Antagonism of the effects of furosemide by in domethacin in normal and hypertensive man

Furosemide and the prostaglandin synthetase inhibitor, indomethacin, were administered singly and in combination to four normal subjects and six patients with essential hypertension in order to determine whether the antihypertensive, natriuretic and other effects of furosemide could be altered by inhibition of prostaglandin synthesis. In all subjects indomethacin treatment alone resulted in a significant elevation of blood pressure and a fall in plasma renin without any change in sodium excretion. Furosemide alone resulted in a significant blood pressure fall with a rise in plasma renin and urinary aldosterone with a marked increase in urinary sodium loss. These effects were either obviated or blunted by addition of indomethacin. The results are compatible with the hypothesis that the antihypertensive and natriuretic effects of furosemide might be mediated at least in part by prostaglandin synthesis. In addition, the effects of indomethacin should be considered when using this drug in hypertensive patients and in subjects requiring diuretic therapy.     

Effect of gamma-irradiation on dye-DNA binding.

The effect of gamma-rays on the binding of proflavine and acridine orange to DNA was investigated by spectrophotometry. The effect of irradiation was observed on the buffered solutions of the free dye and free DNA. A dose of about 35 krad caused a hyperchromicity of 30-40 per cent to the DNA peak at 258 nm, while the same dose introduced a hypochromic effect to the monomer peaks of the dyes by 30 per cent. This implied that gamma-rays have an effect of decreasing the monomer concentration of free-day molecules in solution. From the results, we conclude that more dye is bound to the changed conformation of dye-bound DNA on irradiation. Scratchard-binding isotherms drawn for the unirradiated and irradiated complexes of Pf-DNA showed interesting differences. Similar isotherms could not be obtained for the acridine orange-DNA system.     

A model for cooperative ligand binding at complementary sites of DNA

The process of cooperative binding of ligands to DNA has been classified into different modes. An additional mode of cooperative interaction amongst ligands binding at sites on complementary strands has been emphasised. A statistical mechanical method has been applied to obtain an analytical expression for the fraction of nucleotide sites bound. Theoretical Scatchard plots have been drawn and analysed.     

Clinical and Pathophysiological Characteristics of Cirrhotic Patients with Grade 1 and Minimal Hepatic Encephalopathy

Background and Aims

EASL/AASLD hepatic encephalopathy (HE) guidelines proposed the alternative use of the term ‘Covert HE’ combining minimal HE (mHE) and Grade 1 HE into a single entity. However, longitudinal data to indicate that these are indeed a single entity are lacking. The aims of this study were to determine whether the occurrence of complications of cirrhosis requiring hospital admission and mortality were similar in these sub-groups of patients.

Methods

Clinically-stable cirrhotic patients (n = 106) with no previous history of ‘Overt HE’ were included over a 2-year period and classified as having no HE (n = 23), mHE (n = 39) or Grade 1 HE (n = 44). Standard biochemistry, venous ammonia, bacterial DNA and neutrophil function were measured at inclusion and the patients were followed for a mean of 230±95 days.

Results

Patients with Grade 1 HE had significantly more complications requiring hospitalisation (infection 9/18/34%; HE 4/8/18%; other 13/10/11%; P = 0.02) and significantly greater mortality (4/5/20%; P = 0.04) compared to patients with no HE or mHE respectively. Patients with mHE and grade 1 HE had similar ammonia levels, but higher than the no HE group (P<0.001). MELD score was similar between groups but Grade 1 HE patients had increased frequency of bacterial translocation (P = 0.06) and neutrophil spontaneous respiratory burst (P = 0.02) compared to patients with mHE.

Conclusions

The results of this study show for the first time that ‘Covert HE’ is a heterogeneous entity with significantly greater hospitalisations and mortality in the Grade 1 HE patients compared with mHE. Further prospective longer-term studies are required before EASL/AASLD guidance is fully implemented.     

Synthesis and in vitro antiviral evaluation of 4-substituted 3,4-dihydropyrimidinones

A series of 4-substituted 3,4-dihydropyrimidine-2-ones (DHPM) was synthesized, characterized by IR, ¹H NMR, ¹³C NMR and HRMS spectra. The compounds were evaluated in vitro for their antiviral activity against a broad range of DNA and RNA viruses, along with assessment for potential cytotoxicity in diverse mammalian cell lines. Compound 4m, which possesses a long lipophilic side chain, was found to be a potent and selective inhibitor of Punta Toro virus, a member of the Bunyaviridae. For Rift Valley fever virus, which is another Bunyavirus, the activity of 4m was negligible. DHPMs with a C-4 aryl moiety bearing halogen substitution (4b, 4c and 4d) were found to be cytotoxic in MT4 cells.     

Arterial pulse wave velocity measurement: different techniques, similar results—implications for medical devices

Different characteristic points used for the evaluation of pulse wave velocity (PWV) give significantly different results. Hence, the accuracy of using these points is questionable. There is need for quantitative comparison of different techniques to determine PWV. Previous studies aimed at comparing different PWV measurement techniques have been noted, however, on a limited number of smaller animals (mice, dogs, etc.). This simulation-based study aims to compare different techniques for PWV measurement in a large representative human population. A computer model is developed for simulating the pressure wave propagation between the carotid and femoral arteries. Using relationships observed in clinical trials, the model input parameters for a statistically representative population are expressed in terms of a person’s age, gender and height. The model is used to calculate the carotid–femoral pressure ratio for different individuals, which is then parameterised into a number of features, and the equivalent propagation time is calculated using the phase-slope method. Using this time, the apparent phase velocity is determined and compared with PWV determined by the foot-to-foot technique. The two velocities compare well with a difference of 0.0059±0.0904 m/s. An averaging criterion for the calculation of apparent phase velocity has been tested and shown to give good estimates compared to the foot-to-foot technique. As it does not involve the identification of characteristic points on the measured pressure waves, the phase-slope method is more suitable for implementation in PWV monitors.     

A Novel Copper Chelate Modulates Tumor Associated Macrophages to Promote Anti-Tumor Response of T Cells

BackgroundAt the early stages of carcinogenesis, the induction of tumor specific T cell mediated immunity seems to block the tumor growth and give protective anti-tumor immune response. However, tumor associated macrophages (TAMs) might play an immunosuppressive role and subvert this anti tumor immunity leading to tumor progression and metastasis.Conclusion/SignificanceOur results show the potential usefulness of CuNG in immunotherapy of drug-resistant cancers through reprogramming of TAMs that in turn reprogram the T cells and reeducate the T helper function to elicit proper anti-tumorogenic Th1 response leading to effective reduction in tumor growth.     

Validation of molecular markers associated with perpetual flowering in Octoploid <Emphasis Type="Italic">Fragaria</Emphasis> germplasm

Perpetual-flowering (PF) is a highly desirable trait within cultivated strawberries (Fragaria ×ananassa) for the commercial and home garden markets. The most widely used source of the PF trait was originally introgressed from a wild F. virginiana subsp. glauca accession collected in the Wasatch Mountains near Salt Lake City, UT in 1955. This source is conferred by a single dominant QTL, FaPFRU, and was recently identified in multiple bi-parental populations. Multiple markers have been proposed as diagnostic tests for marker-assisted selection (MAS). These markers were proposed after looking at a relatively small sample of germplasm. To identify the best diagnostic testing procedure for MAS, the markers were evaluated individually and in combination on a training set of cultivars with known genotypes and the best test was used to determine the distribution of the FaPFRU source of PF within a large sample of octoploid Fragaria germplasm. Of the tests evaluated, the microsatellite marker Bx215 alone was found to have the best diagnostic ability for MAS with an accuracy of 93.1% in controlled conditions. When utilizing the test on 390 F. ×ananassa accessions, 164 accessions were identified to likely have the FaPFRU locus. Nine octoploid Fragaria accessions were PF and did not have this marker, indicating possible recombination events or potentially novel sources of the PF trait. Future work will be needed to dissect the PF trait in these nine individuals.