bluuebunny/crossref_metadata_2025_split huggingface dataset:
Guanine Nucleotide Pool Imbalance Impairs Multiple Steps of Protein Synthesis and Disrupts GCN4 Translational Control in Saccharomyces cerevisiae
Authors: Iglesias-Gato Diego , Martín-Marcos Pilar , Santos María A , Hinnebusch Alan G , Tamame Mercedes 
Published: October 2010

Abstract
Purine nucleotides are structural components of the genetic material, function as phosphate donors, participate in cellular signaling, are cofactors in enzymatic reactions, and constitute the main carriers of cellular energy. Thus, imbalances in A/G nucleotide biosynthesis affect nearly the whole cellular metabolism and must be tightly regulated. We have identified a substitution mutation (G388D) that reduces the activity of the GMP synthase Gua1 in budding yeast and the total G-nucleotide pool, leading to precipitous reductions in the GDP/GTP ratio and ATP level in vivo. gua1–G388D strongly reduces the rate of growth, impairs general protein synthesis, and derepresses translation of GCN4 mRNA, encoding a transcriptional activator of diverse amino acid biosynthetic enzymes. Although processing of pre-tRNAiMet and other tRNA precursors, and the aminoacylation of tRNAiMet are also strongly impaired in gua1–G388D cells, tRNAiMet-containing complexes with the macromolecular composition of the eIF2·tRNAiMet.GTP complex (TC) and the multifactor complex (MFC) required for translation initiation accumulate ∼10-fold in gua1–G388D cells and, to a lesser extent, in wild-type (WT) cells treated with 6-azauracil (6AU). Consistently, addition of an external supply of guanine reverts all the phenotypes of gua1–G388D cells, but not those of gua1–G388D Δhpt1 mutants unable to refill the internal GMP pool through the salvage pathway. These and other findings suggest that a defect in guanine nucleotide biosynthesis evokes a reduction in the rate of general protein synthesis by impairing multiple steps of the process, disrupts the gene-specific reinitiation mechanism for translation of GCN4 mRNA and has far-reaching effects in cell biology and metabolism.
The Developmental Timing Regulatorhbl-1Modulates the Dauer Formation Decision inCaenorhabditis elegans
Authors: Karp Xantha , Ambros Victor 
Published: October 2010

AbstractAnimals developing in the wild encounter a range of environmental conditions, and so developmental mechanisms have evolved that can accommodate different environmental contingencies. Harsh environmental conditions cause Caenorhabditis elegans larvae to arrest as stress-resistant “dauer” larvae after the second larval stage (L2), thereby indefinitely postponing L3 cell fates. HBL-1 is a key transcriptional regulator of L2 vs. L3 cell fate. Through the analysis of genetic interactions between mutations of hbl-1 and of genes encoding regulators of dauer larva formation, we find that hbl-1 can also modulate the dauer formation decision in a complex manner. We propose that dynamic interactions between genes that regulate stage-specific cell fate decisions and those that regulate dauer formation promote the robustness of developmental outcomes to changing environmental conditions.
The Use of Periodontal Probes and Radiographs in Clinical Trials of Diagnostic Tests
Authors: Reddy Michael S. 
Published: October 2010

AbstractPeriodontal probing attachment level measurements and intraoral radiographs are used to assess the level of the clinical attachment and bone support in the diagnosis of periodontitis. Together these physical measurements of tooth support comprise the standard against which new diagnostic tests are compared. Since probing and radiographs provide a measure of the severity of attachment or bone loss at one point in time, serial measurements must be compared to determine whether periodontitis is progressive. Periodontal probing may be performed manually or by using controlled force electronic instruments. The resolution, depending on the instrument, will vary from 1.0 mm to 0.1 mm. Variations in probing force, size and shape of tip, location of tip placement, detection or reference landmarks for attachment level probing, degree of gingival inflammation, and transcription may adversely influence accuracy. Electronic probes offer the advantage of improved resolution, force control, and automatic recording, but the literature is inconsistent about the advantages in terms of repeatability and accuracy. Radiographic assessment of alveolar bone loss may be achieved by visual interpretation, measurement, or digital image analysis. While visual interpretation of unstandardized radiographs is insensitive to changes in bone, standardized radiographs can permit measurement of changes on the order of 0.2 mm when computerized methods are used. Newer techniques such as digital subtraction radiography permit detection of bony changes too small to be seen by the unaided eye and are over 95% sensitive and specific in detecting bony changes less than 10 mg. Ann Periodontol 1997;2:113–122.
Evaluation of Components of Gingival Crevicular Fluid as Diagnostic Tests
Authors: Lamster Ira B. 
Published: October 2010

AbstractGingival crevicular fluid (GCF) is an inflammatory exudate that can be collected at the gingival margin or within the gingival crevice. The biochemical analysis of the fluid offers a noninvasive means of assessing the host response in periodontal disease. In recent years, the relationship of measures of the inflammatory response in GCF to risk for development of active periodontal disease (defined as clinical attachment loss or radiographic bone loss) has been studied in longitudinal trials. The greatest interest has focused on Prostaglandin E2, an arachidonic acid metabolite; β‐glucuronidase and neutrophil elastase, markers of lysosomal enzyme release from neutrophils; and aspartate aminotransferase, a cytoplasmic enzyme indicative of cellular necrosis. Analysis of the data allows a number of conclusions to be drawn concerning the potential diagnostic significance of GCF: 1) an exuberant host inflammatory response is associated with progressive disease in patients with Periodontitis; 2) collection of GCF using small precut strips is a reproducible and reliable collection technique; 3) the total amount of the mediator and not concentration of the mediator in the GCF sample can be reported when timed samples are collected; and 4) technology exists for GCF‐based diagnostic tests to be performed in the dental office. Nevertheless, many questions remain. Still to be determined are: 1) the relationship of test results to the development of Periodontitis in patients with gingivitis; 2) the level of test accuracy needed to justify use of these tests; 3) the unit of observation (patient, site) that is being evaluated by the test; and 4) the need for such tests as perceived by clinicians. While these questions are formidable, introduction of GCF‐based diagnostic tests will provide clinicians with an improved, quantitative means of evaluating patients and offer specific criteria to assess the effectiveness of treatment. Ann Periodontol 1997;2:123–137.
Overview of Periodontal Clinical Trials Utilizing AntiInfective or Host Modulating Agents
Authors: Pihlstrom Bruce L. 
Published: October 2010

AbstractIssues in periodontal trials designed to evaluate anti‐infective or host modulating agents for the prevention and treatment of periodontal diseases are reviewed in this paper. Clinical trial designs, prevention versus treatment, disease activity, utility of new measurement technologies, ethical and safety issues, selection of outcome variables, and clinical significance are discussed. In general, randomized parallel arm, doubleblinded, controlled clinical trials are most appropriate for testing anti‐infective and host modulating agents. New measurement technologies may offer increased measurement resolution and automated data capture; but, depending on their specific application and level of examiner reproducibility, these technologies may or may not result in lowered thresholds for declaring change. Mechanical therapy for common plaque‐associated gingivitis and adult Periodontitis is effective, has low risk, and is widely accepted as a minimum standard of care. New agents for treatment of these diseases must carry minimal risk and have equal or greater effectiveness than this standard of care. Outcome variables for gingivitis trials should include a visual index of gingival inflammation and a separate or component index of gingival bleeding. Prevention studies of Periodontitis require a longer duration than treatment studies. Maintenance of mean clinical attachment level should be a primary outcome measure for all prevention studies of adult Periodontitis. Maintenance of alveolar bone support is an essential additional outcome for agents specifically acting on bone. The design and conduct of clinical trials for anti‐infective and host modulating agents depend on the specific hypothesis to be tested and the ethical demands of providing safe and effective care for all study volunteers. Ann Periodontol 1997;2: 153–165.
Regulatory Issues for Evaluation of Therapies to Prevent or Arrest Disease Progression
Authors: Hyman Frederick N. , Welch Michael E. , Cheever James R. 
Published: October 2010

AbstractThe Federal Food Drug and Cosmetic Act gives authority to the US Food and Drug Administration (FDA) to regulate foods, human and veterinary drugs, biological products, and cosmetics which are to be introduced into interstate commerce. The approval of pharmaceutical products for the treatment and/or prevention of periodontal diseases requires presentation of evidence that supports the safety and efficacy of the particular drug therapy in question. Sponsors need to carefully consider each step in the overall development plan beginning with an Investigational New Drug Application and concluding with submission of a New Drug Application for pre‐market approval. This paper focuses specifically on the design, conduct, and analysis of clinical trials of drugs for the prevention or treatment of periodontal diseases. It is based upon a guidance document under development at the time of this presentation by FDA's Center for Drug Evaluation and Research that will include separate chemistry, toxicology, and biopharmaceutics sections. Unlike more formal FDA guidelines, a guidance document can be more easily and regularly updated to reflect changes in the state of the art of periodontal diagnosis and treatment. Ann Periodontol 1997;2:166–179.
International Regulatory Aspects of Clinical Periodontal Research
Authors: Cooley William E. , Castellion Alan W. 
Published: October 2010

AbstractThe Food and Drug Aministration (FDA) was the pioneer regulatory agency to set standards for clinical studies aimed at approval of new drugs. For years the FDA's rules represented the most thorough, stringent, and consistent policy. Now most other developed countries have comparable requirements for the conduct of clinical trials. The European Community (EC), Canadian, and Japanese regulations are most important for United States (US) scientists attempting to globalize their research. Regulations in Eastern Europe, some Asian countries, and Latin America are of growing importance. The Pacific‐Rim appears to be the fastest growing pharmaceutical market in the next decade. Currently, the EC and Japan's Good Clinical Practice (GCP) regulations are more detailed than those of the US. Moreover, the World Health Organization recently published GCP recommendations similar to the EC requirements. Well‐designed and well‐controlled studies done in the EC, US, and other developed countries are generally accepted throughout the world. Japan and some other countries require studies in local patients. American scientists cannot expect to conduct studies in other countries as principal investigators, but many are associated with national clinicians. Mutual recognition of marketing approvals is the ultimate goal for the globalization of drug research. While it is the objective of the Scheme for the Mutual Recognition of Evaluation Reports on Pharmaceutical Products and the EC Decentralized Procedure, it is not apparent when the FDA will totally accept another regulatory body's approval decision. The International Conference on Harmonization involves the EC, Japan, and the US. This most important series of meetings will finally align the major countries more closely in regulating clinical studies and the production of safe, effective, and quality products, especially in these times of worldwide economic considerations and health care reform. It is imperative that US dental scientists become more familiar with pertinent regulations in leading foreign countries. Ann Periodontol 1997;2:18–30.
Design and Implementation of Clinical Trials of Antimicrobial Drugs and Devices Used in Periodontal Disease Treatment
Authors: Newman Michael G. 
Published: October 2010

AbstractThe design and implementation of clinical trials (CTs) carried out to evaluate antimicrobial and anti‐infective drugs and devices are one of the most difficult challenges in contemporary periodontal research and product development. The overwhelming amount of evidence which has established a microbial etiology for periodontitis is the basis for developing and testing antimicrobial treatments. Well‐designed antimicrobial CTs start with a carefully crafted hypothesis and a protocol which explicitly integrates the requirements of the patient, the clinician, the sponsor, and regulatory authorities. Surrogate variables for effectiveness must be clinically relevant, scientifically sound, and statistically valid. Currently, clinical attachment level measurements and alveolar bone assessments are accepted as proof of effectiveness. Indication and claim support of the antimicrobial product guide the design and implementation of the CT. Adverse microbiologic consequences, such as lack of antimicrobial susceptibility, wrong spectrum, incorrect dosage, non‐compliance, and drug interference, must be monitored. Successful CTs balance a large group of variables used to screen, randomize, and assign subjects to experimental and control groups to ensure that prognostic and risk factors are properly accounted for. Ann Periodontol 1997;2:180–198.
The Design and Implementation of Trials of Host Modulation Agents
Authors: Offenbacher S. , Salvi G.E. , Beck J.D. , Williams R.C. 
Published: October 2010

AbstractOver the last two decades it has become more evident that although oral microorganisms are essential agents of periodontal pathogenesis, interpatient variability in the host response is a major determinant of the expression of periodontal disease extent and severity. Data from animal models and human studies have identified many of the components of the host inflammatory response which serve as critical mediators of clinical inflammation, attachment loss, and bone resorption. Studies suggest that certain pharmacologic agents, which act at a molecular level to block specific inflammatory mediators, appear to attenuate disease progression. These promising findings herald a new era in periodontal medicine. Anti‐infective therapies may soon be supplemented with anti‐inflammatory pharmacological agents. However, there are many unanswered issues regarding formulation design, clinical application, potential indication claims, and clinical study design. Furthermore, current considerations of fundamental mechanisms of pathogenesis, as well as new data from epidemiologic studies emphasizing the multifactorial nature of disease, are changing the underlying assumptions which have served to guide our design of anti‐infective drug trials over the last two decades. There are new questions regarding appropriate outcome measurements which are to be reconsidered. For example, the measurement of a change in periodontal disease status, either during progression or in response to therapy, is fundamentally unidimensional and may be only mildly informative when one considers that the disease is multifactorial by nature. Using an example from intensive care medicine, pathophysiologic studies of septic shock have demonstrated that the microbial dose and the host inflammatory mediator response are far better predictors of patient morbidity and mortality than any combination of clinical signs associated with clinical shock. Clinical trials of anti‐cytokine and anti‐inflammatory drugs to treat shock are now designed and conducted taking strategic advantage of this knowledge by including measurements of microbial dose and host response. It appears prudent that the design and implementation of clinical trials of host modulation agents also benefit from our current insights into pathogenesis and not represent a templatedriven adaptation of historical, anti‐infective clinical trial protocols. Ann Periodontol 1997; 2:199–212
Outcome Variables for the Study of Periodontal Regeneration
Authors: Machtei Eli E. 
Published: October 2010

AbstractThe most reliable outcome variable for assessing periodontal regeneration is human histology; however, the morbidity associated with this technique makes it feasible only in isolated case studies designed to prove that a drug, device, or technique is capable of regenerating the lost periodontium including bone, cementum, and functionally oriented periodontal ligament. In the absence of this genuine variable, other “surrogate” variables must be used. Of these, measurement of new bone is the primary alternative. Direct bone measurements, including linear and volumetric assessment, are by far the best tools; however, the need for a second surgical procedure is a definite drawback of this technique. To overcome this problem, other outcomes have been employed: sounding bone measurements is a less invasive method, albeit it is also less accurate. Another tool that has been tested extensively is radiographic analysis. Conventional radiography is not useful in most regenerative trials where minimal or no crestal changes occur. The use of standardized radiographs and image processing techniques to measure alveolar bone changes has not significantly enhanced the applicability of this method. Digital subtraction radiography (DSR) offers some improvement over previous techniques; however, the correlation between the magnitude of clinical bone changes and changes in the digital image is yet to be substantiated. Other variables have been successfully used in regenerative studies. These include clinical attachment level changes, change in probing depth, and gingival recession. The information derived from these variables, especially attachment level changes, supplement and substantiate the direct bone measurements. Other variables that may be monitored are those associated with plaque formation, periodontal pathogens and gingival inflammation; while not direct measures of regeneration, these variables are likely to affect future prognosis and treatment stability. In summary, direct bone measurements are the most ideal surrogate outcome variable, although clinical attachment level measurements are commonly used in large‐scale regenerative clinical trials. Clinical response may be assessed at different time intervals; however, the endpoint measurements for regenerative studies should be taken at least 12‐months postoperatively. Ann Periodontol 1997;2:229–239.
The Use of Biologic Response Modifiers in Human Clinical Trials
Authors: Graves Dana T. 
Published: October 2010

AbstractTo optimize regeneration of the periodontium, new cementum, periodontal ligament, and bone must be formed. Conventional periodontal surgery decreases the likelihood of continued progressive periodontal disease however, it does not lead to significant periodontal regeneration. In vitro studies have identified a class of biologic response modifiers loosely referred to as growth factors, which stimulate the cellular events of tissue regeneration. The most promising are mitogenic and differentiation factors. Based on promising results from animal studies, the application of growth factors to predictably stimulate periodontal regeneration is entering human clinical trials. This manuscript deals with several important considerations in testing biologic response modifiers in humans. Suggestions are made regarding the following parameters: 1) selection of the unit of measurement; 2) patient and lesion selection; 3) identification of controls; 4) selection of outcome parameters; 5) statistical approach; and 6) considerations in treatment regimens.
The Food and Drug Administration and the Regulation of Clinical Trials for Endosseous Implants
Authors: Scott Pamela D. , Runner Susan 
Published: October 2010

AbstractThe Office of Device Evaluation (ODE), within the Center for Devices and Radiological Health of the Food and Drug Administration is the primary component responsible for the premarket review of medical devices. Dental devices are reviewed by the Dental Devices Branch within ODE. Premarket submissions to FDA for dental endosseous implants should include complete characterization of the device and often may necessitate the inclusion of mechanical and other bench testing and clinical data. FDA guidance documents are available which outline the information that should be included in the submissions. The guidance document for premarket approval submissions for dental endosseous implants also provides guidance on clinical trials for dental implants. This guidance document addresses such issues as the number of patients and study sites, length of followup, post‐implant assessment, and pooling of data. The review of dental endosseous implants involves many challenging issues, including success/failure criteria, new designs and new indicated uses. The Dental Branch continues to gather information to address these issues. Ann Periodontol 1997; 2:284– 290.