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Biomedical subjects

L G Forni

Publications and source records attributed to L G Forni.

At least 19 recordsLinked to original sources
PubMed2006

Unexplained acidosis of malnutrition: a study by ion-exchange chromatography/mass spectrometry.

Keto-acidosis is usually associated with uncontrolled diabetes and typically poses few diagnostic problems when presenting as hyperglycaemia, metabolic acidosis and a high anion gap. An emaciated patient suffering from Duchenne Muscular Dystrophy and volume depletion presented with acidosis of unknown origin. Preliminary investigations appeared to rule out lactic acidosis, diabetic keto-acidosis and acidosis due to base loss. We have previously reported a technique utilizing liquid chromatography coupled to mass spectrometry (LC-MS) which can be used to characterize the underlying aetiology of acidosis and applied it to ultrafiltrate derived from a blood sample taken from this patient. The anion profile obtained on the chromatogram showed elevated levels of acetoacetate and hydroxybutyrate but no evidence of lactic acidosis, nor was the profile typical of that seen in 'unexplained' acidosis. We concluded that the patient was suffering from keto-acidosis associated with starvation and dehydration, the biochemical features being obscured by both the patient's chronic malnutrition and minimal muscle mass. A combination of enteral feeding and rehydration led to prompt resolution of the patient's metabolic acidosis.

Acetoacetates↗
PubMed2005

Identifying the sick: can biochemical measurements be used to aid decision making on presentation to the accident and emergency department.

BACKGROUND: Early and accurate identification of patients who may benefit from aggressive optimal medical intervention is essential if improved outcomes in terms of survival are to be achieved. We studied the usefulness of routine clinical measurements and/or markers of metabolic abnormality in the early identification of those patients at greatest risk of deterioration on presentation to the accident and emergency department. METHODS: We conducted a prospective observational study in the accident and emergency department of a 602-bed district general hospital. Routine clinical measurements (heart rate, systolic blood pressure, temperature, oxygen saturation in room air, level of consciousness and ventilatory frequency) and venous blood analysis for metabolic markers (pH, bicarbonate, standard base excess, lactate, anion gap, strong ion difference, and strong ion gap) and biochemical markers (Na+, K+, Ca2+, Cl-, PO4- albumin, urea and creatinine) were recorded from unselected consecutive hospital admissions over two 3-month periods (September-November 2002 and February-April 2003). RESULTS: Logistic regression analysis showed that neither conventional clinical measurements upon presentation to the accident and emergency department nor venous biochemical and metabolic indices have good discriminatory ability when used as single predictors of either hospital mortality or length of hospital stay. Selecting variables from all the clinical and venous blood measurements gave a parsimonious model containing only age, heart rate, phosphate and albumin (area under the receiver operating characteristic curve, 0.82 [95% CI 0.76, 0.87]). CONCLUSIONS: A combination of clinical and venous biochemical measurements in the accident and emergency department proved the best predictors of hospital mortality. Consequently, they may be helpful as a triage tool in the accident and emergency department to help identify patients at risk of deterioration.

Adult↗
PubMed1998

Bicarbonate-based haemofiltration in the management of acute renal failure with lactic acidosis.

Continuous haemofiltration with lactate-based replacement fluid is widely used for the treatment of acute renal failure (ARF). In the presence of lactic acidosis, such treatment exacerbates rather than improves the clinical state. Continuous haemofiltration using a locally-prepared bicarbonate-based replacement fluid was performed in 200 patients over 7 years. All the patients had ARF with concomitant lactic acidosis, or demonstrated lactate intolerance after starting haemofiltration with lactate-based replacement fluids. In every case it was possible to correct the acidosis without inducing either extracellular volume expansion or hypernatraemia. In 89 patients (45%), the lactic acidosis resolved while being treated with bicarbonate-based haemofiltration. Fifty-seven patients (28.5%) survived. Significant differences at presentation in the group who survived, compared with those who died, were seen in age (50.8 vs. 57.1), mean arterial pressure (68.5 vs. 60.0 mmHg) and APACHE II score (32.1 vs. 38.9). Neither the severity of the presenting acidosis nor the arterial blood lactate appeared to predict outcome. Patients who developed ARF and lactic acidosis after cardiac surgery had a low survival rate. The combination of ARF and lactic acidosis that cannot safely be treated by haemofiltration using lactate-based replacement fluids can be managed with bicarbonate-based haemofiltration.

Acidosis, Lactic↗
PubMed1997

Bicarbonate therapy and intracellular acidosis.

1. The correction of metabolic acidosis with sodium bicarbonate remains controversial. Experiments in vitro have suggested possible deleterious effects after alkalinization of the extracellular fluid. Disequilibrium of carbon dioxide and bicarbonate across cell membranes after alkali administration, leading to the phenomenon of 'paradoxical' intracellular acidosis, has been held responsible for some of these adverse effects. 2. Changes in intracellular pH in suspensions of leucocytes from healthy volunteers were monitored using a fluorescent intracellular dye. The effect in vitro of increasing extracellular pH with sodium bicarbonate was studied at different sodium bicarbonate concentrations. Lactic acid and propionic acid were added to the extracellular buffer to mimic conditions of metabolic acidosis. 3. The addition of a large bolus of sodium bicarbonate caused intracellular acidification as has been observed previously. The extent of the intracellular acidosis was dependent on several factors, being most evident at higher starting intracellular pH. When sodium bicarbonate was added as a series of small boluses the reduction in intracellular pH was small. Under conditions of initial acidosis this was rapidly followed by intracellular alkalinization. 4. Although intracellular acidification occurs after addition of sodium bicarbonate to a suspension of human leucocytes in vitro, the effect is minimal when the conditions approximate those seen in clinical practice. We suggest that the observed small and transient lowering of intracellular pH is insufficient grounds in itself to abandon the use of sodium bicarbonate in human acidosis.

Acidosis, Lactic↗
PubMed1996

An inhibitor of the sodium pump obtained from human placenta.

BACKGROUND: Much effort has been expended in the search for an endogenous inhibitor of the cellular sodium/potassium pump, a compound of major physiological importance, which has been implicated in the mechanism of essential hypertension. Others have suggested that ouabain or an isomer of ouabain may be the endogenous pump inhibitor. Neonatal cord serum contains an inhibitor of the sodium pump; we attempted to isolate and characterise this substance from human placentas. METHODS: Homogenised placentas were dialysed and the resulting solutes were trapped on octadecylsilyl silica and then separated by high-performance liquid chromatography. Measurement of the activity of the sodium pump of human leucocytes was used to test each fraction for the presence of the inhibitor. FINDINGS: An inhibitor of the sodium pump was obtained by this technique in a mass spectrometrically pure form with a mass of 370 Da, an empirical formula of C24H34O3 and only one hydroxyl group. The characteristic fragmentation pattern observed in negative-ion mass spectrometry was compared with those of various model compounds; this comparison suggested that the active material was a dihydropyrone-substituted steroid. INTERPRETATION: These results suggest that a dihydropyrone-substituted steroid is an endogenous regulator of the sodium pump in humans and, presumably, other mammals. Proof of the endogenous origin will require the demonstration of a previously unrecognised biosynthetic pathway.

Bufanolides↗
PubMed1988

An investigation of the novel anti-inflammatory agents ONO-3144 and MK-447. Studies on their potential antioxidant activity.

Oxygen-derived free radicals have been implicated as contributors to inflammatory disorders and it has been suggested that certain anti-inflammatory drugs act by scavenging free radicals. In this paper we have studied the free radical scavenging activity of two such experimental anti-inflammatory drugs MK-447 and ONO-3144. Using the technique of pulse radiolysis we have been able to obtain rate constants for the reactions of these compounds with specific free radicals including OH and O2-. We have also investigated the antioxidant capacity of these compounds using rat liver microsomal lipid peroxidation systems. It is suggested that this approach yielding quantitative data concerning defined free radical species will lead to a better understanding of the role of radical scavenging in anti-inflammatory activity.

Animals↗
PubMed1988

Vitamin E analogue Trolox C. E.s.r. and pulse-radiolysis studies of free-radical reactions.

The reactions between Trolox C, a water-soluble vitamin E analogue, and several oxidizing free radicals including the hydroxyl radical and various peroxy radicals were examined by using the pulse-radiolysis technique. The results demonstrate that Trolox C may undergo rapid one-electron-transfer reactions as well as hydrogen-transfer processes; the resulting phenoxyl radical is shown to be relatively stable, in common with the phenoxyl radical derived from vitamin E. The reactions between the Trolox C phenoxyl radical and a variety of biologically relevant reducing compounds were examined by using both pulse radiolysis and e.s.r. The results demonstrate that the Trolox C phenoxyl radical is readily repaired by ascorbate (k = 8.3 x 10(6) dm3.mol-1.s-1) and certain thiols (k less than 10(5) dm3.mol-1.s-1) but not by urate, NADH or propyl gallate. Evidence from e.s.r. studies indicates that thiol-containing compounds may also enter into similar repair reactions with the alpha-tocopherol phenoxyl radical. Kinetic evidence is presented that suggests that Trolox C may 'repair' proteins that have been oxidized by free radicals.

Ascorbic Acid↗
PubMed1987

Electron spin resonance and pulse radiolysis studies on the spin trapping of sulphur-centered radicals.

Thiyl radicals are shown to be readily trapped with the spin traps 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) and 3,3,5,5-tetramethyl-1-pyrroline-N-oxide (TMPO) giving characteristic spin adducts with hyperfine coupling constants aN 1.52-1.58, aH 1.52-1.80 mT, and g values in the range 2.0065-2.0067 for the DMPO adducts and aN 1.50-1.56, aH 1.70-1.92 mT, g 20049-2.0051 for the TMPO adducts. Kinetic data obtained from pulse radiolysis studies show that, in general, thiyl radicals react rapidly with these spin traps with rate constants of the order of 10(7)-10(8) dm3 mol-1 s-1. The tetramethylated spin trap TMPO though giving slightly less intense electron spin resonance (ESR) spectra, produces longer lived adducts, and is suggested to be of greater utility due to the more characteristic nature of the coupling constants of the observed adducts; reaction of certain thiyl radicals with DMPO produces adducts which are superficially similar to the hydroxyl radical adduct to the same trap.

Chemical Phenomena↗
PubMed1987

On the reaction of molecular oxygen with thiyl radicals: a re-examination.

Absolute rate constants for the addition of oxygen to thiyl radicals, i.e. RS. + O2----RSOO., have been determined by applying a new competition method based on RS. formation via one-electron reduction of the corresponding disulphides, and the competition between RS. reacting with O2 and an electron donor such as ascorbate. Bimolecular rate constants have been obtained for the thiyl radicals derived from cysteine (6.1 X 10(7) mol-1 dm3 s-1), penicillamine (2.5 X 10(7) mol-1 dm3 s-1), homocysteine (8.0 X 10(7) mol-1 dm3 s-1), cysteamine (2.8 X 10(7) mol-1 dm3 s-1), 3-thiopropionic acid (2.2 X 10(8) mol-1 dm3 s-1) and glutathione (3.0 X 10(7) mol-1 dm3 s-1), respectively. The values obtained for the O2 addition to the thiyl radicals from glutathione and cysteine are considerable lower (by about two orders of magnitude) than those previously published. This indicates that the RS. + O2 reaction may be of complex nature and is generally a process which is not solely controlled by the diffusion of the reactants.

Ascorbic Acid↗
PubMed1986

Thiyl and phenoxyl free radicals and NADH. Direct observation of one-electron oxidation.

Absolute rate constants for the reaction of NADH with thiyl free radicals derived from various sulphur-containing compounds of biological significance were measured by using the technique of pulse radiolysis. These and related reactions with phenoxyl free radicals are believed to occur through one-electron-transfer processes. Further evidence comes from studies with deuterated NADH. The results support the possibility that, in biochemical systems, thiols may act as catalysts linking hydrogen-atom and electron-transfer reactions.

Electron Transport↗
PubMed1986

Thiyl free radicals and the oxidation of ferrocytochrome c. Direct observation of coupled hydrogen-atom- and electron-transfer reactions.

Absolute rate constants for the reaction of ferrocytochrome c with the thiyl radicals derived from cysteine, GSH, penicillamine and N-(2-mercaptopropionyl)glycine were measured by using the technique of pulse radiolysis. The reaction is believed to occur through a one-electron-transfer process, in agreement with the hypothesis that thiols may act as catalysts linking hydrogen-atom- and electron-transfer reactions.

Cytochrome c Group↗
PubMed1985

Organic free radicals and proteins in biochemical injury: electron- or hydrogen-transfer reactions?

The reactions of organic free radicals, acting as either reductants or oxidants, have been studied by pulse radiolysis in neutral aqueous solution at room temperature. Manyhydroxyl-substituted aliphatic carbon-centred radicals and one-electron adducts have been shown to be good one-electron reductants, while several oxygen-, sulphur- and nitrogen- (but not carbon-) centred free radicals have been shown to be good one-electron oxidants. Several carbon-centred radicals can be reduced rapidly by hydrogen transfer, from undissociated thiol compounds which can thus act as catalysts facilitating the overall reduction of a carbon-centred radical by an electron-donating molecule. Kinetic considerations influenced by the one-electron redox potentials of the radical-molecule couples involved, determine whether a particular reaction predominates. In this paper examples of such reactions, involving a water-soluble derivative of vitamin E (Trolox C) and the coenzyme NADH, are described, together with studies showing (a) that even in complex multi-solute systems some organic peroxy radicals can inactiviate alcohol dehydrogenase under conditions where the superoxide radical does not, and (b) the superoxide radical can be damaging if urate is also present, and this damage can be reduced by the presence of superoxide dismutase.

Alcohol Dehydrogenase↗
PubMed1984

Oxygen-centred free radicals can efficiently degrade the polypeptide of proteoglycans in whole cartilage.

Bovine nasal cartilage slices, biosynthetically labelled in their proteoglycan with 35SO4, were used as substrate for the attack of free radicals generated on exposure to a Co60 source (which allows study of single radical species), and by chemical and enzymatic means. Systems generating hydroxyl (OH.) and superoxide (O2.-) radicals degraded the proteoglycan efficiently, while the hydroperoxy radical (HO2.) was less efficient; addition of appropriate radical scavengers inhibited degradation. The radioactive products were heterogeneous in molecular size, but with doses up to 3600 Gy were the same size range as intact chondroitin sulphate. The contained free amino groups, and more were liberated by aminopeptidase M digestion, implying that at least a small peptide was present. Thus a major site of radical attack may be the polypeptide chain. We suggest that free-radical fragmentation of polypeptides may be important both in extracellular catabolism and in intracellular proteolysis.

Animals↗