A smart tablet application to quantitatively assess the dominant hand dexterity

Background and objective: The Nine-Hole Peg Test (NHPT) is the most used test to assess hand dexterity in clinical practice and is considered the gold standard but only evaluates the time needed to complete the task. The aim of this work is to describe a graphic test on a smart tablet to assess in a quantitative as well qualitative way the dominant hand dexterity and to validate it in a cohort of neurological subjects and healthy controls. Methods: The task consists in asking the subject to connect with a graphic line the start and the end point of a pre-defined path, with two different widths, in the most precise and fastest way possible. The path is constituted by a ‘meander’ and a ‘spiral’ part. The subjects perform the task on a smart tablet with a capacitive pen four times. The three parameters of interest considered at each trial are the execution time, length path, and number of interactions with the border. The app automatically computes these three parameters and stores the completed test files. The results of the digital graphic test are compared to the NHPT results. Healthy and pathological subjects are compared to each other, and performances obtained in different repetitions are compared to assess the learning effect in each population. Results: 53 subjects with a definitive diagnosis of neurodegenerative/genetic neurological disorders (34 men, mean age 59.1 ± 16.1) and 78 healthy controls (33 men, mean age 42.5 ± 16.3) were recruited. Among the pathological subjects, 31 also performed the NHPT. The graphic test clearly distinguish between the two populations for all parameters of interest. Moreover, compared to the gold standard NHPT, time has a moderate positive correlation (r = 0.57, p ≤ 0.001), whereas interactions and length have a strong positive correlation (r = 0.81, p ≤ 0.001) and (r = 0.69, p ≤ 0.001), respectively. Conclusions: The proposed digital test can measure in an accurate, quantitative and qualitative way dominant hand disability and can result more informative with respect to the gold standard NHPT. In homogeneous cohort of subjects (for example affected by multiple sclerosis or Parkinson disease), the digital test can be used as an outcome measure in clinical trials as well as a tool for monitoring disease progression at the dominant hand level

Incidents and injuries in foot launched flying extreme sports: a snap shot from the UK

Background. Participation rates in extreme sports have grown exponentially in the last 40 years,often surpassing traditional sporting activities. The purpose of this study was to examine injury rates in foot launched flying sports, i.e. sports in which a pilot foot-launches into flight with a wing already deployed. Method. This paper is based on a retrospective analysis of the reports of incidents that occurred between 2000 and 2014 among the British Hang Gliding and Paragliding Association members. Results. The majority of the 1411 reported injuries were in the lower limb, followed by the upper limb. The most common lower limb injury was to the ankle and included fractures sprains and dislocations. The distribution of injures was different in each discipline. The calculated yearly fatality rate (fatalities /100,000 participants) was 40.4 in hang gliding, 47.1 in paragliding, 61.9 in powered hang gliding and 83.4 in powered paragliding; the overall value for foot launched flight sports was 43.9. Discussion. Significant differences in injury rates and injury patterns were found among different sport disciplines that can be useful to steer research on safety, and adopt specific safety rules about flying, protective clothing and safety systems in each of these sports

Reactions of Plasmodium falciparum Ferredoxin:NADP(+) Oxidoreductase with Redox Cycling Xenobiotics: A Mechanistic Study

Ferredoxin:NADP+ oxidoreductase from Plasmodium falciparum (PfFNR) catalyzes the NADPH-dependent reduction of ferredoxin (PfFd), which provides redox equivalents for the biosynthesis of isoprenoids and fatty acids in the apicoplast. Like other flavin-dependent electrontransferases, PfFNR is a potential source of free radicals of quinones and other redox cycling compounds. We report here a kinetic study of the reduction of quinones, nitroaromatic compounds and aromatic N-oxides by PfFNR. We show that all these groups of compounds are reduced in a single-electron pathway, their reactivity increasing with the increase in their single-electron reduction midpoint potential (E17). The reactivity of nitroaromatics is lower than that of quinones and aromatic N-oxides, which is in line with the differences in their electron self-exchange rate constants. Quinone reduction proceeds via a ping-pong mechanism. During the reoxidation of reduced FAD by quinones, the oxidation of FADH. to FAD is the possible rate-limiting step. The calculated electron transfer distances in the reaction of PfFNR with various electron acceptors are similar to those of Anabaena FNR, thus demonstrating their similar "intrinsic" reactivity. Ferredoxin stimulated quinone- and nitro-reductase reactions of PfFNR, evidently providing an additional reduction pathway via reduced PfFd. Based on the available data, PfFNR and possibly PfFd may play a central role in the reductive activation of quinones, nitroaromatics and aromatic N-oxides in P. falciparum, contributing to their antiplasmodial action

Validation of a graphic test to quantitatively assess the dominant hand dexterity

Dexterity dysfunction is a key feature of disability in many neurological and non-neurological diseases. The Nine-Hole Peg Test (NHPT) is the most used test to assess hand dexterity in clinical practice but presents limitations. A new graphic test to enhance objective evaluation of the of the dominant hand dexterity is proposed. The task consists in drawing a continuous line in paths composed by a part with multiple orthogonal changes of direction (‘meander’), and a second part derived from the Archimedean spiral (‘spiral’). The test was validated in 200 healthy controls and 93 neurological patients. 48 patients performed also the NHPT. Several parameters were analyzed, among which total time, total length, number of touches and number of crossings. Healthy subjects display statistically significant differences with respect to pathological subjects in the case of total time, number of touches, and number of crossings (p<0.001), but not in the case of total length (p = 0.27) needed to complete the second sheet. Moreover, healthy controls display a learning effect, the time needed to complete the second sheet was significantly lower than for the first sheet (p<0.001), and an inverse correlation with age was observed (r = 0.56, p<0.001). The comparison between the NHPT and the new test showed a strong positive correlation (r = 0.71, p<0.001) whereas touches and crossing a weak positive one (r = 0.35, p = 0.01). The new test distinguishes between a slow but precise performance and a fast but imprecise performance, thus providing additional information with respect to NHPT

Structural bases of the altered catalytic properties of a pathogenic variant of apoptosis inducing factor

The apoptosis-inducing factor (AIF) is a FAD-containing protein playing critical roles in caspase-independent apoptosis and mitochondrial respiratory chain biogenesis and maintenance. While its lethal role is well known, the details of its mitochondrial function remain elusive. So far, nineteen allelic variants of AIF have been associated to human diseases, mainly affecting the nervous system. A strict correlation is emerging between the degree of impairment of its ability to stabilize the charge-transfer (CT) complex between FAD and NAD+ and the severity of the resulting pathology. Recently, we demonstrated that the G307E replacement in murine AIF (equivalent to the pathogenic G308E in the human protein) dramatically decreases the rate of CT complex formation through the destabilization of the flavoprotein interaction with NAD(H). To provide further insights into the structural bases of its altered functional properties, here we report the first crystal structure of an AIF pathogenic mutant variant in complex with NAD+ (murine AIF-G307ECT) in comparison with its oxidized form. With respect to wild type AIF, the mutation leads to an altered positioning of NAD+ adenylate moiety, which slows down CT complex formation. Moreover, the altered balance between the binding of the adenine/nicotinamide portions of the coenzyme determines a large drop in AIF-G307E ability to discriminate between NADH and NADPH

Paradoxical movement of the lower ribcage at rest and during exercise in COPD patients

Paradoxical inward displacement of the costal margin during inspiration is observed in many chronic obstructive pulmonary disease patients at rest but its importance is unclear.The current authors studied 20 patients (forced expiratory volume in one second 32.6 +/- 11.7, functional residual capacity 186 +/- 32% predicted) and 10 healthy controls at rest and during symptom-limited incremental exercise. With optoelectronic plethysmography, the phase shift between pulmonary and abdominal ribcage volumes and the percentage of inspiratory time the ribcage compartments moved in opposite directions were quantified, using control data to define the normal range of movement.Eight patients showed lower ribcage inspiratory paradox at rest (P+), while 12 patients did not (P-). This was unrelated to resting lung function or exercise tolerance. Total end-expiratory chest wall volume (EEVcw) increased immediately when exercise began in P+ patients, but later in exercise in P- patients. This difference in EEVcw was mainly due to a greater increase of end-expiratory pulmonary ribcage volume in P+ patients. During exercise, dyspnoea increased similarly in the two groups, while leg effort increased more markedly in the patients without paradox.In conclusion, lower ribcage paradox at rest is reproducible and associated with early-onset hyperinflation of the chest wall and predominant dyspnoea at end-exercise. When paradox is absent, the sense of leg effort becomes a more important symptom limiting exercise.British Lung FoundationEuropean Respiratory Society (ERS)ERS COEDPolitecn Milan, TBM Lab, Dipartimento Bioingn, I-20133 Milan, ItalyUniv Liverpool, Ctr Clin Sci, Univ Hosp Aintree, Liverpool L69 3BX, Merseyside, EnglandUniversidade Federal de São Paulo, São Paulo, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilEuropean Respiratory Society (ERS): 69Web of Scienc

Structural and functional diversity of ferredoxin-NADP+ reductases

Although all ferredoxin-NADP+ reductases (FNRs) catalyze the same reaction, i.e. the transfer of reducing equivalents between NADP(H) and ferredoxin, they belong to two unrelated families of proteins: the plant-type and the glutathione reductase-type of FNRs. Aim of this review is to provide a general classification scheme for these enzymes, to be used as a framework for the comparison of their properties. Furthermore, we report on some recent findings, which significantly increased the understanding of the structure–function relationships of FNRs, i.e. the ability of adrenodoxin reductase and its homologs to catalyze the oxidation of NADP+ to its 4-oxo derivative, and the properties of plant-type FNRs from non-photosynthetic organisms. Plant-type FNRs from bacteria and Apicomplexan parasites provide examples of novel ways of FAD- and NADP(H)-binding. The recent characterization of an FNR from Plasmodium falciparum brings these enzymes into the field of drug design

Sniff test: does what we measure at the nose reflect what happens in the chest wall?

Nasal pressure measured during sniff (SNIP) is a technically simple voluntary test. Since the contraction of the diaphragm expands the abdomen, the volume variation during sniff manoeuvre should therefore be predominantly abdominal in order to be considered a specific index of diaphragm strength. We aimed to verify if and how SNIP varied according to thoraco-abdominal volume variations. We measured abdominal volume variations, using opto-electronic plethysmography, during quiet breathing (ABQB) and sniff manoeuvres (ABSN) in supine position on 30 patients (age: 42; FVC:47.5%; FEV1:30%) on the waiting list for lung transplant. SNIP was measured simultaneously with ABSN. 68 sniff were analysed and classified into 4 groups according to ABSN: 16 with thoracic paradox, 24 predominantly abdominal, 16 predominantly thoracic and 12 with abdominal paradox. By definition ABSN was different (p<0.001) among the 4 groups, whereas ABQB (~75%; p=0.373) and SNIP (~53 cmH2O, p= 0.792) were similar (figure 1). SNIP did not change with the different thoraco-abdominal strategies. The diaphragm was not weak and leaded inspiration, therefore ABSN varied because the patients misperformed the manoeuvre. In order to not misunderstand the clinical significance of a sniff test, care should be paid also in thoraco-abdominal movement because SNIP, per se, cannot differentiate between thoracic or diaphragmatic manoeuvre with the risk to lose its specificity

Is renalase a novel player in catecholaminergic signaling? The mystery of the catalytic activity of an intriguing new flavoenzyme

Renalase is a flavoprotein recently discovered in humans, preferentially expressed in the proximal tubules of the kidney and secreted in blood and urine. It is highly conserved in vertebrates, with homologs identified in eukaryotic and prokaryotic organisms. Several genetic, epidemiological, clinical and experimental studies show that renalase plays a role in the modulation of the functions of the cardiovascular system, being particularly active in decreasing the catecholaminergic tone, in lowering blood pressure and in exerting a protective action against myocardial ischemic damage. Deficient renalase synthesis might be the cause of the high occurrence of hypertension and adverse cardiac events in kidney disease patients. Very recently, recombinant human renalase has been structurally and functionally characterized in vitro. Results show that it belongs to the p-hydroxybenzoate hydroxylase structural family of flavoenzymes, contains non-covalently bound FAD with redox features suggestive of a dehydrogenase activity, and is not a catecholamine-degrading enzyme, either through oxidase or NAD(P)H-dependent monooxygenase reactions. The biochemical data now available will hopefully provide the basis for a systematic and rational quest toward the identification of the reaction catalyzed by renalase and of the molecular mechanism of its physiological action, which in turn are expected to favor the development of novel therapeutic tools for the treatment of kidney and cardiovascular diseases

Ferredoxin-NADP(+) reductase from Plasmodium falciparum undergoes NADP(+)-dependent dimerization and inactivation: functional and crystallographic analysis

The completion of the Plasmodium falciparum genome sequence has recently promoted the search for new antimalarial drugs. More specifically, metabolic pathways of the apicoplast, a key organelle for survival of the parasite, have been recognized as potential targets for the development of specific new antimalarial agents. As most apicomplexan parasites, P. falciparum displays a plant-type ferredoxin-NADP(+) reductase, yielding reduced ferredoxin for essential biosynthetic pathways in the apicoplast. Here we report a molecular, kinetic and ligand binding characterization of the recombinant ferredoxin-NADP(+) reductase from P. falciparum, in the light of current data available for plant ferredoxin-NADP(+) reductases. In parallel with the functional characterization, we describe the crystal structures of P. falciparum ferredoxin-NADP(+) reductase in free form and in complex with 2'-phospho-AMP (at 2.4 and 2.7 A resolution, respectively). The enzyme displays structural properties likely to be unique to plasmodial reductases. In particular, the two crystal structures highlight a covalent dimer, which relies on the oxidation of residue Cys99 in two opposing subunits, and a helix-coil transition that occurs in the NADP-binding domain, triggered by 2'-phospho-AMP binding. Studies in solution show that NADP(+), as well as 2'-phospho-AMP, promotes the formation of the disulfide-stabilized dimer. The isolated dimer is essentially inactive, but full activity is recovered upon disulfide reduction. The occurrence of residues unique to the plasmodial enzyme, and the discovery of specific conformational properties, highlight the NADP-binding domain of P. falciparum ferredoxin-NADP(+) reductase as particularly suited for the rational development of antimalarial compounds