Writhed Analytical Magnetic Flux Rope Model.

Observations of magnetic clouds, within interplanetary coronal mass ejections (ICMEs), are often well described by flux rope models. Most of these assume either a cylindrical or toroidal geometry. In some cases, these models are also capable of accounting for non-axisymmetric cross-sections but they generally all assume axial invariance. It can be expected that any ICME, and its flux rope, will be deformed along its axis due to influences such as the solar wind. In this work, we aim to develop a writhed analytical magnetic flux rope model which would allow us to analytically describe a flux rope structure with varying curvature and torsion so that we are no longer constrained to a cylindrical or toroidal geometry. In this first iteration of our model we will solely focus on a circular cross-section of constant size. We describe our flux rope geometry in terms of a parametrized flux rope axis and a parallel transport frame. We derive expressions for the axial and poloidal magnetic field components under the assumption that the total axial magnetic flux is conserved. We find an entire class of possible solutions, which differ by the choice of integration constants, and present the results for a specific example. In general, we find that the twist of the magnetic field locally changes when the geometry deviates from a cylinder or torus. This new approach also allows us to generate completely new types of in situ magnetic field profiles which strongly deviate from those generated by cylindrical or toroidal models.

Object localization using a biosonar beam: how opening your mouth improves localization.

Determining the location of a sound source is crucial for survival. Both predators and prey usually produce sound while moving, revealing valuable information about their presence and location. Animals have thus evolved morphological and neural adaptations allowing precise sound localization. Mammals rely on the temporal and amplitude differences between the sound signals arriving at their two ears, as well as on the spectral cues available in the signal arriving at a single ear to localize a sound source. Most mammals rely on passive hearing and are thus limited by the acoustic characteristics of the emitted sound. Echolocating bats emit sound to perceive their environment. They can, therefore, affect the frequency spectrum of the echoes they must localize. The biosonar sound beam of a bat is directional, spreading different frequencies into different directions. Here, we analyse mathematically the spatial information that is provided by the beam and could be used to improve sound localization. We hypothesize how bats could improve sound localization by altering their echolocation signal design or by increasing their mouth gape (the size of the sound emitter) as they, indeed, do in nature. Finally, we also reveal a trade-off according to which increasing the echolocation signal's frequency improves the accuracy of sound localization but might result in undesired large localization errors under low signal-to-noise ratio conditions.

Regulation of beta-cell mass and function by the Akt/protein kinase B signalling pathway.

The insulin receptor substrate-2/phosphoinositide 3-kinase (PI3K) pathway plays a critical role in the regulation of beta-cell mass and function, demonstrated both in vitro and in vivo. The serine threonine kinase Akt is one of the promising downstream molecules of this pathway that has been identified as a potential target to regulate function and induce proliferation and survival of beta cells. Here we summarize some of the molecular mechanisms, downstream signalling pathways and critical components involved in the regulation of beta-cell mass and function by Akt.

Concurrent administration of vinorelbine with human recombinant granulocyte-macrocyte stimulating factor.

Thirty-three patients with incurable neoplasms resistant to standard therapy received vinorelbine 10 mg/m(2)/day by continuous infusion with concurrent administration of rHGM-CSF 4 microg/m(2)/day. The duration of the vinorelbine infusion was individualized; the infusion was continued until early evidence of hematopoietic toxicity was noted. The concurrent administration of GM-CSF permitted a substantial increase in dose intensity of the anti-cancer agent without a corresponding increase in drug toxicity. There was no evidence that the anti-tumor effect of vinorelbine was compromised by the concurrent administration of GM-CSF.

Peripheral blood tumor cell load reflects the clinical activity of the disease in patients with carcinoma of the breast.

Peripheral blood was examined for the presence of tumor cells at multiple time points over a one-year period in 45 patients with a history of surgical resection of breast carcinoma. The number of circulating epithelial cells in 8 of 8 patients with clinically active disease concurred or preceded changes in the disease activity. In 12 of 37 patients with no evidence of disease epithelial cells were found at least at one time point at a frequency larger than the control group. One patient had a recurrence of the breast cancer 4 weeks after circulating epithelial cells were detected in the blood.

Therapy of desmoid tumors and fibromatosis using vinorelbine.

In patients with either desmoids or fibromatosis who do not tolerate vinblastine and methotrexate because of neurotoxicity, the combination of vinorelbine and methotrexate can be substituted in most. Patients with the same condition who had not been previously treated with a combination of vinblastine and methotrexate responded well to the combination of vinorelbine and methotrexate, with significantly less neurotoxicity and a similar objective and subjective response rate. Sixty percent of patients had either a substantial partial remission or a complete remission. In no patients did the disease progress while they were receiving this therapy. Symptomatic relief, primarily of pain, occurred in 80% of patients. While minimal neurotoxicity was seen in 16% of these patients, it did not interfere with the completion of therapy. The combination of vinorelbine and methotrexate appears to be active in the treatment of both desmoid tumors and fibromatosis and is associated with significantly less neurotoxicity then that seen with the combination of vinblastine and methotrexate. No long-term toxicity was seen in any patient in this series.

Concurrent administration of vinorelbine with recombinant human granulocyte colony-stimulating factor: an effective method of increasing dose intensity.

Thirty-three patients with incurable neoplasms resistant to standard therapy received vinorelbine 8 mg/m2 to 10 mg/m2 per day by continuous infusion with concurrent administration of recombinant human granulocyte colony-stimulating factor 5 microm/m2 per day. The duration of the vinorelbine infusion was individualized; the infusion was continued until early evidence of hematopoietic toxicity was noted. The concurrent administration of recombinant human granulocyte colony-stimulating factor permitted a substantial increase in dose intensity of the anticancer agent without a corresponding increase in drug toxicity. There was no evidence that the antitumor effect of vinorelbine was compromised by the concurrent administration of recombinant human granulocyte colony-stimulating factor.

Detection and characterization of carcinoma cells in the blood.

A highly sensitive assay combining immunomagnetic enrichment with multiparameter flow cytometric and immunocytochemical analysis has been developed to detect, enumerate, and characterize carcinoma cells in the blood. The assay can detect one epithelial cell or less in 1 ml of blood. Peripheral blood (10-20 ml) from 30 patients with carcinoma of the breast, from 3 patients with prostate cancer, and from 13 controls was examined by flow cytometry for the presence of circulating epithelial cells defined as nucleic acid+, CD45(-), and cytokeratin+. Highly significant differences in the number of circulating epithelial cells were found between normal controls and patients with cancer including 17 with organ-confined disease. To determine whether the circulating epithelial cells in the cancer patients were neoplastic cells, cytospin preparations were made after immunomagnetic enrichment and were analyzed. Epithelial cells from patients with breast cancer generally stained with mAbs against cytokeratin and 3 of 5 for mucin-1. In contrast, no cells that stained for these antigens were observed in the blood from normal controls. The morphology of the stained cells was consistent with that of neoplastic cells. Of 8 patients with breast cancer followed for 1-10 months, there was a good correlation between changes in the level of tumor cells in the blood with both treatment with chemotherapy and clinical status. The present assay may be helpful in early detection, in monitoring disease, and in prognostication.

Soft-tissue complications of intra-arterial chemotherapy for extremity sarcomas.

High-grade sarcomas have a high rate of local recurrence as well as distant metastases. This has led to the development of intra-arterial chemotherapy (IAC) as part of a multimodal approach to control local disease and/or reduce the extent of surgical resection. Intra-arterial catheters are positioned by an interventional radiologist into the feeding vessels of the tumor. Adriamycin and 5-fluorodeoxyuridine are infused intra-arterially. Cisplatinum, with or without granulocyte colony stimulating factor, is given systemically. Patients usually experience acute self-limited soft-tissue inflammation in the treated area. In our experience of 118 patients, 3 patients experienced soft-tissue necrosis that required excision and reconstruction. The first was treated for synovial sarcoma of a metatarsal. After IAC with Adriamycin, she sloughed the skin, subcutaneous tissue, and some of the posterior compartment musculature of her calf. This tissue was debrided. A gastrocnemius flap and skin graft were used for coverage. She is free of disease and ambulatory. The second patient was treated with IAC Adriamycin for a radial head chondrosarcoma. She developed soft-tissue slough, which became infected with Pseudomonas. She required extensive debridement of the skin, subcutaneous tissue, and muscle, and was subsequently reconstructed with a latissimus flap and a split-thickness skin graft (STSG). She later developed a local recurrence requiring amputation. The latissimus was elevated and used to cover the distal stump. She also is free of disease. The third patient was treated with IAC Adriamycin for Ewing's sarcoma of the right femur. This was complicated by fat necrosis and persistent pain. Subsequent radiotherapy only worsened her symptoms. She underwent wide excision and muscle flap/STSG repair, which relieved her pain. She is currently ambulatory and free of disease. In conclusion, as the use of IAC continues, its complications may become more common. Our experience with this previously unknown entity is illustrated and therapeutic options are discussed.

Infusional chemotherapy combined with recombinant human granulocyte colony stimulating factor: advantages and limitations.

We have studied the simultaneous administration of granulocyte colony stimulating factor (G-CSF), given concomitantly with an infusion of either doxorubicin or ifosphamide--the former, both intraarterially (i.a.) and intravenously (i.v.), the latter, intravenously--to a group of patients with various malignancies. Such simultaneous administration enabled us to substantially increase the dosage intensity of both, thereby increasing the effectiveness of each drug. No untoward effects have been noted to date.

Intraarterial chemotherapy with limb-sparing resection of large soft-tissue sarcomas of the extremities.

Fifteen patients with large (average, 15-cm), high-grade soft-tissue sarcomas of the extremities received prolonged selective intraarterial infusions of chemotherapeutic agents in an attempt to permit limb-sparing resection of these tumors, which would otherwise have required amputation. There were seven malignant fibrous histiocytomas, four liposarcomas, two fibrosarcomas, one leiomyosarcoma, and one rhabdomyosarcoma; 73% were grade III. Seven patients underwent two catheterizations, for a total of 22 infusions, which averaged 11.3 days each. There were four catheterization-related complications, including catheter occlusion or dislodgement in one patient each and two cases of arterial thromboembolism in patients in whom anticoagulant dose was not adequate. Both of the latter patients required thrombectomy; one developed gangrene, which precluded limb-sparing surgery. Thirteen of the 15 patients underwent limb-sparing resections, and two underwent amputations. No wound complications occurred. With a median follow-up of 36 months (mean, 34 months), life-table analysis indicates overall and disease-free survivals of 72% and 59%, respectively, at 2 years and 64% and 59% at 3 years. In comparison to other reported therapies, this technique permits limb salvage in most patients without the high wound complication rate associated with preoperative radiation therapy, with equivalent local disease control and survival.

Extremity osteosarcomas: intraarterial chemotherapy and limb-sparing resection with 2-year follow-up.

Twenty-eight consecutive patients with extremity osteosarcoma (24 stage II, four stage III) received their entire preoperative course of chemotherapy intraarterially in order to maximize local drug concentration and tumor shrinkage to facilitate limb-sparing resection. Eighteen tumors were located in the femur, seven in the tibia, two in the humerus, and one in the fibula. Most patients underwent two catheterizations; thus there was a total of 51 procedures. The average duration of each infusion was 10.4 days. There were eight procedure-related complications, but none precluded completion of intraarterial chemotherapy. Limb-sparing surgery was performed on 25 patients. At a mean follow-up of over 2 years, there was one local recurrence. Among limb-salvage patients with stage II disease, 90% (18 of 20) survived and 75% (15 of 20) are disease-free. Compared with patients from previous studies, this technique permits a high percentage of patients with osteosarcoma to undergo limb-sparing resection without compromise of local disease control or survival.

A pharmacologic approach to dosage intensification.

Using standard pharmacologic concepts, it is possible to show that changes in schedule will influence the relative influx of drug between various normal tissues and tumor. A line of investigation is discussed that should lead to optimization of influx into tumor tissue while minimizing uptake into dose limiting normal tissues.

The catalysis of protein and nucleic acid coupling to an affinity membrane substrate.

With the model ligands studies, which included IgG, HSA, streptavidin, MEA and amine-modified DNA, it was possible to enhance the rate of covalent immobilization by using nucleophilic acylation reaction catalysts. Imidazole, triazole and 2-hydroxypyridine are readily available catalysts that are effective when immobilizing immunoglobins. 4-N,N,Dimethylaminopyridine (DMAP) as a co-reactant or as a prereactant is a potent rate enhancer with all of the molecules that were examined. The precise protocol to be used is probably best derived empirically. In addition to optimizing the amount of ligand bound or the amount of time necessary to bind a fixed quantity of ligand, it is likely that the retained functionality of the ligand may be affected by the use of reaction catalysts.

Low-dose chemotherapy of desmoid tumors.

Eight patients with desmoid tumors, symptomatic, and none a candidate for conservative surgery, were treated with weekly vinblastine, maximum dose 10 mg/week, and methotrexate, maximum dose 50 mg/week. Symptomatic relief was obtained in all patients. Using Eastern Cooperative Oncology Group (ECOG) criteria, two patients had a complete remission, one of which has lasted for 30 months, four patients have had partial remissions, one patient has had a mixed response, and one patient who has been treated for only 4 weeks, a minimal response. Toxicity has been minor and transient. Chemotherapy appears to be an acceptable alternative to radical surgery in selected patients with desmoid tumors.

Varied appearance of AIDS-related lymphoma in the chest.

The authors reviewed all cases of acquired immunodeficiency syndrome (AIDS)-related lymphoma (ARL) seen at their institution between January 1982 and September 1988 to determine the frequency and appearance of ARL in the chest. Of 35 patients with ARL, 11 (31%) had biopsy-proved thoracic involvement. This frequency is significantly greater than that previously reported. The radiologic appearance of the thoracic involvement varied. Pleural effusion, interstitial and alveolar lung disease, nodules, and, infrequently, hilar and mediastinal adenopathy were observed. ARL of the chest was most commonly extranodal. Pleural effusion and lung disease were the two most common manifestations of ARL on chest radiographs and computed tomographic scans. The authors recommend that clinicians treating patients with suspected or known AIDS consider ARL when a pleural effusion or a noninfective interstitial or alveolar process is present.

An improved method for isolating Ca2+-resistant myocytes from the adult rat heart.

Maintaining viability in cardiac myocytes isolated from adult rats using collagenase is difficult in Ca-containing media due to cell damage that occurs on reintroduction of Ca after perfusing the heart with the Ca-free medium needed to isolate myocytes with collagenase. Recently it has been proposed that Ca-free perfusion of isolated rabbit interventricular septa leads to cellular Na overload which, on reintroducing Ca, produces influx of toxic concentrations of Ca due to the Na/Ca exchange mechanism in the sarcolemma. We have found that replacing a portion of the 118 mM NaCl in the Ca-free perfusion medium with 69 mM LiCl dramatically increased the proportion of Ca-tolerant cardiac myocytes isolated from adult male rats with collagenase. Myocyte viability was maintained over a four hour period of incubation at 37 degrees C in 1 mM Ca.