Phosphonomycin. I. Discovery and in vitro biological characterization.
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Biomedical subjects
Publications and source records attributed to M Jackson.
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A mutant of Corynebacterium glutamicum was found to accumulate high concentrations of a material which crystallized upon cooling of the broth. The compound was identified as tetramethylpyrazine. The mutant was found to require isoleucine, valine, leucine, and pantothenate for growth. All four requirements probably result from the loss of a single enzyme of the isoleucine-valine pathway. Since similar mutants of Neurospora crassa accumulate acetoin, the present mutant probably forms tetramethylpyrazine from acetoin. Accumulation of tetramethylpyrazine was dependent upon addition of thiamine. This observation is consistent with the known activity of diphosphothiamine as a cofactor for the formation of acetolactate (a precursor of acetoin) from pyruvate.
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A biotin-requiring coryneform bacterium which produces glutamic acid was mutated to adenine dependency. The adenine-requiring strain, which excreted insoine-5'-monophosphate (IMP), was further mutated to xanthine dependency. As expected, IMP was also excreted by this mutant. The mutant strain was reverted to xanthine independence in an attempt to obtain a culture with an altered IMP dehydrogenase which would be less sensitive to feedback inhibition by guanosine-5'-monophosphate (GMP). A revertant was obtained which produced GMP and IMP, each at 0.5 g per liter. The reversion to xanthine independence had resulted in a concomitant requirement for isoleucine, leucine, and valine. Further mutation to increased nutritional requirements led to culture MB-1802, which accumulated 1 g per liter each of GMP and IMP. Both nucleotides were isolated in pure form. The concentrations of GMP and IMP produced by MB-1802 were four times that of cytidylate, uridylate, or adenylate, indicating that the mechanism of GMP and IMP production was direct and not via ribonucleic acid breakdown.
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Although most microorganisms with genetic blocks in the purine nucleotide sequence excrete breakdown products, a coryneform bacterium was found to accumulate intact 5'-nucleotides in the extracellular medium. Adenineless mutants accumulated 0.4 to 0.6 g of inosine-5'-monophosphate per liter of broth. The yield of this nucleotide was increased to 0.8 to 0.9 g per liter when such mutants were mutated to xanthine dependence. Induction of a specific guanine requirement in adenineless auxotrophs resulted in cultures capable of producing high yields of xanthosine-5'-monophosphate (3 to 4 g per liter). Pure xanthosine-5'-monophosphate was isolated from broth by a procedure involving ion-exchange chromatography, charcoal adsorption, and barium precipitation.
Lower limb venous compliance and transcapillary escape rate of transferrin were measured in eight normotensive, insulin-dependent male diabetic patients and eight control subjects using a dual isotope technique. Technetium-99m labelled autologous erythrocytes were used to measure venous compliance and to correct for local changes in blood volume, whilst Indium-113m labelled transferrin was used to measure transcapillary escape of protein. The diabetic patients were found to have reduced venous compliance 1.5 (0.7 to 3.4) x 10(-2) mmHg-1 compared with controls 3.2 (2.4 to 4.1) x 10(-2) mmHg-1 (p less than 0.01). The diabetic patients were also found to have greater transcapillary escape of transferrin -2.7 (-1.5 to -5.3) x 10(-3), compared with control subjects -5.2 (-4.1 to -8.1) x 10(-3) (p less than 0.02) in response to increasing hydrostatic pressure. These results show reduced venous compliance in patients with a mean duration of diabetes of 15 years and with only at most, early complications of diabetes, and confirm previous observations showing increased transcapillary escape of protein.
PROBLEM: The presence of antiphospholipid antibodies lupus anticoagulant (LAC), anticardiolipin antibody (ACA) as well as antinuclear antibody (ANA) has been associated with early spontaneous pregnancy loss and adverse pregnancy outcome. The purpose of this study was to investigate the possible role of autoimmune antibodies (LAC, ACA, and ANA) as a cause of implantation failure following embryo transfer (ET) after in vitro fertilization (IVF). METHOD: Three groups were studied: Group I, 56 patients who failed to conceive following ET; group II, 14 patients who have conceived following IVF-ET and delivered or are carrying an uncomplicated ongoing pregnancy; and group III, 69 patients who were new candidates for IVF-ET. RESULTS: Eighteen out of 56 (32.1%) of patients who failed to conceive following previous IVF-ET cycle (group I) tested positive for one or more of the autoimmune antibodies. None of the 14 patients of group II tested positive for autoimmune antibodies (P < .02). Seven out of the 69 patients (10%) of group III were found positive to one or more of the autoimmune factor. This rate is significantly lower than the rate of positive autoimmune antibodies detected in group I (P < .003). Fifteen patients of the 18 who tested positive for autoimmune antibodies and who had previously failed to conceive following ET underwent a subsequent IVF-ET cycle while being treated with prednisone and aspirin. Seven out of the 15 (46.6%) conceived and were able to sustain a clinical ongoing pregnancy. CONCLUSIONS: Patients receiving ET are carrying viable embryos within the intrauterine environment. Therefore, in this unique group of patients, failure to demonstrate a positive pregnancy test represents an implantation failure or a very early postimplantation loss. The results of this study suggest that periimplantation events may be affected by autoimmune antibodies. Very early miscarriage or implantation failure may be related to the same pathophysiological mechanism that causes recurrent miscarriages and is diagnosed incorrectly as infertility.
Management of hyperlipidaemia in patients with ischaemic heart disease is suboptimal despite the proven benefit of statin therapy. Significant improvement in management has been shown in the EUROASPIRE II study. It is unclear, however, whether such changes have also occurred in primary care. We aimed to evaluate the use of statin therapy by performing a cross-sectional survey of 300 patients with CHD aged >30 years from three general practices. A total of 249 (83%) of the 300 patients had their cholesterol measured and 141 (47%) were on statin therapy; 129 (43% of total) achieved a target cholesterol of <5 mmol/l, of whom 85 (64%) were on statin therapy. Of the remaining 120 patients whose cholesterol exceeded 5 mmol/l, 56 (47%) were on statin therapy Thus 60% (85/141) of those on statin therapy achieved adequate control compared with 40% (44/108) without statins (p<0.008). Those patients with CHD diagnosed on objective evidence were more likely to receive statin therapy (55.5%). Many patients with CHD are still not receiving appropriate secondary prevention. Those on statin therapy are more likely to achieve target levels <5 mmol/l. The average doses of statins vary and are lower than the evidence-based doses used in previous large-scale studies, which may help explain the persistence of failed treatment.