Muscular development and physical activity as major determinants of femoral bone mass acquisition during growth

[EN] OBJECTIVES: To investigate to what extent bone mass accrual is determined by physical activity and changes in lean, fat, and total body mass during growth. METHODS: Twenty six physically active and 16 age matched control boys were followed up for three years. All subjects were prepubertal at the start of the survey (mean (SEM) age 9.4 (0.3) years). The weekly physical activity of the active boys included compulsory physical education sessions (80-90 minutes a week), three hours a week of extracurricular sports participation, and occasional sports competitions at weekends. The physical activity of the control group was limited to the compulsory physical education curriculum. Bone mineral content (BMC) and areal density (BMD), lean mass, and fat mass were measured by dual energy x ray absorptiometry. RESULTS: The effect of sports participation on femoral bone mass accrual was remarkable. Femoral BMC and BMD increased twice as much in the active group as in the controls over the three year period (p < 0.05). The greatest correlation was found between the increment in femoral bone mass and the increment in lean mass (BMC r = 0.67 and BMD r = 0.69, both p < 0.001). Multiple regression analysis revealed enhancement in lean mass as the best predictor of the increment in femoral bone BMC (R = 0.65) and BMD (R = 0.69). CONCLUSIONS: Long term sports participation during early adolescence results in greater accrual of bone mass. Enhancement of lean mass seems to be the best predictor of this bone mass accumulation. However, for a given muscle mass, a greater level of physical activity is associated with greater bone mass and density in peripubertal boys.

Parasympathetic neural activity accounts for the lowering of exercise heart rate at high altitude

[EN] BACKGROUND: In chronic hypoxia, both heart rate (HR) and cardiac output (Q) are reduced during exercise. The role of parasympathetic neural activity in lowering HR is unresolved, and its influence on Q and oxygen transport at high altitude has never been studied. METHODS AND RESULTS: HR, Q, oxygen uptake, mean arterial pressure, and leg blood flow were determined at rest and during cycle exercise with and without vagal blockade with glycopyrrolate in 7 healthy lowlanders after 9 weeks' residence at >/=5260 m (ALT). At ALT, glycopyrrolate increased resting HR by 80 bpm (73+/-4 to 153+/-4 bpm) compared with 53 bpm (61+/-3 to 114+/-6 bpm) at sea level (SL). During exercise at ALT, glycopyrrolate increased HR by approximately 40 bpm both at submaximal (127+/-4 to 170+/-3 bpm; 118 W) and maximal (141+/-6 to 180+/-2 bpm) exercise, whereas at SL, the increase was only by 16 bpm (137+/-6 to 153+/-4 bpm) at 118 W, with no effect at maximal exercise (181+/-2 bpm). Despite restoration of maximal HR to SL values, glycopyrrolate had no influence on Q, which was reduced at ALT. Breathing FIO(2)=0.55 at peak exercise restored Q and power output to SL values. CONCLUSIONS: Enhanced parasympathetic neural activity accounts for the lowering of HR during exercise at ALT without influencing Q. The abrupt restoration of peak exercise Q in chronic hypoxia to maximal SL values when arterial PO(2) and SO(2) are similarly increased suggests hypoxia-mediated attenuation of Q.

Skeletal Markers of Activity: Methodological and Interpretative Reflections after the study of the whole Frassetto Sassari identified skeletal collection

Entheses (skeletal attachment sites of muscles and ligaments) and their pathologic modifications (enthesopathies) have long been used as skeletal markers of activity in bioarchaeological (reconstruction of past populations lifestyle) and forensic (personal identification) contexts. However, a functional interpretation of these markers have to deal critically with the multifactorial etiology of the same. Factors such as sex, age, genetic factors, mechanical stress, metabolic conditions, etc.. can compete to produce the observed morphological variability at each attachment site. The aim of this thesis has drawn on the ongoing debate about the informativeness of entheseal modifications as skeletal markers of activity and represent a deepening of the actual knowledge about the relationship between these characters and sex, age and physical activity. For this purpose, the whole "Frassetto” identified skeletal collection of Sassari (Sardinia, Italy) was analyzed. The collection includes the skeletal remains of about 600 individuals died in the late 19th and early 20th century for whom information regarding sex, age at death and, in many cases the occupation are known The results obtained highlight the great age importance on the entheseal modifications. The differences observed between sexes may reflect differences in the level or type of activity performed in life, but could also be related to a different bone tissue response to mechanical stress due to hormonal factors and different growth rates. The role of biomechanical stress related to professional activities remains doubtful. This is probably partly attributable to the analyzed sample characteristics (preponderance of farmers compared with other professions, different mean age of the considered professional subsamples), which has hampered the analysis of samples homogenous with regard to age, which is very influential on the entheses and enthesopathies expression.

Packet Level Coding for Mobile Broadcasting

The thesis deals with channel coding theory applied to upper layers in the protocol stack of a communication link and it is the outcome of four year research activity. A specific aspect of this activity has been the continuous interaction between the natural curiosity related to the academic blue-sky research and the system oriented design deriving from the collaboration with European industry in the framework of European funded research projects. In this dissertation, the classical channel coding techniques, that are traditionally applied at physical layer, find their application at upper layers where the encoding units (symbols) are packets of bits and not just single bits, thus explaining why such upper layer coding techniques are usually referred to as packet layer coding. The rationale behind the adoption of packet layer techniques is in that physical layer channel coding is a suitable countermeasure to cope with small-scale fading, while it is less efficient against large-scale fading. This is mainly due to the limitation of the time diversity inherent in the necessity of adopting a physical layer interleaver of a reasonable size so as to avoid increasing the modem complexity and the latency of all services. Packet layer techniques, thanks to the longer codeword duration (each codeword is composed of several packets of bits), have an intrinsic longer protection against long fading events. Furthermore, being they are implemented at upper layer, Packet layer techniques have the indisputable advantages of simpler implementations (very close to software implementation) and of a selective applicability to different services, thus enabling a better matching with the service requirements (e.g. latency constraints). Packet coding technique improvement has been largely recognized in the recent communication standards as a viable and efficient coding solution: Digital Video Broadcasting standards, like DVB-H, DVB-SH, and DVB-RCS mobile, and 3GPP standards (MBMS) employ packet coding techniques working at layers higher than the physical one. In this framework, the aim of the research work has been the study of the state-of-the-art coding techniques working at upper layer, the performance evaluation of these techniques in realistic propagation scenario, and the design of new coding schemes for upper layer applications. After a review of the most important packet layer codes, i.e. Reed Solomon, LDPC and Fountain codes, in the thesis focus our attention on the performance evaluation of ideal codes (i.e. Maximum Distance Separable codes) working at UL. In particular, we analyze the performance of UL-FEC techniques in Land Mobile Satellite channels. We derive an analytical framework which is a useful tool for system design allowing to foresee the performance of the upper layer decoder. We also analyze a system in which upper layer and physical layer codes work together, and we derive the optimal splitting of redundancy when a frequency non-selective slowly varying fading channel is taken into account. The whole analysis is supported and validated through computer simulation. In the last part of the dissertation, we propose LDPC Convolutional Codes (LDPCCC) as possible coding scheme for future UL-FEC application. Since one of the main drawbacks related to the adoption of packet layer codes is the large decoding latency, we introduce a latency-constrained decoder for LDPCCC (called windowed erasure decoder). We analyze the performance of the state-of-the-art LDPCCC when our decoder is adopted. Finally, we propose a design rule which allows to trade-off performance and latency.

A farm-level programming model to compare the atmospheric impact of conventional and organic farming

A model is developed to represent the activity of a farm using the method of linear programming. Two are the main components of the model, the balance of soil fertility and the livestock nutrition. According to the first, the farm is supposed to have a total requirement of nitrogen, which is to be accomplished either through internal sources (manure) or through external sources (fertilisers). The second component describes the animal husbandry as having a nutritional requirement which must be satisfied through the internal production of arable crops or the acquisition of feed from the market. The farmer is supposed to maximise total net income from the agricultural and the zoo-technical activities by choosing one rotation among those available for climate and acclivity. The perspective of the analysis is one of a short period: the structure of the farm is supposed to be fixed without possibility to change the allocation of permanent crops and the amount of animal husbandry. The model is integrated with an environmental module that describes the role of the farm within the carbon-nitrogen cycle. On the one hand the farm allows storing carbon through the photosynthesis of the plants and the accumulation of carbon in the soil; on the other some activities of the farm emit greenhouse gases into the atmosphere. The model is tested for some representative farms of the Emilia-Romagna region, showing to be capable to give different results for conventional and organic farming and providing first results concerning the different atmospheric impact. Relevant data about the representative farms and the feasible rotations are extracted from the FADN database, with an integration of the coefficients from the literature.

Hair: a tool to evaluate the HPA axis activity

Hair cortisol is a novel marker to measure long-term secretion cortisol free from many methodological caveats associated with other matrices such as plasma, saliva, urine, milk and faeces. For decades hair analysis has been successfully used in forensic science and toxicology to evaluate the exposure to exogenous substances and assess endogenous steroid hormones. Evaluation of cortisol in hair matrix began about a decade ago and have over the past five years had a remarkable development by advancing knowledge and affirming this method as a new and efficient way to study the hypothalamic-pituitary-adrenal (HPA) axis activity over a long time period. In farm animals, certain environmental or management conditions can potentially activate the HPA axis. Given the importance of cortisol in monitoring the HPA axis activity, a first approach has involved the study on the distribution of hair cortisol concentrations (HCC) in healthy dairy cows showing a physiological range of variation of this hormone. Moreover, HCC have been significantly influenced also by changes in environmental conditions and a significant positive correlation was detected between HCC and cows clinically or physiologically compromised suggesting that these cows were subjected to repeated HPA axis activation. Additionally, Crossbreed F1 heifers showed significantly lower HCC compared to pure animals and a breed influence has been seen also on the HPA axis activity stimulated by an environmental change showing thus a higher level of resilience and a better adaptability to the environment of certain genotypes. Hair proved to be an excellent matrix also in the study of the activation of the HPA axis during the perinatal period. The use of hair analysis in research holds great promise to significantly enhance current understanding on the role of HPA axis over a long period of time.

In vivo and in vitro investigation of the tissue-specific activity of the human CYP3A4 and CYP3A5 promoters

The human cytochrome P450 3A4 (CYP3A4), the predominant but variably expressed cytochrome P450 in adult liver and small intestine is involved in the metabolism of over 50% of currently used drugs. Its paralog CYP3A5 plays a crucial role in the disposition of several drugs with low therapeutic index, including tacrolimus. Limited information is available for the CYP3A5 transcriptional regulation and its induction by xenobiotics remains controversial. In the first part of this study, we analysed the CYP3A5 transcriptional regulation and its induction by xenobiotics in vivo using transgenic mice. To this end, two transgenic strains were established by pronuclear injection of a plasmid, expressing firefly luciferase driven by a 6.2 kb of the human CYP3A5 promoter. A detailed analysis of both strains shows a tissue distribution largely reflecting that of CYP3A5 transcripts in humans. Thus, the highest luciferase activity was detected in the small intestine, followed by oesophagus, testis, lung, adrenal gland, ovary, prostate and kidney. However, no activity was observed in the liver. CYP3A5-luc transgenic mice were similarly induced in both sexes with either PCN or TCPOBOP in small intestine in a dose-dependent manner. Thus, the 6.2 kb upstream promoter of CYP3A5 mediates the broad tissue activity in transgenic mice. CYP3A5 promoter is inducible in the small intestine in vivo, which may contribute to the variable expression of CYP3A in this organ. rnThe hepato-intestinal level of the detoxifying oxidases CYP3A4 and CYP3A5 is adjusted to the xenobiotic exposure mainly via the xenosensor and transcriptional factor PXR. CYP3A5 is additionally expressed in several other organs lacking PXR, including kidney. In the second part of this study, we investigated the mechanism of the differential expression of CYP3A5 and CYP3A4 and its evolutionary origin using renal and intestinal cells, and comparative genomics. For this examination, we established a two-cell line models reflecting the expression relationships of CYP3A4 and CYP3A5 in the kidney and small intestine in vivo. Our data demonstrate that the CYP3A5 expression in renal cells was enabled by the loss of a suppressing Yin Yang 1 (YY1)-binding site from the CYP3A5 promoter. This allowed for a renal CYP3A5 expression in a PXR-independent manner. The YY1 element is retained in the CYP3A4 gene, leading to its suppression, perhaps via interference with the NF1 activity in renal cells. In intestinal cells, the inhibition of CYP3A4 expression by YY1 is abrogated by a combined activating effect of PXR and NF1 acting on their respective response elements located adjacent to the YY1-binding site on CYP3A4 proximal promoter. CYP3A4 expression is further facilitated by a point mutation attenuating the suppressing effect of YY1 binding site. The differential expression of CYP3A4 and CYP3A5 in these organs results from the loss of the YY1 binding element from the CYP3A5 promoter, acting in concert with the differential organ expression of PXR, and with the higher accumulation of PXR response elements in CYP3A4. rn

Entrepreneurship influential factors in development of rural tourism as diversified rural activity in Republic of Macedonia

Rural tourism is relatively new product in the process of diversification of the rural economy in Republic of Macedonia. This study used desk research and life story interviews of rural tourism entrepreneurs as qualitative research method to identify prevalent success influential factors. Further quantitative analysis was applied in order to measure the strength of influence of identified success factors. The primary data for the quantitative research was gathered using telephone questionnaire composed of 37 questions with 5-points Likert scale. The data was analyzed using Partial Least Squares Structural Equation Modeling (PLS-SEM) by SmartPLS 3.1.6. Results indicated that human capital, social capital, entrepreneurial personality and external business environment are predominant influential success factors. However, human capital has non-significant direct effect on success (p 0.493) nonetheless the effect was indirect with high level of partial mediation through entrepreneurial personality as mediator (VAF 73%). Personality of the entrepreneur, social capital and business environment have direct positive affect on entrepreneurial success (p 0.001, 0.003 and 0.045 respectably). Personality also mediates the positive effect of social capital on entrepreneurial success (VAF 28%). Opposite to the theory the data showed no interaction between social and human capital on the entrepreneurial success. This research suggests that rural tourism accommodation entrepreneurs could be more successful if there is increased support in development of social capital in form of conservation of cultural heritage and natural attractions. Priority should be finding the form to encourage and support the establishment of formal and informal associations of entrepreneurs in order to improve the conditions for management and marketing of the sector. Special support of family businesses in the early stages of the operation would have a particularly positive impact on the success of rural tourism. Local infrastructure, access to financial instruments, destination marketing and entrepreneurial personality have positive effect on success.

Restoration of Akt activity by the bisperoxovanadium compound bpV(pic) attenuates hippocampal apoptosis in experimental neonatal pneumococcal meningitis

Pneumococcal meningitis causes apoptosis of developing neurons in the dentate gyrus of the hippocampus. The death of these cells is accompanied with long-term learning and memory deficits in meningitis survivors. Here, we studied the role of the PI3K/Akt (protein kinase B) survival pathway in hippocampal apoptosis in a well-characterized infant rat model of pneumococcal meningitis. Meningitis was accompanied by a significant decrease of the PI3K product phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) and of phosphorylated (i.e., activated) Akt in the hippocampus. At the cellular level, phosphorylated Akt was decreased in both the granular layer and the subgranular zone of the dentate gyrus, the region where the developing neurons undergo apoptosis. Protein levels and activity of PTEN, the major antagonist of PI3K, were unaltered by infection, suggesting that the observed decrease in PIP(3) and Akt phosphorylation is a result of decreased PI3K signaling. Treatment with the PTEN inhibitor bpV(pic) restored Akt activity and significantly attenuated hippocampal apoptosis. Co-treatment with the specific PI3K inhibitor LY294002 reversed the restoration of Akt activity and attenuation of hippocampal apoptosis, while it had no significant effect on these parameters on its own. These results indicate that the inhibitory effect of bpV(pic) on apoptosis was mediated by PI3K-dependent activation of Akt, strongly suggesting that bpV(pic) acted on PTEN. Treatment with bpV(pic) also partially inhibited the concentration of bacteria and cytokines in the CSF, but this effect was not reversed by LY294002, indicating that the effect of bpV(pic) on apoptosis was independent of its effect on CSF bacterial burden and cytokine levels. These results indicate that the PI3K/Akt pathway plays an important role in the death and survival of developing hippocampal neurons during the acute phase of pneumococcal meningitis.

Time-referenced effects of an internal vs. external focus of attention on muscular activity and compensatory variability

The paralysis-by-analysis phenomenon, i.e., attending to the execution of one's movement impairs performance, has gathered a lot of attention over recent years (see Wulf, 2007, for a review). Explanations of this phenomenon, e.g., the hypotheses of constrained action (Wulf et al., 2001) or of step-by-step execution (Masters, 1992; Beilock et al., 2002), however, do not refer to the level of underlying mechanisms on the level of sensorimotor control. For this purpose, a “nodal-point hypothesis” is presented here with the core assumption that skilled motor behavior is internally based on sensorimotor chains of nodal points, that attending to intermediate nodal points leads to a muscular re-freezing of the motor system at exactly and exclusively these points in time, and that this re-freezing is accompanied by the disruption of compensatory processes, resulting in an overall decrease of motor performance. Two experiments, on lever sequencing and basketball free throws, respectively, are reported that successfully tested these time-referenced predictions, i.e., showing that muscular activity is selectively increased and compensatory variability selectively decreased at movement-related nodal points if these points are in the focus of attention.

Elevated level of metabotropic glutamate receptor 2/3 in the prefrontal cortex in major depression

Clinical, postmortem and preclinical research strongly implicates dysregulation of glutamatergic neurotransmission in major depressive disorder (MDD). Recently, metabotropic glutamate receptors (mGluRs) have been proposed as attractive targets for the discovery of novel therapeutic approaches against depression. The aim of this study was to examine mGluR2/3 protein levels in the prefrontal cortex (PFC) from depressed subjects. In addition, to test whether antidepressants influence mGluR2/3 expression we also studied levels of mGluR2/3 in fluoxetine-treated monkeys. Postmortem human prefrontal samples containing Brodmann's area 10 (BA10) were obtained from 11 depressed and 11 psychiatrically healthy controls. Male rhesus monkeys were treated chronically with fluoxetine (dose escalated to 3mg/kg, p.o.; n=7) or placebo (n=6) for 39 weeks. The mGluR2/3 immunoreactivity was investigated using Western blot method. There was a robust (+67%) increase in the expression of the mGlu2/3 protein in the PFC of depressed subjects relative to healthy controls. The expression of mGlu2/3 was unchanged in the PFC of monkeys treated with fluoxetine. Our findings provide the first evidence that mGluR2/3 is elevated in the PFC in MDD. This observation is consistent with reports showing that mGluR2/3 antagonists exhibit antidepressant-like activity in animal models and demonstrates that these receptors are promising targets for the discovery of novel antidepressants.

Identification of adequate neurally adjusted ventilatory assist (NAVA) during systematic increases in the NAVA level

Neurally adjusted ventilatory assist (NAVA) delivers airway pressure (P(aw)) in proportion to the electrical activity of the diaphragm (EAdi) using an adjustable proportionality constant (NAVA level, cm·H(2)O/μV). During systematic increases in the NAVA level, feedback-controlled down-regulation of the EAdi results in a characteristic two-phased response in P(aw) and tidal volume (Vt). The transition from the 1st to the 2nd response phase allows identification of adequate unloading of the respiratory muscles with NAVA (NAVA(AL)). We aimed to develop and validate a mathematical algorithm to identify NAVA(AL). P(aw), Vt, and EAdi were recorded while systematically increasing the NAVA level in 19 adult patients. In a multistep approach, inspiratory P(aw) peaks were first identified by dividing the EAdi into inspiratory portions using Gaussian mixture modeling. Two polynomials were then fitted onto the curves of both P(aw) peaks and Vt. The beginning of the P(aw) and Vt plateaus, and thus NAVA(AL), was identified at the minimum of squared polynomial derivative and polynomial fitting errors. A graphical user interface was developed in the Matlab computing environment. Median NAVA(AL) visually estimated by 18 independent physicians was 2.7 (range 0.4 to 5.8) cm·H(2)O/μV and identified by our model was 2.6 (range 0.6 to 5.0) cm·H(2)O/μV. NAVA(AL) identified by our model was below the range of visually estimated NAVA(AL) in two instances and was above in one instance. We conclude that our model identifies NAVA(AL) in most instances with acceptable accuracy for application in clinical routine and research.

The link between visual exploration and neuronal activity: A multi-modal study combining eye tracking, functional magnetic resonance imaging and transcranial magnetic stimulation

In the present multi-modal study we aimed to investigate the role of visual exploration in relation to the neuronal activity and performance during visuospatial processing. To this end, event related functional magnetic resonance imaging er-fMRI was combined with simultaneous eye tracking recording and transcranial magnetic stimulation (TMS). Two groups of twenty healthy subjects each performed an angle discrimination task with different levels of difficulty during er-fMRI. The number of fixations as a measure of visual exploration effort was chosen to predict blood oxygen level-dependent (BOLD) signal changes using the general linear model (GLM). Without TMS, a positive linear relationship between the visual exploration effort and the BOLD signal was found in a bilateral fronto-parietal cortical network, indicating that these regions reflect the increased number of fixations and the higher brain activity due to higher task demands. Furthermore, the relationship found between the number of fixations and the performance demonstrates the relevance of visual exploration for visuospatial task solving. In the TMS group, offline theta bursts TMS (TBS) was applied over the right posterior parietal cortex (PPC) before the fMRI experiment started. Compared to controls, TBS led to a reduced correlation between visual exploration and BOLD signal change in regions of the fronto-parietal network of the right hemisphere, indicating a disruption of the network. In contrast, an increased correlation was found in regions of the left hemisphere, suggesting an intent to compensate functionality of the disturbed areas. TBS led to fewer fixations and faster response time while keeping accuracy at the same level, indicating that subjects explored more than actually needed.

Periodontal pathogens affect the level of protease inhibitors in gingival crevicular fluid

In periodontitis, an effective host-response is primarily related to neutrophils loaded with serine proteases, including elastase (NE) and protease 3 (PR3), the extracellular activity of which is tightly controlled by endogenous inhibitors. In vitro these inhibitors are degraded by gingipains, cysteine proteases produced by Porphyromonas gingivalis. The purpose of this study was to determine the level of selected protease inhibitors in gingival crevicular fluid (GCF) in relation to periodontal infection. The GCF collected from 31 subjects (nine healthy controls, seven with gingivitis, five with aggressive periodontitis and 10 with chronic periodontitis) was analyzed for the levels of elafin and secretory leukocyte protease inhibitor (SLPI), two main tissue-derived inhibitors of neutrophil serine proteases. In parallel, activity of NE, PR3 and arginine-specific gingipains (Rgps) in GCF was measured. Finally loads of P. gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia and Treponema denticola were determined. The highest values of elafin were found in aggressive periodontitis and the lowest in controls. The quantity of elafin correlated positively with the load of P. gingivalis, Ta. forsythia and Tr. denticola, as well as with Rgps activity. In addition, NE activity was positively associated with the counts of those bacterial species, but not with the amount of elafin. In contrast, the highest concentrations of SLPI were found in periodontally healthy subjects whereas amounts of this inhibitor were significantly decreased in patients infected with P. gingivalis. Periodontopathogenic bacteria stimulate the release of NE and PR3, which activities escape the control through degradation of locally produced inhibitors (SLPI and elafin) by host-derived and bacteria-derived proteases.