Reversal of epidermal hyperproliferation in psoriasis by insulin-like growth factor I receptor antisense oligonucleotides.

Epidermal hyperplasia is a key feature of the common skin disorder psoriasis. Stimulation of epidermal keratinocytes by insulin-like growth factor I (IGF-I) is essential for cell division, and increased sensitivity to IGF-I may occur in psoriasis. We hypothesized that inhibition of IGF-I receptor expression in the psoriasis lesion would reverse psoriatic epidermal hyperplasia by slowing the rate of keratinocyte cell division. Here we report the use of C5-propynyl-dU,dC-phosphorothioate antisense oligonucleotides to inhibit IGF-I receptor expression in keratinocytes. We identified several inhibitory antisense oligonucleotides and demonstrated IGF-I receptor inhibition in vitro through an mRNA targeting mechanism. Repeated injection of these oligonucleotides into human psoriasis lesions, grafted onto nude mice, caused a dramatic normalization of the hyperplastic epidermis. The findings indicate that IGF-I receptor stimulation is a rate-limiting step in psoriatic epidermal hyperplasia and that IGF-I receptor targeting by cutaneous administration of antisense oligonucleotides forms the basis of a potential new psoriasis therapy.

Oligonucleotide uptake in cultured keratinocytes: influence of confluence, cationic liposomes, and keratinocyte cell type.

The success of anti-sense strategies has been limited, at least in part, by the poor uptake of these agents into the target cells. In keratinocytes, there is conflicting evidence as to the amount and location of oligonucleotide uptake into these cells, with variable proportions of cells reported to take up oligodeoxynucleotide, and also cytoplasmic and nuclear localization reported. In this study, the uptake of oligodeoxynucleotides in cultured normal human keratinocytes and the HaCaT cell line was quantitated in the presence of various lipids designed to enhance uptake and in varying culture conditions. About 12% of cells in a confluent normal human keratinocyte culture showed nuclear uptake, with a small and variable proportion showing cytoplasmic localization after 24 h incubation with 1 microM oligodeoxynucleotide. Uptake of oligodeoxynucleotide was found to be increased by liposome encapsulation (to a maximum of 28.1% +/- 2.1% of cells), low confluence (39.5% +/- 2.5%), and further increased by a combination of the two conditions (55.4% +/- 4.3%). HaCaT cell populations showed sparse but consistent uptake of oligodeoxynucleotide, with about 1% of cells showing nuclear localization in the presence of 1 microM oligodeoxynucleotide, increasing to 13.5% +/- 4.9% in the presence of cationic lipid (Tfx-50) in low confluence HaCaT monolayers. We conclude that normal keratinocytes exhibit reliable, substantial uptake of oligonucleotides in conditions controlled for confluence and aided by liposome encapsulation.

Preoperative evaluation of patients with peripheral vascular disease.

Coronary artery disease is the leading cause of death after revascularization procedures for abdominal aortic aneurysms and peripheral vascular disease. Late survival after vascular procedures is substantially reduced, largely by the high incidence of subsequent cardiac events. At the Lahey Clinic, it is not our practice to perform routine coronary angiography before elective revascularization. Thallium myocardial perfusion imaging should be performed in all patients before operation. Abnormal results on thallium exercise scanning showing multiple perfusion abnormalities or lung uptake at peak exercise identify patients who are candidates for preoperative cardiac catheterization. When severe correctable coronary artery disease is identified, these patients should be considered for coronary artery bypass surgery before vascular operation.

The impact of an inpatient physician program on quality, utilization, and satisfaction.

OBJECTIVE: To evaluate an inpatient physician system initiated in June 1996 for all patients of a health maintenance organization admitted to the general medicine service of an urban teaching hospital. In the new program, attending physician duties were transferred from the patient's own general internist to another internist serving on a hospital-based rotation. STUDY DESIGN: Cohort with historical controls. PARTICIPANTS AND METHODS: We compared the following measures before and after the new inpatient physician program began: (1) hospital length of stay and total charges, (2) outcomes related to quality of care, (3) primary care physician satisfaction, and (4) housestaff satisfaction. Differences before and after initiation of the inpatient physician program were evaluated using multivariate analyses to adjust for patient differences and secular trends. RESULTS: There were 2265 patients discharged from the general medical service in the year following implementation of the inpatient physician program. Postintervention average length of stay decreased from 3.5 to 3.0 days (P < .001). In multivariate analyses, average length of stay was reduced by 0.3 days (P = .008), and total hospital charges were reduced an average of $426 per admission (P = .001). In-hospital mortality rates, percentage of patients discharged home directly, and 30-day readmission rates did not change significantly in the postintervention period. Satisfaction among primary care physicians was high, with 90% of those answering a survey responding that they would recommend a similar program to other primary care groups. Medical housestaff satisfaction with their educational experience also increased. CONCLUSIONS: Implementation of an inpatient physician program at this institution significantly decreased resource utilization while maintaining or improving quality of care. Satisfaction with the program was high among primary care internists and housestaff.

Importance of valvular incompetence after acute deep venous thrombosis.

The color Doppler scanner was used to analyze acute deep venous thrombosis in 14 patients. A thrombus was found in the superficial femoral vein in 4 patients and in the superficial femoral and popliteal veins in 6 patients; a popliteal occlusion was found in 4 patients. All 14 patients were treated with intravenous heparin followed by at least 3 months of warfarin therapy. Patients were re-examined between 24 and 48 months. Six patients were symptomatic; 8 were asymptomatic. Five patients had occluding thrombus in the distal popliteal vein; major competent collateral channels developed from the proximal superficial femoral vein, and they remained asymptomatic. Three patients whose superficial femoral veins recanalized without valvular incompetence were asymptomatic. Valvular incompetence was observed in all of the symptomatic patients. Patients with persistent popliteal occlusion and collateral channels have fewer symptoms than patients with valvular incompetence in the superficial femoral and popliteal veins.