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Biomedical subjects

A Davis

Publications and source records attributed to A Davis.

At least 163 records · Page 9Linked to original sources
PubMed1996

Insulin signaling in mice expressing reduced levels of Syp.

Syp is a protein tyrosine phosphatase implicated in insulin and growth factor signaling. To evaluate the role of syp in insulin's regulation of plasma glucose, we generated knockout mice. Homozygous knockout mice die prior to day 10.5 of embryonic development. Hemizygous mice express half the levels of syp protein compared with their wild type littermates but do not display any gross morphological changes. Total body weight (age 2-10 weeks) and plasma insulin and glucose levels both in fasting and glucose-challenged states were comparable in the wild type and the hemizygous mice. No differences were observed in insulin-induced glucose uptake in soleus muscle and epididymal fat; insulin inhibition of lipolysis was also similar. We injected insulin into the portal vein of the mice to examine upstream events of the insulin signaling cascade. Tyrosine phosphorylation of insulin receptor and insulin receptor substrate-1 (IRS-1) from hemizygous tissue was similar to that of wild type tissue. Association of the p85 subunit of phosphatidylinositol 3-kinase to IRS-1 increased an average of 2-fold in both groups. We did not observe an increase of IRS-1/syp association after insulin administration, but we did note a significant basal association in both wild type and hemizygous tissue. Our results do not support a major role for syp in the acute in vivo metabolic actions of insulin.

Animals↗
PubMed1996

Treatment of advanced CNS malignancies with the recombinant adenovirus H5.010RSVTK: a phase I trial.

Primary CNS malignancies are responsible for approximately 12,000 deaths annually in the United States. There has been little change in the outcome for adults with malignant brain tumors over the past few decades, despite improvements in surgical techniques and advances in radiation therapy. These tumors are uniformly fatal one to two years after diagnosis. The morbidity and mortality of this disease arise from the effects of a locally invasive, non-metastasizing lesion. The patients may suffer from seizures, paralysis, incoordination, aphasia, confusion, memory loss, sensory deficits or visual loss, depending on the regions of the brain affected. In addition, they usually require large doses of corticosteroids early and late in their illness, and may experience disabling side effects of this treatment, such as edema, proximal myopathy, diabetes, fungal infections or deep vein thrombosis. Few patients in the older age group are able to work after the diagnosis. Most of the patients are incapable of self-care for several months before death. The localized transfer of new genes into cancer cells potentially permits the expression of proteins with specific biologic functions that may provide a means to alter the biology of tumor growth through a variety of mechanisms including increasing tumor immunogenicity, inducing the local expression of toxic agents, and sensitization of tumors to chemotherapeutic agents. Gene therapy with the transfer of the drug susceptibility gene Herpes virus thymidine kinase (HSV-TK) has shown promise in a number of animal models, including CNS tumors. This study will evaluate the use of adenovirus-mediated transfer of the HSV-TK gene into primary human brain tumors followed by systemic treatment with ganciclovir. The goals of this phase I study are to evaluate the overall safety and efficacy of this treatment and to gain insight into the parameters that may limit the general applicability of this approach. In this phase I study, patients with recurrent gliomas will receive stereotactic-guided injections of the virus into the brain tumor, followed by intravenous ganciclovir for 14 days. Patients eligible to undergo a palliative debulking procedure will receive the same treatment followed by resection on day 7. At the time of resection a second dose of virus will be administered intra-operatively into the residual, unresectable portion of the tumor, and intravenous ganciclovir will be continued for additional 14 days. Tissue removed at the time of resection will be analyzed for evidence of adenovirus infection, thymidine kinase expression and signs of inflammation. The size and metabolic activity of all tumors will be followed by volumetric MRI scans and Position Emission Tomography Scans, respectively. Patients will be enrolled in groups of three, with each group receiving successively larger doses of adenovirus. This study will quantify the toxicity of this therapy, and provide evidence as to the duration of transgene expression and virus induced inflammation.

Adenoviridae Infections↗
PubMed1996

Evaluation of blood pressure response to the combination of enalapril (single dose) and diltiazem ER (four different doses) in systemic hypertension.

Angiotensin-converting enzyme inhibitors and calcium antagonists are 2 classes of antihypertensive agents frequently used either as monotherapy or in combination. A 6-week, multicenter, randomized, double-blind, placebo-controlled trial was conducted in essential hypertensive patients (diastolic blood pressures [BP] when seated, 95-115 mm Hg) to evaluate the efficacy, dose response, and safety profiles of enalapril combined with a new once-daily formulation of diltiazem. BP and heart rate were measured at 5 (peak) and 24 (trough) hours after dose to assess the efficacy and pharmacodynamic profile of the combination given once daily. There were 336 patients randomly assigned to either enalapril 5 mg plus 1 of 4 dose levels of diltiazem ER (60, 120, 180, or 240 mg), enalapril 5 mg alone, or placebo. Each combination dose level produced statistically significant reductions (p <0.05) in trough diastolic BP when seated, compared with placebo (-6.8, -8.3, -10.1, and -10.3 mm Hg for the diltiazem ER doses of 60, 120, 180, and 240 mg, respectively). The 3 highest combination dose levels resulted in statistically significant (p <0.05) decreases in trough diastolic BP when seated, compared with placebo. There was a significant (p <0.001) linear dose-response relation. A trough-to-peak ratio > or = 0.5 was shown for the 3 highest combination doses. Drug-related adverse events were seen in 8.9% to 19% of the combination patients, 14.3% of the enalapril patients, and 8.6% of the placebo patients. The frequency and type of adverse events were those currently noted with each drug studied when used as monotherapy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Elevated protein kinase CK2 activity in chromatin of head and neck tumors: association with malignant transformation.

We hypothesized that malignant transformation of normal mucosa of the upper aerodigestive tract to squamous cell carcinoma of the head and neck (SCCHN) might be associated with altered CK2 activity in the chromatin compartment of these tumors. We measured CK2 activity in the cytosol and chromatin of 7 surgical specimens of SCCHN, and 5 specimens of normal oropharyngeal mucosa from non-smokers/non-drinkers. CK2 activity in SCCHN tumors was significantly elevated in both the nuclear chromatin (P < 0.0005) and cytosolic (P <0.04) compartments relative to normal mucosa. These data suggest that activation of dysregulation of the chromatin-associated CK2 signal may play a role in the pathobiology od SCCHN.

Amino Acid Sequence↗
PubMed1996

Soft tissue sarcoma of the extremity. Limb salvage after failure of combined conservative therapy.

PURPOSE: To assess the results of salvage therapy using surgery alone or surgery and re-irradiation for patients with locally recurrent extremity soft tissue sarcoma (STS) following conservative surgery and radiotherapy. MATERIALS AND METHODS: 25 patients with locally recurrent STS after conservative surgery and irradiation were assessed between 1990 and 1995. Two patients with concurrent systemic relapse were treated palliatively. Seven patients were not candidates for conservative re-excision and underwent amputation, 11 patients underwent conservative resection without irradiation. Seven of these patients relapsed, and five went on to receive combined conservative surgery and re-irradiation. A further five patients initially received combined retreatment, for a total of ten patients treated with combined conservative surgery and re-irradiation. Six of these ten patients were treated with brachytherapy alone, one with brachytherapy and external beam therapy, and three with external beam therapy alone. The median retreatment dose was 49.5 Gy (range 35-65 Gy), and the median cumulative soft tissue dose was 100 Gy (range 93-120 Gy). RESULTS: The median follow-up from the most recent treatment is 24 months (range 7-42 months). At the last follow-up 14 patients are alive and disease free; two are alive with local disease and four with systemic disease, and five are dead of disease. Overall local control is 19/23 (91%). The local control for patients treated with conservative excision without irradiation is 4/11 (36%) and for conservative excision with re-irradiation 10/10 (100%). Six (60%) of these patients experienced significant post-irradiation would-healing complications, but three have recovered fully. Functional scores for the entire treated group are significantly lower after treatment, as are those for patients undergoing combined surgery and re-irradiation, but 70% of those treated with conservative surgery and re-irradiation and a good or excellent post-treatment functional score. CONCLUSIONS: Combined conservative surgery and re-irradiation provided superior local control to local re-excision alone and a functional outcome superior to amputation. Combined treatment with re-irradiation should be considered the primary salvage therapy for patients who fail combined therapy and who are suitable for conservative re-excision. Systemic relapse is a significant problem, and optimal therapy should minimize the risk of local relapse after the initial therapy. Eighteen patients (72%) had a history of intralesional excision as their initial intervention, and suggests that inappropriate initial management is a risk factor for relapse after combined conservative therapy. Improvements in therapy must include the appropriate education of the primary care physicians.

Adult↗
PubMed1996

Familial paraganglioma.

Non-secreting paragangliomas are rare tumours usually present in the head and neck. We describe an unusual case of familial paraganglioma with cranial nerve palsies. After exhaustive investigation, a vagal paraganglioma, was found and excised. The positive family history of paraganglioma was of significance, although this was only present in one of five generations. The diagnosis and management of non-secreting paragangliomas is discussed.

Cranial Nerve Neoplasms↗
PubMed1996

Residual disease following unplanned excision of soft-tissue sarcoma of an extremity.

Sixty-five patients who had been referred to our unit for additional management after an unplanned excision of a soft-tissue sarcoma of an extremity at another institution were studied retrospectively to determine the prevalence of residual tumor and to identify factors that predict which patients will have a tumor following such an excision. Unplanned excision was defined as excisional biopsy or unplanned resection of the lesion without benefit of preoperative imaging and without regard for the necessity to resect the lesion with a margin of normal tissue. In each patient, histological evaluation of the specimen removed at the unplanned excision had demonstrated positive resection margins, but postoperative physical examination on our unit revealed no gross evidence of residual tumor and no tumor was identified on cross-sectional imaging of the local site. Patients who had evidence of residual disease on physical examination or on imaging were thought to have definite evidence of sarcoma at the site of the operative wound and were therefore excluded from the study. After multidisciplinary consultation, all patients had a repeat resection at our cancer center. Extensive pathological sampling of the specimen from this second procedure was carried out, with sections obtained at mean intervals of 1.2 +/- 0.7 centimeters. Nodules initially thought to indicate disease were identified grossly in twenty-seven (42 percent) of the sixty-five patients, but histological evaluation confirmed the presence of tumor in only sixteen (59 percent). Histological evidence of sarcoma was identified in seven additional patients in whom gross nodules were not apparent in the specimen. Thus, sarcoma was identified in a total of twenty-three (35 percent) of the sixty-five patients. The mean duration of follow-up was forty-six months (range, twenty-four to eighty months; median, thirty-nine months). The margins of the second resection were positive in nine (39 percent) of the twenty-three patients who had residual sarcoma. Five (22 percent) of the twenty-three had a local recurrence. Four of the five patients who had a local recurrence had positive margins on repeat resection. This rate of local recurrence (five of twenty-three patients) was significantly higher than that in the remainder of our patients who had a soft-tissue sarcoma of an extremity (sixteen [7 percent] of 227) (p = 0.03). There was no association between the detection of sarcoma at the second procedure and the initial size or grade of the tumor, the use of irradiation preoperatively, or the interval between the initial, unplanned excision and referral to our cancer center. These data indicate that it is not possible to predict which patients will have residual tumor at the site of the operative wound. Therefore, it is prudent to advise repeat excision for all patients who have had an unplanned excision of a soft-tissue sarcoma of an extremity. Unplanned excision complicates decision-making in the treatment of this disease and should be avoided.

Biopsy↗
PubMed1996

Varus osteotomy of the distal part of the femur. A survivorship analysis.

Varus osteotomy of the distal part of the femur is often the procedure of choice for the treatment of osteoarthrosis of the lateral compartment associated with genu valgum. We followed twenty-one knees (twenty patients) long term or until failure. At the most recent evaluation (average, 133 months; range, ninety-seven to 240 months), thirteen osteotomies were still successful, seven had failed, and one patient (in whom the knee had remained functional) had died. Of the seven failures, three occurred early (at twelve or twenty-four months) and four occurred late (between seventy-two and ninety-eight months). The probability of survival at ten years was 64 per cent (95 per cent confidence interval, 48 to 80 per cent), as determined with use of the Kaplan-Meier method. We concluded that, with proper selection of patients, this procedure is effective for the treatment of gonarthrosis of the lateral compartment associated with valgus deformity.

Adult↗
PubMed1996

Using audiotapes to monitor student-preceptor interactions in a decentralized clerkship.

BACKGROUND: Community-based preceptors are increasingly being used to provide clinical experiences for medical students; therefore, the issue of when and how to monitor the appropriateness of teacher-learner interactions in the clinical setting has become increasingly complex and urgent. This paper describes how an audiotaping program in a department of family medicine was designed to account for preceptor and student needs and what this audiotaping experience revealed about the teaching strengths and weaknesses of full-time and volunteer faculty. METHODS: Audiotaped case discussions between third-year students and preceptors were evaluated using a structured instrument that reflected important responsibilities of clerkship preceptors. Reviews were compared using chi-square to evaluate for significant differences between university and community preceptors in overall quality of interaction with students and in specific deficiency areas. Ninety-five percent confidence intervals were used to evaluate for significant differences in frequency of occurrence among deficiencies. RESULTS: A total of 376 audiotaped case discussions were reviewed between July 1992 and June 1994. University preceptors had significantly more "superior" interactions with students than their community peers (P < .05). However, university and community preceptors had nonsignificant differences when specific deficiency areas were compared. Deficiencies in students who were allowed to present cases and assessments occurred significantly less frequently, while deficiencies in preceptors using open-ended questions occurred significantly more frequently than deficiencies in other areas. CONCLUSIONS: This study shows that volunteer faculty performed comparably to full-time university faculty in both the frequency of deficiencies in teacher-learner interactions identified and in the types of deficiencies identified. Both university and volunteer faculty had the most deficiencies in higher-order teaching skills--those involving synthesizing and assessing student knowledge and selecting appropriate questions based on that information. Audiotaped case discussions have a potentially significant role in monitoring teacher-student interactions, particularly on decentralized clinical rotations.

Chi-Square Distribution↗
PubMed1996

Ethics and ethnicity: end-of-life decisions in four ethnic groups of cancer patients.

In the United States, principled based ethics has molded bioethics to a large extent. These ethical principles, autonomy, non-maleficence, beneficence, veracity and fidelity used in clinical ethics have embedded in them values and assumptions. This research examined the end-of-life decisions made by or for patients who are Chinese-Americans, Black-Americans, Hispanic-Americans, and Anglo-Americans. Patients, their family care-givers and their health care professionals were interviewed. These interviews plus observations in the cancer clinic raise questions about these principles and asks whether, in an ethnically diverse culture, we need to reflect on ethical absolutes and ethical relativism.

Black or African American↗
PubMed1995

Long-term follow-up of efficacy and safety of megavoltage radiotherapy in high-risk giant cell tumors of bone.

PURPOSE: Giant cell tumors of the bone are rare and have variable presentations and natural history. There may be significant functional sequelae as a result of their locally aggressive nature or as a result of treatment. We reviewed the long-term results of radiotherapy for high risk giant cell tumors to assess: the efficacy of radiotherapy and the potential late toxicity of treatment, and to determine indications for radiation treatment. METHODS AND MATERIALS: This report is a retrospective review of 21 localized giant cell tumors of the bone treated with radiotherapy between 1959 and 1991. Radiation was used in the primary management of 13 cases and for recurrent disease in eight cases. In the primary cases, two received radiotherapy as the sole modality (including a massive pelvic lesion and an advanced maxillary sinus tumor with orbital and pterygoid invasion), and in the other 11, 3 had gross residual disease following surgery and 8 had microscopic residual disease. Of eight recurrent cases, five were treated with radiotherapy alone and three with combined surgery and radiation. Sites of origin included extremity bones in nine cases, pelvis in six, spine in four, and skull in two. Extraosseous disease was apparent in 18 tumors and extended to contiguous structures in 14 (including four cases of spinal cord compression, three cases of sacral plexopathy, and one patient with temporal lobe invasion). The most common dose regimen was 35 Gy/15 fractions/3 weeks (14 cases), with varying schedules for the remainder. RESULTS: Mean follow-up time was 15.4 years (2 to 35 years). Local control was achieved in 19 of 21 patients with radiotherapy. The two failures were subsequently salvaged for an ultimate control rate of 100%. One of the two radiotherapy failures was a marginal failure and was subsequently salvaged with combined surgery and radiotherapy. No patient died of giant cell tumor. Radiotherapy was well tolerated, with no serious late toxicity. There were no cases of malignant transformation or radiation-induced cancer. CONCLUSION: Long-term results in this series indicate that radiotherapy in modest doses (35 Gy in 15 fractions or equivalent) is a safe and effective option for primary and recurrent giant cell tumors of the bone. Radiotherapy should be used if surgery would result in significant functional morbidity and should be considered in select sites where the probability of recurrence is high and there is potential for significant morbidity from tumor relapse or subsequent surgery.

Adolescent↗
PubMed1995

Use of acitretin for the skin complications in renal transplant recipients.

AIM: To review our experience using acitretin for the skin complications in renal transplant recipients. METHODS: Fifteen longterm caucasian renal transplant recipients suffering skin complications were treated with acitretin (10-50 mg daily), a second generation retinoid. Indications for its use were progressive actinic keratoses, widespread warts or recurrent skin malignancies. The therapeutic benefit was assessed by the general condition of of the skin and the number of skin malignancies excised, and the side effects by regular enquiry, skin examination and laboratory tests. RESULTS: All 15 patients reported that the skin became softer and smoother. Actinic keratoses and warts improved or disappeared. Six patients had been on acitretin for over 12 months. The number of malignancies decreased in four of these six patients. Nine patients had cutaneous side effects due to acitretin necessitating a reduction in dose in five patients and discontinuation in the remaining four patients. No patient had any disturbance of their liver or renal function tests or lipid profile. No interaction was found between cyclosporin A and acitretin (seven patients). CONCLUSIONS: Most patients treated with acitretin experienced subjective improvement and actinic keratoses and warts improved or disappeared. Its effect on the skin malignancy rate was variable. Acitretin was reasonably well tolerated. The benefits of this drug remain anecdotal, making a prospective, multicentre, placebo controlled study essential.

Acitretin↗