bluuebunny/crossref_metadata_2025 huggingface dataset:
Virtual Connections: Internet Health Care
Authors: Penson Richard T. , Benson Renee C. , Parles Karen , Chabner Bruce A. , Lynch Thomas J.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Understand the increasingly important contribution of the Internet to information and connection for staff and patients with cancer. Evaluate the limited evidence on medical misinformation, isolation, and the limits of the Internet. Learn the best available oncology Internet resources.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded The Kenneth B. Schwartz Center at MGH. The Schwartz Center is a nonprofit organization dedicated to supporting and advancing compassionate health care delivery that provides hope to the patient, support to caregivers, and encourages the healing process. The Center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members.

The 20th century success of the Internet is now translating into changes in 21st century medical practice. The changes brought about by the Internet have at once facilitated and complicated the practice of medicine. Physicians and patients are challenged to take advantage of the increased opportunities afforded by Internet access while being mindful of its drawbacks and the limitations to virtual communication. The case of Karen Parles, one of the authors, is presented. Karen developed locally advanced lung cancer and used the Internet to research her diagnosis. She found the information on lung cancer limited and confusing, and, in response, developed a website devoted to empowering lung cancer patients in their search for information and support (http://www.lungcanceronline.org). Here we discuss issues surrounding patients' use of the Internet for health information and communication with health care providers. The value of information-seeking as a coping mechanism is debated, and concerns are raised regarding confidentiality of electronic communications and the logistics of physicians adopting e-mail as a mechanism for communicating with patients.
Metastatic Pancreatic Cancer: Emerging Strategies in Chemotherapy and Palliative Care
Authors: El Kamar Francois G. , Grossbard Michael L. , Kozuch Peter S.
Published: August 2004

This update is devoted to discussion of optimal supportive and palliative care of patients with pancreatic cancer. Approximately 33,000 new cases of pancreatic cancer are predicted for the U.S. in 2002. Because diagnosis and intervention occur late in the course of this disease, the vast majority of patients already have metastatic disease at the time of diagnosis. These tumors are relatively resistant to systemic chemotherapy, making pancreatic cancer the fourth leading cause of cancer-related death in the U.S. and the Western world. For these reasons, efforts at identifying and treating disease-related symptomatology are priorities. This update overviews symptom management, supportive care strategies, and both standard and emerging palliative chemotherapy options. The incorporation of molecularly targeted therapies into treatment of metastatic pancreatic cancer is reviewed as well. These strategies are of relevance to internists, gastroenterologists, oncologists, and other specialists who care for patients with pancreatic cancer.
Docetaxel, Cisplatin, 5-Fluorouracil (TPF)-Based Induction Chemotherapy for Head and Neck Cancer and the Case for Sequential, Combined-Modality Treatment
Authors: Haddad Robert , Tishler Roy B. , Norris Charles M. , Mahadevan Anand , Busse Paul , Wirth Lori , Goguen Laura A. , Sullivan Christopher A. , Costello Rosemary , Case Mary Ann , Posner Marshall R.
Published: August 2004

Since the publication of the Veterans Affairs study in the early 1990s, much has been learned regarding the role of chemotherapy, radiation therapy, and more importantly, the role of combined-modality treatment with chemoradiation in the therapy of locally advanced head and neck cancer. There continues to be widespread variation and controversy in the timing, schedule, and intensity of chemotherapy and chemoradiation. Herein, we present the various approaches currently used in the year 2003 with a specific emphasis on the role of sequential combined-modality therapy combining chemotherapy, chemoradiotherapy, and surgery in the treatment of these malignancies.
The Forgotten Myeloproliferative Disorder: Myeloid Metaplasia
Authors: Tefferi Ayalew
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Derive a conceptual understanding of the classification as well as the pathogenesis of chronic myeloproliferative disorders with emphasis on myelofibrosis with myeloid metaplasia. Recognize how myelofibrosis with myeloid metaplasia is diagnosed and know what the differential diagnosis constitutes. Be familiar with current therapeutic options in myelofibrosis with myeloid metaplasia.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Myelofibrosis with myeloid metaplasia is a hematologic disorder currently classified with polycythemia vera and essential thrombocythemia as a chronic myeloproliferative disease. The median age at diagnosis is 60 years, and more than 90% of patients are diagnosed after age 40 years. Clinical manifestations include massive splenomegaly, progressive anemia, profound constitutional symptoms, and extramedullary hematopoiesis. The diagnosis is confirmed by bone marrow examination after other causes of myelofibrosis are ruled out. Median survival is 5 years and causes of death include leukemic transformation. Prognosis is adversely affected by the presence of anemia (hemoglobin <10 g/dl), leukopenia or leukocytosis (white blood cells >30,000/μl), circulating blasts, and hypercatabolic symptoms. Conventional treatment is palliative and does not improve survival. In this regard, androgen preparations, corticosteroids, and erythropoietin are useful for the treatment of disease-associated anemia. Symptomatic splenomegaly is best managed by cytoreductive therapy or surgical removal. Radiation therapy is most useful in the treatment of nonhepatosplenic extramedullary hematopoiesis. New treatment approaches include the use of thalidomide alone or in combination with prednisone and hematopoietic stem cell transplantation.
Docetaxel-Based Combined-Modality Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer
Authors: Scagliotti Giorgio V. , Turrisi Andrew T.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Offer a critical analysis of docetaxel radiotherapy clinical studies and provide background basic science support. Discuss dose/administration/timing information, as available, for docetaxel and radiotherapy, and provide a foundation for clinical use and a platform for further research. Explain the potential benefit and outline the toxicities of the combination as used in international studies.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

The cytotoxic agent docetaxel not only has proven activity in non-small cell lung cancer—when used alone or in combination—but is also a potent radiosensitizer, and improved treatments are needed in all stages of this disease. In patients with locoregionally advanced (stage III) disease, docetaxel has shown efficacy with manageable toxicities when used alone or in combination with a platinum compound in a sequential manner before localized radical radiotherapy/surgery. Presently, therapeutic gains appear to be maximized by the use of concurrent chemotherapy and irradiation. This review focuses on research with combinations of docetaxel with either cisplatin or carboplatin and radiotherapy. Overall response and survival rates to date provide data worth pursuing. From phase I data, weekly docetaxel at 20 mg/m2 plus cisplatin at 25 mg/m2 or carboplatin to an area under the concentration time curve of 2 mg/ml•min with concurrent radiotherapy to 60 Gy over 6 weeks appear to be suitable for phase II trials. Predominant toxicities are esophagitis and neutropenia, but a low frequency of pulmonary toxicity is reported. Induction, concurrent, and consolidation docetaxel-based chemoradiotherapy in potentially resectable disease are all being investigated. Future research could include the investigation of computed tomography/ positron emission tomography-derived target volume radiotherapy, dose-escalated therapy, and alternative fractionation schedules in combination with docetaxel-based cytotoxic chemotherapy.
Velcade®: U.S. FDA Approval for the Treatment of Multiple Myeloma Progressing on Prior Therapy
Authors: Kane Robert C. , Bross Peter F. , Farrell Ann T. , Pazdur Richard
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Discuss the rationale and requirements for accelerated cancer drug approval by the U.S. Food and Drug Administration (FDA). Identify the current indications for the use of a recently approved agent, bortezomib (Velcade®, PS-341), in the treatment of multiple myeloma. Describe the plans for the further clinical development of this agent as part of accelerated approval by the FDA. Explain the mechanism of action of bortezomib and its role in cancer treatment.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Bortezomib (formerly PS-341), a promising new drug for the treatment of multiple myeloma, recently received accelerated approval from the U.S. Food and Drug Administration (FDA) for the therapy of patients with progressive myeloma after previous treatment. Two phase II studies of bortezomib used the same schedule of twice-weekly i.v. dosing for the first 2 weeks of each 3-week cycle. In a randomized study of 54 patients, two doses were compared (1.0 and 1.3 mg/m2) and objective responses occurred at both dose levels (23% versus 35%), including one complete response in each arm. In the other phase II study, 202 heavily pretreated patients (median of six prior therapies) all received the same schedule at 1.3 mg/m2. Of 188 evaluable patients, complete responses occurred in five (3%) and partial responses occurred in 47 (25%). The median duration of response was 365 days. The most clinically relevant adverse events were asthenic conditions, nausea, vomiting, diarrhea, thrombocytopenia, and a peripheral neuropathy that often was painful. This report highlights the FDA analysis supporting the accelerated approval.
Topotecan Dosing Guidelines in Ovarian Cancer: Reduction and Management of Hematologic Toxicity
Authors: Armstrong Deborah K.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Describe the hematologic safety profile of topotecan in patients with relapsed ovarian cancer. List the risk factors for increased hematologic toxicity after topotecan therapy. Discuss topotecan dose determination and the management of hematologic toxicity in higher-risk ovarian cancer patients.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Topotecan dosing considerations and alternative dosing schedules to reduce and manage myelosuppression during the treatment of relapsed ovarian cancer were reviewed. The myelosuppression patterns from phase I, II, and III clinical trials were analyzed to evaluate the degree of hematologic toxicity and to determine risk factors predictive of myelosuppression. Additionally, recent publications of alternative topotecan doses and schedules were examined. Extent of prior therapy, prior platinum therapy (particularly carboplatin), advanced age, impaired renal function, and prior radiation therapy were identified as potential risk factors for greater hematologic toxicity after topotecan therapy. Reducing the starting topotecan dose to 1.0 or 1.25 mg/m2/day is recommended to reduce the incidence of severe myelosuppression in high-risk individuals receiving topotecan for 5 consecutive days. Hematopoietic growth factors, transfusion therapy, and schedule adjustments may also help manage myelosuppression. Alternative schedules of 3-day or weekly dosing appear to have less myelotoxicity and are currently under evaluation. The clinical aspects of topotecan-related myelosuppression and results from clinical trials indicate that the dose, and possibly the dosing schedule, of topotecan can be modified to reduce hematologic toxicity and improve tolerance without compromising efficacy. Prospective individualization of topotecan dosing may prevent or minimize dose-limiting myelosuppression and allow patients to achieve the maximum topotecan benefit by improving their ability to complete therapy with fewer treatment delays. Ongoing clinical trials evaluating alternative dosing schedules with superior hematologic tolerability may facilitate the inclusion of topotecan in combination regimens for patients with ovarian cancer. Proposed topotecan dosing guidelines to reduce and manage myelosuppression are outlined.
HER1/EGFR Targeting: Refining the Strategy
Authors: Pérez-Soler Román
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Differentiate between ligand-dependent and ligand-independent human epidermal growth factor receptor tyrosine kinase activation and initiation of signaling. Describe the site of action of tyrosine kinase inhibitors and explain how this might impact their therapeutic profiles. Discuss the influence of all aspects of clinical trial design on measurable outcomes, including dosing regimen, protocol, and patient selection.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Human epidermal growth factor receptor (EGFR), HER, targeting has formed the basis of extensive and growing drug development programs in various companies. However, receptor biology is often poorly explained and confusing. The HER family of four naturally occurring receptors and one tumor-specific mutant can activate signaling via a complex and sophisticated range of mechanisms, which we are only beginning to understand. HER1/EGFR downstream signaling can lead to tumor growth and development via a host of processes, including enhanced cellular proliferation, survival, and metastasis. A range of potential therapeutic targets exists within the HER signaling system, both inside and outside the cell. Monoclonal antibodies and tyrosine kinase inhibitors, acting extracellularly and intracellularly, respectively, comprise two classes of agents most advanced in clinical development or already available for use. Despite promising single-agent activity in chemotherapy-resistant patients with non-small cell lung cancer (NSCLC), disappointing results from two phase III trials of the tyrosine kinase inhibitor gefitinib in NSCLC have been of concern to some. However, many factors may have contributed to this outcome, and it is not necessarily predictive of the future usefulness of these agents. Patient characteristics, lack of patient selection, dosing schedule, and trial design may all have played roles. It is important to remember that intracellular targeting of HER is a relatively novel approach, and our knowledge of how best to optimize such treatment is still unfolding. More clinical experience is needed.
The Evolving Role of Epoetin Alfa in Cancer Therapy
Authors: Henry David H.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Describe the use of epoetin alfa in the prevention and treatment of anemia related to cancer and its treatment. Discuss ongoing clinical issues with epoetin alfa, including alternative dosing options and the benefits of early intervention for anemia. Identify additional nononcologic clinical applications for epoetin alfa currently under investigation.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Since its initial indication as hormone-replacement therapy in the anemia of chronic kidney disease, epoetin alfa has become a mainstay of therapy for chemotherapy-related anemia. Clinical studies have shown that epoetin alfa administered once weekly or three times weekly improves hemoglobin levels, decreases transfusion requirements, and improves quality of life independent of tumor response to chemotherapy. Ongoing research is now evaluating ways to improve the response rate to epoetin alfa, the potential benefits of alternative dosing regimens and early treatment intervention, and nonanemia-related indications (e.g., cognitive impairment, asthenia). In addition, scientists are exploring the role of epoetin alfa in preventing apoptosis and ischemic brain injury, as well as its activity in other nonerythroid tissues. Thus, the role of epoetin alfa is likely to expand in the cancer setting in the coming years.
Help Me Help You: Support Groups in Cancer Therapy
Authors: Penson Richard T. , Talsania Shivali H.G. , Chabner Bruce A. , Lynch Thomas J.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Describe the controversy over survival benefit from group therapy. Outline the evidence-based support for psychotherapies. Discuss the benefit from support groups.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at http://CME.TheOncologist.com

Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded The Kenneth B. Schwartz Center at MGH. The Schwartz Center is a non-profit organization dedicated to supporting and advancing compassionate health care delivery that provides hope to the patient, support to caregivers, and encourages the healing process. The Center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members.

Three invited patients attended rounds and told their compelling stories; these each effectively demonstrated their fight as cancer survivors. Much of the strength that they displayed came from the different types of support they each received, and the invaluable role of the medical team. Each shared a very positive experience with ‘The Wellness Community,’ in Boston. The article discusses issues of support and the role of formal support groups. Types of support intervention, the impact they have on quality of life and survival are reviewed.
NMR Spectroscopy and Pediatric Brain Tumors
Authors: Warren Katherine E.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Define the principal metabolites in the brain evaluated by proton spectroscopy. Identify factors that can potentially interfere with obtaining spectroscopy results. Assess the results from a patient's single or multivoxel spectroscopy analysis.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Proton nuclear magnetic resonance spectroscopy (1H-NMRS) is a noninvasive in vivo technique that utilizes conventional MR imaging hardware to obtain biochemical information from a discrete volume of tissue after suppression of the water signal. MR spectroscopy coupled with conventional MR imaging allows correlation of structural changes with biochemical processes in tissues by measuring specific metabolites present in brain tissue. NMRS is commonly used in the evaluation of patients with brain tumors. This article reviews the basic principles of spectroscopy and its use in evaluating pediatric patients with brain tumors.
Cancer of Unknown Primary: Changing Approaches. A Multidisciplinary Case Presentation from the Joan Karnell Cancer Center of Pennsylvania Hospital
Authors: Mintzer David M. , Warhol Michael , Martin Anne-Marie , Greene Gary
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Describe the newer pathologic techniques for defining the site of origin of unknown primary cancers, including immunohistochemistry and molecular genetic techniques. List the subsets of patients with unknown primary cancers most likely to achieve long-term survival with appropriate therapies. Explain how the newer radiologic techniques such as MRI and PET scanning can help to localize unknown primary cancers.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Cancer of unknown primary is a common clinical syndrome, accounting for 2%–5% of cancer patients. A representative case is presented. This heterogenous group of disorders includes entities such as poorly differentiated carcinoma of unknown primary, adenocarcinoma of unknown primary, neuroendocrine carcinoma of unknown primary, squamous cell carcinoma of unknown primary, poorly differentiated (not otherwise specified) cancer of unknown primary, and melanoma of unknown primary. It is crucial to identify those treatment-responsive presentations of unknown primary with the greatest potential for long-term survival.

This discussion emphasizes newer approaches to the diagnosis and treatment of unknown primary cancer, including advances in pathology with immunoperoxidase and molecular genetic techniques, positron emission tomography, and published chemotherapeutic trials. With the increased sophistication of pathologic and radiologic techniques, the frequency of unknown primary cancers will likely continue to decline. Further, as newer and more targeted therapies for specific types of cancer are identified, the previously held nihilism regarding the search for and identification of the primary may become less supportable.
Primary Pulmonary Synovial Sarcoma: A Case Report and Review of Current Diagnostic and Therapeutic Standards
Authors: Dennison Sheri , Weppler Eric , Giacoppe George
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Describe primary pulmonary synovial sarcoma as a rare tumor that usually arises in young adults as a large pleural-based intrathoracic mass. Explain that the diagnosis is made by histology, immunohistochemical studies, and, more recently, by identification of the SYT-SSX1 or SYT-SSX2 chromosomal translocations. List factors that portend a worse prognosis, including inability to achieve a complete resection, larger tumor size, male sex, older age, high-grade tumor with necrosis, and the SYT-SSX1 variant.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

A 30-year-old female presented with hemoptysis, chest pain, and a rapidly enlarging pleural-based mass, and was found to have primary synovial sarcoma of the lung. Primary pulmonary sarcomas comprise <1% of all primary lung malignancies. They present clinically in young adults with cough, chest pain, shortness of breath, or hemoptysis, with a mass on x-ray and computerized tomography scan. Diagnosis is made by histology and immunohistochemistry. Histologic diagnosis has recently been supplemented by cytogenetic analysis, which offers important prognostic information. The mainstay of treatment remains complete surgical excision. Prognosis is poor, with an overall 5-year survival rate of 50%.
Tamoxifen—What Next?
Authors: Gradishar William J.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Understand the current treatment options available for postmenopausal women with breast cancer. Explain the impact of new clinical trial data on the existing schedule of endocrine therapy. Describe the future direction of endocrine therapy for advanced breast cancer.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Most patients with advanced breast cancer (ABC) ultimately die due to disease progression. Consequently, treatments for ABC are predominantly palliative in nature and, therefore, the tolerability profile of a given treatment is particularly relevant in these patients. While cytotoxic chemotherapy and endocrine therapy exhibit efficacy in hormone-sensitive, advanced disease, it is endocrine therapy that combines efficacy with minimal acute toxicity. Tamoxifen has been the chosen endocrine therapy for postmenopausal, hormone-sensitive, ABC for over 20 years. More recently, new endocrine agents with different mechanisms of action from tamoxifen have been introduced. Evidence indicates that the aromatase inhibitors anastrozole (Arimidex®; AstraZeneca; Wilmington, DE), letrozole (Femara®; Novartis Pharmaceuticals Corp.; East Hanover, NJ) and exemestane (Aromasin®; Pharmacia Corp.; Peapack, NJ) offer superior efficacy and tolerability to tamoxifen in the first-line treatment of postmenopausal, hormone-sensitive ABC. Similarly, after tamoxifen failure, fulvestrant (Faslodex®; AstraZeneca), a new estrogen receptor (ER) antagonist that downregulates the ER, is at least as effective as anastrozole, is well tolerated, and is not cross-resistant with tamoxifen. Unlike tamoxifen, fulvestrant has no known agonist effects. The sequential use of such agents may prolong the time during which endocrine therapies can be used, thereby avoiding the more acute toxicities associated with cytotoxic chemotherapy. Indeed, a series of studies has shown that this sequential use is a relevant, active, and well-tolerated option. Establishing the comparative efficacies and optimal sequences that incorporate the newer endocrine agents will be central in determining the future role of hormonal therapy in ABC; the results of this work will determine the relative place of tamoxifen in what is a rapidly changing therapeutic environment.
Biology and Therapeutic Advances for Pediatric Osteosarcoma
Authors: Marina Neyssa , Gebhardt Mark , Teot Lisa , Gorlick Richard
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Discuss etiologic and biologic factors in osteosarcoma. Select the appropriate diagnostic work-up for patients with newly diagnosed osteosarcoma. Select appropriate multidisciplinary treatment for patients with newly diagnosed osteosarcoma. Discuss various surgical approaches to the management of newly diagnosed osteosarcoma.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Osteosarcoma is the most common malignant bone tumor in children and adolescents. Survival for these patients was poor with the use of surgery and/or radiotherapy. The introduction of multi-agent chemotherapy dramatically improved the outcome for these patients and the majority of modern series report 3-year disease-free survival of 60%–70%. This paper describes current strategies for treating patients with osteosarcoma as well as review of the clinical features, radiologic and diagnostic work-up, and pathology. The authors review the state of the art management for patients with osteosarcoma in North America and Europe including the use of limb-salvage procedures and reconstruction as well as discuss the etiologic and biologic factors associated with tumor development. Therapy-related sequelae and future directions in the biology and therapy for these patients are also discussed.
How U.S. courts have boosted the power of arbitrators
Authors: Meyerson Bruce E.
Published: August 2004

Bruce E. Meyerson, of Phoenix, shows how U.S. courts have evolved from questioning arbitration's integrity to placing “virtually unreviewable discretion” in arbitrators' hands.
ICANN's new ombudsman has a ‘community’ service mission
Authors: Donahey M. Scott
Published: August 2004

The Internet Corporation for Assigned Names and Numbers has a new ombudsman's office. M. Scott Donahey, of Palo Alto, Calif., describes how the troubleshooter's office came about and how it will work.
A straightforward Rojas still riles some practitioners: California's top court endorses mediation law, but ADR professionals remain split about the decision
Authors: Bleemer Russ
Published: August 2004

Two articles sort out this summer's biggest ADR‐related case, the California Supreme Court's Rojas decision. First, Alternatives discusses the holding and the fallout. Then, full‐time neutral Jeff Kichaven, of Los Angeles, who worked on an amicus filing in the case, discusses why he believes the opinion, which backs an almost total ban on litigation discoverability of mediation materials, will hurt the profession.
A straightforward Rojas still riles some practitioners: Commentary: Exalting 'absolute confidentiality' hurts the practice
Authors: Kichaven Jeff
Published: August 2004

Two articles sort out this summer's biggest ADR‐related case, the California Supreme Court's Rojas decision. First, Alternatives discusses the holding and the fallout. Then, full‐time neutral Jeff Kichaven, of Los Angeles, who worked on an amicus filing in the case, discusses why he believes the opinion, which backs an almost total ban on litigation discoverability of mediation materials, will hurt the profession.
Diamonds from the Pressure Cooker—Science or Science Fiction?
Authors: Sachdev Hermann
Published: August 2004

Fragen bleiben zu einigen der Belege und Methoden, die Q. Chen und Mitarbeiter in ihren Beiträgen zur Synthese von Diamanten unter milden Bedingungen vorgestellt haben: Sind die angegebenen Daten ausreichend, um die neue Synthesemethode zu belegen? Wie wurden die postulierten Reaktionsintermediate nachgewiesen? Gibt es andere Gründe für die Entstehung von Diamant?
Untersuchung des Wärmeschutzes von Außenecken über unbeheizten Kellern in Wohngebäuden – die Achillesferse von massiven Außenwänden mit äußerer Wärmedämmung?
Authors: Geyer Christoph
Published: August 2004

Außenwände von Wohngebäuden werden häufig als massive Mauerwerkswände mit einer außenliegenden Wärmedämmung erstellt. Bei dieser Wandkonstruktion trennt aber der Mauerwerkssockel der massiven Außenwand im Erdgeschoß die Wärmedämmebene der Außenwand von der Wärmedämmebene der Kellerdecke über einem unbeheizten Keller. Hierdurch entsteht eine linienförmige Wärmebrücke. Die für den Mindestwärmeschutz kritischste Stelle tritt an der Außenecke im Erdgeschoß auf, wo sich je zwei dieser linienförmigen Wärmebrücken überlagern. Daher wird die minimale raumseitige Oberflächentemperatur an dieser Ecke für die Beurteilung des Mindestwärmeschutzes der Konstruktion herangezogen. Durch eine Vielzahl von dreidimensionalen Wärmebrückenberechnungen werden die Konstruktionseigenschaften der angrenzenden ebenen Bauteile herausgearbeitet, welche die minimale, raumseitige Oberflächentemperatur in der Außenecke über einem unbeheizten Keller und damit den Mindestwärmeschutz der Konstruktion beeinflussen. Es zeigt sich, daß eine minimale raumseitige Oberflächentemperatur in der Außenecke von 12, 6 °C erst mit Wärmedurchlaßwiderständen der Tragschale bzw. der gesamten Wandkonstruktion nachgewiesen werden kann, die wesentlich höher als 1, 2 m2K/W sind. Damit ist für diese Art von Außenwänden ein Mindestwärmeschutz nach Tabelle 3, DIN 4108‐2 [1] mit einer Anforderung an den Wärmedurchlasswiderstand von R ≥ 1,2 m2K/W nicht ausreichend, um den Mindestwärmeschutz auch für die Außenecke im Erdgeschoß rechnerisch nachweisen zu können. Es wird daher vorgeschlagen, ergänzende Hinweise in die Norm aufzunehmen.
Risks of selected congenital malformations among offspring of mixed race‐ethnicity
Authors: Yang Juan , Carmichael Suzan L. , Kaidarova Zhanna , Shaw Gary M.
Published: August 2004

BACKGROUND

Little is known about the occurrence of specific congenital malformations among offspring of mixed race‐ethnicity.

METHODS

Using data from a population‐based registry, we explored the occurrence of selected malformation phenotypes in offspring to parents who were of different race‐ethnicity. Data were derived from the California Birth Defects Monitoring Program, a population‐based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 2.6 million live births and stillbirths occurred during 1989–2000. Information on parental race‐ethnicity (non‐Hispanic white, Hispanic, black, and Asian) was obtained from birth certificates and fetal death files. Malformation phenotypes studied were spina bifida, anencephaly, cleft lip, cleft palate, tetralogy of Fallot, d‐transposition of great arteries, hypospadias, small intestinal atresia, preaxial polydactyly, microtia, and hypertrophic pyloric stenosis.

RESULTS

A total of 11.2% of births were to parents of mixed race‐ethnicity. Compared to births of parents who were both white, moderately increased risks (risk ratio ≥ 1.7) of anencephaly, polydactyly, and microtia, and decreased risks (risk ratio ≤ 0.6) of hypospadias and hypertrophic pyloric stenosis were observed among births of several mixed race‐ethnicity groups. For anencephaly, polydactyly, and microtia, but not other phenotypes, the risks were different depending on whether maternal versus paternal race‐ethnicity was considered. Risks observed between births of a nonwhite parent and a white parent and births of parents who were both nonwhite were similar for most malformation phenotypes.

CONCLUSIONS

Some malformation phenotypes appear to vary in their risk based on mixed racial‐ethnic groupings. Birth Defects Research (Part A), 2004. © 2004 Wiley‐Liss, Inc.
Developmental toxicity evaluation of butylparaben in Sprague‐Dawley rats
Authors: Daston George P.
Published: August 2004

The developmental toxicity potential of butylparaben (CAS No. 94‐26‐8) was evaluated in rats. Sprague‐Dawley rats were administered butylparaben in 0.5% carboxymethylcellulose by oral gavage at dose levels of 0, 10, 100, or 1,000 mg/kg/day on gestation days (GD) 6–19 (sperm positive day=GD 0). Caesarean sections were performed on GD 20 and fetuses were evaluated for viability, growth, and external, visceral, and skeletal abnormalities. Each group consisted of 25 females, with at least 21 per group being pregnant. The highest dose level caused decreases in maternal weight gain during some of the measurement intervals and was statistically significant during the GD 18–20 interval. Maternal food consumption was significantly decreased in the highest dose group over the dosing period (GD 6–20). There were no differences from control in any of the developmental parameters measured, including embryo/fetal viability, fetal weight, malformations, or variations. Based on the results of this study, the maternal NOAEL for butylparaben was 100 mg/kg/day. Butylparaben does not have the potential to cause developmental toxicity in the Sprague‐Dawley rat at oral dosages up to 1000 mg/kg/day. Birth Defects Res B 71:296–302, 2004. © 2004 Wiley‐Liss, Inc.
Chemiluminescence assay of lipase activity using a synthetic substrate as proenhancer for luminol chemiluminescence reaction
Authors: Ichibangase Tomoko , Ohba Yoshihito , Kishikawa Naoya , Nakashima Kenichiro , Kuroda Naotaka
Published: August 2004

A novel chemiluminescence (CL) assay method for lipase (triacylglycerol lipase, E.C.3.1.1.3) activity was developed by using the lauric acid ester of 2‐(4‐hydroxyphenyl)‐4,5‐diphenylimidazole (HDI) as a substrate. The method is based on the enhanced CL reaction of luminol–hydrogen peroxide–horseradish peroxidase (HRP) with HDI that is liberated from the substrate by enzymatic hydrolysis. To simplify the assay procedure, both the hydrolysis of the substrate and the enhanced CL reaction were performed in the same reaction mixture. Lipases from Candida cylindracea and porcine pancreas were successfully determined with the detection limits (blank signal + 3 SD) of 0.05 and 50.0 mU/tube, respectively. The method is simple and rapid, permitting the completion of single assay within 5 min. The reproducibilities obtained with replicate assays were relative standard deviations (RSDs) of ⪋ 4.7% for within‐day and ⪋ 6.0% for between‐day assays. Copyright © 2004 John Wiley & Sons, Ltd.
Evaluation of the degree of medical radiation damage with a highly sensitive chemiluminescence method
Authors: Zhu Debin , Xing Da , Wei Yadong , Li Xian , Gao Bo
Published: August 2004

A highly sensitive chemiluminescence (CL) method for evaluation of medical radiation damage degree is presented. According to the principle of cell stress response to ionizing radiation, lymphocytes will produce reactive oxygen species (ROS) after irradiation. The ROS produced can react with 2‐methyl‐6‐(p‐methoxyphenyl)‐3,7‐dihydroimidazo[1,2‐α] pyrazin‐3‐one (MCLA), a speciﬁc CL probe for superoxide anion (O·‐2) and singlet oxygen (1O2), to emit light at 465 nm. The CL intensity is positively related to the amount of generated ROS detected 30 min after irradiation. Cell viability, which is inversely related to cell mortality, was determined by MTT assay after 3 days' culture. The results show that both CL intensity and cell mortality of lymphocytes increase with the increase of the radiation dose when the dosage is no more than 3 Gy, suggesting a positive relationship between the degree of lymphocyte cell damage and the amount of ROS generated. In addition, the effects of catalase, Cu–Zn superoxide dismutase (SOD), mannitol, sodium azide (NaN3), and D2O on MCLA‐dependent CL of lymphocytes are discussed. We believe that the MCLA‐dependent CL method would potentially provide an easy way for evaluating the degree of lymphocyte damage induced by radiation. Copyright © 2004 John Wiley & Sons, Ltd.
Single nucleotide polymorphism detection in aldehyde dehydrogenase 2 (ALDH2) gene using bacterial magnetic particles based on dissociation curve analysis
Authors: Maruyama Kohei , Takeyama Haruko , Nemoto Etsuo , Tanaka Tsuyoshi , Yoda Kiyoshi , Matsunaga Tadashi
Published: August 2004

Single nucleotide polymorphism (SNP) detection for aldehyde dehydrogenase 2 (ALDH2) gene based on DNA thermal dissociation curve analysis was successfully demonstrated using an automated system with bacterial magnetic particles (BMPs) by developing a new method for avoiding light scattering caused by nanometer‐size particles when using commercially available fluorescent dyes such as FITC, Cy3, and Cy5 as labeling chromophores. Biotin‐labeled PCR products in ALDH2, two allele‐specific probes (Cy3‐labeled detection probe for ALDH2*1 and Cy5‐labeled detection probe for ALDH2*2), streptavidin‐immobilized BMPs (SA‐BMPs) were simultaneously mixed. The mixture was denatured at 70°C for 3 min, cooled slowly to 25°C, and incubated for 10 min, allowing the DNA duplex to form between Cy3‐ or Cy5‐labeled detection probes and biotin‐labeled PCR products on SA‐BMPs. Then duplex DNA‐BMP complex was heated to 58°C, a temperature determined by dissociation curve analysis and a dissociated single‐base mismatched detection probe was removed at the same temperature under precise control. Furthermore, fluorescence signal from the detection probe was liberated into the supernatant from completely matched duplex DNA‐BMP complex by heating to 80°C and measured. In the homozygote target DNA (ALDH2*1/*1 and ALDH2*2/*2), the fluorescence signals from single‐base mismatched were decreased to background level, indicating that mismatched hybridization was efficiently removed by the washing process. In the heterozygote target DNA (ALDH2*1/*2), each fluorescence signals was at a similar level. Therefore, three genotypes of SNP in ALDH2 gene were detected using the automated detection system with BMPs. © 2004 Wiley Periodicals, Inc.
Evaluation of baculovirus expression vectors with enhanced stability in continuous cascaded insect‐cell bioreactors
Authors: Pijlman Gorben P. , de Vrij Jeroen , van den End Fred J. , Vlak Just M. , Martens Dirk E.
Published: August 2004

Continuous protein production with baculovirus expression vectors in insect‐cell bioreactors is characterized by a dramatic drop in heterologous protein production within a few weeks. This is mainly due to the spontaneous deletion of the heterologous gene(s) from the baculovirus genome and/or to the rapid accumulation of defective interfering baculoviruses (DIs). Cell culture experiments with bacmid‐derived baculoviruses showed that spontaneous deletions in the foreign bacterial artificial chromosome (BAC) sequences readily occurred. These deletions correlated with a low density of baculovirus homologous (repeat) regions (hrs), which are located dispersed throughout the baculovirus genome and are believed to act as origins of viral DNA replication (oris). To test the hypothesis that deletions are more likely to occur in regions with a low ori density, the properties of bacmid‐derived baculoviruses with an additional hr in the unstable BAC sequences were compared to the standard bacmid‐derived baculovirus in a continuous cascaded insect‐cell bioreactor configuration. All viruses were equipped with a green fluorescent protein (GFP) gene and a gene encoding the classical swine fever virus E2 glycoprotein (CSFV‐E2). The insertion of an extra hr in the BAC vector led to improved genetic stability of adjacent sequences, resulting in prolonged protein expression. The maintenance of the BAC sequences appeared to be dependent on the orientation of the inserted hr. The advantages of the utilization of hrs to improve the stability of baculovirus expression vectors for the large‐scale protein production in insect‐cell bioreactors are discussed. © 2004 Wiley Periodicals, Inc.
Influence of power supply in the feasibility of Phaeodactylum tricornutum cultures
Authors: Brindley Alías C. , García‐Malea López M.C. , Acién Fernández F.G. , Ferníndez Sevilla J.M. , García Sánchez J.L. , Molina Grima E.
Published: August 2004

The influence of fluid‐dynamic conditions on the yield of Phaeodactylum tricornutum microalgal cultures was analyzed in two stages: first, the influence of air flow rate; second, the influence of using fluid‐moving pumps for recirculating the culture. With respect to the air flow rate, the yield of the cultures increased with the aeration rate up to values of 2.0 v/v/min, then stress was observed and the yield of the cultures decreased. With respect to the influence of mechanical power supply for liquid impulsion, three different types of pumps—centrifugal, pulse, and peristaltic—were essayed at different power supplies. The cultures were stressed for the three types of pumps essayed. For each pump, the higher the power supply the lower was the Fv/Fm value and the higher was the stress at which cells were exposed. The highest measured stress was when the culture was moved with the centrifugal pump. Despite measured stress, for all the experiments stable steady states were reached, thus indicating that cells reduced their yield but did not die, as was verified by cell viability measurements. It was observed that the increase of the power supply improved the frequency of light exposition thus enhancing the yield of the cultures. However, the higher the power supply, the lower the microeddy length scale; therefore, stress could appear. Data demonstrated that the microeddy length scale was always much higher than cell size and therefore the turbulence was not responsible for stress. Also, the mass transfer was discarded as responsible for yield reduction. It was concluded that the shear rate was the factor determining the existence of stress phenomena. The evaluation of these shear rates demonstrated that values above 30–80 s−1 damaged the cells strongly. These data were verified in an outdoor pilot‐scale tubular photobioreactor that was implemented with the same type of pumps, thus demonstrating the necessity to take into account this factor in the design and scale‐up of microalgal photobioreactors. © 2004 Wiley Periodicals, Inc.
Preparation, optimization, and structures of cross‐linked enzyme aggregates (CLEAs)
Authors: Schoevaart R. , Wolbers M.W. , Golubovic M. , Ottens M. , Kieboom A.P.G. , van Rantwijk F. , van der Wielen L.A.M. , Sheldon R.A.
Published: August 2004

The broad applicability of the cross‐linking of enzyme aggregates to the effective immobilisation of enzymes is demonstrated and the influence of many parameters on the properties of the resulting CLEAs is determined. The relative simplicity of the operation ideally lends itself to high‐throughput methodologies. The aggregation method was improved up to 100% activity yield for any enzyme. For the first time, the physical structures of CLEAs are elucidated. © 2004 Wiley Periodicals, Inc.
Generation of an α‐L‐rhamnosidase library and its application for the selective derhamnosylation of natural products
Authors: Monti Daniela , Pišvejcová Andrea , Křen Vladimír , Lama Marco , Riva Sergio
Published: August 2004

A screening of 16 different fungal strains was performed under different cultivation conditions, using L‐rhamnose or L‐rhamnose‐containing flavonoid glycosides (rutin, hesperidin, and naringin) as specific inducers. No significant constitutive production of α‐L‐rhamnosidases was detected in noninduced cultures, while high levels of these glycosidase activities were obtained using different inducers. New species, so far unknown for the production of α‐L‐rhamnosidases, were identified.

More than 30 different α‐L‐rhamnosidase samples were prepared by ammonium sulfate precipitation. Substrate specificity of this α‐L‐rhamnosidase library was tested with various L‐rhamnose‐containing natural compounds (flavonoids, terpenoids, and saponins). Most of the enzymatic preparations showed broad substrate specificity, and some of them were also acting on sterically hindered substrates (e.g., quercitrin). The screening of the library under different reaction conditions showed the coexistence, in the same preparation, of more than one α‐L‐rhamnosidase activities with different substrate specificity and different stability towards organic cosolvents.

To exploit this enzymatic library for synthetic applications, the presence of contaminating α‐L‐arabinosidases and β‐D‐glucosidases was investigated. The latter enzymes were observed in several preparations, while α‐L‐arabinosidase content was generally quite low.

The selective derhamnosylation of the saponin desglucoruscin was performed on a preparative scale. The enzyme obtained by rhamnose induction of the Aspergillus niger K2 CCIM strain showed high activity towards this substrate and negligible α‐L‐arabinosidase contamination. Therefore, it was chosen as a catalyst for the selective derhamnosylation reaction, which provided the desired product in 70% yield. © 2004 Wiley Periodicals, Inc.
Gene transfer in wound healing
Authors: Eriksson E , Velander P
Published: August 2004

Exciting research with the promise of clinical application