Metformin overdose causes platelet mitochondrial dysfunction in humans

Introduction. We have recently demonstrated that metformin intoxication causes mitochondrial dysfunction in several porcine tissues, including platelets. The aim of the present work was to clarify whether it also causes mitochondrial dysfunction (and secondary lactate overproduction) in human platelets, in-vitro and ex-vivo. Methods. Human platelets were incubated for 72 h with saline or increasing dose of metformin (in-vitro experiments). Lactate production, respiratory chain complex activities (spectrophotometry), mitochondrial membrane potential (flow-cytometry after staining with JC-1) and oxygen consumption (Clark-type electrode) were then measured. Platelets were also obtained from ten patients with lactic acidosis (arterial pH 6.97\ub10.18 and lactate 16\ub17 mmol/l) due to accidental metformin intoxication (serum drug level 32\ub114 mg/l) and ten healthy volunteers of similar sex and age. Respiratory chain complex activities were measured as above (ex-vivo experiments). Results. In-vitro, metformin dose-dependently increased lactate production (p<0.001), decreased respiratory chain complex I activity (p=0.009), mitochondrial membrane potential (p=0.003) and oxygen consumption (p<0.001) of human platelets. Ex-vivo, platelets taken from intoxicated patients had significantly lower complex I (p=0.045) and complex IV (p<0.001) activity compared to controls. Conclusions. Depending on dose, metformin can cause mitochondrial dysfunction and lactate overproduction in human platelets in-vitro and, possibly, in-vivo. Trial registration. NCT 0094212

THE CONCEPT OF LAW AND EFFICACY

Jedno od značenja izraza ‘učinkovitost’ odnosi se na činjenicu da se adresati pravnih normi stvarno ponašaju onako kako to od njih zahtijevaju pravne norme. To se značenje izraza obično koristi u filozofskopravnim raspravama glede toga je li učinkovitost bitan element pojma prava. Prema pravnom pozitivizmu, učinkovitost je u nekim slučajevima i na određene načine uvjet važenja (vrijeđenja) pravnih normi i pravnih sustava. S druge strane, pravni je realizam sklon potpunom poistovjećivanju pravnog važenja s učinkovitosti ili njegovu svođenju na učinkovitost. Prema tome, u oba je filozofskopravna pravca učinkovitost u pravilu uključena u oblikovanje njihovih pojmova prava. Međutim, dok pravnopozitivističko shvaćanje ne utječe na najuobičajenije značenje važenja pravne norme (pripadanje pravne norme pravnom sustavu), a utvrđivanjem učinkovitosti kao kriterija postojanja pravnog sustava ne dodaje mnogo objašnjenju pojma prava, pravnorealističko se shvaćanje suočava s ozbiljnim prigovorima glede svoje objašnjavalačke prikladnosti.One of the senses of the term ‘efficacy’ refers to the fact that norm-addresses actually behave as is required of them by legal norms. This sense of the term is one which is generally used within the jurisprudential discussions about whether efficacy is the essential element of the concept of law. According to legal positivism, efficacy is in some cases and in certain ways the condition of legal validity of both legal norms and legal systems. On the other hand, legal realism tends to entirely identify legal validity or reduce it to efficacy. Thus, in both jurisprudential approaches, efficacy tends to play a role in shaping their respective concepts of law. However, while the legal positivistic view does not affect the most standard sense of legal validity of the legal norm (i.e. the legal norms’ membership in the legal system), and does not add much to the explanation of the concept of law by identifying efficacy as the criterion of legal systems’ existence, the legal realistic view is faced with some serious objections regarding its explanatory adequacy

Brettanomyces bruxellensis yeasts: impact on wine and winemaking

Yeasts belonging to the Brettanomyces/Dekkera genus are non-conventional yeasts, which affect winemaking by causing wine spoilage all over the world. This mini-review focuses on recent results concerning the presence of Brettanomyces bruxellensis throughout the wine processing chain. Here, culture-dependent and independent methods to detect this yeast on grapes and at the very early stage of wine production are encompassed. Chemical, physical and biological tools, devised for the prevention and control of such a detrimental species during winemaking are also presented. Finally, the mini-review identifies future research areas relevant to the improvement of wine safety and sensory profiles

The effects of protein dietary sources on serum cholesterol and bile acid microbiological transformation in rabbits

The effects of feeding different protein sources on plasma cholesterol and bile acid microbiological transformations has been investigated in rabbits fed casein or soy protein diets. Casein fed rabbits exhibit higher serum cholesterol levels while in vitro observations show an impairment of primary bile acid bacterial 7a- dehydroxylation. The protein dietary source does not seem to modify the microflora composition as long as groups and genera are concerned, however we observed differences in the relative frequencies of some species of Bacteroidaceae: B. thetaiotaomicron, B. distasonis, B. uniformis and B. vulgatus