Contrast of response to dacarbazine,mitomycin, doxorubicin,and cisplatin (DMAP) plus GM-CSF between patients with advanced malignant gastrointestinal stromal tumors and patients with other advanced leiomyosarcomas

BACKGROUND: Previous observations have suggested that leiomyosarcomas, and especially gastrointestinal leiomyosarcomas, may be less responsive to cancer chemotherapy than other histologic types of non-osseous sarcomas; however, this difference has not been characterized well until quite recently, with the recognition of the special identity of gastrointestinal stromal tumors (GIST). Prior to the general acceptance of this new histologic classification, we decided to study patients with gastrointestinal leiomyosarcomas in concert with other leiomyosarcomas for relative responsivity to a combination cytotoxic regimen developed specifically for leiomyosarcomas. PATIENTS AND METHODS: Adult patients with advanced leiomyosarcomas received intravenous chemotherapy as outpatients with dacarbazine 750 micrograms/m2, mitomycin 6 mg/m2, doxorubicin 40 mg/m2, and cisplatin 60 mg/m2 on day 0, with granulocyte macrophage colony stimulating factor (GM-CSF, sagramostim) 250 mcg/m2 given s.c. every 12 hr on days -6 to -3 and on days 1-14 of each 4-week treatment cycle. Our original plan to escalate dacarbazine doses to 1000 mg/m2 following cycle one was abandoned after the first six patients because of toxicity. RESULTS: We studied 21 patients with GIST and 18 patients with other types of leiomyosarcomas, for a total of 131 treatment cycles, with a median of four cycles per patient in each of the two groups of patients. Toxicity was significant, with 33% having grade 3 vomiting at some time during treatment. Grade 3 leukopenia occurred in 42%, and grade 3 thrombocytopenia was observed in 68% of our patients. In one patient, grade 4 pulmonary toxicity developed during the fourth cycle, and this was considered a major factor in her death. Objective tumor regression was observed in one of 21 (1.8%) (95%CI = 0-14.5%) GIST and in 11 of 18 (61%) (95%CI = 38-84%) other leiomyosarcomas, including eight of 10 uterine cases. In five cases, we interrupted chemotherapy to attempt complete surgical excision of residual tumor, and four of the patients were rendered apparently free of disease. Median survivals for the two groups have been similar with 16.7 months (95%CI = 8.8-27.5 months) for the GIST and 17.5 mos (95%CI = 10.9-35.3%) for the other leiomyosarcomas. Three patients with uterine leiomyosarcomas are still alive more than 2 years after completing this chemotherapy and subsequent secondary surgical excision (+/- irradiation) and two of them are free of disease. CONCLUSIONS: While this regimen is ineffective against GIST, its value against uterine leiomyosarcomas deserves further study in a larger population.     

Fluorescent zinc indicators for neurobiology

Mounting evidence indicates that zinc has multiple roles in cell biology, viz. as a part of metalloenzyme catalytic sites, as a structural component of gene regulatory proteins, and (like calcium) as a free signal ion, particularly in the cortex of the brain. While most Zn(II) in the brain is tightly bound, such that free Zn(II) levels extracellularly and intracellularly are likely to be picomolar, a subset of glutamatergic neurons possess weakly bound zinc in presynaptic boutons which is released at micromolar levels in response to a variety of stimuli. Key to further progress in understanding the multiple roles of zinc will be the availability of fluorescent indicator systems that will permit quantitative determination and imaging of zinc fluxes and levels over a broad concentration range both intracellularly and extracellularly using fluorescence microscopy. Towards that end, we have compared a variety of fluorescent indicators for their sensitivity to Zn(II) and Cu(II), selectivity for Zn(II) in the presence of potential interferents such as Ca(II) or Mg(II), and potential for quantitative imaging. The commercially available probes Fura-2, Mag-Fura-5, Newport Green DCF, and FuraZin-1 were compared with the carbonic anhydrase-based indicator systems for selectivity and sensitivity. In addition, intracellular levels of Zn following excitotoxic insult were determined by single pixel fluorescence lifetime microscopy of Newport Green DCF, and extracellular levels of free zinc following stimulus of rat hippocampal slices were determined ratiometrically with a carbonic anhydrase-based indicator system. These results suggest that zinc ion at high nM to microM levels can be accurately quantitated by FuraZin-1 ratiometrically or by Newport Green DCF by fluorescence lifetime; and at levels down to pM by intensity ratio, lifetime, or polarization using carbonic anhydrase-based systems.     

Peak exercise capacity of electrically induced ambulation in persons with paraplegia

INTRODUCTION: Persons with spinal cord injury (SCI) are generally limited to exercise activities using the relatively smaller, less productive upper extremities with limited benefits as compared with leg exercise training. Functional electrical stimulation (FES) assisted ambulation has previously been demonstrated to allow persons with paraplegia to stand and ambulate limited distances. PURPOSE: This study compared the peak physiological responses of persons with paraplegia during FES ambulation and voluntary arm exercise. METHODS: Fifteen subjects (T -T ) previously habituated to FES ambulation, completed peak testing of both arm cranking (AC) and FES walking to the point of exhaustion. The AC tests were performed using a graded incremental protocol to exhaustion in 3-min stages and 10-W power output increments. The FES walking test consisted of successive 10-m walking bouts, each trial progressively increased in pace. Metabolic activity was continuously monitored via open-circuit spirometry with heart rate (HR) determined by a 12-lead electrocardiograph for AC and by direct palpation during FES. RESULTS: Peak VO(2) did not differ between AC (22.9 +/- 3.8 mL x kg x min(-1)) and FES (22.7 +/- 3.9 mL x kg x min(-1)). FES ambulation elicited significantly greater peak values of HR (191 beats x min(-1) versus 179 beats x min(-1)) and lower peak values of respiratory exchange ratio (1.06 vs 1.12) compared with AC. There were no significant differences in peak values of any other variables. CONCLUSION: This study indicates that FES ambulation performance, in persons with paraplegia, elicits similar exercise capacity, as indicated by similar peak oxygen consumption, as voluntary arm exercise.     

Evaluation of an alternative radiochemical purity testing method for technetium-99m sestamibi

OBJECTIVE: Our study evaluated the accuracy and reliability of 3 radiochemical purity (RCP) measurement methods of 99mTc-sestamibi. A regular-sized (1.0 cm x 9.0 cm) Whatman 31 ET Chr paper strip (regular 31 ET) also was included in our evaluation because of its ease in handling. METHODS: The miniaturized and regular 31 ET methods were compared with the standard RCP testing method (aluminum oxide-coated plastic thin-layer chromatography [TLC] plate, with > or = 95% ethanol as the developing solvent). A total of 30 experimental runs were performed in triplicate (n = 90) over an RCP range of 82%-98%. The 99mTc-sestamibi preparations were reconstituted purposely to ensure that 50% of the tested samples had RCP values below the 90% limit. RESULTS: The evaluated RCP ranges were 89.9% +/- 6.3%, 91.0% +/- 3.8%, and 91.4% +/- 4.3% for the TLC, miniature 31 ET, and regular 31 ET methods, respectively (n = 30 each). A strong correlation was found between the TLC and miniature 31 ET methods (r = 0.92), as well as between the TLC and regular 31 ET methods (r = 0.94). Both alternative methods tended to overestimate RCP value as determined by the TLC method, especially in an RCP range below 95%. This resulted in a false-positive rate of 27% for the miniature 31 ET method and 33% for the regular 31 ET method. The test/retest reliability was 99% for both the TLC and regular 31 ET methods, and 91% for the TLC and miniature 31 ET methods. CONCLUSION: The miniature and regular 31 ET methods produced a high false-positive rate, which makes them unacceptable for the determination of RCP value of 99mTc-sestamibi.     

Postnatal lethality of P-cadherin/desmoglein 3 double knockout mice: demonstration of a cooperative effect of these cell adhesion molecules in tissue homeostasis of stratified squamous epithelia

To investigate the cooperativity of different cell adhesion molecules in maintaining the structural integrity of the epidermis, we have generated mice deficient for both a classical cadherin, P-cadherin, and a desmosomal cadherin, desmoglein 3. In epithelial cells, P-cadherin is localized to the adherens junction, whereas desmoglein 3 is found in desmosomes. Previous studies have shown that these two junctional complexes are important for keratinocyte cell-cell adhesion. Both P-cadherin and desmoglein 3 expression are restricted to the basal and most immediate suprabasal cells of the epidermis, whereas both proteins are found throughout the oral mucosal epithelium. Although P-cadherin mutant mice have no apparent defect in epithelial cell adhesion, the desmoglein 3 mutant phenotype resembles that of patients with the autoimmune disease pemphigus vulgaris, in that the mice develop spontaneous mucous membrane blisters and trauma-induced skin blisters. The oral lesions in DSG3-/- mice reduce their food intake, resulting in a runted phenotype; however, most animals recover and live past weaning age. In contrast, animals mutant for both P-cadherin and desmoglein 3 die before weaning. The majority of the double mutant animals die around 1 wk after birth, apparently due to malnutrition. These studies suggest that loss of P-cadherin leads to a more severe desmoglein 3 mutant phenotype in the double knockout mice. This is the first in vivo evidence of possible synergism between a classical and desmosomal cadherin.     

叶托马尾藻中的生物活性甾体成分

目的 研究褐藻叶托马尾藻的活性成分。方法 采用稻瘟霉模型生物活性追踪方法，应用多种色谱手段和光普分析方法分离和鉴定化合物。结果 鉴定了7个甾体类化合物，分别为岩藻甾醇（Ⅰ）,24－乙基－4，24（28）－胆甾二烯－3－酮（Ⅱ），24－乙基－4，24（28）－胆甾二烯－3，6－二酮（Ⅲ），马尾藻甾醇（Ⅳ），24R，28R－和24S，28S－环氧－24－乙基胆甾醇（Ⅴ），胆甾醇－24－酮（Ⅵ）和豆甾醇（－3－O－葡萄糖苷（Ⅶ）。结论 Ⅱ－Ⅶ为首次从该海藻中分离得到，Ⅰ和Ⅲ－Ⅵ具有诱导稻瘟霉菌比来形活性。     

Loosening and osteolysis with the press-fit condylar posterior-cruciate-substituting total knee replacement

BACKGROUND: Aseptic loosening and osteolysis are rarely associated with cemented posterior-cruciate-substituting total knee replacements. Consequently, there is a paucity of information on this topic. METHODS: After a mean follow-up interval of fifty-six months (range, thirty-seven to eighty-nine months), sixteen (2.9%) of 557 posterior-cruciate-substituting primary total knee replacements were revised by a single surgeon because of loosening and osteolysis. Clinical, radiographic, and retrieval analyses were conducted to determine the mechanism of loosening and to identify associated risk factors. RESULTS: All sixteen knees (fifteen patients) were rated as good or excellent at one year after the primary replacement, with mean clinical and functional Knee Society scores of 95 and 86 points, respectively. Nine of the fifteen patients who had a revision because of loosening and osteolysis had had a total knee arthroplasty on the contralateral side compared with only 18% of the patients who did not have a revision (p = 0.026). No evidence of transmission of substantial anteroposterior stresses from the posterior-cruciate-substituting mechanism was found. All twelve retrieved knee implants, however, had damage to the lateral and medial side walls of the polyethylene posterior-cruciate-substituting post. Damage to the inferior surface of the polyethylene inserts had a rotational pattern, with the axis of rotation in the medial compartment. Surface damage in a rotational pattern was also present on the superior and inferior surfaces of the titanium tibial base-plates. CONCLUSIONS: In the knees in our study, rotational forces were generated by impingement of the side walls of the intercondylar box on the polyethylene post. Such box-post impingement can occur throughout the range of motion. Rotational stresses are transmitted to the modular interfaces and to the metal-cement interfaces, resulting in loosening and osteolysis. A reduction in rotational constraint would be desirable. Patients with bilateral total knee replacement may be at increased risk for this type of loosening.     

Zinc-induced anemia and neutropenia in an adolescent

We report an adolescent who developed anemia, leukopenia, and neutropenia after prolonged use of over-the-counter zinc for treatment of acne. Hypocupremia and sideroblastic anemia may result from long-term or excessive exposure to zinc.