Biomedical subjects
A Williams
Publications and source records attributed to A Williams.
Compromised antioxidant status and persistent oxidative stress in lung transplant recipients.
Oxidative stress may be a key feature, and hence important determinant, of tissue injury and allograft rejection in lung transplant recipients. To investigate this, we determined the antioxidant status (urate, ascorbate, thiols and alpha-tocopherol) and lipid peroxidation status (malondialdehyde) in bronchoalveolar lavage (BAL) fluid and blood serum of 19 consecutive lung transplant recipients 2 weeks and 1, 2, 3, 6, and 12 months post-surgery. BAL fluid and blood samples from 23 control subjects and blood from 8 patients two days before transplantation were obtained for comparison. Before surgery, the antioxidant status of patients was poor as serum ascorbate and total thiol concentrations were significantly (p < 0.05) lower than control subjects. Two weeks post-surgery, ascorbate and total thiol concentrations were still low and urate concentrations had fallen compared to control subjects (p < 0.01). At this time, BAL fluid urate concentration was higher (p < 0.01), ascorbate concentration was lower (p < 0.01) and reduced glutathione concentrations were similar to control subjects. MDA, a product of lipid peroxidation, was higher (p < 0.01) in both BAL fluid and serum obtained from transplant patients compared to control subjects. During the first 12 months post-surgery, little improvement in antioxidant status or extent of lipid peroxidation was seen in transplant recipients. Regression analysis indicated no difference in serum or BAL fluid antioxidant status in patients with acute rejection compared to those without. In conclusion, lung transplant recipients have a compromised antioxidant status before surgery and it remains poor for at least the first year following the operation. In addition, these patients have elevated MDA concentrations in both their lung lining fluid and blood over most of this time. Oxidative stress is not, however, a sufficiently sensitive endpoint to predict tissue rejection in this group.
Evidence among blood donors for a 30-year-old epidemic of human T lymphotropic virus type II infection in the United States.
The demographic and geographic determinants of human T lymphotropic virus types I and II (HTLV-I and -II) are not well defined in the United States. Antibodies to HTLV-I and -II were measured in 1.7 million donors at five US blood centers during 1991-1995. Among those tested, 156 (9.1/10(5)) were HTLV-I seropositive and 384 (22.3/10(5)) were HTLV-II seropositive. In contrast to monotonously increasing age-specific HTLV-I seroprevalence, HTLV-II prevalence rose until age 40-49 years and declined thereafter, suggesting a birth cohort effect. HTLV-II infection was independently associated with an age of 40-49 years (odds ratio [OR], 12.4; 95% confidence interval [CI], 8.8-18.9), female sex (OR, 3.3; 95% CI, 2.6-4.1), high school or lower education (OR, 1.7; 95% CI, 1.3-2.1), hepatitis C seropositivity (OR, 25.0; 95% CI, 17.5-35.8), and first-time blood donation (OR, 3.6; 95% CI, 2.8-4.7). HTLV-II seroprevalence was highest at the two West Coast blood centers. These data are consistent with a 30-year-old epidemic of HTLV-II in the United States due to injection drug use and secondary sexual transmission and with an apparent West Coast focus.
Serum concentrations and peripheral secretion of the beta chemokines monocyte chemoattractant protein 1 and macrophage inflammatory protein 1alpha in alcoholic liver disease.
BACKGROUND: Alcoholic liver disease is associated with increased hepatic expression of monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1alpha (MIP-1alpha). AIMS: To determine whether concentrations of chemokines in the peripheral circulation reflect disease activity, and whether chemokine secretion is restricted to the liver or is part of a systemic inflammatory response in alcoholic liver disease. PATIENTS: Fifty one patients with alcoholic liver disease and 12 healthy controls. METHODS: Peripheral vein (and hepatic vein in patients undergoing transjugular liver biopsy) chemokine concentrations were measured by ELISA. Chemokine secretion and transcription in isolated peripheral mononuclear cells were assessed using ELISA and in situ hybridisation in patients with severe alcoholic hepatitis. RESULTS: Serum MCP-1 concentrations were higher in alcoholic hepatitis compared with cirrhosis or healthy controls. MIP-1alpha concentrations were below the assay sensitivity in most patients. Serum MCP-1 concentrations correlated significantly with serum aspartate aminotransferase and creatinine. In severe alcoholic hepatitis, MCP-1 concentrations were higher in hepatic compared with peripheral veins; in mild alcoholic hepatitis there was no difference. Mononuclear cell secretion of both MCP-1 and MIP-1alpha was higher in severe alcoholic hepatitis compared with healthy controls, and chemokine mRNA was identified in monocytes. CONCLUSIONS: Serum MCP-1 concentrations are raised in alcoholic liver disease and reflect severity of hepatic inflammation. Monocyte secretion of both MCP-1 and MIP-1alpha is increased in severe alcoholic hepatitis. Both intrahepatic sources and peripheral mononuclear cells contribute to the raised serum MCP-1 concentrations.
Activity and expression of the 20S proteasome are increased in skeletal muscle during sepsis.
Recent studies suggest that sepsis stimulates ubiquitin-dependent protein breakdown in skeletal muscle. In this proteolytic pathway, ubiquitinated proteins are recognized, unfolded, and degraded by the multicatalytic 26S protease complex. The 20S proteasome is the catalytic core of the 26S protease complex. The role of the 20S proteasome in the regulation of sepsis-induced muscle proteolysis is not known. We tested the hypothesis that sepsis increases 20S proteasome activity and the expression of mRNA for various subunits of this complex. Proteolytic activity of isolated 20S proteasomes, assessed as activity against fluorogenic peptide substrates, was increased in extensor digitorum longus muscles from septic rats. The proteolytic activity was inhibited by specific proteasome blockers. Northern blot analysis revealed an approximately twofold increase in the relative abundance of mRNA for the 20S alpha-subunits RC3 and RC9 and the beta-subunit RC7. However, Western blot analysis did not show any difference in RC9 protein content between sham-operated and septic rats. The increased activity and expression of the 20S proteasome in muscles from septic rats lend further support for a role of the ubiquitin-proteasome-pathway in the regulation of sepsis-induced muscle proteolysis.
Standardized visual evoked potentials for telematic electrodiagnosis from five laboratories in three European countries.
The pattern-reversal visual evoked potential (PR VEP) is an electrodiagnostic test which uses an alternating checkerboard pattern as the visual stimulus. To validate the performance of an automated testing system, the equipment was installed in five locations in three countries (the UK, Greece and Cyprus). PR VEPs require accurate control of stimulus size, luminance, contrast, timing, multichannel recordings and various modes of signal processing. Recordings were obtained from 70 subjects, 18-34 years old (seven male and seven female in each laboratory). The data were transmitted by telephone line to the central station in Bristol. Only in Bristol were the operators experienced. There were no significant differences between laboratories in latency or amplitude of the N70 and P100 components. There were no significant differences between eyes. There were significant differences between the sexes but this was related to head size. Decreased square size used in stimulation produced an increased latency in both components. The amplitude of the N70 component increased while that of the P100 decreased with reduced square size. The results confirmed the ability of the automated system to produce standardized PR VEP recordings comparable to those obtainable in advanced laboratories. The system performed well in different locations using inexperienced operators. The system is suitable for multicentre research studies and telemedicine.
Evaluation of the first international teleconference in ophthalmology.
The First International Teleconference in Ophthalmology was held during March 1998 between five sites in the UK, USA, Greece and Malaysia. ISDN transmission at 128 kbit/s was used to reduce costs while maintaining the clarity of the presented material. Specialized lecture theatres were not available at all sites and conventional halls had to be adapted for videoconferencing. For this reason initial point-to-point testing was carried with Bristol to simplify problem solving. Thereafter, a multipoint bridge was used to connect all sites together. During the conference a number of individual presentations were given, all followed by extensive discussion periods. Special instructions were given beforehand on the production of slide material, with particular reference to font sizes and colour combinations. Full use was made of various presentation media, including slides, videos and live demonstrations. The conference was attended by over 500 delegates, all of whom were specialists in ophthalmology. The technology employed was ideal for teaching purposes. However, if used in a clinical field, it should be kept in mind that the choice of transmission rate makes certain features not easily apparent in images but they become clearer when pointed out by the presenter.
Meniscal movement. An in-vivo study using dynamic MRI.
We present the first study in vivo of meniscal movement in normal knees under load. Using an open MR scanner, allowing imaging in physiological positions in near to real-time, 16 young footballers were scanned moving from full extension to 90 degrees flexion in the sagittal and coronal planes. Excursion of the meniscal horns, radial displacement and meniscal height were measured. On weight-bearing, the anterior horn of the medial meniscus moves through a mean of 7.1 mm and the posterior horn through 3.9 mm, with 3.6 mm of mediolateral radial displacement. The height of the anterior horn increases by 2.6 mm and that of the posterior horn by 2.0 mm. The anterior horn of the lateral meniscus moves 9.5 mm and the posterior horn 5.6 mm, with 3.7 mm of radial displacement. The height of the anterior horn increases by 4.0 mm, and that of the posterior horn by 2.4 mm. In non-weight-bearing, the anterior horn of the medial meniscus moves 5.4 mm and the posterior horn 3.8 mm, with 3.3 mm of radial displacement. The anterior horn of the lateral meniscus moves 6.3 mm, and the posterior horn 4.0 mm, with 3.4 mm of radial displacement. The most significant differences between weight-bearing and non-weight-bearing were the movement and vertical height of the anterior horn of the lateral meniscus.
A comparison of morning-only and morning/late afternoon Adderall to morning-only, twice-daily, and three times-daily methylphenidate in children with attention-deficit/hyperactivity disorder.
OBJECTIVE: 1) To compare standard twice-daily methylphenidate (MPH) dosing with a single morning dose of MPH and of Adderall during a typical school-day time period, and 2) to conduct a dose-response study of the effects of a late-afternoon (3:30 PM) dose of MPH and Adderall on evening behavior and side effects. DESIGN: Within-subject, placebo-controlled, crossover design. SETTING: Intensive summer treatment program with a comprehensive behavioral approach. STUDY PARTICIPANTS: Twenty-one children with attention-deficit/hyperactivity disorder (19 boys and 2 girls), between the ages of 6 and 12 years. INTERVENTIONS: Children received, in random order with daily crossovers, each of the following conditions: 1) placebo, 2) 0.3 mg/kg of MPH received 3 times, 3) 0.3 mg/kg of MPH received twice (7:30 AM and 11:30 AM) with 0.15 mg/kg received at 3:30 PM, 4) 0.3 mg/kg of MPH received once in the morning only, 5) 0.3 mg/kg of Adderall received at 7:30 AM and at 3:30 PM, 6) 0.3 mg/kg of Adderall once in the morning with 0.15 mg/kg received at 3:30 PM, 7) 0.3 mg/kg of Adderall received in the morning only. OUTCOME MEASURES: Daily rates of behaviors in social and academic settings, and standardized ratings from counselors and teachers, were assessed for the hours between 8:00 AM and 3:30 PM (a typical school-day). Relative sizes of the medication effects were compared hourly between first daily ingestion (7:30 AM) and 4:45 PM to assess the time course of the 2 drugs. Effects of the 3:30 PM doses on functioning in the evenings at home were evaluated using parent ratings of behavioral and side effects. RESULTS: A single morning dose of Adderall produced equivalent behavioral effects to those of MPH received twice-daily and behavioral effects of that single morning dose lasted throughout the school-day period. One morning dose of MPH was less effective than either 2 daily doses of MPH or 1 dose of Adderall, and seemed to wear off in the early to mid-afternoon. For some children a single morning dose of MPH maintained their behavior for an entire school day in the context of the summer treatment program. On parent ratings of evening behavior, 0.3 mg/kg of MPH at 3:30 PM was superior to 0.15 mg/kg at 3:30 PM, but there was no difference between the 2 doses of Adderall. Compared with placebo at 3:30 PM, only the 0.3 mg/kg dose of MPH caused significant improvement in parent ratings. In placebo versus Adderall comparisons, all doses, even the condition that consisted of Adderall in the morning and placebo at 3:30 PM, produced a significant change in evening behavior. CONCLUSIONS: The results show that, at least in the context of an intensive behavioral intervention, a single morning dose of Adderall had behavioral effects throughout an entire school day period that were equivalent to standard twice-daily MPH dosing. These results indicate that Adderall may be used as a long-acting stimulant for children for whom midday dosing is a problem. Further study including dose-response comparisons, effects in regular school settings, and direct comparisons with comparable doses of MPH and d-amphetamine will help to clarify the time course and relative advantages of Adderall.
Depression, self-defeating, and self-destructive behaviors as predictors of suicide ideation in males and females.
Previous studies have implicated depression, self-defeating behaviors, and self-destructive behaviors in suicide ideation. The present research directly compared these three concepts as predictors of both males' (n = 51) and females' (n = 78) suicide ideation. Analysis confirmed sex differences, with depression and self-defeating behaviors predicting females' suicide ideation, and self-destructive behaviors predicting males' suicide ideation. These results suggest that suicide may be related to these subtle yet relevant factors which may not be easily detected by mental health workers.
Bridging the gap. Bringing new antiretroviral medications into the clinic.
Highly active antiretroviral therapy (HAART) is a strategy in which clinicians introduce potent combinations of antiretroviral medications early in the course of HIV infection. The intent is to suppress viral replication as completely as possible to forestall irreversible immune system damage. Antiretroviral agents fall into two major classes reverse transcriptase inhibitors and protease inhibitors. Each class interferes with viral replication at a different point in the viral life cycle. Recent research findings demonstrate clearly that antiretroviral treatment should begin as soon as the patient is willing and able to take the multidrug regimens. The best strategy for meeting the challenge of antiretroviral resistance is prevention. If you completely halt viral replication with potent therapy, the development of resistant strains is prevented.
"One-stop" surgery: implications for anesthesiologists of an expedited pediatric surgical process.
BACKGROUND: "One-stop surgery" (OSS) allows pediatric patients to undergo initial surgical evaluation, anesthesia, surgery, and discharge home, on the same day. METHODS: Patients referred for umbilical hernia repair, circumcision, or central venous catheter removal completed a screening questionnaire, after which they were scheduled for initial surgical and anesthesia evaluation if eligible and had surgery if indicated on the same day. RESULTS: Three patients had comorbidity precluding OSS, two patients refused indicated surgery, two patients did not require surgery, and 12 patients did not keep their appointment. Eighty patients had surgery without complications. Average total time was significantly shorter for OSS than non-OSS for circumcision (120 vs 142 min) and umbilical hernia repair (139 vs 165 min) but similar for catheter removal (100 vs 109 min). All families were satisfied with OSS. CONCLUSIONS: One-stop surgery appears to be a safe, efficient, and convenient alternative to the traditional process for patients and their families.
Myocardial abscess: an unusual complication of long-term hemodialysis line presence.
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An A/G polymorphism in the promoter of mitochondrial aldehyde dehydrogenase (ALDH2): effects of the sequence variant on transcription factor binding and promoter strength.
INTRODUCTION: The strong protective effect of the ALDH2*2 mutation on risk of alcoholism suggests that other mutations that reduce mitochondrial aldehyde dehydrogenase (ALDH) activity in the liver might also deter drinking. This study describes a polymorphic locus found in the promoter of the ALDH2 gene that affects expression of reporter constructs. METHODS: Polymerase chain reaction (PCR)-based sequencing was used to search for polymorphisms. The ability of the promoter variants to bind transcription factors apolipoprotein A regulatory protein 1 (ARP-1) and chicken ovalbumin upstream promoter-transcription factor (COUP-TF) was tested in gel retardation assays using in vitro synthesized transcription factors. The variant promoters were tested for transcriptional activity using a heterologous promoter system and transient transfection assays. RESULTS: A common polymorphism (A or G) in the human ALDH2 promoter region was found at -361 base pair (bp) from the translation start site. This polymorphism was found at different frequencies in African Americans, Caucasians, and Asians. The polymorphism occurs adjacent to the core binding motif for the transcription factors COUP-TF and ARP-1. Competition and binding affinity determinations did not show differences in the ability of these two sequences to bind the factors. Reporter genes containing these elements upstream of a basal thymidine kinase promoter had similar activity when transfected into a fibroblast (CV-1) cell line. However, the reporter containing the G allele was more active than that containing the A allele in hepatoma (H4IIEC3) cells. CONCLUSIONS: The -361 bp A/G polymorphism is common in all racial groups tested. The G allele was more active than the A allele in a transfection assay. The basis for this difference is not known. If the differences in activity of the promoter constructs were paralleled by differences in ALDH2 enzyme activity in the liver, this polymorphism could affect risk of alcoholism.
An assessment of community palliative care needs: the case of Niagara.
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Advances in secondary prevention of stroke.
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Neuroprotection (focal ischemia) and neurotoxicity (electroencephalographic) studies in rats with AHN649, a 3-amino analog of dextromethorphan and low-affinity N-methyl-D-aspartate antagonist.
AHN649, an analog of dextromethorphan (DM) and a relatively selective low-affinity N-methyl-D-aspartate antagonist, was evaluated for neuroprotective effects using the rat intraluminal filament model of temporary middle cerebral artery occlusion. Rats were subjected to 2 h of focal ischemia followed by 72 h of reperfusion. In vehicle-treated rats, middle cerebral artery occlusion resulted in neurological deficits and severe infarction measuring 232 +/- 25 mm(3), representing approximately 25% contralateral hemispheric infarction. Post-treatment with AHN649 (0.156-20 mg/kg i.v.) or DM (0.156-10 mg/kg i.v.) significantly reduced cortical infarct volume by 40 to 60% compared with vehicle-control treatments. AHN649 neuroprotection was linear and dose dependent (ED(50) = 0.80 mg/kg), whereas DM neuroprotection (ED(50) = 1.25 mg/kg) was nonlinear and less effective at the higher doses (2.5-10 mg/kg). Although impaired neurological function scores improved in all groups by 24 to 72 h, the most dramatic improvement was associated with AHN649 treatments. In a rat electroencephalographic model of brain function, separate neurotoxicity experiments revealed that acute i.v. doses of DM caused seizures (ED(50) = 19 mg/kg) and death (LD(50) = 27 mg/kg). In contrast, AHN649 failed to induce seizure activity at doses up to 100 mg/kg (LD(50) = 79 mg/kg). Collectively, AHN649 is described as a potent, efficacious neuroprotective agent devoid of serious central nervous system neurotoxicity and possessing potential therapeutic value as antistroke treatment. Furthermore, the feasibility of targeting low-affinity N-methyl-D-aspartate-site ligands as postinjury therapy for ischemic brain injury has been confirmed.
The expression of genes in the ubiquitin-proteasome proteolytic pathway is increased in skeletal muscle from patients with cancer.
BACKGROUND: The intracellular mechanisms of muscle cachexia in patients with cancer are not known. To assess the role of the ubiquitin-proteasome proteolytic pathway in cancer-induced muscle breakdown, we determined messenger RNA levels for ubiquitin and several 20S proteasome subunits in muscle from patients undergoing surgery for cancer METHODS: A biopsy specimen was obtained from the rectus abdominis muscle in patients undergoing laparotomy for cancer (n = 6) or noncancer disease (n = 6). Tissue levels of mRNA for ubiquitin and the 20S proteasome subunits HC3, HC5, HC7, and HC9 were determined by dot blot analysis. RESULTS: The mRNA levels for ubiquitin and the 20S proteasome subunits were 2 to 4 times higher in muscle from patients with cancer than in muscle from control patients. CONCLUSION: This is the first report of increased expression of genes in the ubiquitin-proteasome proteolytic pathway in muscle tissue from patients with cancer. Cancer-induced muscle catabolism may at least in part reflect ubiquitin-proteasome-dependent protein breakdown.