Biomedical subjects
Publications and source records attributed to N Lawrence.
UAL has not provided the promised ideal of "fat dissolution without surgery." In extremely fibrous areas and second procedure liposuction, internal UAL may be a valuable tool once it is further perfected. UAL equipment continues to evolve and as it improves we hope to see a better safety profile, a mechanism for smaller entrance sites, and greater time efficiency in the procedure.
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ZD1694 (Tomudex, raltitrexed) is a specific quinazoline antifolate thymidylate synthase inhibitor that relies on polyglutamation for high potency. Antibodies to ZD1694 have been used to establish a sensitive radioimmunoassay as an alternative to high-performance liquid chromatography (HPLC). The radioimmunoassay is reproducible, accurate and provides a means of determining low levels of ZD1694 in plasma (< 1 nM). By virtue of the high cross-reactivity of the antibodies with polyglutamated forms of ZD1694, it is also possible to measure the total concentration of drug in tissues. Results obtained in L1210 mouse leukaemia cells and in mouse tissues were similar to those previously determined using radiolabelled drug. Pharmacokinetic studies in mice have confirmed that the compound is rapidly eliminated from the plasma and that there is a prolonged terminal elimination phase. ZD1694 was measured in plasma (0.56 ng ml(-1); 1.2 pmol ml(-1)) up to 7 days after a single i.p. dose of 100 mg kg(-1) ZD1694. Liver, kidney and gut epithelium had a substantially higher level of ZD1694 immunoreactivity than plasma. For example, 24 h after a single i.p. dose at 1, 10 and 100 mg kg(-1), total drug levels in the liver were 480, 325 and 152 times higher than plasma levels respectively. In kidney and gut epithelium, total drug levels at these doses were approximately 55 and 34 times those of plasma. The high tissue to plasma ratios were maintained for at least 7 days after administration. Similarly, high tissue to plasma ratios (> 100) were found in dogs treated with a clinically relevant dose of ZD1694. These were maintained for 4 weeks in liver and kidney tissue (> 100). Total gastrointestinal concentrations of ZD1694 were approximately 10 times higher than plasma 3 days after administration, but levels were near to the limit of detection at 4 weeks. These results are consistent with extensive polyglutamation of ZD1694 within tissues in both mice and dog and provide further support for the infrequent schedule that has been used clinically. Although it has not been possible to measure individual polyglutamated forms of ZD1694, the radioimmunoassay provides a convenient means of assessing total drug levels in tissues and is currently the only method suitable for measuring the extent of drug retention in normal tissue and tumour biopsies obtained from patients treated with ZD1694.
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BACKGROUND: Melasma can be resistant to topical therapy. OBJECTIVE: Our purpose was to evaluate the efficacy of superficial peels in conjunction with topical tretinoin and hydroquinone in patients with melasma and to evaluate the ability of Wood's light examination to predict response to treatment. METHODS: We measured increased light reflectance in melasma areas with a colorimeter. Clinical observations were scored through an index designed to weigh numerically homogeneity, intensity of color, and area of melasma. RESULTS: Colorimetric analysis showed an average lightening of 3.14 +/- 3.1 on the glycolic acid-treated side and 2.96 +/- 4.84 on the Jessner's solution-treated side. There was no statistically significant difference between the right and left. There was an overall decrease in melasma area and severity of 63%. CONCLUSION: Superficial peels hasten the effects of topical therapy in melasma. Wood's light examination did not help predict response to treatment.
BACKGROUND: Few studies have examined the long-term efficacy of fluorouracil (FU) or chemical peels for the treatment of actinic keratoses (AK). Our earlier work examined the efficacy and safety of a medium-depth chemical peel compared with the standard regimen of topical FU in the treatment of widespread facial AK through 12 months. OBJECTIVES: To determine long-term efficacy of both treatments by extending our observations through 32 months. METHODS: Fifteen patients with severe facial actinic damage were treated on the left side with a single application of Jessner's solution and 35% trichloroacetic acid and on the right side with twice daily applications of 5% FU cream for 3 weeks. Parameters evaluated at 1, 6, 12, and 32 months included counts of visible AK, random skin biopsies from both treatment areas, development of intercurrent neoplasms, and surveys assessing sun exposure. RESULTS: Eight patients were available for reevaluation at 32 months. Both treatment sides showed a reduction in mean number of AK at 12 months followed by an increase in mean AK number between 12 and 32 months. Improvements in biopsies of clinically actinically damaged skin were seen in keratinocytic atypia, hyperkeratosis, parakeratosis, and inflammation at all treatment times during the study with both treatments. Three squamous cell carcinomas developed in the patients after initial treatment; one developed on the side treated with the peel, and two developed on the side treated with fluorouracil. Surveys failed to demonstrate an association between sun exposure and clinical response. CONCLUSION: Based on these findings, patient with widespread actinic keratoses treated with medium-depth chemical peel or with 5% FU should be reevaluated yearly or every 1.5 years for reappearance of AK and retreatment.
The use of ultrasound to facilitate liposuction is a new and potentially exciting area of clinical and research interest. Whether or not this will result in important changes in the practice of liposuction remains to be determined.
This study was designed to investigate postprandial responses to a mixed meal in simulated shift work conditions. Nine normal healthy subjects (six males and three females) were studied on two occasions at the same clock time (1330 h) after consuming test meals, first in their normal environment and secondly after a 9 h phase advance (body clock time 2230 h). Plasma glucose, insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), triacylglycerol (TAG) and non-esterified fatty acids (NEFAs) were determined at intervals for 6 h after each test meal. Postprandial plasma glucose, insulin, GIP and GLP-1 profiles were evaluated by calculating areas under the curve (AUC) for the first 2 h and the last 4 h of the sampling together with total AUC. Significantly higher postprandial glucose responses (total AUC) were observed after the phase shift than before (AUC 0-360 min, 2.01 (1.51-2.19) vs 1.79 (1.56-2.04) mmol/l.min; P < 0.02; mean (range)). No significant difference was observed when the first 2 h of each response was compared, but significantly higher glucose levels were observed in the last 4 h of the study after the phase shift than before (AUC 120-360 min, 1.32 (1.08-1.42) vs 1.16 (1.00-1.28) mmol/l.min; P < 0.05). Similar results were obtained for insulin (AUC 0-360 min, 81.72 (30.75-124.97) vs 58.98 (28.03-92.57) pmol/l.min; P < 0.01; AUC 120-360 min, 40.73 (16.20-65.25) vs 25.71 (14.25-37.33) pmol/l.min; P < 0.02). No differences were observed in postprandial plasma GIP and GLP-1 responses before and after the phase shift. Postprandial circulating lipid levels were affected by phase shifting. Peak plasma TAG levels occurred 5 h postprandially before the phase shift. Postprandial rises in plasma TAG were significantly delayed after the phase shift and TAG levels continued to rise throughout the study. Plasma postprandial NEFA levels fell during the first 3 h both before and after the phase shift. Their rate of return to basal levels was significantly delayed after the phase shift compared with before. This study demonstrates that a simulated phase shift can significantly alter pancreatic B-cell responses and postprandial glucose and lipid metabolism.
CB30900 is a novel, potent thymidylate synthase inhibitor which can not be polyglutamated and may be active in cancers expressing low or defective folylpolyglutamate synthetase. Pharmacokinetics were studied in mouse tumors and tissues after bolus or infusion protocols. Elimination was triphasic after 100 mg kg-1 i.v. (T 1/2 alpha, 2.8 min; T 1/2 beta, 19.1 min and T 1/2 gamma, 4.1 hr). Peak concentrations were 716 microM; clearance, 1.19 ml g-1 hr-1; and area under the curve (AUC 0-2 hr), 131 microM hr. Biphasic elimination occurred after i.p. administration and was comparable to the i.v. route giving complete i.p. bioavailability. Kidney concentrations were similar to plasma (AUC 0-2 hr, 84.3 microM hr). CB30900 concentrations in the gut increased steadily with time (AUC 0-2 hr, 645 microM hr) and liver drug concentrations were 7-fold greater than plasma (AUC 0-2 hr, 847 microM hr). Peak tumor concentrations occurred at 30 min and were 27% of plasma concentrations, but tumor drug clearance was markedly slower than for plasma (T 1/2, 51 +/- 8.2 min, mean +/- S.E.). CB30900 was remarkably stable in vivo with 93% of an administered dose recovered unchanged after 48 hr. Plasma drug binding was concentration-dependent, ranging from 93.3 to 76% over 1 to 500 microM. During 24 hr infusion (50 mg kg-1 s.c.), steady-state plasma concentrations were 3 microM, giving an AUC 0-24 hr of 71 microM hr. Kidney drug levels were similar to plasma but liver concentrations were elevated 7-fold. By contrast, tumor drug concentrations were about 0.5 microM (AUC 0-24 hr, 14.6 microM hr). However, these low plasma drug concentrations are growth inhibitory in vitro (24-hr exposure).
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BACKGROUND AND DESIGN: We compared the efficacy and safety of a medium-depth chemical peel with those of the standard regimen of topical fluorouracil in the treatment of widespread facial actinic keratoses (AK). Fifteen patients with severe facial actinic damage and similar numbers of AK on both sides of the face were treated on the left side with a single application of Jessner's solution and 35% trichloroacetic acid and on the right side with twice daily applications of 5% fluorouracil cream for 3 weeks. Evaluations were conducted before treatment and at 1, 6, and 12 months after treatment. Visible AK were counted, random skin biopsies performed, adverse effects monitored, and patients questioned about preference and perception of efficacy. RESULTS: Both treatments reduced the number of visible AK by 75% and produced equivalent reductions in keratinocyte atypia, hyperkeratosis, parakeratosis, and inflammation, with no significant alteration of preexisting solar elastosis and telangiectasia. Except for erythema that lasted 3 months in one patient, no untoward side effects were observed with the chemical peel. The majority of patients preferred the peel over fluorouracil because of the single application and less morbidity. CONCLUSION: The medium-depth peel induced by Jessner's solution and 35% trichloroacetic acid is a useful alternative therapeutic option for widespread facial AK, particularly for poorly compliant patients, because it equals fluorouracil in efficacy while being superior in terms of the convenience of a single application with little associated morbidity.
BACKGROUND: Perineural invasion of squamous cell carcinoma of the skin causes increased mortality. OBJECTIVE: We compared survival rates for treatment with Mohs surgery with previous studies of conventional surgery and postoperative radiotherapy. METHODS: With a computerized tumor registry we identified 44 cases of squamous cell carcinoma with perineural invasion recurrence, and hazard rates were calculated. RESULTS: Of 44 patients treated with Mohs surgery, three had recurrences. On this basis a survival probability of 88.7% was calculated. Calculation of hazard rate showed highest probability of recurrence 3 to 6 years after Mohs surgery. The clinical characteristics associated with perineural tumor invasion were male sex, size of tumor (> 2 cm), forehead location, and previous therapy. CONCLUSION: When compared with conventional surgical excision and postoperative radiotherapy, early detection and treatment by Mohs surgery of squamous cell carcinoma with perineural invasion result in a much improved survival probability.
BACKGROUND: Soft tissue augmentation with processed fat has been used clinically for several years. This material has been termed "autologous collagen" since it was presumed it was composed primarily of collagen and fibrous tissue from lipocyte cell walls. OBJECTIVE: To examine the histologic behavior of dermis implanted with processed fat. METHOD: Volunteers were injected with processed fat intradermally in the post auricular area and these sites were biopsied at one week, one month, and three months. RESULTS: Early biopsies revealed no intact adiopocytes but a significant inflammatory infiltrate. Subsequently biopsies revealed replacement of the inflammatory reaction with cellular fibrosis and expansion of the dermis. CONCLUSION: Intradermal injection of processed fat results in deposition of fibrous material and collagen due to the response of the recipient site. The material itself contains very little collagen.
BACKGROUND: The tumescent local anesthetic approach is now being used more widely in dermatologic surgery. Although the original formula contains 12.5 mEq sodium bicarbonate per 50 mL of lidocaine, traditionally buffered solutions contain 1 mEq per 10 mL. OBJECTIVE: This study examines the effects of changing the concentrations of sodium bicarbonate in the tumescent formula. METHODS: Various concentrations of sodium bicarbonate in tumescent anesthetic preparations were measured for pH. RESULTS: Tumescent anesthetic preparations containing 5 mEq/L have a more physiologic pH (7.41) than the classic formula of 12.5 mEq/L (7.73). Clinical use of this reduced sodium bicarbonate solution showed no difference from the original formula. CONCLUSIONS: Sodium bicarbonate can be used in a 1 mEq per 10 mL of lidocaine ratio similar to other buffered anesthetic solutions. This solution is physiologic in pH. However, some thought should also be given to the pKa of lidocaine, which is at pH 7.9. To achieve this even higher concentration (20 mEq/L) bicarbonate must be added to the tumescent solution. Thought must be given to these concepts when tumescent solutions are used in large volumes.
An unusual, persistent, corregated-to-honeycombed thickening of the palms accompanied by tenderness around the fingernails was found to be a cutaneous marker for internal malignancy. This combination of signs and symptoms has been reported under two clinical entities: Bazex's syndrome and tripe palm. This paraneoplastic syndrome is of interest to head and neck surgeons due to the location of the primary tumor, the site of metastatic disease, and the ability to cure the cutaneous disease by surgical removal of the primary tumor. In our patient, a squamous cell carcinoma of the lung not detectable on chest x-ray presented as a cervical mass accompanied by cutaneous changes on the palms and fingernails. Recognition of the relationship of the dermatologic changes to malignancy of a specific body region eventually led to the detection of the primary tumor. The characteristics of these paraneoplastic syndromes were reviewed in this report.
The implications of cytologic atypia, patterns of growth, stromal refractoriness, and immune responses in actinic keratoacanthoma are examined here in a speculative manner with the following conclusion: keratoacanthoma is a generic designation for a spectrum of invasive, keratinocytic hyperplasias. In this context, hyperplasia may affect both genomically normal and abnormal keratinocytes. In keratoacanthoma, it does so indiscriminately. The universality of the process in which both benign and neoplastic clones are affected qualifies as immunostimulation. The affected keratinocytes, regardless of genomic characteristics, extend beyond their sustaining stroma into retinaculum and the basement membrane, as an immunologic barrier, is disrupted. Following a period in which the stroma and the immune response are refractory, one or more clones of keratinocytes are exposed to an immune response. For the adnexal contributions, the eventual encounter with the immune response is brief and short-lived. The fate of these genomically intact cells is predictable: complete regression is the inviolate pathway. For the genomically deranged populace, the results of the encounter are unpredictable and potentially manifold. The options, variably expressed, include regression, spatial progression (expansion in space), and neoplastic progression (expansion in the number and types of neoplastic clones). In some actinic keratoacanthomas, neoplastic clones are represented in either focal or extensive carcinomalike patterns from the inception of the hyperplasia. In them, a potential for neoplastic progressions is inherent. If autonomous, aggressive clones are selected in the progressions, the transition from universal hyperplasia (keratoacanthoma) to malignancy (carcinoma) is effected. In the transition, hyperplastic, genomically intact, follicular keratinocytes are not affected; actinically deranged keratinocytes are. The final pathway for an individual evolving lesion is unpredictable, but in some cases it leads to biologic carcinoma (carcinoma ex-keratoacanthoma).