[Retrospective study on the effects of a whey protein concentrate on body composition in 262 sarcopenic tube fed patients]. / Studio retrospettivo sugli effetti di un concentrato di proteine del siero del latte sulla composizione corporea di 262 pazienti in nutrizione enterale affetti da sarcopenia.

AIM: As pointed in ESPEN guidelines on the use of bioelectrical impedance analysis (BIA), "body cell mass (BCM) is the protein rich compartment which is affected in catabolic states, and loss of BCM is associated with poor clinical outcome". Whey proteins are known to improve lean mass in many conditions. We retrospectively evaluated the effects of a WP concentrate with high cysteine content (WPHCC) on BCM of 262 sarcopenic tube fed patients (pts). METHODS: Two hundred sixty-two sarcopenic tube fed pts (130 males, mean age 68,1±15,6 years) were given daily supplemental WPHCC (0.7±0.2 g/kg body weight) after their usual feeding formula, with the aim to improve their BCM. Each patient received a multifrequency impedance test before and after the beginning of WPHCC supplementation (mean follow-up: 4.2±2.8 months). Fifty percent of patients were affected by neurodegenerative diseases, 36% by cancer, 14% by other conditions. RESULTS: BCM, body weight and fat mass significantly improved (P<0.01) after treatment. No severe side effects were recorded. A slight increase in blood urea was observed. CONCLUSION: In our population WPHCC have been safe and effective in improving BCM. WPHCC could be useful to improve BCM in sarcopenic tube fed pts, although renal function should be monitored.

Thioalbamide inhibits FoF1-ATPase in breast cancer cells and reduces tumor proliferation and invasiveness in breast cancer in vivo models.

OBJECTIVE: Thioalbamide is a ribosomally synthesized and post-translationally modified peptide (RiPP) belonging to the family of thioamitides, a rare class of microbial specialized metabolites with unusual post-translational modifications and promising biological activities. Recent studies have demonstrated the ability of thioalbamide to exert highly selective cytotoxic effects on tumor cells by affecting their energy metabolism, thus causing abnormal ROS production and triggering apoptosis. This study is aimed to investigate the molecular mechanisms underlying the antitumor activity of thioalbamide in order to identify its exact molecular target. METHODS: Wild type MCF-7 and MDA-MB-231 breast cancer cell lines as well as cancer cells deprived of mitochondrial DNA (ρ0 cells) were employed in order to assess thioalbamide effects on tumor bioenergetics. In this regard, metabolic profile was evaluated by a Seahorse XFe96 analyzer, and the activity of the enzyme complexes involved in oxidative phosphorylation was quantified by spectrophotometric assays. Thioalbamide effects on tumor invasiveness were assessed by gelatin zymography experiments and invasion assays. In vivo experiments were carried out on breast cancer xenograft and "experimental metastasis" mouse models. RESULTS: Experiments carried out on ρ0 breast cancer cells, together with Seahorse analysis and the application of spectrophotometric enzymatic assays, highlighted the ability of thioalbamide to affect the mitochondrial respiration process, and allowed to propose the FoF1-ATPase complex as its main molecular target in breast cancer cells. Additionally, thioalbamide-mediated OXPHOS inhibition was shown, for the first time, to reduce tumor invasiveness by inhibiting metalloproteinase-9 secretion. Furthermore, this study has confirmed the antitumor potential of thioalbamide in two different in vivo models. In particular, experiments on MCF-7 and MDA-MB-231 xenograft mouse models have confirmed in vivo its high anti-proliferative and pro-apoptotic activity, while experiments on MDA-MB-231 ″experimental metastasis" mouse models have highlighted its ability to inhibit breast cancer cell invasiveness. CONCLUSIONS: Overall, our results shed more light on the molecular mechanisms underlying the pharmacological potential of thioamidated peptides, thus reducing the gap that separates this rare class of microbial metabolites from clinical studies, which could validate them as effective tools for cancer treatment.

Involvement of transcribed lncRNA uc.291 and SWI/SNF complex in cutaneous squamous cell carcinoma.

While non-melanoma skin cancers (NMSCs) are the most common tumours in humans, only the sub-type cutaneous squamous cell carcinoma (cSCC), might become metastatic with high lethality. We have recently identified a regulatory pathway involving the lncRNA transcript uc.291 in controlling the expression of epidermal differentiation complex genes via the interaction with ACTL6A, a component of the chromatin remodelling complex SWI/SNF. Since transcribed ultra-conserved regions (T-UCRs) are expressed in normal tissues and are deregulated in tumorigenesis, here we hypothesize a potential role for dysregulation of this axis in cSCC, accounting for the de-differentiation process observed in aggressive poorly differentiated cutaneous carcinomas. We therefore analysed their expression patterns in human tumour biopsies at mRNA and protein levels. The results suggest that by altering chromatin accessibility of the epidermal differentiation complex genes, down-regulation of uc.291 and BRG1 expression contribute to the de-differentiation process seen in keratinocyte malignancy. This provides future direction for the identification of clinical biomarkers in cutaneous SCC. Analysis of publicly available data sets indicates that the above may also be a general feature for SCCs of different origins.

Energetic assessment of trunk postural modifications induced by a wearable audio-biofeedback system.

This paper investigates the trunk postural modifications induced by a wearable device which assesses the trunk sway and provides biofeedback information through sonification of trunk kinematics. The device is based on an inertial wearable sensing unit including three mono-axial accelerometers and three rate gyroscopes embedded and mounted orthogonally. The biofeedback device was tested on nine healthy subjects during quiet stance in different conditions of sensory limitation eyes closed on solid surface, eyes open on foam cushion surface, eyes closed on foam cushion surface. Five trials were performed for each condition; the order of the trials was randomized. The results reported in this paper show how subjects reduced their rotational kinetic energy by using the biofeedback information and how this reduction was related to the limitation of sensory information.

An ancient remedial repurposing: synthesis of new pinocembrin fatty acid acyl derivatives as potential antimicrobial/anti-inflammatory agents.

Five new pinocembrin derivatives (MC1-MC5) were synthesized by Steglich reaction, and investigated for their antimicrobial, antioxidant, and anti-inflammatory activity. MC2 (oleoyl derivative) and MC3 (linoleoyl derivative) have shown the highest inhibitory effects on bacterial proliferation, with MIC values of 32 µg/mL against Staphylococcus aureus. The docosahexaenoyl derivative MC5 displayed the highest anti-inflammatory activity, decreasing NO production in LPS-stimulated macrophages with an IC50 value of 15.51 µg/mL higher than the positive control diclofenac (IC50 of 39.71 µg/mL). All new synthesized compounds showed no anti-proliferative effects on RAW 264.7 cells. Results demonstrated as the introduction of fatty acid substituents improved the biological profile of pinocembrin. Moreover, the chemical nature of substituents significantly affects the bioactivity. These preliminary results outline the importance to investigate the synthesis of pinocembrin fatty acids derivatives as new and safe anti-microbial/anti-inflammatory agents.

Corrigendum to: Phosphonium Salt Displays Cytotoxic Effects Against Human Cancer Cell Lines.

Due to an oversight one of the author's name was published wrong in the article entitled "Phosphonium Salt Displays Cytotoxic Effects Against Human Cancer Cell Lines" in "Anti-Cancer Agents in Medicinal Chemistry, 2015, Vol. 17, No. 13. pp. 1796."The correct names of all authors are given below:Dhanyalayam D, Palma G, Cappello AR, Mariconda A, Sinicropi MS, Giordano F, Del Vecchio V, Ramunno A, Arra C, Longo P, Saturnino C.

Phosphonium Salt Displays Cytotoxic Effects Against Human Cancer Cell Lines.

Aims/Objective: Phosphonium salts are compounds whose structural characteristics enable them to cross the plasma and mitochondrial membrane with ease. Cancer cells have higher plasma membrane potentials than normal cells; phosphonium salts selectively accumulate in the mitochondria of neoplastic cells and inhibit mitochondrial function. METHOD: In the present work, we investigated the cytotoxic activity of lipophilic phosphonium salt (11- methoxy11-oxo-undecyl) triphenylphosphonium bromide (MUTP) as well as of the two new phosphine oxide salts, 3,3'-(methylphosphoryl) dibenzenaminium chloride (SBAMPO) and 3,3' (phenylphosphoryl) dibenzenaminium chloride (SBAPPO) on the proliferation of breast cancer cell line (MCF-7) and human uterin cervix adenocarcinoma cells (HeLa). RESULT: We showed that only MUTP exhibits antiproliferative effects on both cell lines, without affecting the normal breast epithelial cell proliferation. More specifically, we demonstrated that MUTP treatment of breast cancer cells is associated with impaired cell-cycle progression and metabolically induces mitochondrial damage and triggers apoptotic cell death in MCF-7 and HeLa cells. Taken together, these findings suggest that MUTP may be capable of selectively targeting neoplastic cell growth and therefore has potential applications as anticancer agent.

Human postural response to lower leg muscle vibration of different duration.

Body lean response to bilateral vibrations of soleus muscles were investigated in order to understand the influence of proprioceptive input from lower leg in human stance control. Proprioceptive stimulation was applied to 17 healthy subjects by two vibrators placed on the soleus muscles. Frequency and amplitude of vibration were 60 Hz and 1 mm, respectively. Vibration was applied after a 30 s of baseline. The vibration duration of 10, 20, 30 s respectively was used with following 30 s rest. Subjects stood on the force platform with eyes closed. Postural responses were characterized by center of pressure (CoP) displacements in the anterior-posterior (AP) direction. The CoP-AP shifts as well as their amplitudes and velocities were analyzed before, during and after vibration. Vibration of soleus muscles gradually increased backward body tilts. There was a clear dependence of the magnitude of final CoP shift on the duration of vibration. The amplitude and velocity of body sway increased during vibration and amplitude was significantly modulated by duration of vibration as well. Comparison of amplitude and velocity of body sway before and after vibration showed significant post-effects. Presented findings showed that somatosensory stimulation has a long-term, direction-specific influence on the control of postural orientation during stance. Further, the proprioceptive input altered by soleus muscles vibration showed significant changes in postural equilibrium during period of vibration with interesting post-effects also.

Device to measure intra-operatively the primary stability of cementless hip stems.

The primary stability of cementless prostheses is critical for the long-term outcome of the operation. Surgeons are currently driven only by their experience in evaluating the extent of stem stability achieved. The aim of the present work was to develop a new device that enables the stability of a cementless stem to be quantitatively assessed intraoperatively. The angle of the stem/femur rotation under torsion and the torque are acquired and compared in real-time to a pre-set threshold inferred from the literature. The device indicates whether the stem is stable or not. It was extensively tested and finally validated in vitro on cadaveric and composite femurs hosting different sizes of the same kind of prostheses, implanted with different levels of press-fitting. The overall accuracy (23%) takes into account not only the overall measurement error but also the variability due to differences in bone quality and stem press-fitting. This error was deemed sufficient to discriminate between stable and unstable implants.

Bergamot (Citrus bergamia Risso) Flavonoids and Their Potential Benefits in Human Hyperlipidemia and Atherosclerosis: an Overview.

Elevated serum cholesterol, triglycerides and LDL levels are often associated with an increased incidence of atherosclerosis and coronary artery disease. The most effective therapeutic strategy against these diseases is based on statins administration, nevertheless some patients, especially those with metabolic syndrome fail to achieve their recommended LDL targets with statin therapy, moreover, it may induce many serious side effects. Several scientific studies have highlighted a strong correlation between diets rich in flavonoids and cardiovascular risk reduction. In particular, Citrus bergamia Risso, also known as bergamot, has shown a significant degree of hypocholesterolemic and antioxidant/radical scavenging activities. In addition, this fruit has attracted considerable attention due to its peculiar flavonoid composition, since it contains some flavanones that can act as natural statins. Hence, the study of bergamot flavonoids as metabolic regulators offers a great opportunity for screening and discovery of new therapeutic agents. Cholesterol metabolism, flavonoid composition and potential therapeutic use of C. bergamia Risso will be discussed in the following review.

Optimal CT scanning plan for long-bone 3-D reconstruction.

Digital computed tomographic (CT) data are widely used in three-dimensional (3-D) reconstruction of bone geometry and density features for 3-D) modeling purposes. During in vivo CT data acquisition the number of scans must be limited in order to protect patients from the risks related to X-ray absorption. Aim of this work is to automatically define, given a finite number of CT slices, the scanning plan which returns the optimal 3-D) reconstruction of a bone segment from in vivo acquired CT images. An optimization algorithm based on a Discard-Insert-Exchange technique has been developed. In the proposed method the optimal scanning sequence is searched by minimizing the overall reconstruction error of a two-dimensional (2-D) prescanning image: an anterior-posterior (AP) X-ray projection of the bone segment. This approach has been validated in vitro on three different femurs. The 3-D reconstruction errors obtained through the optimization of the scanning plan on the 2-D) prescanning images and on the corresponding 3-D data sets have been compared. Two-dimensional and 3-D data sets have been reconstructed by linear interpolation along the longitudinal axis. Results show that direct 3-D optimization yields root mean square reconstruction errors which are only 4%-7% lower than the 2-D-optimized plan, thus proving that 2-D-optimization provides a good suboptimal scanning plan for 3-D reconstruction. Further on, 3-D reconstruction errors given by the optimized scanning plan and a standard radiological protocol for long bones have been compared. Results show that the optimized plan yields 20%-50% lower 3-D reconstruction errors.

A model-based method for the reconstruction of total knee replacement kinematics.

A better knowledge of the kinematics behavior of total knee replacement (TKR) during activity still remains a crucial issue to validate innovative prosthesis designs and different surgical strategies. Tools for more accurate measurement of in vivo kinematics of knee prosthesis components are therefore fundamental to improve the clinical outcome of knee replacement. In the present study, a novel model-based method for the estimation of the three-dimensional (3-D) position and orientation (pose) of both the femoral and tibial knee prosthesis components during activity is presented. The knowledge of the 3-D geometry of the components and a single plane projection view in a fluoroscopic image are sufficient to reconstruct the absolute and relative pose of the components in space. The technique is based on the best alignment of the component designs with the corresponding projection on the image plane. The image generation process is modeled and an iterative procedure localizes the spatial pose of the object by minimizing the Euclidean distance of the projection rays from the object surface. Computer simulation and static/dynamic in vitro tests using real knee prosthesis show that the accuracy with which relative orientation and position of the components can be estimated is better than 1.5 degrees and 1.5 mm, respectively. In vivo tests demonstrate that the method is well suited for kinematics analysis on TKR patients and that good quality images can be obtained with a carefully positioning of the fluoroscope and an appropriate dosage. With respect to previously adopted template matching techniques, the present method overcomes the complete segmentation of the components on the projected image and also features the simultaneous evaluation of all the six degrees of freedom (DOF) of the object. The expected small difference between successive poses in in vivo sequences strongly reduces the frequency of false poses and both the operator and computation time.

Global asymptotic stability of bone remodeling theories: a new approach based on non-linear dynamical systems analysis.

Mathematical tools for the analysis of nonlinear dynamical systems are applied to the study of stability of bone remodeling theories. As a practical application, the same problem studied by Harrigan and Hamilton (1992) and Cowin et al. (1994b) is analysed using these tools, and their findings on the necessary and sufficient conditions to ensure local asymptotic stability are easily confirmed. Using a general approach based on Lyapunov's method the same condition has been found to be necessary and sufficient also for the global asymptotic stability, thus confirming a result obtained by Harrigan and Hamilton (1994) by variational methods applied to finite-element models. The proof is based on the discretization of the spatial domain but the results for the continuum can be easily extrapolated.

Mechanical validation of whole bone composite femur models.

Composite synthetic models of the human femur have recently become commercially available as substitutes for cadaveric specimens. Their quick diffusion was justified by the advantages they offer as a substitute for real femurs. The present investigation concentrated on an extensive experimental validation of the mechanical behaviour of the whole bone composite model, compared to human fresh-frozen and dried-rehydrated specimens for different loading conditions. First, the viscoelastic behaviour of the models was investigated under simulated single leg stance loading, showing that the little time dependent phenomena observed tend to extinguish within a few minutes of the load application. The behaviour under axial loading was then studied by comparing the vertical displacement of the head as well as the axial strains, by application of a parametric descriptive model of the strain distribution. Finally, a four point bending test and a torsional test were performed to characterize the whole bone stiffness of the femur. In all these tests, the composite femurs were shown to fall well within the range for cadaveric specimens, with no significant differences being detected between the synthetic femurs and the two groups of cadaveric femurs. Moreover, the interfemur variability for the composite femurs was 20-200 times lower than that for the cadaveric specimens, thus allowing smaller differences to be characterized as significant using the same simple size, if the composite femurs are employed.

Skin movement artefact assessment and compensation in the estimation of knee-joint kinematics.

In three dimensional (3-D) human movement analysis using close-range photogrammetry, surface marker clusters deform and rigidly move relative to the underlying bone. This introduces an important artefact (skin movement artefact) which propagates to bone position and orientation and joint kinematics estimates. This occurs to the extent that those joint attitude components that undergo small variations result in totally unreliable values. This paper presents an experimental and analytical procedure, to be included in a subject-specific movement analysis protocol, which allows for the assessment of skin movement artefacts and, based on this knowledge, for their compensation. The effectiveness of this procedure was verified with reference to knee-joint kinematics and to the artefacts caused by the hip movements on markers located on the thigh surface. Quantitative validation was achieved through experimental paradigms whereby prior reliable information on the target joint kinematics was available. When position and orientation of bones were determined during the execution of a motor task, using a least-squares optimal estimator, but the rigid artefactual marker cluster movement was not dealt with, then knee joint translations and rotations were affected by root mean square errors (r.m.s.) up to 14 mm and 6 degrees, respectively. When the rigid artefactual movement was also compensated for, then r.m.s errors were reduced to less than 4 mm and 3 degrees, respectively. In addition, errors originally strongly correlated with hip rotations, after compensation, lost this correlation.

Effects of hip joint centre mislocation on gait analysis results.

Methods to determine the hip joint centre (HJC) location are necessary in gait analysis. It has been demonstrated that the methods proposed in the literature involve large mislocation errors. The choice should be made according to the extent by which HJC location errors distort the estimates of angles and resultant moments at the hip and knee joints. This study aimed at quantifying how mislocation errors propagate to these gait analysis results. Angles and moments at the hip and knee joint were calculated for five able-bodied subjects during level walking. The nominal position of the HJC was determined as the position of the pivot point of a 3D movement of the thigh relative to the pelvis. Angles and moments were then re-calculated after having added to HJC co-ordinates errors in the range of +/-30 mm. Angles and moments at both hip and knee joints were affected by HJC mislocation. The hip moments showed the largest propagation error: a 30 mm HJC anterior mislocation resulted in a propagated error into flexion/extension component of about -22%. The hip abduction/adduction moment was found the second largest affected quantity: a 30 mm lateral HJC mislocation produced a propagated error of about -15%. Finally, a 30 mm posterior HJC mislocation produced a delay of the flexion-to-extension timing in the order of 25% of the stride duration. HJC estimation methods with minimum antero-posterior error should therefore be preferred.

Comparison of algorithms for tracking short-term changes in arterial circulation parameters.

Three recursive methods especially suited for identification of systems with rapidly changing parameters are applied to tracking of the viscoelastic properties of the systemic arterial bed. These methods include two least squares (LS) algorithms with constant or variable forgetting factor (RLS and LSVF) and a LS algorithm incorporating both a constant forgetting factor and covariance modification (CFCM). The methods are presented in a unified framework and their sensitivity with respect to the design variables is investigated using noisy data from computer simulations. All analysed methods have shown themselves to be able to satisfactory track rapid changes in peripheral resistance. The LSVF method, which offers slightly better performances than the classical RLS, may be preferred when calculation efficiency is the prime requirement. The CFCM algorithm, although maintaining reasonable simplicity, shows the best tracking ability also on varying of the noise sequence.

Influence of flow pattern on the parameter estimates of a simple breathing mechanics model.

The first-order model of breathing mechanics is widely used in clinical practice to assess the viscoelastic properties of the respiratory system. Although simple, this model takes the predominant features of the pressure-flow relationship into account but gives highly systematic residuals between measured and model-predicted variables. To achieve a better fit of the entire data set, an approach hypothesizing deterministic time-variations of model parameters, summarized by information-weighted histograms was recently proposed by Bates and Lauzon. The present study uses flow and pressure data measured in intensive care patients to evaluate the real potential of this approach in clinical practice. Information-weighted histograms of the model parameters, estimated by an on-line identification algorithm, were first constructed by taking into account the parameter percentage standard deviations. Then, the influence of the respiratory flow pattern on the calculated histograms was evaluated by the Kolmogorov-Smirnov statistical test. The results show that the method gives good reproducibility under stable experimental conditions. In addition, for a given airflow waveform, an increase in respiratory frequency shifts the histograms representing time-varying viscous properties strongly versus lower values, whereas it shifts the histograms representing time-varying elastic properties slightly versus higher values. On the other hand, the same histograms were highly dependent on the airflow waveform, especially for the viscous properties. Even in a limited experimental work, in all the conditions considered, the method provides results which agree well with the physiological knowledge of nonlinear and multicompartment behavior of respiratory mechanics.

Two new algorithms for tracking arterial parameters in nonstationary noise conditions.

Two new algorithms with reduced sensitivity to the changing environment are applied to tracking arterial circulation parameters. They are variants of the Least-Squares (LS) algorithm with Variable Forgetting factor (LSVF), and of the Constant Forgetting factor-Covariance Modification (CFCM) LS algorithm, devised to overcome their main practical deficiencies related to noise level sensitivity and the high number of design variables, respectively. To this end, adaptive mechanisms are incorporated to estimate observation noise variance in LSVF and the rate of change for the different parameters in CFCM. Specific computer simulation experiments are presented to compare their effectiveness with the original counterparts and to provide guidelines for their optimal tuning at different noise levels. Moreover, algorithm performance degradation, consequent on changes in the noise level compared to that assumed during the tuning phase, is analyzed. In particular, it is shown that, when the noise level changes with respect to the tuning value, the new LSVF algorithm is much more robust than the original one, whose performance degrades rapidly. The new CFCM algorithm is characterized by a reduced number of design variables with respect to its original counterpart. Nevertheless, it can be preferred only when low noise signals are used for estimation.

Surface-marker cluster design criteria for 3-D bone movement reconstruction.

When three-dimensional (3-D) human or animal movement is recorded using a photogrammetric system, bone-embedded frame positions and orientations are estimated from reconstructed surface marker trajectories using either nonoptimal or optimal algorithms. The effectiveness of these mathematical procedures in accommodating for both photogrammetric errors and skin movement artifacts depends on the number of markers associated with a given bone as well as on the size and shape characteristics of the relevant cluster. One objective of this paper deals with the identification of marker-cluster design criteria aimed at the minimization of error propagation from marker coordinates to bone-embedded frame position and orientation. Findings allow for the quantitative estimation of these errors for any given cluster configuration and suggest the following main design criteria. A cluster made up of four markers represents a good practical compromise. Planar clusters are acceptable, provided in quasi-isotropic distribution. The root mean square distance of the markers from their centroid should be greater than ten times the standard deviation of the marker position error. The second objective of this paper deals with the identification of the optimal cluster position and orientation on the limb aimed at the minimization of error propagation to anatomical landmark laboratory coordinates. Cluster position should be selected to minimize skin movement artifacts. The longest principal axis of the marker distribution should be oriented toward the relevant anatomical landmark position.