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Biomedical subjects

J M Ford

Publications and source records attributed to J M Ford.

At least 19 recordsLinked to original sources
PubMed2001

Cortical responsiveness during talking and listening in schizophrenia: an event-related brain potential study.

BACKGROUND: Failures to recognize inner speech as self-generated may underlie positive symptoms of schizophrenia-like auditory hallucinations. This could result from a faulty comparison in auditory cortex between speech-related corollary discharge and reafferent discharges from thinking or speaking, with misattribution of internal thoughts to external sources. Although compelling, failures to monitor covert speech (thoughts) are not as amenable to investigation as failures to monitor overt speech (talking). METHODS: Effects of talking on auditory cortex responsiveness were assessed in 10 healthy adults and 12 patients with schizophrenia (DSM-IV) using N1 event-related potentials (ERPs) to acoustic and visual probes during talking aloud, listening to one's speech played back, and silent baseline. Trials contaminated by muscle artifact while talking were excluded. RESULTS: Talking and listening affected N1 to acoustic but not to visual probes, reflecting modality specificity of effects. Patterns of responses to acoustic probes differed between control subjects and patients. N1 to acoustic probes was reduced during talking compared with baseline in control subjects, but not in patients. Listening reduced N1 equivalently in both groups. CONCLUSIONS: Although the failure of N1 to be reduced during talking was not related to current hallucinations in patients, it may be related to the potential to hallucinate.

Adult↗
PubMed2001

N1 and P300 abnormalities in patients with schizophrenia, epilepsy, and epilepsy with schizophrenialike features.

BACKGROUND: The scalp-recorded N1 and P300 components of the event-related brain potential (ERP) are commonly reduced in patients with schizophrenia but not in patients with epilepsy. Epilepsy patients with interictal chronic schizophrenialike features (EPI-SZ) provide a comparison group for determining whether the ERP amplitude abnormalities seen in schizophrenic patients are associated with shared clinical features of EPI-SZ and schizophrenic patients or overlapping pathophysiologies, or are specific to a distinct schizophrenia etiology. METHODS: Patients with schizophrenia (n = 24) were compared with normal control subjects (n = 32) and patients with epilepsy syndromes on visual and auditory oddball ERP paradigms. Epilepsy patients included those with chronic interictal schizophrenialike features (n = 6) and those without (n = 16). RESULTS: Auditory P300 amplitude was reduced in both schizophrenic and EPI-SZ patients, whose positive or negative symptoms did not differ. In contrast, N1 amplitude was reduced only in schizophrenic patients. Delays in both N1 and P300 were associated with epilepsy patients and EPI-SZ but not schizophrenic patients. CONCLUSIONS: The schizophrenialike symptoms in epilepsy probably represent a phenocopy of schizophrenia with common clinical features and some common pathophysiologies but distinct etiologies. P300 amplitude appears to be sensitive to schizophrenialike features, regardless of whether they occur in the context of schizophrenia or epilepsy. N1 amplitude reduction appears to be specific to schizophrenia, suggesting its sensitivity to the distinct etiology of schizophrenia.

Adult↗
PubMed2001

The p53-regulated cyclin-dependent kinase inhibitor, p21 (cip1, waf1, sdi1), is not required for global genomic and transcription-coupled nucleotide excision repair of UV-induced DNA photoproducts.

The p53 tumor suppressor gene is a transcriptional activator involved in cell cycle regulation, apoptosis, and DNA repair. We have shown that p53 is required for efficient nucleotide excision repair of UV-induced DNA photoproducts from global genomic DNA but has no effect on transcription-coupled repair. In order to evaluate whether p53 influences repair indirectly through cell cycle arrest following DNA damage or plays a direct role, we examined repair in vivo in human cells genetically altered to disrupt or regulate the function of p53 and p21. Both primary human fibroblasts and HCT116 colon carcinoma cells wild type for p53 but in which the p21 gene was inactivated through targeted homologous recombination showed no decrease in global repair of UV photoproducts. Human bladder carcinoma cells mutant for p53 and containing a tetracycline-regulated p21 cDNA showed no significant enhancement of repair upon induction of p21 expression. All of the cell lines, including the mismatch repair-deficient, MLH1 mutant HCT116 cells, were proficient for transcription-coupled repair. Clonogenic survival of HCT116 cells following UV irradiation showed no dependence on p21. Therefore, our results indicate that p53-dependent nucleotide excision repair does not require the function of the p21 gene product and is independent of p53-regulated cell cycle checkpoints.

Cell Line↗
PubMed2001

Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.

BACKGROUND: BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML). Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML. METHODS: We conducted a phase 1, dose-escalating trial of STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase. STI571 was administered orally to 83 patients with CML in the chronic phase in whom treatment with interferon alfa had failed. Patients were successively assigned to 1 of 14 doses ranging from 25 to 1000 mg per day. RESULTS: Adverse effects of STI571 were minimal; the most common were nausea, myalgias, edema, and diarrhea. A maximal tolerated dose was not identified. Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy. Of the 54 patients treated with doses of 300 mg or more, cytogenetic responses occurred in 29, including 17 (31 percent of the 54 patients who received this dose) with major responses (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome); 7 of these patients had complete cytogenetic remissions. CONCLUSIONS: STI571 is well tolerated and has significant antileukemic activity in patients with CML in whom treatment with interferon alfa had failed. Our results provide evidence of the essential role of BCR-ABL tyrosine kinase activity in CML and demonstrate the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer.

Adult↗
PubMed2001

Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.

BACKGROUND: BCR-ABL, a constitutively activated tyrosine kinase, is the product of the Philadelphia chromosome. This enzyme is present in virtually all cases of chronic myeloid leukemia (CML) throughout the course of the disease, and in 20 percent of cases of acute lymphoblastic leukemia (ALL). On the basis of the substantial activity of the inhibitor in patients in the chronic phase, we evaluated STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase, in patients who had CML in blast crisis and in patients with ALL who had the Ph chromosome. METHODS: In this dose-escalating pilot study, 58 patients were treated with STI571; 38 patients had a myeloid blast crisis and 20 had ALL or a lymphoid blast crisis. Treatment was given orally at daily doses ranging from 300 to 1000 mg. RESULTS: Responses occurred in 21 of 38 patients (55 percent) with a myeloid-blast-crisis phenotype; 4 of these 21 patients had a complete hematologic response. Of 20 patients with a lymphoid blast crisis or ALL, 14 (70 percent) had a response, including 4 who had complete responses. Seven patients with a myeloid blast crisis continue to receive treatment and remain in remission from 101 to 349 days after starting the treatment. All but one patient with a lymphoid blast crisis or ALL has relapsed. The most frequent adverse effects were nausea, vomiting, edema, thrombocytopenia, and neutropenia. CONCLUSIONS: The BCR-ABL tyrosine kinase inhibitor STI571 is well tolerated and has substantial activity in the blast crises of CML and in Ph-positive ALL.

Adult↗
PubMed2001

Adjuvant chemoradiotherapy for "unfavorable" carcinoma of the ampulla of Vater: preliminary report.

HYPOTHESES: Adjuvant chemoradiotherapy decreases the risk of local recurrence in patients with adenocarcinoma of the ampulla of Vater and high-risk features. Adjuvant chemoradiotherapy for this population can be administered safely and without much morbidity. DESIGN: Controlled, prospective, single-arm study. SETTING: Tertiary care referral hospital. PATIENTS: From June 1995 to March 1999, 12 patients (7 men and 5 women; median age, 66 years; age range, 38-78 years) with "unfavorable" ampullary carcinoma were treated with adjuvant chemoradiotherapy. All patients underwent pancreaticoduodenectomy, and all pathologic findings were confirmed at Stanford University Medical Center, Stanford, Calif. Unfavorable features were defined as involved lymph nodes (n = 10), involved surgical margins (n = 1), poorly differentiated histological features (n = 3), tumor size greater than 2 cm (n = 6), or the presence of neurovascular invasion (n = 4). INTERVENTIONS: Four to 6 weeks after undergoing pylorus-preserving pancreaticoduodenectomy with regional lymphadenectomy, patients began adjuvant chemoradiotherapy consisting of concurrent radiotherapy (45 Gy) and fluorouracil by protracted venous infusion (225-250 mg/m(2) per day, 7 days per week) for 5 weeks. MAIN OUTCOME MEASURES: Local recurrence, distant recurrence, overall survival rate, and treatment-related toxic effects. RESULTS: All patients completed the prescribed treatment course. Toxic effects were assessed twice a week during treatment and graded according to the National Cancer Institute Common Toxicity Criteria Scale. One patient required a treatment interruption of 1 week for grade III nausea/vomiting. No grade IV or V toxic effects were observed. At median follow-up of 24 months (range, 13-50 months), 8 of 12 patients were alive and disease free. One patient was alive but had disease recurrence. Three patients died of this disease (liver metastases). Actuarial overall survival at 2 years was 89%, and median survival was 34 months. One surviving patient developed a local recurrence and a lung lesion. Actuarial overall survival and median survival were better than in a parallel cohort with resected high-risk pancreatic cancer (n = 26) treated with the same adjuvant chemoradiotherapy regimen (median survival, 34 vs 14 months; P<.004). CONCLUSIONS: Adjuvant chemoradiotherapy for carcinoma of the ampulla of Vater is well tolerated and might improve control of this disease in patients with unfavorable features.

Actuarial Analysis↗
PubMed2001

Event-related brain potential evidence of spared knowledge in Alzheimer's disease.

The authors recorded event-related brain potentials (ERPs) to picture primes and word targets (picture-name verification task) in patients with Alzheimer's disease (AD) and in elderly and young participants. N400 was more negative to words that did not match pictures than to words that did match pictures in all groups: In the young, this effect was significant at all scalp sites; in the elderly, it was only at central-parietal sites; and in AD patients, it was limited to right central-parietal sites. Among AD patients pretested with a confrontation-naming task to identify pictures they could not name, neither the N400 priming effect nor its scalp distribution was affected by ability to name pictures correctly. This ERP evidence of spared knowledge of these items was complemented by 80% performance accuracy. Thus, although the name of an item may be inaccessible in confrontation naming, N400 shows that knowledge is intact enough to prime cortical responses.

Adult↗
PubMed2001

Protracted venous infusion 5-fluorouracil with concomitant radiotherapy compared with bolus 5-fluorouracil for unresectable pancreatic cancer.

Radiation therapy (RT) with concurrent 5-fluorouracil (5-FU) administered by protracted venous infusion (PVI) replaced our prior institutional protocol of RT with bolus administration of 5-FU as standard therapy for unresectable pancreatic cancer in 1994. In this article, we compare the treatment intensity, toxicity, and outcome for patients with unresectable pancreatic cancer treated on these sequential protocols. Fifty-four patients, 27 on each protocol, with biopsy-confirmed pancreatic cancer received chemoradiotherapy. The radiotherapy field included the gross tumor volume and regional lymph nodes to a dose of 45 Gy, followed by "boost" to the gross tumor volume to 54 Gy to 60 Gy. From 1987 to 1994, patients received concurrent 5-FU administered by bolus injection, at a dose of 500 mg/m2 on days 1 to 3 and days 29 to 31 of RT. After December 1994, 5-FU was administered by PVI (200-250 mg/m2) beginning on day 1 and continuing until the completion of RT. The chemotherapy treatment intensity was increased in the group receiving 5-FU by PVI, as evidenced by an increased average weekly and cumulative dose of 5-FU (p < 0.01). The radiotherapy treatment intensity was equivalent between the two groups. The incidence of objectively quantified toxicity was not statistically different between treatment groups. Overall survival remained poor in both treatment groups. With a median follow-up of 18 months (range: 3-30 months) for surviving patients, the 6-month, 1-year, and 2-year survivals for the PVI 5-FU-treated group versus the bolus 5-FU-treated group were 56% versus 52%, 34% versus 18%, and 22% versus 13%, respectively (p = 0.9). Radiotherapy with concomitant 5-FU by PVI results in a greater weekly and total dose of chemotherapy. The method of 5-FU administration (bolus versus PVI) did not change the RT treatment intensity, experienced toxicity, or overall survival.

Adult↗
PubMed2001

Cortical responsiveness during inner speech in schizophrenia: an event-related potential study.

OBJECTIVE: The study assessed the effects of inner speech on auditory cortical responsiveness in schizophrenia. METHOD: Comparison subjects (N=15) and patients with schizophrenia (N=15) were presented with acoustic and visual stimuli during three conditions: while subjects were silent, when spontaneous inner speech might occur; during directed inner speech, while subjects repeated a statement silently to themselves; and while subjects listened to recorded speech. N1 event-related potentials were recorded during the three conditions. RESULTS: N1 event-related potentials elicited by acoustic stimuli, but not by visual stimuli, were lower during directed inner speech than during the silent baseline condition in the comparison subjects but not in the patients. CONCLUSIONS: Abnormal auditory cortical responsiveness to inner speech in patients with schizophrenia may be a sign of corollary discharge dysfunction, which may potentially cause misattribution of inner speech to external voices.

Acoustic Stimulation↗
PubMed2001

Neurophysiological evidence of corollary discharge dysfunction in schizophrenia.

OBJECTIVE: Speaking is hypothesized to generate a corollary discharge of motor speech commands transmitted to the auditory cortex, dampening its response to self-generated speech sounds. Event-related potentials were used to test whether failures of corollary discharge during speech contribute to the pathophysiology of schizophrenia. METHOD: The N1 component of the event-related potential elicited by vowels was recorded while the vowels were spoken by seven patients with schizophrenia and seven healthy comparison subjects and while the same vowels were played back. RESULTS: In the healthy subjects, the N1 elicited by spoken vowels was smaller than the N1 elicited by played-back vowels. This reduction in N1 elicited by spoken vowels was not observed in the patients with schizophrenia. CONCLUSIONS: These findings provide direct neurophysiological evidence for a corollary discharge that dampens sensory responses to self-generated, relative to externally presented, percepts in healthy comparison subjects and its failure in patients with schizophrenia.

Adult↗
PubMed2001

Chronic myelogenous leukemia.

The treatment recommendations for chronic myelogenous leukemia (CML) are evolving rapidly. In the past year, pegylated interferon and STI571 (Gleevec, imatinib mesylate), a Bcr-Abl tyrosine kinase inhibitor, have become commercially available and non-myeloablative stem cell transplants continue to be refined. Clinicians and patients face a bewildering array of treatment options for CML. In this article Dr. Sawyer reviews the clinical results with STI571 and ongoing investigations into mechanisms of resistance to STI571. Given the newness of STI571, a practical overview on the administration of STI571 is presented by Drs. Druker and Ford, focusing on aspects such as optimal dose, management of common side effects, and potential drug interactions. The most recent data on interferon-based regimens are reviewed by Dr. Baccarani in the third section. In the last section Dr. Goldman presents recent results of allogeneic stem cell transplants, including the reduced intensity conditioning regimens. Lastly, the proposed place of each of these treatments in the management of CML patients is addressed to assist in deciding amongst treatment options for CML patients.

Antineoplastic Agents↗
PubMed2001

Patterns of chemotherapy administration in patients with intermediate-grade non-Hodgkin's lymphoma.

Records from 653 patients treated between 1991 and 1998 in the Oncology Practice Patterns Study (OPPS) were analyzed to determine contemporary chemotherapy delivery patterns in patients with intermediate-grade non-Hodgkin's lymphoma (NHL). Of the 653 patient records reviewed, 90 (14%) omitted an anthracycline or mitoxantrone (Novantrone) from primary therapy. Among patients receiving CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone) or CNOP (cyclophosphamide, mitoxantrone, vincristine, prednisone), 134 (27%) of 492 received an average relative dose intensity of less than 80% of the literature-referenced dose, due either to an inadequate planned or delivered dose. Of 181 advanced-stage patients with responsive disease, 28 (15%) failed to receive at least six treatment cycles. Overall, 283 (43%) of 653 patients potentially received suboptimal chemotherapy due either to choice of regimen or chemotherapy delivered. Patient age > or = 65 years and cardiac comorbidity appeared to have the greatest influence on a physician's decision regarding chemotherapy administration. Among the 492 patients who received CHOP or CNOP, 235 (48%) experienced a delay or reduction in chemotherapy dose (usually neutropenia-related), 100 (20%) developed mucositis, and 116 (24%) were hospitalized for febrile neutropenia. Growth factor was administered to 261 patients (53%), and its primary prophylactic use was associated with a significant reduction in the incidence of hospitalizations for febrile neutropenia in all patient subgroups receiving appropriate chemotherapeutic dose intensity (P = .02). This assessment of chemotherapy delivery to patients with intermediate-grade NHL showed significant variation from current standards. Further analysis of factors influencing chemotherapy delivery might improve therapeutic outcomes.

Adolescent↗
PubMed2000

Adjuvant radiotherapy and concomitant 5-fluorouracil by protracted venous infusion for resected pancreatic cancer.

PURPOSE: To assess the toxicity and clinical benefit from adjuvant chemoradiotherapy consisting of protracted venous infusion 5-fluorouracil (5-FU) and concomitant radiotherapy in patients with resected pancreatic cancer. METHODS AND MATERIALS: Between 1994 and 1999, 52 patients who underwent pancreaticoduodenectomy received adjuvant chemoradiotherapy. The tumor bed and regional nodes received a dose of 45 Gy in fractions of 1.8 Gy followed by boost to the tumor bed if the surgical margins were involved (total dose, 54 Gy). The patients also received concomitant 5-FU by protracted venous infusion (200-250 mg/m(2)/day, 7 days/week) during the entire radiotherapy course. RESULTS: Fifty-two patients (30 men, 22 women) were enrolled and treated on this protocol. The median age was 63 years (range, 38-78 years), and the median Karnofsky Performance Status was 80 (range, 70-100). Thirty-five percent had involved surgical margins and 59% had involved lymph nodes. All patients completed therapy, and there were no Grade IV/V toxicities observed. With median follow-up of 24 months (range, 3-52 months) for surviving patients, the median survival is 32 months, and 2-year and 3-year survivals are 62%, and 39%, respectively. CONCLUSION: Radiotherapy with concomitant 5-FU by protracted venous infusion as adjuvant treatment for resected pancreatic cancer is well tolerated. This approach allows for greater dose intensity with reduced toxicity. The median survival of this cohort of patients compares favorably with our earlier experience and other published series.

Adult↗
PubMed2000

Decreased UV sensitivity, mismatch repair activity and abnormal cell cycle checkpoints in skin cancer cell lines derived from UVB-irradiated XPA-deficient mice.

Xeroderma pigmentosum group A gene (XPA)-deficient mice are defective in nucleotide excision repair (NER) and are therefore highly sensitive to ultraviolet (UV)-induced skin carcinogenesis. We established cell lines from skin cancers of UVB-irradiated XPA-deficient mice to investigate the phenotypic changes occurring during skin carcinogenesis. As anticipated, the skin cancer cell lines were devoid of NER activity but were less sensitive to killing by UV-irradiation than the XPA(-/-) fibroblast cell line. The lines were also more resistant to 6-thioguanine (6-TG) than XPA(-/-) and XPA(+/+) fibroblasts, which was suggestive of a mismatch repair (MMR) defect. Indeed, in vitro mismatch binding and MMR activity were impaired in several of these cell lines. Moreover, these cell lines displayed cell cycle checkpoint derangements following UV-irradiation and 6-TG exposure. The above findings suggest that MMR downregulation may help cells escape killing by UVB, as was seen previously for methylating agents and cisplatin, and thus that MMR deficient clones are selected for during the tumorigenic transformation of XPA(-/-) cells.

Animals↗
PubMed2000

P300 reduction and prolongation with illness duration in schizophrenia.

BACKGROUND: The P300 component of the auditory event-related potential (ERP) is both reduced in amplitude and delayed in schizophrenia. P300 is prolonged and, less consistently, reduced with normal aging. Additional latency delays are observed in neurodegenerative disorders. We asked whether P300 is reduced and delayed with longer illness duration in schizophrenia, consistent with a neurodegenerative process. METHODS: P300 amplitude and latency were recorded to infrequent auditory target stimuli from 35 men with schizophrenia (DSM-III-R) and 26 control men. Effects of current age, age of onset, and duration of illness on P300 were assessed using regression analysis. RESULTS: P300 amplitude showed no age-related decrease in either group; however, among schizophrenic participants, P300 amplitude correlated positively with onset age and negatively with illness duration. P300 latency correlated positively with age in schizophrenic participants and also tended to increase with age in controls. Slopes of the latency-age relationships were significantly greater in schizophrenic participants than in control participants. Latency also correlated positively with illness duration but showed no relationship to onset age. CONCLUSIONS: P300 amplitude and latency are reduced and delayed with longer illness duration in schizophrenia, consistent with a progressive pathophysiological process. Reduced P300 amplitude may also be a marker of an early onset variant of schizophrenia.

Adult↗
PubMed2000

Trait and state aspects of P300 amplitude reduction in schizophrenia: a retrospective longitudinal study.

BACKGROUND: The P300 component of the auditory event-related brain potential (ERP) is consistently reduced in schizophrenia. Longitudinal data are examined to determine whether P300 amplitude is a trait marker of schizophrenia or a state marker tracking clinical fluctuations over time. METHODS: Schizophrenic men (DSM-III-R) (n = 36) received ERP and the Brief Psychiatric Rating Scale (BPRS) assessments on multiple occasions, at varying intervals, under varying medication states. Automatically elicited auditory P3a and effortfully elicited auditory and visual P3b amplitudes were assessed. Brief Psychiatric Rating Scale scores were regressed on P300 amplitude within patients using both multiple regression models and nonparametric analyses of individual patient slopes. Event related brain potentials in patients were compared to ERPs from 34 age-matched control men, and stability of P300 over time was estimated with intraclass correlations. RESULTS: P300 amplitude, regardless of elicitation method or sensory modality, tracked BPRS Total and positive symptom scores over time, decreasing with symptom exacerbations and increasing with improvements. In addition, effortful auditory and visual P3b amplitudes tracked negative symptoms, and automatic auditory P3a tracked depression-anxiety symptoms. When analyses were limited to unmedicated occasions, auditory P3a and P3b persisted in tracking BPRS Total scores, with additional tracking of positive symptoms by P3b and mood symptoms by P3a. Mean auditory and visual P3bs, averaged over all measurement occasions for each individual, were inversely related to mean negative symptoms. Auditory P3a and P3b, but not visual P3b, amplitudes were smaller in patients than control subjects, even when patients were least symptomatic. P300 amplitudes showed high test-retest reliability in control subjects and patients and moderate stability over time in patients. CONCLUSIONS: Auditory, and possibly visual, P300 amplitudes track fluctuations in clinical state, but only auditory P300 amplitude is a trait marker of schizophrenia.

Adult↗
PubMed2000

Left temporal deficit of P300 in patients with schizophrenia: effects of task.

P300 is often, but not always, observed to be more reduced over left than right temporal lobes in patients with schizophrenia. The possibility that task differences contribute to the inconsistency in the literature was explored in this study. ERPs were collected from 17 right-handed men with schizophrenia (DSM-IIIR) and 11 right-handed healthy male community controls, performing three auditory oddball tasks - respond to a target tone by: (1) counting; (2) pressing a response button with the right index finger; or (3) pressing a response button with the left index finger. Although patients with schizophrenia had smaller and later P300 amplitudes than controls, they did not have smaller P300s over the left temporal scalp (T3) than over the right (T4). P300 recorded over the left (C3) and right (C4) motor cortices indicated sensitivity to responding hand, with greater negativity being associated with contralateral button pressing. Failure to find P300 asymmetry is not related to the presence or absence of a button pressing task, or the hand used for button pressing. Rather, P300 asymmetry may be related to structural neuroanatomical asymmetries.

Adult↗