The Efficacy of a Dietary Supplement with Carnosine and Hibiscus Sabdariffa L. (AqualiefTM) in Patients with Xerostomia: a Randomized, Placebo-Controlled, Double-Blind Trial.

The purpose of this study was to test the safety and efficacy of AqualiefTM in patients affected by xerostomia. The main ingredients of AqualiefTM are carnosine and dried calyces of Hibiscus sabdariffa L. (karkadè) for their buffering effect at pH 7 as well as for their antioxidant, antimicrobial and lenitive properties. In a Randomized, Placebo-Controlled, Double-Blind Trial, sixty patients with xerostomia (RTOG/EORTC grade 1-2) were randomly assigned to receive either placebo, or AqualiefTM tablets (three times/day after meals) for 6 consecutive days. A questionnaire was used to evaluate dry mouth symptoms before and after 6 days of AqualiefTM or placebo application. Unstimulated and stimulated salivary flow rates and pH were measured before and after application. Treatment with AqualiefTM for 6 days induced a significant increase in saliva pH from 6.2 ± 0.5 to 6.4 ± 0.6 (P < 0.05) while placebo was ineffective (from 6.2 ± 0.5 to 6.3 ± 0.5). AqualiefTM also induced a significant increase in the pH of stimulated saliva from 6.3 ± 0.5 to 6.6 ± 0.5 (P < 0.01). Placebo was ineffective also in this setting (from 6.2 ± 0.5 to 6.3 ± 0.5). Besides an expected normalization of the saliva pH value, AqualiefTM treatment for 6 days greatly increased (56%, P < 0.0001) saliva production. Placebo induced a 19% increase (P < 0.05), which was likely due to mechanical stimulation. AqualiefTM also increased stimulated saliva production (27% increase with respect to day 0, P < 0.05), while placebo was ineffective. AqualiefTM was effective in regulating the saliva pH, in increasing saliva production and improving dry mouth symptoms in xerostomic patients.

Fascicular nerve stimulation and recording using a novel double-aisle regenerative electrode.

OBJECTIVE: As artificial prostheses become more refined, they are most often used as a therapeutic option for hand amputation. By contrast to extra- or intraneural interfaces, regenerative nerve electrodes are designed to enable electrical interfaces with regrowing axonal bundles of injured nerves, aiming to achieve high selectivity for recording and stimulation. However, most of the developed designs pose an obstacle to the regrowth mechanisms due to low transparency and cause impairment to the nerve regeneration. APPROACH: Here we present the double-aisle electrode, a new type of highly transparent, non-obstructive regenerative electrode. Using a double-side thin-film polyimide planar multi-contact electrode, two nerve fascicles can regenerate without physical impairment through two electrically isolated aisles. MAIN RESULTS: We show that this electrode can be used to selectively record and stimulate fascicles, acutely as well as chronically, and allow regeneration in nerve gaps of several millimeters without impairment. SIGNIFICANCE: This multi-aisle regenerative electrode may be suitable for neuroprosthetic applications, such as prostheses, for the restoration of hand function after amputation or severe nerve injuries.

A three-dimensional self-opening intraneural peripheral interface (SELINE).

OBJECTIVE: In this study we present the development and testing in a rat model of the self-opening neural interface (SELINE), a novel flexible peripheral neural interface. APPROACH: This polyimide-based electrode has a three-dimensional structure that provides an anchorage system to the nerve and confers stability after implant. This geometry has been achieved by means of the plastic deformation of polyimide. Mechanical and electrochemical characterizations have been performed to prove the integrity of the electrode with very good results. Functionality of SELINEs for fascicular stimulation has been tested during in vivo acute experiments in the rat. Chronic implants were made to test the biocompatibility of the device. MAIN RESULTS: Results showed that SELINEs significantly improve mechanical anchorage to the nerve. Stimulation stability is considerably enhanced compared to common planar transversal electrodes and stimulation selectivity is increased for some motor fascicles. Chronic experimental results showed that SELINEs neither produce changes in the fascicular organization of sciatic nerves nor signs of nerve degeneration. SIGNIFICANCE: The presented three-dimensional electrode provides an effective anchorage system to the nervous tissue that can improve the stability of the implant for acute and chronic studies.

La curación de las heridas de gran superficie y la medicina regenerativa / Wound healing of large surface and regenerative medicine

La medicina regenerativa, con los conocimientos de la biología celular y molecular, llegó a las especialidades quirúrgicas y así a la atención del paciente. Se describen los fundamentos teóricos de un nuevo concepto de curación de las superficies cruentas. Se explica un nuevo procedimiento de curación de las heridas no infectadas a través del uso de un epitelio transitorio que al evitar la evaporación protege a las señales electromagnéticas de información entre célula y célula, así como la regeneración de un nuevo tejido mediante el uso de ADM. Se presentan cinco pacientes críticos, cuatro de ellos con indicación de amputación por la gravedad del traumatismo.

Regenerative medicine with knowledge of cell and molecular biology, reached the surgical specialities and thereby patient care. It describes the theoretical basis of a new concept of wound healing and a new procedure for healing of uninfected wounds through the use of a transitional epithelium to prevent evaporation that protects information of the electromagnetic signals between the cells, and regeneration of a new tissue using ADM. We present five critical patients, four of them with an indication of amputation due to the severity of the injury.

La curación de las heridas de gran superficie y la medicina regenerativa / Wound healing of large surface and regenerative medicine

La medicina regenerativa, con los conocimientos de la biología celular y molecular, llegó a las especialidades quirúrgicas y así a la atención del paciente. Se describen los fundamentos teóricos de un nuevo concepto de curación de las superficies cruentas. Se explica un nuevo procedimiento de curación de las heridas no infectadas a través del uso de un epitelio transitorio que al evitar la evaporación protege a las señales electromagnéticas de información entre célula y célula, así como la regeneración de un nuevo tejido mediante el uso de ADM. Se presentan cinco pacientes críticos, cuatro de ellos con indicación de amputación por la gravedad del traumatismo. (AU)

Regenerative medicine with knowledge of cell and molecular biology, reached the surgical specialities and thereby patient care. It describes the theoretical basis of a new concept of wound healing and a new procedure for healing of uninfected wounds through the use of a transitional epithelium to prevent evaporation that protects information of the electromagnetic signals between the cells, and regeneration of a new tissue using ADM. We present five critical patients, four of them with an indication of amputation due to the severity of the injury. (AU)

Preliminary results on the design of a tool for inserting of transverse intrafascicular multichannel electrodes (TIME) into the peripheral nervous system.

Transverse intrafascicular multichannel electrodes (TIMEs) are polyimide-based microelectrodes, which are potentially very interesting to restore sensorimotor functions in disabled people. By means of microstimulation of the nerve stump of an amputee, it can be possible to manipulate the phantom limb sensation, to provide sensory feedback to upper limb amputees, and to investigate methods of treatment of phantom limb pain. The current insertion procedure of TIMEs is completely done by hand. This makes the task difficult. This paper presents the preliminary results related to the development of a robotic tool to increase the accuracy in electrode placement and reduced size of the working area. The possibility to manage insertion parameters such as force, velocity, and positioning, could decrease the risk of damaging the nervous tissue, improving the coordination, and making placements repeatable. With the aim of solving the issues avbove, we developed a first prototype of a 4DoF multi-axis device. Additional strategies concerning system components and control are discussed. We performed characterization of implantation mechanics to derive mechanical design specifications for the robotic device. Force caracterization of the pig peripheral nerve during penetration of the needle at three velocities (1, 30, 40mm/sec) was executed. Results shown inverse relationship between maximal force and velocities values. The force values extracted varied between 0.081-0.174 N.

Activities on PNS neural interfaces for the control of hand prostheses.

The development of interfaces linking the human nervous system with artificial devices is an important area of research. Several groups are working on the development of devices able to restore sensory-motor function in subjects affected by neurological disorders, injuries or amputations. Neural electrodes implanted in peripheral nervous system, and in particular intrafascicular electrodes, seem to be a promising approach for the control of hand prosthesis thanks to the possibility to selectively access motor and sensory fibers for decoding motor commands and delivering sensory feedback. In this paper, activities on the use of PNS interfaces for the control of hand prosthesis are presented. In particular, the design and feasibility study of a self-opening neural interface is presented together with the decoding of ENG signals in one amputee to control a dexterous hand prosthesis.

Outstanding survival and regeneration process by the use of intelligent acellular dermal matrices and mesenchymal stem cells in a burn pig model.

A pig model with a deep large burn was used to study the regeneration process induced by mesenchymal stem cells (MSCs) and acellular pig dermal matrices, made intelligent by the combination with biodegradable nanofibers loaded with growth factors (granulocyte-macrophage colony-stimulating factor and epidermal growth factor) and coated with the anti-CD44 monoclonal antibody (intelligent acellular dermal matrices, IADMs). These IADMs are specially designed to integrate in the wound bed as new biological scaffolds as well as to specifically recruit and attach circulating and/or externally applied MSCs through the anti-CD44 antibody while delivering precise amounts of growth factors. In this way, the reparative process as well as the aesthetic and functional results were enhanced in our burn model. The animal survived, the wound was completely closed, and total regeneration of the skin was obtained without much scarring. Surprisingly, hair follicles and other skin appendages developed despite the severity and deepness of the burn. Even burned muscles and ribs seemed to have undergone a regenerative process by the end of the study. Based on these findings, we have proposed the use of IADMs and autologous, allogeneic or xenogeneic MSCs, as a new paradigm for the future treatment of large burns and probably other dermatological and cosmetic human conditions.

Preliminary investigations on laminin coatings for flexible polyimide/platinum thin films for PNS applications.

The aim of this work was to investigate the possibility to obtain stable bioactive coatings for polyimide/platinum neural interfaces based on thin film technology for applications into the peripheral nervous system (PNS). Laminin (LI), a glycoprotein of the extracellular matrix, which guides and promotes differentiation and growth of neurons, was selected to deposit bioactive coatings. Dip-coating was performed on dummy structures at different LI concentrations. Indirect methods allowed to identify and characterize laminin on coated samples. Mechanical stability was also confirmed by indirect evaluations. Pilot experiments with differentiated PC12 cells, by the addition of nerve growth factor (NGF), showed improved neurite outgrowth on the coated probes compared to bare polyimide samples.

The next generation of burns treatment: intelligent films and matrix, controlled enzymatic debridement, and adult stem cells.

We describe a novel technology based on nanoengineered multifunctional acellular biologic scaffolds combined with wound dressings and films of the same kind. This method allows selective delivery and release of shielded biomaterials and bioactive substances to a desired wound or damaged tissue while stimulating the selective anchoring and adhesion of endogenous circulating repairing cells, such as mesenchymal stem cells, to obtain a faster and more physiologic healing process. We also present a new controlled enzymatic debridement process for more effective burned tissue scarolysis. In light of our preliminary in vitro and in vivo data, we are convinced that these approaches can include the use of other kinds of adult stem cells, such as endometrial regenerative cells, to improve the vascularization of the constructs, with great potential in the entire tissue and organ regeneration field but especially for the treatment of severely burned patients, changing the way these lesions may be treated in the future.

Matrix superhighways configurations: new concepts for complex organ regeneration.

New ideas and experimental models for tissue and organ regeneration are urgently needed. There are several exciting challenges in the field of organogenesis that need to be defined. The integrated signals and molecular repertoires that shape the particular architecture of specific organs like the kidney or the liver are not completely understood yet. To develop a new scientific platform to be able to build up complex organs we have established a research program using basically Acellular Xenogeneic Isomorphic Matrices (AXIMs) and mesenchymal stem cells (MSCs) generating the necessary concepts for the definition, production, and application of the specific configurations of these matrices for organ regeneration. New and interesting pathways for MSC differentiation were identified. We believe that all extracellular matrices were created fundamentally equal or at least very similar in nature. We also believe that there are true "matrix superhighway configurations" with different three-dimensional geometrical architectures as well as biochemical, electrical, and molecular properties that are tissue and organ specific that influence cell differentiation and organogenesis and will be fundamental for the in vitro regeneration of complex organs for transplantation.

Bloodstream cells phenotypically identical to human mesenchymal bone marrow stem cells circulate in large amounts under the influence of acute large skin damage: new evidence for their use in regenerative medicine.

OBJECTIVES: Recent work has shown that human bone marrow contains mesenchymal stem cells (MSCs). However, little is known about their presence in peripheral blood. Since these cells are potentially responsible for tissue repair after injury, their number should be increased during these situations. To demonstrate their number during these situations, we measured MSCs in the peripheral blood of healthy donors and burn patients. MATERIALS AND METHODS: Blood samples were obtained from 15 acute burn patients and 15 healthy donors. We performed flow cytometric analysis, using a large monoclonal antibody panel: CD44, CD45, CD14, DR, CD34, CD19, CD13, CD29, CD105, CD1a, CD90, CD38, CD25. MSC phenotype was considered positive for CD44, CD13, CD29, CD90, and CD105, and negative for the other monoclonals. The testing was performed on day 3 after injury. We correlated the results with the age, sex, and size and type of burns. RESULTS: Cells expressing the MSC phenotype were detected in the peripheral blood of both groups. Noteworthy, compared with samples from healthy donors (0.0078 +/- 0.0044), blood obtained from burn patients showed a higher MSC percentage (0.1643 +/- 0.115; P < .001). The percentage of MSCs correlated with the size and severity of the burn. Increased values were also observed among younger patients. CONCLUSIONS: MSCs have an important role in regenerative processes of human tissues. We found cells phenotypically identical to MSCs circulating in physiological number in normal subjects, but in significantly higher amounts during acute large burns. Therefore, they may represent a previously unrecognized circulatory component to the process of skin regeneration.

Experiments on the development and use of a new generation of intra-neural electrodes to control robotic devices.

The development of interfaces linking the human nervous system with artificial devices is an important area of research and several groups are now addressing it. Interfaces represent the key enabling technology for the development of devices usable for the restoration of motor and sensory function in subjects affected by neurological disorders, injuries or amputations. For example, current hand prostheses use electromyographic (EMG) signals to extract volitional commands but this limits the possibility of controlling several degrees of freedom and of delivering sensory feedback. To achieve these goals, implantable neural interfaces are required. Among the candidate interfaces with the peripheral nervous system intra-neural electrodes seem to be an interesting solution due to their bandwidth and ability to access volition and deliver sensory feedback. However, several drawbacks have to be addressed in order to increase their usability. In this paper, experiments to address many of these issues are presented as part of the development of a new generation of intra-neural electrodes. The results showed seem to confirm that these new interfaces seem to have interesting properties and that they can represent a significant improvement of the state of the art. Extensive experiments will be carried out in the future to validate these results.

Human mesenchymal stem cells are tolerized by mice and improve skin and spinal cord injuries.

INTRODUCTION: We sought to use human mesenchymal stem cells (HMSC) for skin and spinal cord repair in mice. MATERIALS AND METHODS: Human bone marrow obtained from a young healthy donor was used to separate and culture human mesenchymal stem cells (HMSC). Ten mice were included in each of four groups. A full-thickness skin defect was surgically performed on all mice in groups 1 and 2. A transverse complete medullar section was performed in groups 3 and 4. Groups 1 and 3 received HMSC IV infusion and local HMSC polymer implant. Groups 2 and 4 received only the IV HMSC infusion. Five control animals from each group went through the same lesions but they didn't receive treatment. RESULTS: After local administration of HMSC into the fibrin polymer combined with the IV infusion of HMSC, there was no immune rejection; all skin defects healed without scar or retraction at a median time of 14 days. Sixty percent of the animals treated with IV infusion and polymer with HMSC simultaneously had improved neurological activities, while all control mice with spinal cord injury experiments died or perpetuated their paralysis with worsening muscular atrophy and increasing propensity to skin damage. CONCLUSIONS: HMSC are not immunologically reactive and can trespass species defense barriers. Animals treated with these cells repaired injuries better than controls. In this way we propose that universal HMSC from donors can be cultured, expanded, and cryopreserved to be used in human organ or tissue regeneration.

Striatal degeneration induced by mitochondrial blockade is prevented by biologically delivered NGF.

Consistent with the notion that a defect in cellular energy metabolism is a cause of human neurodegenerative disease, systemic treatment with the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NPA) can model the striatal neurodegeneration seen in Huntington's disease. Previously, we have found that nerve growth factor (NGF), delivered biologically by the implantation of a genetically altered fibroblast cell-line, can protect locally against striatal degeneration induced by infusions of high doses of glutamate receptor agonists. We now report that implantation of NGF-secreting fibroblasts reduces the size of adjacent striatal 3-NPA lesions by an average of 64%. We conclude that biologically delivered NGF protects neurons against excitotoxicity and mitochondrial blockade--both energy-depleting processes--implying that appropriate neurotrophic support in the adult brain could protect against neurodegenerative diseases caused in part by energy depletion.

Age dependence of striatal neuronal death caused by mitochondrial dysfunction.

Several lines of evidence point to a decline in mitochondrial efficiency with age. The relationship between age and sensitivity to Huntington disease-like neuronal death in the striatum induced by the mitochondrial inhibitor 3-nitropropionic acid (3-NP) was examined. 3-NP has been shown to cause degeneration of striatum, hippocampus, and thalamus in rat and of caudate-putamen in humans. We administered single doses of 3-NP intraperitoneally to rats of various ages. Animals older than 4 months exhibited a far greater susceptibility to striatal neurotoxicity and mortality compared with younger animals. These results are discussed in the context of age-dependent metabolic impairment, which may be a key factor in the etiology of neurodegenerative disorders such as Huntington's disease and Alzheimer's disease.

[Comparison of HbA1c, fructosamine and the main metabolic parameters in a non-insulin-dependent diabetic population]. / Confronto tra HbA1c, fruttosamina e principali parametri metabolici in una popolazione di diabetici N.I.D.

Our objective was the checking of clinical data obtainable from the assay of some parameters in NID diabetic individuals. To this end, we studied 133 patients--57 males and 76 females, average age 74.36 +/- 1.01 years, 72.6% of which were above 65 years of age. The control population was subdivided as follows: 50 subjects, 26 F and 24 M; average age 71.25 +/- 1.32 years, with normal glucidic tolerance as assessed by OGTT. Current glycemia, average glycemia, fructosamine, glycosylated hemoglobin, triglycerides, LDL-cholesterol and apolipoprotein B were obviously much higher than normal in the individuals admitted to the study. A statistically significant correlation was found between average glycemia, glycosylated hemoglobin, LDL-cholesterol and blood triglycerides (p less than 0.05). No correlation was found between current glycemia, fructosamine and glycosylated hemoglobin. Similarly, serum fructosamine was unrelated to the parameters studied. In our study, fructosamine, glycosylated hemoglobin and current glycemia offered unrelatable data. Hence, in our opinion it is necessary to assay these three parameters contemporaneously for a reliable assessment of metabolic compensation.