Binding of a hairpin polyamide in the minor groove of DNA: sequence-specific enthalpic discrimination.

Hairpin polyamides are synthetic ligands for sequence-specific recognition in the minor groove of double-helical DNA. A thermodynamic characterization of the DNA-binding properties exhibited by a six-ring hairpin polyamide, ImPyPy-gamma-PyPyPy-beta-Dp (where Im = imidazole, Py = pyrrole, gamma = gamma-aminobutyric acid, beta = beta-alanine, and Dp = dimethylaminopropylamide), reveals an approximately 1-2 kcal/mol greater affinity for the designated match site, 5'-TGTTA-3', relative to the single base pair mismatch sites, 5'-TGGTA-3' and 5'-TATTA-3'. The enthalpy and entropy data at 20 degrees C reveal this sequence specificity to be entirely enthalpic in origin. Correlations between the thermodynamic driving forces underlying the sequence specificity exhibited by ImPyPy-gamma-PyPyPy-beta-Dp and the structural properties of the heterodimeric complex of PyPyPy and ImPyPy bound to the minor groove of DNA provide insight into the molecular forces that govern the affinity and specificity of pyrrole-imidazole polyamides.     

Increased renal responses to exogenous parathyroid hormone in postsurgical hypoparathyroidism

Prior exposure to excess PTH desensitizes the kidney to subsequent doses of the hormone. We tested the hypothesis that prior deficiency of PTH would increase renal responsiveness to the agent. Ten normal subjects and nine patients with treated chronic postsurgical hypoparathyroidism received infusions of synthetic human PTH fragment 1-34 [hPTH-(1-34), Armour], 200 U over 10 min. All subjects responded to hPTH-(1-34) infusion with marked increases in plasma and urinary cAMP and phosphaturia. Mean (and median) urinary cAMP responses in the hypoparathyroid subjects were 62% (and 91%) above the responses in normal subjects, while mean (and median) nephrogenous cAMP responses were 65% (and 88%) higher than those in normal subjects. Mean (and median) phosphaturic responses to hPTH-(1-34) in hypoparathyroidism were 49% (and 52%) above normal subjects' responses. All of these differences were statistically significant. These data and others from the literature suggest that chronic hypoparathyroidism enhances renal responses to PTH, consistent with the concept of hormonal regulation of tissue sensitivity to the hormone.     

A randomised, open-label comparison of three highly active antiretroviral therapy regimens including two nucleoside analogues and indinavir for previously untreated HIV-1 infection: the OzCombo1 study

BACKGROUND: Highly active antiretroviral therapy (HAART) including two nucleoside analogues and a potent protease inhibitor is standard of care initial therapy for HIV-infected adults. The best-tolerated and most potent initial HAART regimen is unknown and was investigated in this study. METHODS: One hundred and nine HIV-infected adults with no prior antiretroviral therapy, and CD4 lymphocyte counts < 500 x 10(6) cells/l or plasma HIV RNA > 30,000 copies/ml were randomized to zidovudine-lamivudine-indinavir (ZDV-3TC-IDV), stavudine-lamivudine-indinavir (d4T-3TC-IDV) or stavudine-didanosine-indinavir (d4T-ddI-IDV) for 52 weeks. The primary endpoints were plasma HIV RNA and drug-related adverse events. Other assessments were overall safety, adherence and adverse events, CD4 lymphocyte counts, cutaneous delayed type hypersensitivity (DTH) responses and quality of life (Euroqol). RESULTS: Only 58% patients had HIV RNA < 50 copies/ml plasma at 12 months, with no significant difference between the three regimes (P = 0.34). Drug-related adverse events sufficiently severe to warrant drug discontinuation were less common (P = 0.06) in patients receiving d4T-3TC-IDV (18%) than in those receiving ZDV-3TC-IDV (34%) or d4T-ddI-IDV (41%). The percentages of patients who remained on their assigned therapy with plasma HIV RNA < 50 copies/ml at 52 weeks were 60% with d4T-3TC-IDV, 53% with ZDV-3TC-IDV and 35% with d4T-ddI-IDV. Virological failure at 52 weeks was more likely in those whose adherence was estimated to be < 100% in the first 4 weeks of therapy (P = 0.02), but not in those who developed grade 3 or 4 drug-related adverse events. At 52 weeks, the mean CD4 lymphocyte count increase was 200 x 10(6) cells/l with only 7% of patients having counts lower than at baseline; DTH responses improved but remained clinically impaired in most patients. Quality of life improved significantly in all groups. CONCLUSIONS: Initial HAART regimens including IDV failed to suppress plasma HIV RNA to < 50 copies/ml in > 40% patients after only 12 months of therapy although there was significant overall improvement immunologically and in quality of life. The type of dual nucleoside combination used was less important in predicting virological failure than was imperfect adherence early in therapy. Consideration should be given to modifying a HAART regimen relatively early in non-adherent patients.     

Nucleotide sequence and the encoded amino acids of human apolipoprotein A-I mRNA.

The cDNA clones encoding the precursor form of human liver apolipoprotein A-I (apoA-I), preproapoA-I, have been isolated from a cDNA library. A 17-base synthetic oligonucleotide based on residues 108-113 of apoA-I and a 26-base primer-extended, dideoxynucleotide-terminated cDNA were used as hybridization probes to select for recombinant plasmids bearing the apoA-I sequence. The complete nucleic acid sequence of human liver preproapoA-I has been determined by analysis of the cloned cDNA. The sequence is composed of 801 nucleotides encoding 267 amino acid residues. PreproapoA-I contains an 18-amino-acid prepeptide and a 6-amino-acid propeptide connected to the amino terminus of the 243-amino acid mature apoA-I. Southern blotting analysis of chromosomal DNA obtained from peripheral blood indicated the apoA-I gene is contained in a 2.1-kilobase-pair Pst I fragment and there is no gross difference in structural organization between the normal apoA-I gene and the Tangier disease apoA-I gene.     

Postoperative Pain: An Analysis on Evolution of Research in Half-Century

IntroductionExamining the evolution of research parameters helps scientists to discover the well-developed and neglected aspects of knowledge. Pain after root canal treatment is a health problem affecting millions of patients. Research in this field has a meaningful impact on quality of lives. The aim of this study was to analyze the evolution of research on postoperative pain over the past 50 years.MethodsElectronic searches were performed in Scopus and MEDLINE databases to identify studies on pain after nonsurgical root canal treatments/retreatments. The full texts of eligible articles were reviewed to determine the study category and to extract and analyze the methodological variables. A series of statistical analyses were performed to determine the trend of publications based on the variable of interest over time.ResultsFour hundred twenty-four articles were included. There was a positive trend for systematic reviews, studies with sample size <200, studies on single-visit treatment, and clinical trials on instrumentation and adjunct treatments (P < .05). There was a negative trend for the use of numeric rating scales, studies on multiple-visit treatments, clinical trials on medication/medicament, and studies on pain in maxillary incisors (P < .05). No trend was observed based on pulpal diagnosis or for studies with longer observation periods (>8 weeks) (P > .05).ConclusionsA paradigm shift is needed toward clinical studies with larger sample sizes, longer observation periods, and more focus on pulpal diagnoses associated with higher rates of postoperative pain. There is a need to view postoperative pain as an important patient-centered outcome and to develop and disseminate standard reporting guidelines for future studies.