Clinical and pathophysiological outcomes of the robotic-assisted Heller-Dor myotomy for achalasia: a single-center experience.

Laparoscopic Heller myotomy and Dor fundoplication is considered a safe and effective treatment for achalasia. Robotic-assisted Heller-Dor procedure (RAHD) has emerged as an alternative approach due to improved visualization and fine motor control. The aim of this prospective study was to evaluate clinical, and functional results of RAHD. We evaluated a group of 66 patients with achalasia that underwent robotic-assisted Heller-Dor operation. Before treatment all patients underwent a diagnostic work-up such as upper endoscopy, esophageal barium swallow and high resolution manometry. The presence of postoperative gastroesophageal reflux disease was diagnosed by impedance and pH monitoring (MII-pH). Dysphagia improved in 92.4% of patients after treatment. Barium swallow series showed esophageal emptying in 100% of patients and a significant reduction of the esophageal diameter (p = 0.00235). Forty-five of 66 patients (68.2%) underwent upper endoscopy and 35 of 66 (53%) underwent MII-pH. Esophageal erosions were found in 4/45 (8,8%) and MII-pH showed abnormal results in 3/35 patients (8.6%). RAHD ensures a meticulous esophageal and gastric myotomy, allowing to visualize and divide each muscle fibers with a low rate of intraoperative and postoperative complications. resulting in turn in good clinical outcomes, radiological findings and functional results even if robotic tecnique definitely increases the surgical cost in the treatment of these functional esophageal disorders.

Current and emerging avenues for Alzheimer's disease drug targets.

Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic, and so far, there is neither cure nor treatment to alter its progression. The most important feature of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described as amyloid beta (Aß) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD. Moreover, therapeutics using these targets can help AD brains to sustain function during the development of AD pathology. Here, we review broadly recent information for potential targets that can modify AD through diverse pharmacological and nonpharmacological approaches including gene therapy. We propose that AD could be tackled not only using combination therapies including Aß and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood-brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near-future strategy.

Comparison between videofluoroscopy, fiberoptic endoscopy and scintigraphy for diagnosis of oro-pharyngeal dysphagia.

The purpose of this study was to compare videofluoroscopy (VFS), fiberoptic endoscopic evaluation of swallowing (FEES) and oro-pharyngo- oesophageal scintigraphy (OPES) with regards to premature spillage, post-swallowing residue and aspiration to assess the reliability of these tests for detection of oro-pharyngeal dysphagia. Sixty patients affected with dysphagia of various origin were enrolled in the study and submitted to VFS, FEES and OPES using a liquid and semi-solid bolus. As a reference, we used VFS. Both the FEES and the OPES showed good sensitivity with high overall values (≥ 80% and ≥ 90% respectively). The comparison between FEES vs VFS concerning drop before swallowing showed good specificity (84.4% for semi-solids and 86.7% for liquids). In the case of post-swallowing residue, FEES vs VFS revealed good overall validity (75% for semi-solids) with specificity and sensitivity well balanced for the semi-solids. OPES vs. VFS demonstrated good sensitivity (88.6%) and overall validity (76.7%) for liquids. The analysis of FEES vs. VFS for aspiration showed that the overall validity was low (≤ 65%). On the other hand, OPES demonstrated appreciable overall validity (71.7%). VFS, FEES and OPES are capable of detecting oro-pharyngeal dysphagia. FEES gave significant results in the evaluation of post-swallowing residues.

How does radiotherapy impact swallowing function in nasopharynx and oropharynx cancer? Short-term results of a prospective study.

The objective of this study is to report the initial results of a prospective trial assessing instrumental deglutition function in nasopharynx and oropharynx cancers after radio or chemoradiotherapy using intensity-modulated radiotherapy (IMRT). IMRT was delivered aiming to spare the swallowing organ at risk (SWOARs) for Stage II-IV naso- and oropharynx cancer. Objective instrumental assessment included videofluoroscopy (VFS), fiberoptic endoscopic evaluation of swallowing (FEES) and oro-pharyngeal-oesophageal scintigraphy (OPES) at baseline and at 1 month after radiotherapy. Dysphagia parameter scores were calculated at each exam after liquid (L) and semi-liquid (SL) bolus intake: pre-deglutition penetration, aspiration, pharyngeal transit time (PTT) and hypopharyngeal retention index (HPRI). Overall, 20 patients (6 nasophaynx and 14 oropharynx) completed treatment and instrumental assessment after 1 month. Comparison between pre- and post-treatment HPRI score values showed a significant worsening in both FEES-L (p = 0.021) and SL (p = 0.02) and at VFS-L (p = 0.008) and SL (p = 0.005). Moreover, a relationship between HPRI worsening at FEES-L and FEES-SL (p = 0.005) as well as at VFS-L and VFS-SL (p < 0.001) was observed. PTT was not significantly affected by radiotherapy (p > 0.2). Only a few patients experienced pre-deglutition penetration (1 patient with base of tongue cancer at FEES-L and SL) and aspiration (1 patient with nasopharynx cancer at OPES-L and FEES-SL) after radiotherapy. Our early results showed that IMRT-SWOARs sparing caused a significant increase in the post-deglutition HPRI score. Longer follow-up will be necessary to evaluate if the increase of HPRI is related to a high risk of developing late aspiration.

Measurement of the velocity of neutrinos from the CNGS beam with the large volume detector.

We report the measurement of the time of flight of ∼17 GeV ν(µ) on the CNGS baseline (732 km) with the Large Volume Detector (LVD) at the Gran Sasso Laboratory. The CERN-SPS accelerator has been operated from May 10th to May 24th 2012, with a tightly bunched-beam structure to allow the velocity of neutrinos to be accurately measured on an event-by-event basis. LVD has detected 48 neutrino events, associated with the beam, with a high absolute time accuracy. These events allow us to establish the following limit on the difference between the neutrino speed and the light velocity: -3.8 × 10(-6) < (v(ν)-c)/c < 3.1 × 10(-6) (at 99% C.L.). This value is an order of magnitude lower than previous direct measurements.

Combined drug release from biodegradable bilayer coating for endovascular stents.

In this work, the characterization of a biodegradable bilayer system, used as controlled and combined drug delivery platform, is reported. For this aim, a bilayer system, composed of poly(lactic-co-glycolic acid) and poly(3-hydroxybutyric-co-3-hydroxyvaleric acid), was investigated under physicochemical and functional aspects by evaluating polymer/polymer and polymer/stent material interactions, the kinetic of in vitro degradation, and drug release properties, comparing results with the monolayer reference systems. Obtained results showed that the bilayer system allowed increasing the total amount of eluted Tacrolimus and Paclitaxel drugs with respect to the monolayer systems in the considered testing period and conditions. This evidence was associated to a faster degradation of the tested copolymers in the bilayered configuration, excluding a synergic effect of two drugs on delivery performance. In addition, a macromolecular relaxation process was identified to govern the PLX release from poly(lactic-co-glycolic acid), whereas a pure Fickian diffusion occurred in the delivery of Tacrolimus from poly(3-hydroxybutyric-co-3-hydroxyvaleric acid).

Randomized placebo-controlled trial on local applications of opioids after hemorrhoidectomy.

BACKGROUND: Hemorrhoidectomy is associated with considerable postoperative pain. This study assessed whether a small dose of morphine or oxycodone administered in the embedded sponge set in the anus at the end of a hemorrhoidectomy intervention reduced postoperative pain. METHODS: The presence of opioid receptors was assessed in the anal mucosa excised from ten patients with perianal condyloma acuminata and 19 patients with symptomatic third-fourth degree hemorrhoids. A double-blind prospective randomized placebo-controlled trial was then conducted in 135 patients with hemorrhoids. Hemorrhoidectomy patients were randomized to morphine (MG), oxycodone (OG), or control (CG) groups, each patient having an absorbable sponge dressing left in the anus embedded with 1 mg of morphine, 1 mg oxycodone, or vehicle, respectively. The mean time for the first dose of analgesic drugs, the use of analgesics, and the mean time to void bladder was evaluated. RESULTS: The presence of kappa- and delta-opioid receptor immunoreactivity was detected in the anal mucosa excised from patients with perianal condyloma acuminata and hemorrhoids. Furthermore, there was a significant (P < 0.001) upregulation of kappa receptor immunoreactive-like material in hemorrhoidectomy patients. The mean time for the first analgesic administration was significantly increased (P < 0.001) in MG versus CG. A further significant increase (P < 0.001) was observed in the OG patient group. The mean time for voiding was significantly higher in CG when compared to the MG and OG patient groups. CONCLUSION: The local administration of very low doses of kappa-opioid agonist decreased hemorrhoidectomy postoperative pain through the interaction with specific opioid receptors located on anal mucosa.

Benefit of statins in daily practice? A six-year retrospective observational study.

This observational retrospective study analysed the association of adherence to statins with the achievement of a target total cholesterol level (CL, <200mg/dl), and any association of adherence with the time to first hospital admission for coronary event in hypercholesterolemic patients treated with statins, in one Italian Local Health Authority between 1998 and 2003. The study population consisted of 3516 patients who were prescribed statins and for whom full cholesterol results were available. After three months of treatment, there were significant reductions in CL (p<0.001) in the three treatment groups stratified by adherence (good adherents -24%, poor adherents -22%, and nonadherents -14%). Patients more likely to achieve the target CL were older, male and more adherent to the statins. The risk of first hospitalization was associated positively with increased age and male gender. Patients with co-treatments were more likely to be hospitalized. Surprisingly, better adherence to statin treatment increased the risk of hospitalization.

Acrylic copolymers as candidates for drug-eluting coating of vascular stents.

The aim of the present work is the synthesis and characterization of polymer materials showing good adhesion, drug loading, and delivery properties, for potential cardiovascular application. In particular, poly(methylmethacrylate-co-acrylic acid) copolymers are prepared in different compositions by a radical polymerization and investigated as potential materials to coat metallic stents and to carry out a local drug release. Films obtained by dissolving the copolymer in an appropriate organic solvent (also loaded with an anti-restenosis drug, such as tacrolimus) are investigated: physicochemical properties, adhesiveness to metallic stent material, and kinetics of drug release in physiological environment are studied.

Weight excess of school materials and its risks factors in South Brazil. A cross sectional study.

AIM: There is little information about weight excess of school materials in Brazil. The aim of this study was to determine the prevalence and risk factors of excess weight of school materials in a private and a public school in the city of Pelotas, Brazil. METHODS: A cross-sectional study was performed to examine students' equipment in both a private and a public school. Demographic data were collected and children were weighed and measured. The types of schoolbag, notebook, snack, and other materials taken to school were identified and weighed separately from Monday to Friday. An excess weight of school material was defined for schoolbags weighing more than 10% of each student's weight. RESULTS: The study included 226 (48.8%) students from a private school and 237 (51.2%) students from a public school. From this sample, 38.2% of the total students carried an excess weight of school materials, 68.5% (155 children) of whom were private school students compared to 9.3% (22 children) of public school students, giving a prevalence ratio (PR) of 7.4 (CI95%, 4.9-11.1). After differentiating the sample in terms of school type, the association between weight excess of school material and school bag type (trolley pack), notebook type (hard back or spiral notebook) and transport of snacks were positively reported. CONCLUSION: Due to the higher income of the families of private school children, the type of school equipment carried was more costly and was the heaviest. These data should be considered in educational campaigns in order to reduce school equipment weight.

Synergism between fluoxetine and the mGlu2/3 receptor agonist, LY379268, in an in vitro model for antidepressant drug-induced neurogenesis.

We examined the interaction between the selective serotonin reuptake inhibitor, fluoxetine, and group-II metabotropic glutamate (mGlu) receptors using progenitor cells isolated from cultured cerebellar granule cells, considered as an in vitro model of antidepressant-drug induced neurogenesis. These cells expressed mGlu3 receptors negatively coupled to adenylyl cyclase. A 72-h treatment with either fluoxetine or low concentrations of mGlu2/3 receptor agonists (LY379268 or 2R,4R-APDC) enhanced cell proliferation. The action of fluoxetine was mediated by the activation of 5-HT(1A) receptors. We found a strong synergism between fluoxetine and LY379268 in enhancing cell proliferation and inhibiting cAMP formation. The increased cell proliferation induced by fluoxetine+LY379268 was abrogated by the cAMP analogue, 8-Br-cAMP, as well as by drugs that inhibit the mitogen-activated protein kinase and phosphatidyilinositol-3-kinase pathways. Interestingly, fluoxetine and LY379268 also acted synergistically in promoting neuronal differentiation when progenitor cells were incubated in the presence of serum. These data support the hypothesis that a combination between classical antidepressants and mGlu2/3 receptor agonists may be helpful in the experimental treatment of depression.

Degradable block polyurethanes from nontoxic building blocks as scaffold materials to support cell growth and proliferation.

Linear degradable polyurethanes were prepared and proposed for tissue engineering applications. Biocompatible segments were selected for the synthesis to promote their integration with the biological environment. Physicochemical and morphological characterization (SEC, DSC, DMTA, AFM) revealed that the properties of these polymeric systems can be easily tuned by varying the nature and the composition of the constituent segments. In vitro biological assays (citotoxicity, fibroblast adhesion, and proliferation) showed that all polymers are not toxic, promoting the adhesion and proliferation of fibroblast cells, with slight differences depending on the material hydrophilicity.

Design of an advanced temporary hip prosthesis for an effective recovery of septic mobilizations: a preliminary study.

The purpose of this study was the design and preliminary feasibility study of an advanced temporary hip prosthesis acting as an in-site drug dispensing system. An interactive device was designed to improve the recovery of bone infections compared to the mechanical spacers currently used in septic mobilizations. A commercial device was chosen and modified specifically for the purpose. First of all, the device was provided with a hydraulic multi-channel system connected via catheter to a subcutaneous valve, refillable with a drug aqueous solution from the outside. Moreover, since it allows samples of biological fluids for analyses to be drawn directly from the implantation site, this chemical dispensing system was designed to allow the course of infections to be monitored and customized therapies to be dosed. The insertion of biocompatible membranes inside the channel ends was considered essential to prevent their occlusion by fibrous tissue growth, thereby preserving the device functionality. Moreover, a biodegradable spongy ring was designed to be fixed onto the stem in distal position both to give primary stability to the implant and to act simultaneously as a scaffold for bonelike cell growth.

Resource consumption and costs of treating pain in patients affected by cancer in a district of northeast Italy.

WHO declared that pain is a relevant problem in public health and that opioids are the gold standard therapy for the treatment of moderate to severe pain. The present retrospective, epidemiological, observational study is aimed to evaluate resource consumption therapy in patients treated with opioids and died with a diagnosis of cancer in Treviso, a district in northeast Italy. For the monetisation of resource consumed, the Italian National Health Service perspective was adopted. For each patient, resource monetized were drugs (opioids, NSAIDs and adjuvants), hospitalizations with cancer diagnosis, diagnostic examinations and laboratory tests. All databases were linked in order to obtain patient profile of resource consumption. A total of 935 patients were included in the study. The incident opioid prescribed were for 60% morphine, 37% fentanyl, and 2.5% buprenorphine. The average length of treatment with opioids was 105+/-73 days. Of the patients included in the study, 79% received an anti-inflammatory drug (traditional NSAIDs and/or COX2 inhibitors), while 21% of patients treated with opioids never had an anti-inflammatory reimbursed prescription during the observation period. The average length of anti-inflammatory treatment was 133+/-83 days. For the vast majority of prescribed anti-inflammatory drugs, the received daily dose (RDD) was widely greater then the defined daily dose (DDD) before and during treatment with opioids, while for opioids the RDD was in line with the revised DDD for fentanyl, and less than the DDD for morphine and buprenorphine. The total daily cost per patient before the first prescription of opioids was euro 11.36 while after the first prescription of opioids, it increased to euro 21.12. This study confirms the under utilization of opioids in Italy both in terms of dosages and length of therapy.

New biomedical devices with selective peptide recognition properties. Part 1: Characterization and cytotoxicity of molecularly imprinted polymers.

Molecular imprinting is a technique for the synthesis of polymers capable to bind target molecules selectively. The imprinting of large proteins, such as cell adhesion proteins or cell receptors, opens the way to important and innovative biomedical applications. However, such molecules can incur into important conformational changes during the preparation of the imprinted polymer impairing the specificity of the recognition cavities. The "epitope approach" can overcome this limit by adopting, as template, a short peptide sequence representative of an accessible fragment of a larger protein. The resulting imprinted polymer can recognize both the template and the whole molecule thanks to the specific cavities for the epitope. In this work two molecularly imprinted polymer formulations (a macroporous monolith and nanospheres) were obtained using the protected peptide Z-Thr-Ala-Ala-OMe, as template, and Z-Thr-Ile-Leu-OMe, as analogue for the selectivity evaluation, methacrylic acid, as functional monomer, and trimethylolpropane trimethacrylate and pentaerythritol triacrylate (PETRA), as cross-linkers. Polymers were synthesized by precipitation polymerization and characterized by standard techniques. Polymerization and rebinding solutions were analyzed by high performance liquid chromatography. The highly cross-linked polymers retained about 70% of the total template amount, against (20% for the less cross-linked ones). The extracted template amount and the rebinding capacity decreased with the cross-linking degree, while the selectivity showed the opposite behaviour. The PETRA cross-linked polymers showed the best recognition (MIP 2-, alpha=1.71) and selectivity (MIP 2+, alpha'=5.58) capabilities. The cytotoxicity tests showed normal adhesion and proliferation of fibroblasts cultured in the medium that was put in contact with the imprinted polymers.

Poly(methyl methacrylate) membranes with controlled porosity for advanced multi-step drug elution.

Most of the systems developed for controlled drug delivery applications depend on membrane technology and their preparation parameters. For some applications, a dense membrane structure used in controlled-release systems can excessively prolong drug release due to the low permeability of the coating to the drug or to the low solubility of the drug in water. In these cases, to increase the drug delivery rate, asymmetric membranes can be prepared by a phase-inversion technique, allowing a different drug delivery approach with respect to dense membranes. In this study, porous poly(methyl methacrylate) membranes with different vacuum degrees were prepared through the phase-inversion process. Ternary homogeneous solutions, obtained by mixing polymer, tetrahydrofuran (THF) and water in the desired amounts, were precipitated by the evaporation of a solvent (THF) and a non-solvent (water) at a controlled temperature and ventilation. Membrane morphology, investigated by scanning electron microscopy, showed it to have a diffuse porosity with a regular arrangement and geometry of pores on the top surface. The porosity degree of the membranes, mainly relying on the starting polymer concentration, was also investigated by the use of the software Image-Pro Plus, indicating the presence of a relationship between porosity and permeability characteristics. Membranes, containing folic acid as a model drug, were tested for their transport characteristics and drug delivery both in diffusive and in convective- diffusive conditions. Transport and release parameters, as well as permeability and effective diffusivity, were found to be dependent on the porosity and vacuum degree, which could be controlled by varying the preparation conditions. Furthermore, these membranes showed high hydraulic permeability and rapid drug release, suggesting their use for applications where an intensive therapy in the first few days is required, followed by a constant and slow release for a longer time (two-step drug delivery).

Composite membranes modified with recognition-able nanobeads as potential adsorbers for purification of biological fluids.

Therapeutic approaches in the clinical field require advanced properties for delivery or recognition of clinical species. The molecular imprinting method allows selective cavities to be inserted into a polymeric material built ""around"" a stamp molecule (template) through polymerization or phase inversion. This study focuses on the application of both methods in the realization of polymeric membranes with selective recognition and adsorption properties. Imprinted polymethacrylic acid (PMAA) particles, exhibiting specific binding sites for cholesterol molecule (template), were realized via precipitation polymerization in the shape of nanobeads and loaded in the bulk or on the surface of methylmethacrylate-acrylic acid P(MMA-co-AA) membranes obtained by the non-solvent induced phase separation (NIPS) technique. In this way, specific cavities were introduced into the membrane network to enhance and specialize uptake performances of the porous membranes taking advantage of the particle characteristics. Rebinding performances towards cholesterol in a physiological environment were tested showing very interesting results: the adsorption of cholesterol molecules from physiological solution was increased by using composite membrane-nanobead systems instead of control membranes (a quantitative increase of 14 mg of cholesterol per g of polymer matrix in respect of blank membrane was detected). The results obtained showed an improved performance of composite membranes, but also an unmodified behavior of loaded nanobeads (with respect to free ones) concerning the recognition capability in aqueous medium, which is the most difficult obstacle to overcome in molecular imprinting. The absolute rebinding capacity and the imprinting efficiency of membranes were in the range (and in some case higher) of other efficient systems, but the real improvement was that molecularly imprinted embranes showed an excellent recognition capacity in physiological medium instead of organic solvents.

Transglutaminase reactivity with gelatine: perspective applications in tissue engineering.

Gelatine was crosslinked by means of an enzymatic treatment using tissue transglutaminase (tTGase) (Sigma) and microbial transglutaminase (mTGase) (Ajinomoto) which catalyses the formation of isopeptide bonds between the gamma-carbonyl group of a glutamine residue and the epsilon-amino group of a lysine residue. The reaction is an interesting alternative to the traditional glutaraldehyde crosslinking, which has several drawbacks (e.g., in medical application) due to the toxicity of the chemical reagent. To further investigate the possibility to utilize the modified protein for tissue engineering application, TGase crosslinked gelatine was incorporated in a gellan matrix, a polysaccharide, to enhance the stability in aqueous media. Films obtained by casting were characterized by thermal analysis, chemical imaging, swelling behaviour and cell adhesion.