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Biomedical subjects

J M Ford

Publications and source records attributed to J M Ford.

At least 55 records · Page 3Linked to original sources
PubMed1996

Sclerosis of lytic metastatic bone lesions during treatment with pamidronate in a patient with adenocarcinoma of unknown primary site.

Pamidronate disodium is a second-generation biphosphonate, a group of compounds that are being used increasingly to inhibit bone resorption in disorders that are characterized by excessive bone loss such, as hypercalcemia of malignancy, osteoporosis, and Paget's disease. The precise mechanisms whereby bisphosphonates inhibit bone resorption are still not completely understood. Pamidronate has previously been reported to induce sclerosis of lytic bone metastases in patients with breast cancer. We have had a similar experience in a patient with multiple bone metastases due to adenocarcinoma of unknown primary site who developed massive consolidation of lytic bone lesions after therapeutic infusions of pamidronate, leading to a satisfactory quality of life.

Adenocarcinoma↗
PubMed1996

Variability in the plasma protein binding of velnacrine (1-hydroxy tacrine hydrochloride). A potential agent for Alzheimer's disease.

OBJECTIVES: To quantify the protein binding of velnacrine in healthy individuals and investigate potential sources of variability. SETTING: Medical School Unit, Southmead Hospital, Bristol. SUBJECTS: Plasma samples were obtained from the following groups: a) 11 healthy volunteers aged 18 to 30 years; b) 10 healthy volunteers aged 73 to 87 years; c) 10 patients aged 65 to 85 years hospitalised for a variety of acute illnesses. METHODS: Aliquots of plasma from the above subjects were incubated with various concentrations of velnacrine, in the presence and absence of tacrine hydrochloride. Standard solutions of human serum albumin and alpha 1 acid glycoprotein were incubated with velnacrine. The degree of protein binding was determined using the Amicon centrifree micropartition system. RESULTS: 1) Over the range of concentrations from 10 to 320 ng.ml-1, there was a decrease in protein binding from 59.1 to 46.7%. 2) At 40 ng.ml-1 the plasma protein binding of velnacrine was 54.8% in the group a subjects, 51.9% in the group b subjects and 53.0% in the group c subjects (NS). 3) The mean total plasma protein concentration was significantly lower in the samples from elderly subjects. The mean albumin and alpha 1 acid glycoprotein concentrations were lower and higher respectively in patients with acute disease. 4) Velnacrine was shown to bind to both albumin and alpha 1-acid glycoprotein, but together they did not account for total binding. 5) The binding of velnacrine was significantly decreased from 59.3 to 43.9% in the presence of a therapeutic concentration (25 ng.ml-1) of THA. There was no evidence that velnacrine displaced THA. CONCLUSION: Protein binding can be discounted as a major source of variation in the relationship between drug concentration and effect.

Acute Disease↗
PubMed1996

N400 evidence of abnormal responses to speech in Alzheimer's disease.

The status of semantic priming in Alzheimer's disease (AD) was examined using the speech elicited N400 component of the event-related brain potential (ERP). Speech was naturally paced, with 1 s of silence before the final word. In the semantic task, subjects attended to the meaning of the sentences for a subsequent memory test. In the phonemic monitoring task, they counted the words beginning with the letter 'p'. The effects of age were assessed by comparing young and elderly, and the effects of disease by comparing elderly and AD subjects. In healthy young and elderly subjects, N400s were large to semantically unprimed words and small to semantically primed words. In AD subjects, N400s were large to primed words, reflecting a failure of the sentence stem to prime the final word, and probably an impairment in semantic knowledge. The N400 priming effect was not smaller during the phonemic than semantic task in any group, suggesting that the semantic qualities of speech are processed even when subjects are attending to phonemic qualities. N400 latency was delayed with age and further delayed with dementia.

Adult↗
PubMed1996

Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: results from a multinational randomized controlled trial. The Aredia Multinational Cooperative Group.

PURPOSE: Bone metastases are a major cause of morbidity in breast cancer, resulting in complications that include pain, loss of mobility, pathologic fracture, and tumor-induced hypercalcemia (TIH). Inhibition of osteoclast-mediated bone destruction using bisphosphonates represents a promising new management approach. PATIENTS AND METHODS: Breast cancer patients with bone metastases were randomly allocated to receive chemotherapy alone (152 patients) or chemotherapy plus pamidronate 45 mg in 250 mL of saline as a 1-hour intravenous infusion every 3 weeks (143 patients). Whenever possible, treatment continued until progression of disease (PD) in bone appeared on radiographs or bone scan. Time to PD in bone and pain reduction according to a self-assessment six-point scale were selected as primary end points. PD in bone was verified during extramural review (EMR) of all imaging studies by blinded observers, and these data were used as the main efficacy criterion. Analgesic intake, World Health Organization (WHO) performance status, and complications of bone metastases (radiotherapy, TIH, fractures, orthopedic surgery) were also compared in the two groups. RESULTS AND CONCLUSION: At EMR, median time to PD in bone was increased by 48% in patients who received pamidronate (249 v 168 days; P = .02, Wilcoxon test). Marked pain relief, defined as a two-point decrease lasting for > or = 6 weeks, was reported by 44% of pamidronate patients and by 30% of controls (P = .025, chi 2 test). The infusions (median, nine per patient; range, 0 to 39) were well tolerated, with no major toxicities reported. Pamidronate by repeated infusion can significantly slow the progression of bone metastases and reduce attendant morbidity.

Adult↗
PubMed1995

Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance.

We investigated whether mutations in the p53 tumor suppressor gene alter UV sensitivity and/or repair of UV-induced DNA damage in primary human skin fibroblasts from patients with Li-Fraumeni syndrome, heterozygous for mutations in one allele of the p53 gene (p53 wt/mut) and sublines expressing only mutant p53 (p53 mut). The p53 mut cells were more resistant than the p53 wt/mut cells to UV cytotoxicity and exhibited less UV-induced apoptosis. DNA repair analysis revealed reduced removal of cyclobutane pyrimidine dimers from overall genomic DNA in vivo in p53 mut cells compared with p53 wt/mut or normal cells. However, p53 mut cells retained the ability to preferentially repair damage in the transcribed strands of expressed genes (transcription-coupled repair). These results suggest that loss of p53 function may lead to greater genomic instability by reducing the efficiency of DNA repair but that cellular resistance to DNA-damaging agents may be enhanced through elimination of apoptosis.

Apoptosis↗
PubMed1995

Elderly men and women are less responsive to startling noises: N1, P3 and blink evidence.

Previously we observed that the P3 component of the event-related brain potential (ERP) elicited by startling noises, and to a lesser extent P3 to target tones, is reduced in the elderly (Ford & Pfefferbaum, 1991). In the current experiment, we tried to eliminate possible effects of age-related hearing deficits on the responses to noises by filtering them to include only frequencies heard best by the elderly (0-1000 Hz) and by setting noise intensity relative to each subject's threshold (sensation level, SL). Twelve younger (mean 22 years) and 12 older (mean 69 years) men and women listened to three sequences of tones (80%, 500 Hz, 70 dB SPL) and noises (20%). One type of noise occurred in each sequence (wide band noise set to 107 dB SPL, narrow band noise set to 107 dB SPL, or narrow band noise set to approximately 65 dB SL). The order of the three sequences was counterbalanced across age and sex. Younger subjects blinked to the noise 4-5 times more often than older subjects and had N1 and P3 amplitudes that were 2-3 times larger, regardless of the noise type. N1 amplitude to the background frequent tones and non-startle blinks did not differ between groups. Thus, even when noises were narrow band and set relative to each subject's threshold, older subjects were less responsive to startling auditory stimuli than were younger.

Acoustic Stimulation↗
PubMed1995

Pamidronate infusions as single-agent therapy for bone metastases: a phase II trial in patients with breast cancer.

Pamidronate is a potent biphosphonate which modulates tumour-induced osteolysis (TIO) by inhibiting osteoclast-mediated bone resorption. In a phase II trial, 69 breast cancer patients with symptomatic progressive bone metastases were given infusions of pamidronate 60 mg over 1 or 4 h every 2 weeks for a maximum of 13 infusions or until progressive disease (PD) at any site. No other systemic anticancer therapy was allowed. Pain was measured using a visual analogue scale, mobility using a detailed eight-point questionnaire and analgesic intake using a six-point scale. Improvements in pain, mobility and analgesic scores occurred in 61, 50 and 30% of patients, respectively, with 33, 21 and 16% achieving a 40% improvement for > or = 8 weeks. At trial discontinuation, baseline levels of pain and mobility had improved by 27% (P = 0.001) and 20% (P = 0.004), respectively, despite a one category reduction in analgesic intake in 27% of patients. Using this relatively high dose of pamidronate, symptomatic response was independent of the number of bone metastases and also of infusion rate. The infusions were well tolerated with no major toxicities reported. Pamidronate infusions provide useful palliation for breast cancer patients with symptomatic bone metastases.

Adult↗
PubMed1995

Modulators of multidrug resistance. Preclinical studies.

The study of the cellular, biochemical, and molecular biology and pharmacology of MDR has provided one of the most active and exciting areas within cancer research for translation into potential clinical benefit. Although convincing evidence for the functional role of P-gp in mediating clinical drug resistance in humans remains scant, studies of the clinical expression of P-gp and trials of chemosensitizers with cancer chemotherapy suggest "resistance modification" strategies may be effective in some tumors with intrinsic or acquired drug resistance. However, even if P-gp-associated MDR proves to be a relevant and reversible cause of clinical drug resistance, numerous problems remain to be solved before effective clinical chemosensitization may be achieved. Such factors as absorption, distribution, and metabolism, the effect of chemosensitizers on chemotherapeutic drug clearance, toxicity to normal tissues expressing P-gp, and the most efficacious modulator regimens all remain to be defined in vivo. Clearly, the identification of more specific, more potent, and less clinically toxic chemosensitizers for clinical use remains critical to the possible success of this approach. However, the finding that a number of pharmacologic agents can antagonize a well-characterized form of experimental drug resistance provides promise for potential clinical applications. Further study of chemosensitizers in humans and the rational design of novel chemosensitizers with improved activity should define the importance of MDR to clinically resistant cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Ultrasonic head controller for powered wheelchairs.

This report describes an evaluation by the Department of Veterans Affairs, Rehabilitation Research and Development Service, Technology Transfer Section (TTS). The Ultrasonic Head Controller Unit (UHCU) is the result of research and development conducted by the Palo Alto VA Rehabilitation Research and Development Center, under sponsorship of the Paralyzed Veterans of America and the VA Rehabilitation Research and Development Service. The UHCU provides an alternative to currently available human/machine interfaces for severely disabled individuals. Unlike switches or proportional joysticks, the UHCU operates without physical contact between the unit and the user. The UHCU produces analog signals in direct response to changes in the head position of the user. These signals can be used to control a variety of communication, robotic, mobility, and recreational devices. This clinical evaluation explored the use of the UHCU for powered wheelchair control by quadriplegic individuals.

Evaluation Studies as Topic↗
PubMed1994

ERPs in schizophrenia: effects of antipsychotic medication.

Thirty unmedicated schizophrenics were compared to 29 age-matched controls on auditory and visual event-related brain potential (ERP) paradigms. Twenty-one of these patients were tested again after 1 week on placebo and after 4 weeks on antipsychotic medication. Before treatment, N1, N2, and P3 components of the auditory ERP were smaller in the schizophrenics than in the controls. Although visual N2 was smaller in schizophrenics, visual P3 was not. In spite of significant clinical improvement with antipsychotic treatment, amplitudes of auditory and visual N1, N2, and P3 were not significantly changed. Higher blood levels of antipsychotic medication were related to reductions in auditory P3 latency, however. In addition, higher levels of cerebrospinal fluid (CSF) MHPG (methoxyhydroxyphenylglycol) were associated with larger auditory N1s and larger auditory and visual P3s, suggesting an influence of arousal on these components in schizophrenics. In spite of this influence, reduction of the auditory P3 in schizophrenia is an enduring trait of the disease, which is not affected by antipsychotic medication or clinical improvement.

Adult↗
PubMed1994

Schizophrenics have fewer and smaller P300s: a single-trial analysis.

Because P300 is typically measured from an average of single trials, variations among individual trials may account for P300 amplitude reduction so often seen in patients with schizophrenia. We tested three hypotheses regarding single-trial contribution to small average P300s in schizophrenics: normal P300s are elicited on some trials and no P300s on others, all trials have consistently small P300s, or P300 latency varies over trials. Nineteen schizophrenics and 35 controls were tested on a two-tone auditory oddball event-related potential (ERP) paradigm. ERPs recorded from the parietal electrode (Pz) were subjected to a P300-screening procedure in which a 2 Hz half-sine wave template was moved across the electroencephalogram (EEG) to find the point of best fit. If, for the point of best fit, the EEG:Template covariance was greater in the signal epoch (280-600 msec) than in the noise epoch (610-930 msec), and if the EEG:Template correlation was statistically significant, the trial passed the P300-screen and was deemed to have a P300. Three types of average ERPs were constructed: Traditional Average from all good (artifact-free, correct response) trials, P300-Screen Average from all good trials that also passed the P300-screen, and Latency Adjusted Average by aligning the P300-screen trials at the latency of maximum covariance. Traditional average ERPs were significantly smaller in schizophrenics than in controls. The results of the P300-screen confirmed all three hypotheses: schizophrenics had fewer trials passing the P300-screen, smaller P300s on each trial, and P300s that were more variable in latency across trials.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Preferential repair of ultraviolet light-induced DNA damage in the transcribed strand of the human p53 gene.

Mutations in the p53 tumor suppressor gene have been found in most human tumors. Analyses of the spectrum of p53 mutations in certain tumor types have shown a bias for mutations originating from lesions presumed to be in the untranscribed strand of the gene. This implies strand specificity for the formation or repair of DNA damage. We measured the induction and repair of ultraviolet light-induced cyclobutane pyrimidine dimers (CPD) in each strand of the human p53 gene in a normal human lung fibroblast cell line using quantitative Southern hybridization. We found that the removal of CPD from the transcribed strand was more rapid than that from the untranscribed strand of this gene, although the frequency of CPD induction was similar in both strands. Preferential repair of the transcribed strand of the p53 gene may account for the mutational spectra of this gene in human tumors.

Cells, Cultured↗
PubMed1994

Characteristics of plasma protein binding of tacrine hydrochloride: a new drug for Alzheimer's disease.

The aim of this study was to characterise the plasma protein binding of tacrine hydrochloride (THA) in vitro. Binding was assessed in the plasma of 11 healthy individuals aged 20 to 27 years using ultrafiltration followed by HPLC assay. At THA concentrations from 10 to 100 ng/ml protein binding ranged from 78.6 to 71.0%. Binding to commercially available human albumin ranged from 41.7 to 38.3% and to human alpha 1-acid glycoprotein from 23.1 to 12.4% over the THA concentrations from 25 to 100 ng/ml. THA binding and total plasma protein, plasma albumin and alpha 1-acid glycoprotein were measured in healthy young subjects (n = 13), healthy elderly individuals (n = 12) and patients hospitalised with acute illnesses (n = 8). There were significant differences between the groups in total plasma protein, plasma albumin and in alpha 1-acid glycoprotein but no differences in the protein binding of THA which remained constant at about 75%. There was no correlation between THA binding and any plasma protein concentration. The THA binding was not high enough to be of major significance clinically or to reduce the validity of total plasma THA measurement in therapeutic monitoring.

Adolescent↗
PubMed1994

The relationship between P300 amplitude and regional gray matter volumes depends upon the attentional system engaged.

Event-related potentials (ERPs) and brain magnetic resonance images (MRIs) were acquired from 28 normal men, age 21-60 years. ERPs were recorded during 3 paradigms designed to elicit automatic or effortful attention, and a combination of both. MRI-derived measures of brain gray matter, white matter and cerebral spinal fluid (CSF) volumes were computed from frontal, parietal and temporal lobes. P300 amplitude correlated significantly with gray matter volumes but not with white matter or CSF volumes. Furthermore, the relationships between P300 amplitude and gray matter volumes reflected functional rather than direct topographical relationships: P300 recorded at Pz during automatically elicited attention correlated significantly with frontal but not parietal lobe gray matter volumes, P300 recorded during effortful attention correlated significantly with parietal but not frontal lobe gray matter volumes, and P300 recorded when both types of attention were invoked correlated significantly with both frontal and parietal gray matter volumes. Startle blinks, also elicited during automatic attention-engaging paradigms, were significantly correlated with frontal but not parietal lobe gray matter volumes. There was no evidence for a direct spatial relationship between P300 amplitude and the gray matter volumes underlying the recording electrode.

Adult↗
PubMed1994

Intravenous pamidronate: infusion rate and safety.

In view of previous animal studies showing that pamidronate (Aredia) can cause renal damage, and human data indicating that pamidronate in doses of 60-90 mg is more effective in the control of tumor-induced hypercalcemia than when given at lower doses, we decided to investigate whether pamidronate 90 mg infused over 60 minutes at weekly intervals had any adverse effects on renal function in patients with bone metastases. Twelve patients, 7 female (all with breast cancer) and 5 male (4 with prostate cancer, 1 with bladder cancer) were entered into the trial. Each patient received weekly intravenous infusions of pamidronate 90 mg in 250 ml normal saline over 60 minutes for 4 weeks. 51Cr-EDTA clearances showed no significant changes in renal function. Urinary N-acetyl-B-D-glucosaminidase/creatinine ratios fluctuated considerably, but no consistent changes were found. No patient with a normal level of urinary beta 2-microglobulin had elevated levels at the end of the trial. Serum creatinine levels did not change significantly, though 1 patient had a corrected serum calcium level of < 2 mmol/L on a single occasion on day 8. No evidence of renal toxicity was detected. However, the possibility that neprohtoxicity would ultimately appear cannot be excluded, and these favourable short-term results cannot be extrapolated to patients with impaired renal function.

Adult↗
PubMed1994

Delayed progression of bone metastases with pamidronate therapy in breast cancer patients: a randomized, multicenter phase III trial.

A total of 295 patients with lytic bone metastases from breast cancer were randomized to receive chemotherapy or chemotherapy plus pamidronate (Aredia) 45 mg intravenously every 3 weeks. Primary endpoints were time to progressive bone disease (evaluated by blind extramural review), and improvement in pain (according to a 6-point self-assessment scale). Secondary endpoints included incidence of bone-related complications (pathological fractures, tumor-induced hypercalcemia, need for radiotherapy), sclerotic response of lytic lesions, WHO performance status, and analgesic score. Median time to bone progression was 249 days and 168 days in the pamidronate and control groups respectively (p = 0.02). Marked improvement in bone pain was observed in 44% of patients receiving pamidronate compared to 30% in controls (p = 0.025). With respect to secondary endpoints, pamidronate reduced the need for radiotherapy (66 times vs. 82 times in controls), and median time to radiotherapy was 697 days with pamidronate, 571 in the control arm. No severe adverse reactions or worsening of chemotherapy-induced toxicities were observed during 1598 pamidronate infusions. We conclude that intravenous pamidronate is well tolerated, significantly prolongs time to progressive bone disease, and significantly improves bone pain in patients with osteolytic metastases from breast cancer.

Adult↗