Preclinical pharmacokinetics, manufacturing, and safety studies supporting a multicenter cancer gene therapy trial.
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Clinical Trials as Topic↗
Biomedical subjects
S Parker
Publications and source records attributed to S Parker.
Clinical significance of nontuberculous mycobacteria isolates in a Canadian tertiary care center.
To determine the epidemiology and clinical features of disease due to nontuberculous mycobacteria (NTM) in our institution, we reviewed the medical records of all patients from whom NTM isolates were recovered from 1988 to 1990 to extract selected clinical and laboratory data. On the basis of the likelihood of infection, patients were classified as having definite, probable, or unlikely NTM disease as defined by published guidelines. Of 80 patients who met the inclusion criteria, 17 had definite NTM disease, and 23 had probable NTM disease. No differences in age, sex, presence of underlying pulmonary or nonpulmonary disease, or chest radiographic abnormalities were noted between patients with and without NTM disease. More than 85% of all definite or probable cases were caused by Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium fortuitum complex. The diagnosis of NTM disease was often delayed or missed, which resulted in unsatisfactory management of patients. There is a need to educate physicians about the diagnosis and management of NTM infections.
Academic Medical Centers↗
Review of liver trauma management in Tasmania: an analysis of risk factors for mortality and morbidity.
A review of liver trauma treated by the major trauma care facilities of Tasmania in the 5 year period between 1989 and 1993 is presented. The aim of this retrospective review was to provide an audit of the management of liver trauma in the island of Tasmania and to analyse the risk factors contributing to mortality and major morbidity. Thirty-seven patients were treated with a median Injury Severity Score (ISS) of 14 (range 9-34). The overall mortality rate of this series was 5.8%. Age, mechanism of injury (blunt or penetrating), delay prior to hospital presentation and modality of treatment (operative or non-operative) were not significant risk factors for mortality and morbidity; however, transfusion requirement of over 10 units of blood (P < 0.005), ISS score of over 20 (P < 0.0005), haemodynamic instability at presentation (P < 0.05) and a Hepatic Injury Score (HIS) grade of 3 or more (P < 0.05) were statistically significant risk factors.
Abdominal Injuries↗
Silent victims revisited: the special case of domestic violence.
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Child↗
Preventive pediatrics--new models of providing needed health services.
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Child↗
Soft lining materials--a review.
Soft linings are compliant, viscoelastic materials used to form all or part of the fit surface of a denture. Their complete function is debatable, but they serve to distribute the forces of mastication more evenly and to absorb energy. Other uses include obturators and maxillo-facial prostheses. This review will cover both the so-called 'permanent' soft-lining materials and temporary soft reline materials, often referred to as tissue conditioners.
Absorption↗
Phospholipid prodrug inhibitors of the HIV protease. Antiviral activity and pharmacokinetics in rats.
The aspartyl protease of the human immunodeficiency virus (HIV) is an important target for chemotherapeutic intervention because of its key role in cleaving the HIV gag-pol polyprotein during viral assembly and budding. Short peptides and peptidomimetics, which bind to the active site of the HIV aspartyl protease and inhibit processing of the polyprotein, have been synthesized. These compounds are active against HIV in vitro, but many face substantial development problems because of their rapid elimination from the body in bile and urine. Refinement of these agents appears to be necessary if they are to become useful clinically. Recently, we developed a novel chemical strategy for increasing plasma levels of HIV protease inhibitory peptides, which involves the attachment of a biodegradable phospholipid group to the C-terminus of a pentapeptide, iBOC-[L-Phe]-[D-beta-Nal]-Pip-[alpha-(OH)-Leu]-Val (7194). We coupled phosphatidylethanolamine to the C-terminal valine of 7194 to make a phospholipid prodrug (7196). In vitro assays in HT4-6C cells infected with HIV-1 showed that the antiviral activity of the C-terminal phospholipid prodrug, 7196, was equal to that of the free peptide, 7194. Similar results were obtained in vitro when a related pentapeptide (7140) was derivatized at the N-terminal with dipalmitoylphosphatidylethanolamine-succinic acid (7172). Tritium-labeled 7194 and 7196 were prepared and injected intravenously into rats at 3 mumol/kg; then the plasma was assayed for native compound and metabolites by HPLC radioactivity flow detection. The peak plasma level of the tritium-labeled lipid prodrug (7196) was 36 microM versus 1.6 microM for the free protease inhibitor pentapeptide (7194). The area under the curve of the phospholipid prodrug (7196) was 48-fold greater and its mean residence time was increased 43-fold versus the free peptide (7194). Phospholipid prodrugs appear to offer an alternative approach to optimizing in vivo performance of HIV protease inhibitors and other small peptides.
Amino Acid Sequence↗
A suppressor of a mating-type limited zygotic lethal allele also suppresses uniparental chloroplast gene transmission in Chlamydomonas monoica.
Uniparental inheritance of Chlamydomonas chloroplast genes is thought to involve modification of maternal (mt+) chloroplast genomes to protect against a nuclease that is activated after gamete fusion. The mating-type limited mtl-1 mutant strain of Chlamydomonas monoica is unable to protect mt(+)-derived chloroplast DNA. Zygotes homozygous for mtl-1 lose all chloroplast DNA and fail to germinate. We have selected for suppression of this zygote-specific lethality, and have obtained 20 mutant strains that produce viable homozygotes despite the continued presence of the mtl-1 allele. Genetic analysis indicates that the suppressor mutations are all recessive alleles at a single locus (sup-1) which is unlinked to mtl-1. Crosses between sup-1 strains carrying distinctive chloroplast antibiotic resistance markers also show predominantly biparental chloroplast gene transmission. Chloroplast nucleoids of both parental origins (stained with the DNA-specific fluorochrome, DAPI) are retained in the zygotes homozygous for sup-1. The data are compatible with the idea that the sup-1 (suppressor of uniparental inheritance) locus may encode a chloroplast DNA nuclease that is expressed from both parental genomes.
Alleles↗
The effect of a comprehensive, intensive inpatient treatment program on lung function and exercise capacity in patients with cystic fibrosis.
BACKGROUND AND PURPOSE: The purpose of this investigation was to measure the effects of a 10- to 14-day comprehensive, intensive hospital treatment program on peak exercise capacity, endurance capacity, respiratory function, weight change, and maximum inspiratory and expiratory mouth pressures in patients with cystic fibrosis with a pulmonary exacerbation. SUBJECTS: Fourteen young adults with cystic fibrosis admitted to a hospital for an exacerbation of their pulmonary disease were studied. METHODS: Subjects performed pulmonary function tests, inspiratory and expiratory mouth pressure tests, and stationary bicycle exercise tests at admission and discharge. Comprehensive therapy provided during the hospital admission consisted of intravenous antibiotics, physical therapy, high-calorie diet, and daily medical review. RESULTS: The patients showed improvements in forced expiratory volume in 1 second (46%-55% of predicted values) and forced vital capacity (62%-68% of predicted values). Maximum inspiratory and expiratory mouth pressures also improved (118%-131% and 78%-92% of predicted values, respectively). There was a mean weight gain of 2 kg. Maximum work capacity on a bicycle ergometer improved from a mean of 45% to 52% of predicted values. The most impressive result was the marked increase in exercise endurance time from a mean of 9.5 minutes on admission to 16.6 minutes at discharge. CONCLUSION AND DISCUSSION: This study indicates that young adults with cystic fibrosis and an exacerbation of their pulmonary disease obtain measurable benefits from a comprehensive, intensive treatment program, particularly improvement in their capacity for endurance exercise.
Adolescent↗
Use of anonymous newborn serosurveys to evaluate antenatal HIV screening programmes.
OBJECTIVE: To evaluate the extent to which antenatal HIV screening programmes identify HIV infected women who go to term. DESIGN: Comparison of results of two surveillance systems. An anonymous neonatal HIV serosurvey was used to estimate the numbers of HIV infected women giving birth; reporting by obstetricians was used to assess the proportion who had been identified. SETTING: Three Thames regions. RESULTS: 729,105 neonatal blood samples were tested, of which 484 were HIV seropositive. Newborn HIV seroprevalence is increasing, at different rates, in inner London, suburban London, and in non-metropolitan districts. During the past four years the proportion of infected women who have been identified before delivery is 16.9%, but less than half of these were diagnosed during pregnancy. In 1993 only five of the 128 (4%) previously undiagnosed infected women delivering babies were identified by antenatal screening. CONCLUSION: Despite increased emphasis on antenatal testing for HIV in areas of higher prevalence the number of undiagnosed women delivering babies continues to increase. Consideration should be given to alternative strategies for offering antenatal HIV testing. Antenatal screening programmes should be monitored continuously by comparing anonymous neonatal seroprevalence with clinical reports from obstetricians.
Confidence Intervals↗
Benefits of nocturnal nasal CPAP in patients with cystic fibrosis.
Patients with cystic fibrosis (CF) often hypoventilate during sleep with marked falls in oxygen saturation (SaO2%). This occurs most commonly during REM sleep, when there is a reduction in rib cage excursion and a fall in end-expiratory lung volume (EELV). The aim of this study was to examine the effect of nocturnal nasal continuous positive airway pressure (nCPAP) on SaO2 and the respiratory disturbance index (RDI) during sleep in patients with CF and severe lung disease. Seven patients (FEV1% pred, 23 +/- 5; range, 14 to 28%) were evaluated during sleep on two nights, control and nCPAP (11 +/- 2 cm H2O; range, 8 to 16 cm H2O), with four patients breathing room air and three patients breathing supplemental oxygen on both nights. Mean awake SaO2 was 91 +/- 1% (range, 89 to 93%). All patients showed significant oxyhemoglobin desaturation and respiratory disturbance in the control study. The maximal falls in SaO2 (15 +/- 10%) were most often associated with phasic eye movements, and a decline in rib cage excursion and the sum signal (Respitrace) during REM sleep. Nasal CPAP resulted in a significant improvement in the mean minimum oxygen saturation (MMOS) during both NREM (nCPAP 91 +/- 3% vs control 88 +/- 2%, p < 0.05) and REM sleep (nCPAP 89 +/- 6% vs control 83 +/- 6%, p < 0.05). Transcutaneous CO2 measurements were not significantly different between the control and the nCPAP studies. The RDI was also significantly reduced with nCPAP especially during REM sleep (9 +/- 7 events per hour vs control 25 +/- 11 events per hour, p < 0.05). Nasal CPAP caused no change in total sleep time or sleep efficiency yet significantly reduced the RDI and improved baseline SaO2 during both NREM and REM sleep.
Adolescent↗
The stimulus range effect: evidence for top-down control of sensory intensity in audition.
The influence of intensity range on the perceived magnitude of a stimulus is well documented and usually attributed to response biases. Recent studies, however, have suggested that the range effect might be sensory in origin. To test this notion, we had one set of subjects compare loudness intervals in three conditions: a broad-range condition (15 tones, 23-95 dB SPL), a soft short-range condition (the lowest 10 tones from the broad-range condition), and a loud short-range condition (the highest 10 tones). Nonmetric scaling showed that the broad-range and loud short-range conditions had identical loudness functions. However, the second derivative of the loudness function was larger for the soft short-range condition than for the broad-range condition. This pattern of results is consistent with the notion of a nonlinear amplifier whose gain and degree of nonlinearity are adjusted under top-down control, so as to prevent distortion and increase discriminability.
Adult↗
Immunolocalization of connexin 43 in the tooth germ of the neonatal rat.
Rabbit polyclonal antibodies to amino acids 346-360 of connexin 43, the 'heart' gap junction protein, were employed to immunolocalize connexin 43 gap junctions in the neonatal rat molar tooth germ. Connexin 43 appears early in the differentiation of both ectodermally derived and ectomesenchymally derived cells of the developing tooth. Connexin 43 immunoreactivity is present in the epithelial components of the enamel organ, including the area of the proximal and distal junctional complexes of the ameloblast layer, and the stratum intermedium, stellate reticulum and outer enamel epithelium. Secretory odontoblasts and developing alveolar bone also display a pattern of connexin 43 immunostaining. Both the epithelial and ectomesenchymally-derived components of the developing tooth acquire connexin 43 channels in a manner that correlates with cell differentiation. In addition, three regions can be defined by connexin 43 immunostaining: the epithelia of the enamel organ that are derived from the oral epithelium, the odontoblast layer derived from the ectomesenchyme, and the alveolar bone. The results suggest that connexin 43 may provide the mechanism for functional compartmentalization of the tissues associated with tooth formation. Compartmentalization suggested by connexin 43 expression could play important roles in the development and functions of these tissues.
Animals↗
Acyclovir diphosphate dimyristoylglycerol: a phospholipid prodrug with activity against acyclovir-resistant herpes simplex virus.
Infection with herpes simplex viruses (HSVs) resistant to treatment with acyclovir (9-[(2-hydroxyethoxy)-methyl]guanine, Zovirax) is a growing clinical problem in patients with AIDS and other immunosuppressed states. Most virus isolates resistant to acyclovir are deficient or defective in virally coded thymidine kinase (TK), which converts acyclovir to acyclovir monophosphate in virus-infected cells. To restore acyclovir efficacy, we synthesized acyclovir diphosphate dimyristoylglycerol, an analog of a naturally occurring phospholipid, CDP-diacylglycerol. Its biological activity was tested in WI38 human lung fibroblasts infected with the acyclovir-resistant DM21 strain of HSV, which is TK negative due to an 816-base-pair deletion in the TK coding region. Acyclovir diphosphate dimyristoylglycerol has substantial activity in DM21-infected cells (IC50 = 0.25 microM), whereas acyclovir and acyclovir monophosphate were ineffective (IC50 > 100 microM). Similar results were obtained in TK-altered and TK-deficient strains of HSV-1 and in acyclovir-resistant isolates of HSV-2 obtained from two AIDS patients. The phospholipid prodrug is active by means of TK-independent metabolic pathways that liberate acyclovir monophosphate inside the host cell. Acyclovir phosphates were 56 times greater in WI38 human lung fibroblasts incubated for 24 hr with [8-3H]acyclovir diphosphate dimyristoylglycerol relative to acyclovir. Acyclovir monophosphate added to the culture medium (outside the cell) did not circumvent the acyclovir resistance of the TK-negative DM21 mutant, presumably due to its conversion to acyclovir by phosphatases. Acyclovir diphosphate diacylglycerol prodrugs may be useful in treating TK-deficient mutant and wild-type strains of HSV.
Acquired Immunodeficiency Syndrome↗
Antituberculous drug resistance in Manitoba from 1980 to 1989.
OBJECTIVES: To estimate the magnitude of antituberculous drug resistance and identify the risk factors for its development in tuberculosis patients in Manitoba over a 10-year period. As well, to examine the clinical course of the patients whose initial or subsequent isolates of Mycobacterium tuberculosis were resistant to one or more drugs. DESIGN: Comparison of drug-resistant and non-drug-resistant cases of tuberculosis. SETTING: Manitoba. PATIENTS: All people with tuberculosis reported to the Central Tuberculosis Registry of Manitoba between Jan. 1, 1980, and Dec. 31, 1989. MAIN OUTCOME MEASURES: Of 1478 cases of active tuberculosis 1086 were culture positive, and drug susceptibility testing was performed in these cases. The clinical course, including outcome of treatment, of all drug-resistant cases was described. RESULTS: Of 1086 culture-positive cases of tuberculosis 77 (7.1%) were drug resistant. Odds ratios suggested that the risk of drug resistance was significantly higher among the immigrants than among the other Canadians. Compared with the other Canadians the risk of drug resistance was 9.9 times greater among the immigrants in whom tuberculosis developed within the first year after arrival in Canada and 5.4 times greater among the immigrants in whom it developed 2 to 5 years after arrival in Canada. Of the 71 patients with drug-resistant disease whose type of resistance was known 62% had never taken antituberculous drugs before and 38% had. Most (91%) of the 77 cases of drug-resistant disease were resistant to first-line drugs, especially isoniazid and streptomycin. Thirty-two (42%) of the 77 cases were resistant to two or more first-line drugs. Of patients with drug-resistant disease a subgroup of 10 had disease that became resistant to several drugs over the 10-year period. The outcome of treatment in these individuals was poor, and they presented a particular public health problem. CONCLUSION: Resistance to one or more first-line antituberculous drugs continues to complicate the treatment of tuberculosis and may facilitate the spread of the disease.
Adolescent↗
Evaluation of a breast mass.
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Biopsy, Needle↗
Two successive outbreaks of SRSV-associated gastroenteritis in South Africa.
Two successive outbreaks of gastroenteritis in South Africa were investigated to identify the aetiological agents. Some patients were involved in both outbreaks. Enteropathogenic bacteria or parasites were not evident in either outbreak. Small round structured viruses (SRSVs) were demonstrated in both outbreaks by direct electron microscopy. SRSV UK3/Hawaii virus was identified by immune electron microscopy as the causative agent in the first outbreak. Using new recombinant Norwalk virus (rNV) immunoassays for antibodies and antigen, Norwalk virus was implicated in the second outbreak. Preexisting antibodies to Norwalk virus were not protective and there was no cross protection between Hawaii and Norwalk viruses. There was no anamnestic response to Norwalk virus following the SRSV UK3/Hawaii outbreak although those affected had preexisting antibodies to Norwalk virus. To our knowledge, this is the first definitive diagnosis of SRSV-associated gastroenteritis in South Africa.
Adult↗
Efficacy of a recombinant Norwalk virus protein enzyme immunoassay for the diagnosis of infections with Norwalk virus and other human "candidate" caliciviruses.
A recombinant Norwalk virus antigen enzyme immunoassay (rNV EIA) for the detection fo Norwalk virus (NV) antibodies was evaluated using sera from volunteers and patients infected with Norwalk, Hawaii, Snow Mountain Agent, small round structured viruses (SRSV), and human calicivirus (HuCV) strains. The results for NV antibodies correlated well with previous results obtained using a NV radioimmunoassay. The test rNV EIA was found to be highly specific for NV. The results of tests on sera obtained from patients involved in confirmed outbreaks of SRSV in the UK showed that only 1/12 was due to Norwalk virus. Further evidence is presented that SRSV strain UK2 is antigenically related to NV.
Adult↗