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PubMed2005

Dissociation analysis in polymerase chain reaction and 1X SSC buffer as a prerequisite for selection of 13mer microarray probe sets with uniform hybridization behavior.

Homogeneous probe hybridization is a prerequisite for the robust design of microarrays. Elaborate algorithms were developed to select for probe sets with uniform melting temperatures (Tm). However, at least short oligonucleotides (< 20 bp) show large variation in the on-chip hybridization efficiency even if designed with state-of-the-art algorithms. This variation can be explained by steric effects and interferences on the solid surface as well as by chemical conditions that may deviate from conditions used to develop the algorithms. We designed 412 random 13mer duplexes to study the differences between the Tm of nearest-neighbor algorithms and the Tm values measured by dissociation analysis in polymerase chain reaction (PCR) and 1X SSC buffer. We tested the effects of theoretical vs empirical Tm values on the hybridization variation of 40 duplexes on-chip. Although the empirical approach resulted in a slightly better prediction of hybridization efficiency, less than one-fifth (17%) of the observed variation could be explained by the factor Tm alone. We conclude that state-of-the-art algorithms can be used for a first selection of short oligonucleotide probes, but that it is then necessary to perform an on-chip selection to obtain a probe set with a uniform hybridization behavior.

Algorithms↗

PubMed2001

On painting and philosophy: Sir Henry Raeburn.

This article considers the 18 century European Enlightenment as an example of the cross-fertilization between philosophy propounding rationalist-empirical approach, and arts. The example of Sir Henry Raeburn, a Scottish portraitist, is given to illustrate the influence of the concepts of perception developed by Thomas Reid, the founder of the Scottish school of common sense philosophy, on the style of painting.

History, 17th Century↗

PubMed2006

Clinicians' management of children and adolescents with acute pharyngitis.

OBJECTIVE: Sore throat is a common complaint in children and adolescents. With increasing antimicrobial resistance because of antimicrobial overuse, accurate diagnosis is imperative. Appropriate management of acute pharyngitis depends on proper use and interpretation of clinical findings, rapid antigen-detection tests, and throat cultures. We surveyed pediatricians and family physicians to evaluate their management strategies for children and adolescents with acute pharyngitis and to assess the availability and use of diagnostic tests in office practice. METHODS: In 2004, surveys were mailed to a random sample of 1000 pediatrician members of the American Academy of Pediatrics and 1000 family physician members of the American Academy of Family Physicians. We assessed factors associated with physicians using an appropriate management strategy for treating acute pharyngitis. RESULTS: Of 948 eligible responses, 42% of physicians would start antimicrobials before knowing diagnostic test results and continue them despite negative results, with 27% doing this often or always. When presented with clinical scenarios of patients with acute pharyngitis, < or =23% chose an empirical approach, 32% used an inappropriate strategy for a child with pharyngitis suggestive of group A Streptococcus, and 81% used an inappropriate strategy for a child with findings consistent with viral pharyngitis. Plating cultures in the office was associated with an appropriate management strategy, although not statistically significant. Solo/2-person practice and rural location were both independent factors predicting inappropriate strategies. CONCLUSIONS: There is much room for improvement in the management of acute pharyngitis in children and adolescents. Most physicians use appropriate management strategies; however, a substantial number uses inappropriate ones, particularly for children with likely viral pharyngitis. Efforts to help physicians improve practices will need to be multifaceted and should include health policy and educational approaches.

Acute Disease↗

PubMed2004

Requirement of diverse T-helper responses elicited by HIV vaccines: induction of highly targeted humoral and CTL responses.

With the continued spread of the HIV/AIDS epidemic at alarming proportions there is a sense of urgency for an effective prophylactic HIV vaccine. However, in addition to the social, geopolitical and public health problems, the scientific challenges often seem insurmountable. Empirical approaches to develop an HIV/AIDS vaccine have been unsuccessful and this, coupled with the recent failure of the first Phase III clinical trials, calls for a strong rational approach based on a deeper scientific understanding of the correlates of immunity observed in both preclinical and clinical settings. While the field has been polarized between those who have been proponents of vaccines that induce strong cytotoxic T-cell responses, and those who advocate inducing neutralizing antibody responses, we have maintained middle ground. Based on our early preclinical observations in rigorous nonhuman primate vaccine efficacy studies, we have focused on vaccine strategies that induce potent T-helper immune responses capable of driving both cytotoxic, as well as broad highly effective neutralizing antibodies. The critical issue remains in the selection of the specific vaccine antigens. To date, our approach has been to utilize multiple structural as well as regulatory HIV antigens containing highly conserved epitopes. The current challenge faced is to design novel antigens based on mimicking envelope structures capable of inducing broad neutralizing antibodies. Our aim is to combine these with immunization strategies capable of eliciting potent cellular as well as humoral immune responses with the ultimate goal of providing mucosal barriers to HIV entry.

AIDS Vaccines↗

PubMed2002

Membrane proteins: functional and structural studies using reconstituted proteoliposomes and 2-D crystals.

Reconstitution of membrane proteins into lipid bilayers is a powerful tool to analyze functional as well as structural areas of membrane protein research. First, the proper incorporation of a purified membrane protein into closed lipid vesicles, to produce proteoliposomes, allows the investigation of transport and/or catalytic properties of any membrane protein without interference by other membrane components. Second, the incorporation of a large amount of membrane proteins into lipid bilayers to grow crystals confined to two dimensions has recently opened a new way to solve their structure at high resolution using electron crystallography. However, reconstitution of membrane proteins into functional proteoliposomes or 2-D crystallization has been an empirical domain, which has been viewed for a long time more like "black magic" than science. Nevertheless, in the last ten years, important progress has been made in acquiring knowledge of lipid-protein-detergent interactions and has permitted to build upon a set of basic principles that has limited the empirical approach of reconstitution experiments. Reconstitution strategies have been improved and new strategies have been developed, facilitating the success rate of proteoliposome formation and 2-D crystallization. This review deals with the various strategies available to obtain proteoliposomes and 2-D crystals from detergent-solubilized proteins. It gives an overview of the methods that have been applied, which may be of help for reconstituting more proteins into lipid bilayers in a form suitable for functional studies at the molecular level and for high-resolution structural analysis.

Crystallization↗

PubMed2004

[Caring for children and adolescents with cancer: the intrathecal chemotherapy phase].

This study aims to explore the experiences of children and adolescents with cancer during the intrathecal chemotherapy phase, by means of a qualitative approach. Empirical data were collected on the basis of semi-structured interviews. Study participants were eleven children/adolescents who received intrathecal chemotherapy, between 07 and 16 years old, from both genders, attended at a hospital school in the interior of São Paulo State, Brazil. Results converged towards the following issues: intrathecal routine; fear, pain and relief fantasies and strategies. This study gave access to important information with a view to caring for children/adolescents during the intrathecal chemotherapy phase, which is considered as one of the most stressing situations. With respect to nursing implications, we identified the vital nature of information for children/adolescents with cancer since this makes it possible to minimize uncertainties and negative feelings and makes them collaborate and participate in treatment.

Adaptation, Psychological↗

PubMed2001

Selected novel anticancer treatments targeting cell signaling proteins.

Empirical approaches to discovery of anticancer drugs and cancer treatment have made limited progress in the cure of cancer in the last several decades. Recent advances in technology and expanded knowledge of the molecular basis of tumorigenesis and metastasis have provided unique opportunities to design novel compounds that rationally target the abnormal molecular and biochemical signals leading to cancer. Several such novel agents have completed advanced stages in clinical development. The excellent clinical results achieved by some of these compounds are creating new paradigms in management of patients with neoplastic diseases. Clinical development of these agents also raises challenges to the traditional methods of drug evaluation and measurement of efficacy.

Antineoplastic Agents↗

PubMed2005

Modeling multicellular response to nonuniform distributions of radioactivity: differences in cellular response to self-dose and cross-dose.

Radiopharmaceuticals are distributed nonuniformly in tissue. While distributions of radioactivity often appear uniform at the organ level, in fact, microscopic examination reveals that only a fraction of the cells in tissue are labeled. Labeled cells and unlabeled cells often receive different absorbed doses depending on the extent of the nonuniformity and the characteristics of the emitted radiations. The labeled cells receive an absorbed dose from radioactivity within the cell (self-dose) as well as an absorbed dose from radioactivity in surrounding labeled cells (cross-dose). Unlabeled cells receive only a cross-dose. In recent communications, a multicellular cluster model was used to investigate the lethality of microscopic nonuniform distributions of 131I iododeoxyuridine (131IdU). For a given mean absorbed dose to the tissue, the dose response depended on the percentage of cells that were labeled. Specifically, when 1, 10 and 100% of the cells were labeled, a D37 of 6.4, 5.7 and 4.5 Gy, respectively, was observed. The reason for these differences was recently traced to differences in the cellular response to the self- and cross-doses delivered by 131IdU. Systematic isolation of the effects of self-dose resulted in a D37 of 1.2 +/- 0.3 Gy. The cross-dose component yielded a D37 of 6.4 +/- 0.5 Gy. In the present work, the overall survival of multicellular clusters containing 1, 10 and 100% labeled cells is modeled using a semi-empirical approach that uses the mean lethal self- and cross-doses and the fraction of cells labeled. There is excellent agreement between the theoretical model and the experimental data when the surviving fraction is greater than 1%. Therefore, when the distribution of 131I in tissue is nonuniform at the microscopic level, and the cellular response to self- and cross-doses differs, multicellular dosimetry can be used successfully to predict biological response, whereas the mean absorbed dose fails in this regard.

Animals↗

PubMed1977

Extending sequence-class membership with matching to sample.

Three normal adults were first trained to point sequentially to each member of several pairs of visual stimuli. This baseline training established one class of stimuli to which subjects responded first, and another class of stimuli to which they responded second. Then, in a matching-to-sample procedure, baseline-sequence stimuli served as samples and new visual stimuli served as comparisons. Subjects were trained to choose one group of new comparisons when the sample was a "first" stimulus from the sequence baseline, and to choose the other new comparison stimuli when the sample was a "second" from the sequence baseline. When the new stimuli were then presented as pairs in the posttest, two subjects pointed to them in sequences predictable on the basis of the stimulus-class membership established during matching to sample. The failure of one subject to demonstrate sequential transfer was shown to be a consequence of the failure of the matching-to-sample procedure to establish stimulus classes. The production of sequences that were not directly trained suggested an empirical approach to the analysis of simple grammatical behavior.

Journal Article↗

PubMed2002

Public health needs and scientific opportunities in research on Latinas.

Much of the research on women's health has not deepened our understanding of health issues affecting Latinas. Yet integration of research on Latinas into the women's health agenda is important for at least 2 reasons. First, critical public health issues facing Latinas must be better understood if effective interventions designed to eliminate racial and ethnic disparities in health are to be developed and implemented. Second, studies on the health of Latinas represent unique opportunities to advance scientific understandings of underlying processes relevant to the health of other populations. Such research can further our knowledge of the processes underlying cultural adaptation and negotiation of changing sex roles and how these issues affect the health of women. Critical research and empirical approaches that help us to understand how race, ethnicity, sex, and class shape the health of Latinas will inform broader public health issues.

Acculturation↗

PubMed2005

Error and individual difference in cardiovascular responses to orthostatic stress in humans.

Variations in cardiovascular responses to orthostatic stress were investigated in terms of physiological polymorphism. Variations of physiological measurements are subdivided into individual differences and measurement errors. However, individual differences are often considered to be an error in statistical analysis due to its limitations in experimental design. In order to discuss about the relative contribution of individual difference in cardiovascular responses to postural changes, percent contribution (PC) was estimated using the Taguchi method. Six healthy male adults (age range: 21-27) were subjected to orthostatic stress by inducing a postural inclination of 60 degrees head-up-tilting to the horizontal, and the responses were measured thrice in each subject on different days. The respective changes of heart rate (HR) and stroke volume (SV) in the period from the resting supine to the head-up-tilt position were significantly increased (p < 0.01) and decreased (p < 0.01) without affecting the mean blood pressure (MBP). The PC of individual difference in HR showed a significantly higher ratio of individual difference during the head-up-tilt (71.4-76.2%) compared with supine rest (0.0-50.4%). While the main variations of HR during supine rest were not the individual differences between the subjects, the day-to-day differences within the subject were significant. The PC of individual differences in MBP and SV constantly displayed a significant difference between the subjects. These results suggest that the strategy for maintaining stable cardiovascular regulation may be different even in normal subjects. In the perspective of physiological parameters, PC monitoring may serve as an empirical approach to evaluate physiological polymorphism.

Adult↗

PubMed2001

A risk-benefit assessment of treatments for infantile spasms.

Infantile spasms are a devastating epileptic encephalopathy of the young child. The continuing spasms and hypsarrhythmia have a deleterious effect on brain maturation and further cognitive development. Corticotropin (adrenocorticotropic hormone) or corticosteroids have been the gold standard treatment for the last 40 years, but there is little agreement on the best agent to use, or the dosage and duration of the treatment. Despite this empirical approach, corticotropin or corticosteroids are effective in controlling spasms and normalising electroencephalograms in about 60% of cases. The major concern with this treatment is the occurrence of frequent and severe adverse effects. The introduction of vigabatrin in the 1990s improved the outcome of infantile spasms. Vigabatrin shows an efficacy at least equal to that of corticosteroids, and even higher in specific groups such as those with tuberous sclerosis. The major advantages of vigabatrin are the ability to initiate treatment at the full dosage. rapid efficacy, suitability for outpatient treatment and particularly good tolerability with only minor adverse effects. Recently, however, the safety of vigabatrin has caused concern since a specific visual field loss has been reported in treated adults. The current problem is determining the risk-benefit ratio of vigabatrin and corticosteroids/corticotropin in children with infantile spasms, and to specify the groups where their use could be optimal. Visual field loss is usually asymptomatic and can be detected only by perimetric visual field studies. In children, especially in the young or disabled, it is difficult if not impossible to detect the visual field loss and it is not yet known if children are at higher or lower risk for this adverse effect. Until a clear answer about the occurrence of this adverse effect in children has been established through randomised study, vigabatrin may still be considered first-line therapy in infantile spasms. Children who do not achieve a good response to vigabatrin should be switched to corticotropin/corticosteroid therapy. Despite the efficacy of corticosteroids and vigabatrin, the use of the conventional antiepileptic drugs, the newly developed antiepileptic drugs and some promising results with ketogenic diet, 25 to 30% of patients with infantile spasms continue to have spasms and experience psychomotor regression. These drug-resistant patients could be candidates for surgery.

Adrenocorticotropic Hormone↗

PubMedDate not supplied

Clinical pharmacokinetics and pharmacodynamics of warfarin. Understanding the dose-effect relationship.

The simplest complete system accounting for the time-course of changes in the prothrombin time induced by warfarin requires the combination of 4 independent models: A pharmacokinetic model for the absorption, distribution, and elimination of warfarin. Warfarin is essentially completely absorbed, reaching a maximum plasma concentration between 2 and 6 hours. It distributes into a small volume of distribution (10 L/70kg) and is eliminated by hepatic metabolism with a very small clearance (0.2 L/h/70kg). The elimination half-life is about 35 hours. A pharmacodynamic model for the effect of warfarin on the synthesis of clotting factors (prothrombin complex). Prothrombin complex synthesis is inhibited 50% at a warfarin concentration of about 1.5 mg/L. Warfarin concentrations associated with therapeutic anticoagulation are of similar magnitude. A physiological model for the synthesis and degradation of the prothrombin complex. The synthesis rate is about 5%/h/70kg and the elimination half-life estimated from changes in prothrombin time is approximately 17 hours. On average it will take 3 days for the anticoagulant effect of warfarin to reach a stable value when warfarin concentrations are constant. A model for the relationship between the activity of prothrombin complex and the prothrombin time. In general there is a hyperbolic relationship between these quantities. Its exact shape depends upon the method used for measuring the prothrombin time. Attempts to integrate these models into a single system have used essentially the same pharmacokinetic, physiological, and prothrombin activity models. Four distinct pharmacodynamic models have been proposed: linear, log-linear, power and Emax. One might be preferred on theoretical grounds (Emax) but its performance is not clearly different from the others. Empirical methods for warfarin dose prediction as well as those based on the combined pharmacokinetic-pharmacodynamic-physiological-prothrombin system have been proposed. Only one (which was also the first) [Sheiner 1969] has been adequately described and compared with the performance of an unaided physician. The programme compared favourably with decisions made by those physicians normally responsible for adjusting warfarin dose, but was not tested prospectively. A sizeable body of theoretical and experimental observations has contributed to our understanding of the warfarin dose-effect relationship. It remains to be demonstrated that any alternative method is superior to the traditional empirical approach to warfarin dose adjustment.

Dose-Response Relationship, Drug↗

PubMed1979

Drug prescribing in hepatobiliary disease.

Liver disease in man is associated with a variety of pathophysiological processes which may influence the disposition of drugs in several ways. Interpretation of the observed pharmacokinetic changes in liver disease requires an understanding of the relationship between systemic drug clearance (Cls), volume of distribution (Vd) and the elimination half-life [t1/2(beta)], i.e. t1/2(beta) = 0.693 . Vd/Cls. Half-life will be a measure of the fluctuation in drug level one may expect with continued administration of a drug while clearance will determine the dose required to achieve a particular steady state level. Liver disease may affect clearance and volume of distribution and so produce changes in half-life; in addition, alterations in plasma binding of drugs may occur and so influence free (unbound) drug levels. It is also possible that the end organ response, particularly in the case of sedative drugs, may be affected by liver disease. Other factors such as age, nutrition, smoking, and concomitant drug therapy may also influence drug elimination in patients with liver disease. At the present time, caution should be exercised in prescribing drugs to patients with liver disease and the dose should be titrated to the clinical response. The development of liver 'function' tests using model or marker drugs may offer some help to the prescriber in the future and enable a less empirical approach.

Adrenal Cortex Hormones↗

PubMed2005

Dications that target the DNA minor groove: compound design and preparation, DNA interactions, cellular distribution and biological activity.

Fluorescence microscopy of trypanosomes from drug treated mice shows that biologically active heterocyclic diamidines that target the DNA minor groove bind rapidly and specifically to parasite kinetoplast DNA (k-DNA). The observation that the kinetoplast is destroyed, generally within 24 hours, after drug treatment is very important for understanding the biological mechanism, and suggests that the diamidines may be inhibiting some critical opening/closing step of circular k-DNA. Given the uncertainties in the biological mechanism, we have taken an empirical approach to generating a variety of synthetic compounds and DNA minor groove interactions for development of improved and new biological activities. Furamidine, DB75, is a diphenyl-diamidine that has the curvature to match the DNA minor groove as expected in the classical groove interaction model. Surprisingly, a linear diamidine with a nitrogen rich linker has significantly stronger binding than furamidine due to favorable linker and water-mediated DNA interactions. The water interaction is very dependant on compound structure since other linear compounds do not have similar interactions. Change of one phenyl of furamidine to a benzimidazole does not significantly enhance DNA binding but additional conversion of the furan to a thiophene (DB818) yields a compound with ten times stronger binding. Structural analysis shows that DB818 has a very favorable curvature for optimizing minor groove interactions. It is clear that there are many ways for compounds to bind to k-DNA and exert specific effects on kinetoplast replication and/or transcription that are required to obtain an active compound.

Animals↗

PubMed2005

Purine derivatives as ligands for A3 adenosine receptors.

Selective agonists and antagonists for A3 adenosine receptors (ARs) are being explored for the treatment of a variety of disorders, including brain and heart ischemic conditions, cancer, and rheumatoid arthritis. This review covers both the structure activity relationships of nucleoside agonist ligands and selected antagonists acting at this receptor and the routes of synthesis. Highly selective agonists have been designed, using both empirical approaches and a semi-rational approach based on molecular modeling. The prototypical A3 agonists IB-MECA 10 and the more receptor-subtype-selective Cl-IB-MECA 11, both of which have affinity in binding to the receptor of approximately 1 nM, have been used widely as pharmacological probes in the elucidation of the physiological role of this receptor. In addition to the exploration of the effects of structural modification of the adenine and ribose moieties on A3AR affinity, the effects of these structural changes on the intrinsic efficacy have also been studied in a systematic fashion. Key structural features determining A3AR interaction include the N6-benzyl group, 2-position substitution such as halo, substitution of ribose (e.g., the (N)-methanocarba ring system, various 2'- and 3'-substitutions and 4'-thio substitution of oxygen). Conformational studies of the ribose moiety and its equivalents indicate that the ring oxygen is not required and the North (N) ring conformation is preferred in binding to the A3AR. Using these observations, a series of ring constrained (N)-methanocarba 5'-uronamide derivatives was recently reported to be highly selective A3AR agonists, the most notable amongst them was MRS3558 113 having a Ki value in binding to the human A3 receptor of 0.3 nM.

Adenosine A3 Receptor Agonists↗

PubMed1995

Application of the Cornell Net Carbohydrate and Protein model for cattle consuming forages.

Accurate prediction of forage biological values and performance with animals fed forages requires accurately accounting for factors that influence animal requirements and feedstuff utilization. The Cornell Net Carbohydrate and Protein System (CNCPS) is an application model that uses a combination of mechanistic and empirical approaches to account for the effects of variation in animal factors and feed carbohydrate and protein fractions on animal performance. Thus, accurate animal and environmental descriptions, DMI, feed carbohydrate, and protein fractions and their digestion rates are required inputs. In 25 growth periods with calves fed high-forage diets, the CNCPS accounted for 74, 81, and 83%, respectively, of the variation in ADG predicted to be supported by the ME, metabolizable protein, and essential amino acid intake, the first-limiting of all three accounting for 81% of the variation with a -1% bias. Thus, the CNCPS can be used to accurately describe forage quality and the effects of changes in forage composition on animal performance. The model was sensitive to variations in NDF, CP, protein solubility, NDF and starch digestion rates, feed and microbial amino acid composition, maintenance protein requirement, body protein amino acid content, and the coefficient of efficiency of use of absorbed protein. Analysis of several trials indicates an improved efficiency of ME use with improved amino acid balances. Uses of the CNCPS discussed include interpreting, planning and applying research, teaching, developing tables of requirements and biological values for feeds, complex nutritional accounting, and predicting performance and profits.

Animal Feed↗

PubMed1991

The application of biotechnology to the treatment of wastes produced from the nuclear fuel cycle: biodegradation and bioaccumulation as a means of treating radionuclide-containing streams.

Recent concerns on the radiotoxicity and longevity of nuclides have prompted the development of new technologies for their removal from wastes produced from nuclear power programs and nuclear fuel reprocessing activities. Alongside developments from traditional chemical treatment processes, interest has also centered on the application of biotechnology for efficient waste treatment. Many biological techniques have relied on empirical approaches in simple model systems, with scant regard to the nature and volume of actual target wastes; such considerations may limit the application of the new technologies in practice. This review aims to identify some of the likely problems, to discuss the various approaches under current consideration, and to evaluate ways in which either the target waste or the detoxifying biomass may be modified or presented for the most efficient treatment.

Bacteria↗