substitution in RT, and by week 11 displayed a 1000-fold reduction in susceptibility with an additional V1081 substitution. CONCLUSIONS: High-level resistance to DMP 266 may develop by at least two pathways and experimental conditions influence the genotype selected. The continued absence of detectable virus in the PBMC cultures grown at 0.96 microM is supportive evidence that maintaining trough plasma levels of DMP 266 which result in sustained antiviral activity in vivo may delay emergence of highly resistant viral variants. Confirmation of this hypothesis will require clinical trials.

Alkynes↗

PubMed1996

Maxillary premolar crown morphology. A preliminary study.

There seems to be a reluctance to use the Osborn terminology for identifying crown structures in the premolars of man. This may be attributed to the lack of studies on the premolars of man in which their topography has been compared with molars. We have attempted to do this using the principles of serial homology. Our study confirms that the two major maxillary premolar cusps in man are the paracone and protocone. We suggest that the lingual cingulum and the metacone have been lost and that remnants of the metaconule have made a contribution to the distal crown margin.

Bicuspid↗

PubMed1995

Development of spontaneous seizures over extended electrical kindling. II. Persistence of dentate inhibitory suppression.

The effect of an extended program of perforant path or amygdala kindling on paired-pulse suppression in the dentate gyrus was studied in male hooded rats. Repeated kindling stimulations were delivered twice or three times daily until either 300 stimuli had been delivered or generalized convulsions had been observed to occur spontaneously. Paired-pulse suppression was monitored prior to and over the course of kindling using a standard variable interval paradigm. We also used a variable intensity paradigm in which the intensity of the conditioning pulse was varied while the test pulse intensity was fixed at 600 microA and the interpulse interval was fixed at 30 ms. Both procedures revealed progressive increases in paired-pulse suppression which persisted over the course of kindling. This increased inhibition also persisted in animals which developed spontaneous seizures. The variable intensity paired-pulse procedure also allowed us to monitor facilitation effects which were relatively uncontaminated by recurrent inhibition (when the conditioning pulse intensity was low). Kindling was found to increase paired-pulse facilitation. With the standard variable interval paradigm, these increases in facilitation masked the increases in suppression.

Amygdala↗

PubMed1995

Cell lineage and patterns of migration in the developing cortex.

Knowledge of cell lineage in the cortex is important for understanding normal development as well as brain malformations. We studied cell lineage in rats by injecting a library of up to 3400 retroviruses, distinguishable by PCR analysis and encoding alkaline phosphatase, at E14-19. Histological analysis at P15 revealed normal cell morphology and allowed identification of about 80% of all labelled cells. PCR amplification of DNA tags allowed clonal analysis. Cortical cells labelled at E15 formed clustered or widespread clones with equal frequency. Clustered clones contained one to four cells within about 1 mm that had similar morphology and laminar location. However, 48% of cortical clones contained multiple cell types with widely different locations (2.1-6.7 mm; mean, 3.8 mm). Widespread clones contained two to four 'subunits' (one to five neurons each), spaced at apparent intervals of 2-3 mm, with each subunit morphologically indistinguishable from a clustered clone. Distinct subunits in the same clone usually differed in laminar location suggesting sequential formation. Clones labelled at E17 contained fewer neurons and up to two subunits. Clustered clones seem to be produced by stationary progenitors, whereas progenitors of clusters may themselves be produced by migratory, multipotential cells.

Animals↗

PubMed1995

Psychological responses to malignant melanoma. An investigation of traumatic stress reactions to life-threatening illness.

A cross-sectional study of 95 individuals with malignant melanoma was conducted to investigate posttraumatic stress responses to a diagnosis of melanoma and to validate the use of the Impact of Event Scale (IES) as a measure of the response to the trauma of life-threatening disease. The diagnosis and progression of malignant disease are likely to present a range of acute and chronic trauma to the individual and the individual's family. The findings suggest that the IES is a reliable and valid measure of this distress, with scores varying according to disease progression and prognostic status of nonmetastatic disease patients. This indicates the importance of clinical attention to the specific symptoms that may best reflect the traumatic impact of life-threatening illness and its progression, and the applicability of posttraumatic stress syndromes in understanding the psychological distress of this clinical population.

Adult↗

PubMed1995

Seromuscular colocystoplasty lined with urothelium: experience with 16 patients.

OBJECTIVES: Report of initial clinical experience with seromuscular colocystoplasty lined with urothelium (SCLU), a new operation to increase bladder capacity and compliance without incorporating intestinal mucosa into the urinary tract. We have previously reported the technique and results of this procedure in a canine model. METHODS: Sixteen patients underwent SCLU at two institutions. Their charts were reviewed retrospectively. The patients have been observed for a mean of 12 months. RESULTS: Postoperatively, the bladder capacity increased an average of 2.4-fold from a mean of 139 mL (+/- 23.7 SEM) to 335 mL (+/- 38.9 SEM) in 14 patients (P < 0.001). Two patients required reaugmentation. Preoperative and postoperative bladder end filling pressures were available in 13 patients and decreased from a mean of 51.6 cm H2O (+/- 4.2 SEM) to 27.7 cm H2O (+/- 2.4 SEM) (P < 0.001). Of the 16 patients, 13 were incontinent preoperatively; 5 had renal insufficiency. Three patients have undergone renal transplantation following SCLU. After SCLU, 13 patients were dry day and night, 1 incontinent at night only, and 2 remained incontinent. Ten patients have undergone postoperative bladder biopsy. Seven demonstrate urothelium covering the augmented portion of the bladder, 2 have regrowth of colonic mucosa, and 1 shows a mixture of colonic mucosa and urothelium. CONCLUSIONS: The results presented suggest that SCLU is a viable alternative to the more conventional forms of bladder augmentation in selected patients.

Adolescent↗

PubMed1995

Functional evaluation of the results of hypospadias surgery with uroflowmetry.

To determine the role of uroflowmetry in the evaluation of the functional results of hypospadias repair we retrospectively reviewed the records of 32 patients who underwent hypospadias repair with urethral reconstruction (mean age 2.4 years and mean followup 3.6 years). Patients with a plateau pattern and a maximum flow rate 2 standard deviations below the mean for age, body surface and voided volume on more than 1 determination were considered to have urethral obstruction. Urethroplasty had been performed with a meatal based flap in 11 cases, an onlay preputial flap in 5 and a tubularized preputial island flap in 16. Two of 11 patients with a meatal based flap, 5 of 16 with a tubularized preputial island flap and none with an onlay preputial flap had uroflow evidence of urethral stenosis. The 2 patients in the meatal based flap group responded to dilation with a normal flow. Of the tubularized preputial island flap group 3 patients required urethroplasty to correct a stricture and 2 had improvement with dilation alone. Three patients in the tubularized preputial island flap group had normal flow after treatment and 2 had improvement. Only 2 of the 7 patients with strictures were symptomatic. We conclude that uroflow examination is an important noninvasive tool to evaluate the functional results of urethroplasty in children and detect asymptomatic strictures.

Child↗

PubMed1995

Immunological factors and risk of infection in plateau phase myeloma.

AIMS: A series of patients with myeloma were investigated to assess whether immunological risk factors predisposing to serious infection could be identified. METHODS: Patients (n = 102) with predominantly plateau phase myeloma were monitored prospectively for infections. Immunological parameters including total non-paraprotein immunoglobulins and specific antibody titres were measured in all patients and compared with a control population of healthy individuals of a similar age; response to immunisation with Pneumovax II, tetanus and diphtheria toxoids and IgG subclasses were measured in a subgroup of 41 patients. Other characteristics investigated for any association with infection included age, sex, paraprotein type, disease stage, and chemotherapy. RESULTS: Specific antibody titres to pneumococcal capsular polysaccharides and tetanus and diphtheria toxoids were significantly reduced compared with the control population. Low antipneumococcal and anti Escherichia coli titres correlated with risk of serious infection and low anti-pneumococcal titres with severity of non-paraprotein immunosuppression. In 41 immunised patients responses to Pneumovax II, tetanus and diphtheria toxoids were poor; IgG subclass levels were significantly reduced and a poor IgG response to Pneumovax II immunisation was associated with an increased risk of septicaemia and low IgG2 levels. The overall serious infection rate was 0.92 infections per patient year and was four times higher during periods of active disease (1.90) compared with plateau phase myeloma (0.49). The predominant site of infection was the respiratory tract. Clinical and laboratory parameters showed only male sex and reduced non-paraprotein IgG and IgA levels to be significantly associated with at least one serious infection. CONCLUSIONS: A subgroup of patients with myeloma with poor IgG responses to exogenous antigens, who are at increased risk of serious infection, can be identified and may benefit from replacement immunoglobulin therapy to reduce the risk of infection.

Aged↗

PubMed1995

Cardiovascular risk reduction: a randomized trial of two health promotion strategies for lowering risk in a community with low socioeconomic status.

AIM: To compare the effects of information pamphlets with those of group counselling on cardiovascular risk among individuals from a community with low socioeconomic status. METHODS: Risk factors for coronary heart disease were assessed in 1131 men and women from a community with low socioeconomic status in suburban Melbourne. Individuals deemed to be at moderate risk, on the basis of an integrated risk score greater than 65, were asked to participate in a randomized trial comparing two simple interventions designed to reduce cardiovascular risk. One hundred and sixty-four individuals were randomly assigned to group A (n = 85) and participated in a single group counselling session lasting between 1.5 and 2.0 h. Group B (n = 79) received a specially prepared pamphlet that provided brief written information concerning risk-factor modification. Both groups were asked to attend a follow-up assessment of risk factors 3 and 6 months after entry. RESULTS: There were no significant difference in the change in risk-factor levels between those receiving information pamphlets and those attending the group counselling session after 3 or 6 months of follow-up. Small but significant decreases (P<0.05) were seen in systolic and diastolic blood pressures (-5/4 mmHg for group A, -5/3 mmHg for group B), total plasma cholesterol level (-0.30 mmol/l for groups A and B) and overall coronary risk score (-14.4 and -13.9 for groups A and B, respectively). Body weight remained unchanged during the study period in both groups. CONCLUSION: Screening together with 1.5-2h group counselling had no more influence on cardiovascular risk factors than screening together with provision of information pamphlets in a population with low socioeconomic status.

Adolescent↗