Federico Formenti

Regulation of human metabolism by hypoxia- inducible factor

The hypoxia-inducible factor (HIF) family of transcription factors directs a coordinated cellular response to hypoxia that includes the transcriptional regulation of a number of metabolic enzymes. Chuvash polycythemia (CP) is an autosomal recessive human disorder in which the regulatory degradation of HIF is impaired, resulting in elevated levels of HIF at normal oxygen tensions. Apart from the polycythemia, CP patients have marked abnormalities of cardiopulmonary function. No studies of integrated metabolic function have been reported. Here we describe the response of these patients to a series of metabolic stresses: exercise of a large muscle mass on a cycle ergometer, exercise of a small muscle mass (calf muscle) which allowed noninvasive in vivo assessments of muscle metabolism using 31P magnetic resonance spectroscopy, and a standard meal tolerance test. During exercise, CP patients had early and marked phosphocreatine depletion and acidosis in skeletal muscle, greater accumulation of lactate in blood, and reduced maximum exercise capacities. Muscle biopsy specimens from CP patients showed elevated levels of transcript for pyruvate dehydrogenase kinase, phosphofructokinase, and muscle pyruvate kinase. In cell culture, a range of experimental manipulations have been used to study the effects of HIF on cellular metabolism. However, these approaches provide no potential to investigate integrated responses at the level of the whole organism. Although CP is relatively subtle disorder, our study now reveals a striking regulatory role for HIF on metabolism during exercise in humans. These findings have significant implications for the development of therapeutic approaches targeting the HIF pathway.

Hypoxia-inducible factor 2α regulates key neutrophil functions in humans, mice, and zebrafish

Neutrophil lifespan and function are regulated by hypoxia via components of the hypoxia inducible factor (HIF)/von Hippel Lindau/hydroxylase pathway, including specific roles for HIF-1α and prolyl hydroxylase-3. HIF-2α has both distinct and overlapping biological roles with HIF-1α and has not previously been studied in the context of neutrophil biology. We investigated the role of HIF-2α in regulating key neutrophil functions. Human and murine peripheral blood neutrophils expressed HIF-2α, with expression up-regulated by acute and chronic inflammatory stimuli and in disease-associated inflammatory neutrophil. HIF2A gain-of-function mutations resulted in a reduction in neutrophil apoptosis both ex vivo, through the study of patient cells, and in vivo in a zebrafish tail injury model. In contrast, HIF-2α-deficient murine inflammatory neutrophils displayed increased sensitivity to nitrosative stress induced apoptosis ex vivo and increased neutrophil apoptosis in vivo, resulting in a reduction in neutrophilic inflammation and reduced tissue injury. Expression of HIF-2α was temporally dissociated from HIF-1α in vivo and predominated in the resolution phase of inflammation. These data support a critical and selective role for HIF-2α in persistence of neutrophilic inflammation and provide a platform to dissect the therapeutic utility of targeting HIF-2α in chronic inflammatory diseases.

A common perceptual parameter for stair climbing for children, young and old adults.

In this paper we examine whether a common perceptual parameter is available for guiding old adults, young adults and children in climbing the highest stair mountable in a bipedal fashion. Previous works have shown that the ratio between the height of the stair and the hip height was the body-scaled invariance adopted as information for selecting the highest stair by young adults [Journal of Experimental Psychology: Human Perception and Performance 10 (1984) 683-703] but not by older adults [Journal of Experimental Psychology: Human Perception and Performance 3 (1992) 691-697]. Indeed, for older adults additional bio-mechanical parameters needed to be added to the model due to their decrease in leg strength and flexibility.Up to now, no perceptual invariant has been identified yet for determining the relevant information used for guiding the stair climbing action for normal healthy people. We propose a new parameter as the angle defined by the ratio between the height of the stair and the distance taken from the feet to the top edge of the stair before the initiation of the movement. We show that this angle is the same for children, young adults and older adults despite the different kinematics of the motion, the anthropometrics and the skill ability exhibit by the participants. In summary we show that even when the climbability judgments, based on the simple ratio leg length-stair height, are influenced by differences in age, participants use a common perceptual variable when they are coordinating their stair climbing action.

Human locomotion on snow: determinants of economy and speed of skiing across the ages

We explore here the evolution of skiing locomotion in the last few thousand years by investigating how humans adapted to move effectively in lands where a cover of snow, for several months every year, prevented them from travelling as on dry ground. Following historical research, we identified the sets of skis corresponding to the ‘milestones’ of skiing evolution in terms of ingenuity and technology, built replicas of them and measured the metabolic energy associated to their use in a climate-controlled ski tunnel. Six sets of skis were tested, covering a span from 542 AD to date. Our results show that: (i) the history of skiing is associated with a progressive decrease in the metabolic cost of transport, (ii) it is possible today to travel at twice the speed of ancient times using the same amount of metabolic power and (iii) the cost of transport is speed-independent for each ski model, as during running. By combining this finding with the relationship between time of exhaustion and the sustainable fraction of metabolic power, a prediction of the maximum skiing speed according to the distance travelled is provided for all past epochs, including two legendary historical journeys (1206 and 1520 AD) on snow. Our research shows that the performances in races originating from them (Birkebeiner and Vasaloppet) and those of other modern competitions (skating versus classical techniques) are well predicted by the evolution of skiing economy. Mechanical determinants of the measured progression in economy are also discussed in the paper.

A fibre optic oxygen sensor that detects rapid PO2 changes under simulated conditions of cyclical atelectasis in vitro

Highlights • Real time detection of cyclical atelectasis is fundamental for individualised mechanical-ventilation therapy in ARDS.• Intra-arterial oxygen sensors could be used to detect the breath-by-breath oscillations in PO2 during cyclical atelectasis.• The fidelity with which oxygen sensors can detect these arterial PO2 oscillations depends on the sensors’ speed of response.• We present a system for testing fast-response fibre optic oxygen sensors under simulated conditions of cyclical atelectasis.• We show that a prototype fibre optic oxygen sensor, compatible with clinical use, can detect rapid PO2 changes in vitro.

Human locomotion on ice: the evolution of ice-skating energetics through history

SUMMARY More than 3000 years ago, peoples living in the cold North European regions started developing tools such as ice skates that allowed them to travel on frozen lakes. We show here which technical and technological changes determined the main steps in the evolution of ice-skating performance over its long history. An in-depth historical research helped identify the skates displaying significantly different features from previous models and that could consequently determine a better performance in terms of speed and energy demand. Five pairs of ice skates were tested, from the bone-skates, dated about 1800 BC, to modern ones. This paper provides evidence for the fact that the metabolic cost of locomotion on ice decreased dramatically through history, the metabolic cost of modern ice-skating being only 25% of that associated with the use of bone-skates. Moreover, for the same metabolic power, nowadays skaters can achieve speeds four times higher than their ancestors could. In the range of speeds considered, the cost of travelling on ice was speed independent for each skate model, as for running. This latter finding, combined with the accepted relationship between time of exhaustion and the sustainable fraction of metabolic power, gives the opportunity to estimate the maximum skating speed according to the distance travelled. Ice skates were probably the first human powered locomotion tools to take the maximum advantage from the biomechanical properties of the muscular system: even when travelling at relatively high speeds, the skating movement pattern required muscles to shorten slowly so that they could also develop a considerable amount of force.

Variations in Alveolar Partial Pressure for Carbon Dioxide and Oxygen Have Additive Not Synergistic Acute Effects on Human Pulmonary Vasoconstriction

The human pulmonary vasculature constricts in response to hypercapnia and hypoxia, with important consequences for homeostasis and adaptation. One function of these responses is to direct blood flow away from poorly-ventilated regions of the lung. In humans it is not known whether the stimuli of hypercapnia and hypoxia constrict the pulmonary blood vessels independently of each other or whether they act synergistically, such that the combination of hypercapnia and hypoxia is more effective than the sum of the responses to each stimulus on its own. We independently controlled the alveolar partial pressures of carbon dioxide (Paco 2) and oxygen (Pao 2) to examine their possible interaction on human pulmonary vasoconstriction. Nine volunteers each experienced sixteen possible combinations of four levels of Paco 2 (+6, +1, −4 and −9 mmHg, relative to baseline) with four levels of Pao 2 (175, 100, 75 and 50 mmHg). During each of these sixteen protocols Doppler echocardiography was used to evaluate cardiac output and systolic tricuspid pressure gradient, an index of pulmonary vasoconstriction. The degree of constriction varied linearly with both Paco 2 and the calculated haemoglobin oxygen desaturation (1-So 2). Mixed effects modelling delivered coefficients defining the interdependence of cardiac output, systolic tricuspid pressure gradient, ventilation, Paco 2 and So 2. No interaction was observed in the effects on pulmonary vasoconstriction of carbon dioxide and oxygen (p>0.64). Direct effects of the alveolar gases on systolic tricuspid pressure gradient greatly exceeded indirect effects arising from concurrent changes in cardiac output.

Experimental investigation of the effect of polymer matrices on polymer fibre optic oxygen sensors and their time response characteristics using a vacuum testing chamber and a liquid flow apparatus

Very fast sensors that are able to track rapid changes in oxygen partial pressure (PO2) in the gas and liquid phases are increasingly required in scientific research – particularly in the life sciences. Recent interest in monitoring very fast changes in the PO2 of arterial blood in some respiratory failure conditions is one such example. Previous attempts to design fast intravascular electrochemical oxygen sensors for use in physiology and medicine have failed to meet the criteria that are now required in modern investigations. However, miniature photonic devices are capable of meeting this need. In this article, we present an inexpensive polymer type fibre-optic, oxygen sensor that is two orders of magnitude faster than conventional electrochemical oxygen sensors. It is constructed with biologically inert polymer materials and is both sufficiently small and robust for direct insertion in to a human artery. The sensors were tested and evaluated in both a gas testing chamber and in a flowing liquid test system. The results showed a very fast T90 response time, typically circa 20 ms when tested in the gas phase, and circa 100 ms in flowing liquid.

Determinants of ventilation and pulmonary artery pressure during early acclimatization to hypoxia in humans

Lung ventilation and pulmonary artery pressure rise progressively in response to 8 h of hypoxia, changes described as ‘acclimatization to hypoxia’. Acclimatization responses differ markedly between humans for unknown reasons. We explored whether the magnitudes of the ventilatory and vascular responses were related, and whether the degree of acclimatization could be predicted by acute measurements of ventilatory and vascular sensitivities. In 80 healthy human volunteers measurements of acclimatization were made before, during, and after a sustained exposure to 8 h of isocapnic hypoxia. No correlation was found between measures of ventilatory and pulmonary vascular acclimatization. The ventilatory chemoreflex sensitivities to acute hypoxia and hypercapnia all increased in proportion to their pre‐acclimatization values following 8 h of hypoxia. The peripheral (rapid) chemoreflex sensitivity to CO2, measured before sustained hypoxia against a background of hyperoxia, was a modest predictor of ventilatory acclimatization to hypoxia. This finding has relevance to predicting human acclimatization to the hypoxia of altitude.

Optimizing design for polymer fiber optic oxygen sensors

The development of a clinically useful fiber-optic oxygen sensor based on oxygen fluorescence quenching is described in this paper. The fiber optic oxygen sensor was formed by coating a thin polymer matrix, which contains an oxygen sensitive fluorophore, on the tapered end of a polymer optical fiber. Three acrylate polymers have been used for the matrix, and the sensitivity and time-response of the oxygen sensors were tested. The results showed that the sensitivity and time response of the sensors can be modified using different polymer matrices. Using these modifications, a very fast time response of the polymer fiber-based oxygen sensor could be readily achieved and the fastest T10-90 response time were <;100 ms.