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PubMedDate not supplied

Cyclization of nucleotide analogues as an obstacle to polymerization.

Cyclization of activated nucleotide analogues by intramolecular phosphodiester-bond formation is likely to compete very effectively with template-directed condensation except in the cases of ribo- and arabinonucleotides. This could have excluded derivatives of most sugars from growing polyribonucleotide chains and thus reduced chain-termination in prebiotic polynucleotide synthesis.

Chemistry, Organic↗
PubMed2004

Obstacles to flow cytometric analysis of rumen microbial samples.

Several methods were tested that would improve the fluorescence signal from hybridized rumen bacterial cells. Disruption of cell envelopes by lysozyme, EDTA, proteinase K and/or SDS caused only a minor increase in fluorescence signal. Use of helper unlabeled oligonucleotide probes was successful only with the Puni[H672] probe which, however, when used with specific PBBl4-labeled probe, gave fluorescence signal drop. No substantial rise in fluorescence signal was also observed with cells subjected to growth-without-cell-division treatment. Further improvements are needed to make the fluorescent in situ hybridization (FISH)-flow cytometry combination applicable to rumen bacteria.

Animals↗
PubMed1998

Macromolecular cytosolic delivery: cell membranes as the primary obstacle.

The "evolution" of a thing, a custom, an organ is thus by no means its progressus toward a goal, even less a logical progressus by the shortest route and with the least expenditure of force, but a succession of more or less profound, mutually independent processes of subduing, plus the resistances they encounter, the attempts at transformation for the purpose of defense and reaction, and the results of successful counteractions. The form is fluid, but the "meaning" is even more so.

Bacteria↗
PubMed2001

Failing to live up to the fanfare? A personal perspective on obstacles to the clinical development of thrombopoietic agents.

A number of hematopoietic growth factors have been identified that are active on megakaryocytes and platelets, but only 2, interleukin-11 (IL-11) and thrombopoietin, are being actively pursued clinically, with IL-11 approved for treatment of thrombocytopenia. The development of these agents in general has been disappointing, and in part this reflects the inherent biology of these factors with a failure to match clinical need with physiological function. The delayed action of these factors is also a consequence of the intrinsic biology of megakaryocytes and platelets, and thus is likely to be limiting regardless of which factor is employed. In addition, the development of these agents has occurred at a time when there is something of a decreasing demand for platelets, at least in the context of chemotherapy-induced thrombocytopenia. This decrease is the result of increased use of blood stem cells to support intensive chemotherapy procedures, reduced thresholds for platelet transfusion, and a decreasing role for intensive chemotherapy. These issues are discussed.

Animals↗
PubMed2001

The elaboration of the 'Stockholm convention' on persistent organic pollutants (POPs): a negotiation process fraught with obstacles and opportunities.

The conclusion in December 2000 of the negotiations for the 'Stockholm Convention' can clearly be labeled as a success. The Convention text was negotiated in merely five sessions of the Intergovernmental Negotiating Committee (INC) and accomplished after its fifth session despite the fact that numerous controversial issues, such as the inclusion of new substances under the ambit of the Convention, the acknowledgement of the precautionary principle or--clearly most controversial--the financing mechanisms, remained to be resolved. This paper attempts to provide a somewhat impressionistic account of the negotiations leading to the conclusion of the 'Stockholm Convention' as experienced by the members of the Swiss delegation participating in the negotiations of the INC. Besides a brief overview on the 'history' of the negotiations, it will focus on some issues of special interest--and controversy--to the negotiators, and finally attempt to provide an outlook on the future of the work performed by the INC and the implementation of the Convention. Issues of special interest are environmental policy issues, capacity building and financing, trade-related issues, precautionary principles, and technical and scientific issues.

Commerce↗
PubMed2005

[The 12th amendment to the German Drug Law. Chances and obstacles for investigator-initiated clinical trials].

The European Union's so called Clinical Trials Directive 2001/20/EC was implemented in national law in Germany in August 2004, leading to the 12th amendment of the German Drug Law (Arzneimittelgesetz). The directive is intended to harmonize the clinical trial's regulatory environment across the European Union and to improve protection of human subjects. It lays down the principles and guidelines of Good Clinical Practice (GCP). As the regulation applies to all clinical trials on medicinal products for human use, and as only non-interventional studies are excluded, academic, investigator-initiated clinical trials will also have to comply with the EU clinical trials directive implemented in the German Drug Law. In an investigator-initiated trial in which the investigator takes the responsibility of a sponsor, the investigator-sponsor must take total legal and financial responsibility for the clinical trial. Since publicly funded clinical trials make a large contribution to improved care, concern has been expressed that non-commercial research projects will be reduced and the vital medical research conducted at academic institutions curtailed. Nonetheless GCP ensures a valid study design, qualified data management, analysis and monitoring of the trial and thereby promotes more valid data and protection of study participants. The trials are more likely to lead to reliable results leading to new therapies, strategies or a better understanding of diseases. What is needed, therefore, is an increase in public funding and the establishment of clinical trial units/organizations associated with the universities or hospitals where independent researchers have the possibility to obtain theoretical advice and practical help, professional training and support. In the end, the directive may serve as a stimulus to build a better national research environment and to promote public funding, and may lead to fewer but more valid clinical trials.

Clinical Trials as Topic↗
PubMed1998

Clinical evaluation of biologically targeted drugs: obstacles and opportunities.

Recent insights into the molecular mechanisms of cancer have indicated that a variety of fundamental cellular processes are dysregulated in malignant cells. These processes include cell cycle control, signal transduction pathways, apoptosis, telomere stability, angiogenesis, and interactions with the extracellular matrix. Remarkable advances in molecular genetics, enzymology, and medicinal chemistry have permitted the design of compounds that modulate some of these processes with specificity that was unimaginable a decade ago. As these novel, biologically targeted compounds enter the clinic, they will require a strategy for clinical evaluation and development different from that used commonly for cytotoxic antineoplastic agents. This review examines the development of cancer drugs directed against angiogenesis, metastasis, signal transduction, telomerase, and molecular message (antisense), outlines strategies for the clinical testing of agents directed at these processes, and contrasts these efforts with traditional approaches to cancer drug testing.

Animals↗
PubMed1999

Endoscopic intrauterine surgery in primates: overcoming technical obstacles.

Current protocols for fetal surgery require cesarean section and partial fetal extraction, both of which impart significant risks to the mother and fetus. Endoscopic fetal surgery is less invasive and will likely reduce some of these risks, but the technical difficulties and feasibility in a primate model have yet to be explored fully. Four pregnant baboons (95 days gestation) were anesthetized, their uteruses exposed via an abdominal incision, and blunt-tipped flanged endoscopic ports inserted. Amniotic fluid was removed, and warmed saline was infused to dilate the uterus. To evaluate instrumentation and wound closure, the tip of the snout was externalized and bilateral cleft lip-like defects made. The lips were then endoscopically repaired by suture (Endostitch, U.S. Surgical) or unique nonpenetrating clips (VCS, U.S. Surgical). The saline was then removed, amniotic fluid returned, and the ports carefully removed. After 4 weeks, the fetuses were delivered and evaluated. Eight cleft lip-like defects were successfully repaired in all four cases. Operative time averaged 83 min. No infections, amniotic leaks, or adhesions developed. Survival was 50% with two fetuses delivering within 48 hours postoperatively: one from preterm labor, the other with fetal demise from retroperitoneal hemorrhage after operative blunt abdominal trauma. We demonstrate the feasibility of endoscopic fetal surgery in primates. The use of blunt-tipped flanged ports provides a fluid tight seal and allows appropriate closure of the fetal membranes, but requires laparotomy and uterine exposure. Distension of the uterus with warmed saline affords a larger operating field, enhancing visualization and instrumentation of the fetus. Grasping the fetus through the exposed uterus gives excellent control for repair. However, such control is also needed in a percutaneous approach. Further instrumentation development is needed to accomplish similar control for the percutaneous approach.

Animals↗
PubMed2000

Evolution of and obstacles in surgical treatment for hepatocellular carcinoma over the last 25 years: differences over four treatment eras.

This study was designed to clarify what differences the last 25 years have made in surgical results for patients with hepatocellular carcinoma (HCC). We examined results for 716 hepatectomized patients in four treatment eras: first era (1973-1980; n = 58), second era (1981-1985; n = 155), third era (1986-1990; n = 243), and fourth era (1991-1997; n = 260). Patient background, tumor characteristics, type of hepatectomy, treatment for intrahepatic recurrences, and surgical results in the four eras were compared by univariate analysis to clarify the factors that have contributed to or impeded progress in the surgical treatment of HCC. Although there were no significant chronological differences in liver pathology and surgical resectability, operative mortality was reduced to 2% in the fourth era, from 29% in the first era. With an increasing proportion of early-stage HCCs (TNM, stages I and II), the cumulative survival rate at 5 years improved in the course of the eras in our overall population of patients (12%, 31%, 38%, and 51%, respectively, for the first, second, third, and fourth eras) and in a subset of the population divided according to tumor stage. Also, we found a chronological improvement in the survival rate at 3 years after intrahepatic recurrence (10%, 28%, 36%, and 44%, respectively in the first second, third, and fourth eras). This improvement was associated with the establishment of an early detection program for intrahepatic recurrences. However, the recurrence rate was similar in any subset of the population through the four eras. Although this univariate study could not determine independent factors that contributed to the chronological progress in results for HCC surgery in the four eras, it is conceivable that the establishment of indication criteria for hepatectomy, an early detection program for primary and recurrent lesions, and the introduction of multimodal treatment for recurrence were contributory factors in this improvement. A strategy for alleviating the frequent recurrences originating from posthepatectomy metachronous carcinogenesis remains to be established.

Analysis of Variance↗
PubMed2005

A call to restructure the drug development process: government over-regulation and non-innovative late stage (Phase III) clinical trials are major obstacles to advances in health care.

The history of drug/vaccine development has included major advances guided primarily by risk/benefit analyses concerning the innovative agent, not by evidence-based clinical trials (Phase I-IV). Because the approval for new drugs is hindered under the present process, the system requires restructuring. The Phase I/II study period should be more flexible, using the "environment of knowledge" about the new agent, plus risk/benefit assessments. Phase III, as presently constructed, does not add new adverse events data, it provides a narrower profile of drug efficacy than properly done Phase II studies, and placebo-controlled trials continue to raise unresolved ethical and social issues. Phase III studies should be abandoned for most drugs, and substituted with properly powered Phase II dose-ranging studies plus careful post-marketing surveillance. Phase III should be a penalty for poor drug development, not a regulatory requirement. To accomplish efficient drug development, greater cooperation between pharmaceutical companies and governments in developing clinical trials is needed rather than over-regulation. These changes will synchronize the drug development and regulatory process with the current rapid drug discovery process, reduce drug development time and cost, and improve patient care.

Animals↗