Clinical utility of the solid meal test during high-resolution esophageal manometry. A study in a Latin American population.

INTRODUCTION AND AIMS: The solid test meal (STM) is a challenge test that is done during esophageal manometry and appears to increase the diagnostic yield of the study. The aim of our analysis was to establish the normal values for STM and evaluate its clinical utility in a group of Latin American patients with esophageal disorders versus healthy controls. MATERIAL AND METHODS: A cross-sectional study was conducted on a group of healthy controls and consecutive patients that underwent high-resolution esophageal manometry, in which STM was done at the final part of the study and consisted of asking the subjects to eat 200 g of precooked rice. The results were compared during the conventional protocol and the STM. RESULTS: Twenty-five controls and 93 patients were evaluated. The majority of the controls (92%) completed the test in under 8 min. The STM changed the manometric diagnosis in 38% of the cases. The STM diagnosed 21% more major motor disorders than the conventional protocol; it doubled the cases of esophageal spasm and quadrupled the cases of jackhammer esophagus, whereas it demonstrated normal esophageal peristalsis in 43% of the cases with a previous diagnosis of ineffective esophageal motility. CONCLUSIONS: Our study confirms the fact that complementary STM during esophageal manometry adds information and enables a more physiologic assessment of esophageal motor function to be made, compared with liquid swallows, in patients with esophageal motor disorders.

3D printed porous PEEK created via fused filament fabrication for osteoconductive orthopaedic surfaces.

Due to its unique and advantageous material properties, polyetheretherketone (PEEK) is an attractive biomaterial for implantable devices. Though concerns exist regarding PEEK for orthopaedic implants due to its bioinertness, the creation of porous networks has shown promising results for interaction with surrounding tissue. In this study, we created porous PEEK via clinically-available fused filament fabrication (FFF, 3D printing) and assessed the pore structure morphology, mechanical properties, and biologic response. The designs of the porous structures were based on a simple rectilinear pattern as well as triply periodic minimal surfaces (TPMS), specifically gyroid and diamond types. The material characteristics, including porosity, yield strength, and roughness, were evaluated using µCT, static compression testing, and optical profilometry. The porous PEEK, along with 3D printed solid PEEK, was then seeded with MC3T3-E1 preosteoblast cells for evaluation of cell proliferation and alkaline phosphatase (ALP) activity. The samples were then imaged via scanning electron microscopy (SEM) to observe cell morphology. µCT imaging showed the porous networks to be open and interconnected, with porous sizes similar (p > 0.05) to the as-designed size of 600 µm. Average compressive properties ranged from 210 to 268 MPa for elastic modulus and 6.6-17.1 MPa for yield strength, with strength being greatest for TPMS constructs. SEM imaging revealed cells attaching to and bridging micro-topological features of the porous constructs, and cell activity was significantly greater for the porous PEEK compared to solid at multiple time points.

Aggrecan-like biomimetic proteoglycans (BPGs) composed of natural chondroitin sulfate bristles grafted onto a poly(acrylic acid) core for molecular engineering of the extracellular matrix.

Biomimetic proteoglycans (BPGs) were designed to mimic the three-dimensional (3D) bottlebrush architecture of natural extracellular matrix (ECM) proteoglycans, such as aggrecan. BPGs were synthesized by grafting native chondroitin sulfate bristles onto a synthetic poly(acrylic acid) core to form BPGs at a molecular weight of approximately ∼1.6 MDa. The aggrecan mimics were characterized chemically, physically, and structurally, confirming the 3D bottlebrush architecture as well as a level of water uptake, which is greater than that of the natural proteoglycan, aggrecan. Aggrecan mimics were cytocompatible at physiological concentrations. Fluorescently labeled BPGs were injected into the nucleus pulposus of the intervertebral disc ex vivo and were retained in tissue before and after static loading and equilibrium conditioning. BPGs infiltrated the tissue, distributed and integrated with the ECM on a molecular scale, in the absence of a bolus, thus demonstrating a new molecular approach to tissue repair: molecular matrix engineering. Molecular matrix engineering may compliment or offer an acellular alternative to current regenerative medicine strategies. STATEMENT OF SIGNIFICANCE: Aggrecan is a natural biomolecule that is essential for connective tissue hydration and mechanics. Aggrecan is composed of negatively charged chondroitin sulfate bristles attached to a protein core in a bottlebrush configuration. With age and degeneration, enzymatic degradation of aggrecan outpaces cellular synthesis resulting in a loss of this important molecule. We demonstrate a novel biomimetic molecule composed of natural chondroitin sulfate bristles grafted onto an enzymatically-resistant synthetic core. Our molecule mimics a 3D architecture and charge density of the natural aggrecan, can be delivered via a simple injection and is retained in tissue after equilibrium conditioning and loading. This novel material can serve as a platform for molecular repair, drug delivery and tissue engineering in regenerative medicine approaches.

Evaluation of friction properties of hydrogels based on a biphasic cartilage model.

Characterizing hydrogels using a biphasic cartilage model, which can predict their behavior based on structural properties, such as permeability and aggregate modulus, may be useful for comparing active lubrication modes of cartilage and hydrogels for the design of articular cartilage implants. The effects of interstitial fluid pressurization, inherent matrix viscoelasticity and tension-compression nonlinearity on mechanical properties of the biphasic material were evaluated by linear biphasic (KLM), biphasic poroviscoelastic (BPVE) and linear biphasic with anisotropy cartilage models, respectively. The BPVE model yielded the lowest root mean square error and highest coefficient of determination when predicting confined and unconfined compression stress-relaxation response of hydrogels (n=15): 0.220±0.316MPa and 0.93±0.08; and 0.017±0.008MPa and 0.98±0.01 respectively. Since the differences in error between models were not statistically significant, the simplest model we considered, KLM model, was sufficient to predict the mechanical response of this family of hydrogels. The coefficient of friction (COF) of a hydrogel-ceramic articulation was measured at varying loads and pressures to explore the full range of lubrication behavior of hydrogel. Material parameters obtained by biphasic models correlated with COF. Based on the linear biphasic model, COF correlated positively with aggregate modulus (spearman's rho=0.5; p<0.001) and velocity (rho=0.3; p<0.001), and negatively with permeability (rho=-0.3; p<0.001) and load (rho=-0.6; p<0.001). Negative correlation of COF with load and positive correlation with velocity indicated that hydrogel-ceramic articulation was separated by a fluid film. These results together suggested that interstitial fluid pressurization was dominant in the viscoelasticity and lubrication properties of this biphasic material.

Terminal-end functionalization of chondroitin sulfate for the synthesis of biomimetic proteoglycans.

Chondroitin sulfate (CS) based bottle brush proteoglycan mimetics may be employed to restore tissue functionality. Synthesis of CS bottle brush structures requires immobilization of CS at its terminal end. In this study, we investigated commercially available natural CS for use in CS bottle brush synthesis. A terminal primary amine on CS was identified and utilized to conjugate amine-reactive vinyl monomers (i.e. acrylic acid and allyl glycidyl ether). Conjugation of vinyl monomers to the CS terminal amine was confirmed using a fluorescamine assay, (1)H NMR, and ATR-FTIR. CS was also immobilized onto epoxy functionalized surfaces via the CS terminal primary amine as confirmed by contact angle measurements of surface wettability. Attachment of polymeriziable end groups to CS and attachment of CS to functionalized substrates demonstrated here are the first steps towards synthesis of CS bottle brush PG mimics.

Large-scale survey of naturally occurring HBV polymerase mutations associated with anti-HBV drug resistance in untreated patients with chronic hepatitis B.

Drug resistance is a major limitation for the long-term efficacy of antiviral therapy with nucleos(t)ide analogues (NAs) in chronic hepatitis B (CHB). Antiviral resistance mutations may pre-exist in the overall viral population of untreated patients. We aimed to assess the prevalence of such hepatitis B virus (HBV) variants in a large cohort of NAs-naïve patients with CHB and to explore possible association with viral and host variables. Serum samples from 286 NAs-naïve consecutive patients with CHB were tested for serum HBV-DNA, and 255 of them having HBV-DNA > 1000 IU/mL were further analysed for drug resistance mutations by INNO-LiPA HBV DRv2/v3. NAs-naïve patients analysed were mainly men (73%), Caucasians (85%), hepatitis B e Antigen (HBeAg) negative (79%) and genotype D (69%), with a mean age of 43.2 ± 13.4 years. HBV mutations associated with antiviral drug resistance were detected in 13 (5%) patients: three patients infected with HBV genotype C had the rtM204V + rtL180M mutations associated with lamivudine (LMV) resistance. Four patients had the rtI233V mutation that may reduce sensitivity to adefovir, and three patients had the rtM250L/V mutation typical of entecavir resistance. LMV compensatory mutations rtL80V and rtV173L were seen in two and one patients, respectively. No relationship was seen between presence of resistant or compensatory mutations and HBV-DNA levels, HBeAg/anti-HBe status or previous IFN therapy. These results confirm that HBV mutations, which confer resistance against currently available anti-HBV NAs, may already exist in patients who have never received the drug.

Hyperinsulinaemia reduces the 24-h virological response to PEG-interferon therapy in patients with chronic hepatitis C and insulin resistance.

Insulin resistance (IR) reduces response to pegylated-interferon (PEG-IFN)/ribavirin in chronic hepatitis C (CHC), but the mechanisms are still undefined. We examined the relationship between baseline insulin levels, the main component affecting homeostasis model of assessment - insulin resistance (HOMA-IR) for assessment of IR in non-diabetic patients, and the 'acute' virological response to PEG-IFN measured 24 h after the first injection and taken as correlate of intracellular interferon signalling. In 62 patients treated with PEG-IFN/Ribavirin, serum insulin and HOMA-IR were assessed at baseline, while hepatitis C virus (HCV)-RNA was measured at baseline and 24 h, 1, 2, 4 and 12 weeks after treatment initiation. Sustained virological response was examined 24 weeks after therapy discontinuation. Mean baseline insulin was 11.52 +/- 8.51 U/L and mean HOMA-IR was 2.65 +/- 2.01 both being significantly higher with advanced liver fibrosis. Hepatitis C virus-RNA decay observed 24 h after the first injection of PEG-IFN was significantly lower (0.7 +/- 0.8 log) in patients with HOMA > or =3 compared with those with HOMA <3 (1.7 +/- 0.8, P = 0.001). A highly significant (r = -0.42) inverse correlation was observed between baseline insulin levels and the 24-h HCV-RNA decay. The difference in early viral kinetics between patients with HOMA > or =3 or <3 resulted in a significant difference in the percentage of patients achieving rapid (week 4) and sustained virological response. Multivariate analysis, inclusive of patient age, HCV genotype and fibrosis stage, identified baseline insulin levels as the main independent variable affecting the 24-h response to PEG-IFN. Hyperinsulinaemia reduces the cellular response to Pegylated-interferon in CHC with IR. Strategies to reduce insulin levels before initiation of treatment should be pursued to improve efficacy of anti-viral treatment.

Prevalence, clinical spectrum and atypical symptoms of gastro-oesophageal reflux in Argentina: a nationwide population-based study.

BACKGROUND: Population-based data on gastro-oesophageal reflux in Latin America are lacking. AIM: To assess gastro-oesophageal reflux symptom prevalence, clinical spectrum and association with the atypical symptoms in our country. METHODS: Gastro-oesophageal reflux self-report questionnaires validated at Mayo Clinic, USA, were submitted to a sample of 1000 residents (aged 18-80 years) from 17 representative geographical areas of Argentina. The samples were selected and stratified according to age, gender, geographical areas and size of town of residence provided by the Argentine Bureau of Statistics and Census. RESULTS: The overall prevalence of any typical gastro-oesophageal reflux symptom experienced in the previous year was 61.2% (95% CI, 57.9-64.6), the prevalence of frequent gastro-oesophageal reflux symptoms was 23.0% (95% CI, 20.1-25.9) and the prevalence of gastro-oesophageal reflux disease was 11.9% (95% CI, 9.6-14.1). Frequent gastro-oesophageal reflux symptoms were associated with dysphagia (OR 2.12, 95% CI, 1.27-3.54, P < 0.01), globus (OR 2.22, 95% CI, 1.35-3.66, P < 0.01) and non-cardiac chest pain (OR 1.55, 95% CI, 1.04-2.31, P < 0.05). CONCLUSIONS: In Argentina, typical symptoms of gastro-oesophageal reflux are highly prevalent at the national level, and frequent gastro-oesophageal reflux symptoms are significantly associated with dysphagia, globus and non-cardiac chest pain.

Comparison of defibrillation thresholds using monodirectional electrical vector versus bidirectional electrical vector.

BACKGROUND: Currently, two main lead configurations are used for implantable cardioverter-defibrillators (ICD). One generates a monodirectional electrical vector by using the can surface as an active part (hot can) together with a right ventricular defibrillation coil. The other one (TRIAD) produces a bidirectional electrical vector by adding a proximal defibrillation electrode on the same lead. The purpose of this prospective study was to determine whether there is a difference between these configurations in terms of the acute defibrillation threshold (DFT). The secondary objective was to evaluate the possible sequential effect of successive arrhythmia induction and defibrillation shocks on the final DFT value. METHODS: In 44 patients (37 males, 7 females, mean age 59.18 +/- 12.05 years; mean ejection fraction 35.21 +/- 11.69%), a Hot Can Ventak family ICD (Guidant, St. Paul, MN, USA) was implanted in a left pectoral pocket. During the implant procedure, step-down to failure DFT testing was performed twice in each patient using the two different above-mentioned configurations: the bidirectional and the monodirectional. The first configuration to be tested was determined by a 1:1 randomization by center. RESULTS: The step-down DFT protocol was followed in 35 patients. The average DFT was 8.6 +/- 4.0 J for TRIAD and 10.4 +/- 4.3 J for the monodirectional (p = 0.009) lead configuration; this represents a 16.3% decrease in the DFT using a bidirectional configuration. Furthermore, no relationship between the final DFT and the number of ventricular fibrillation inductions and shocks received was observed, confirming the secondary objective. CONCLUSIONS: Compared to the monodirectional electrical vector, the bidirectional electrical vector is clearly more beneficial for the patient.

Bioactive glass fiber/polymeric composites bond to bone tissue.

Bioactive glass fibers were investigated for use as a fixation vehicle between a low modulus, polymeric composite and bone tissue. In an initial pilot study, bioactive glass fiber/polysulfone composites and all-polysulfone control rods were implanted into the rabbit tibia; the study was subsequently expanded with implantation into the rabbit femur. Bone tissue exhibited direct contact with the glass fibers and adjacent polymer matrix and displayed a mechanical bond between the composite and bone tissue after six weeks implantation. Interfacial bond strengths after six weeks implantation averaged 12.4 MPa, significantly higher than those of the all-polymer controls. Failure sites for the composite at six weeks generally occurred in the bone tissue or composite, whereas the failure site for the polymer implants occurred exclusively at the implant/tissue interface. The bioactive glass fiber/polysulfone composite achieved fixation to bone tissue through a triple mechanism: a bond to the bioactive glass fiber, mechanical interlocking between the tissue and glass fibers, and close apposition and possible chemical bond between the portions of the polymer and bone tissue. This last mechanism resulted from an overspill of bioactivity reactions from the fibers onto the surface of the surrounding polymer which we call the "halo" effect.

Surface reaction layer formation in vitro on a bioactive glass fiber/polymeric composite.

In order to provide a fixation vehicle between a polymeric composite femoral hip prosthesis and bone tissue, we fabricated bioactive glass fibers. The glass fibers had a tensile strength of 596 MPa, 14 times that of bulk bioactive glass. After immersion in protein-free simulated body fluid for 10 days, we observed the development of a calcium phosphate layer (specifically, partially crystallized, calcium-deficient carbonated hydroxyapatite) on the surface of the glass fibers. The stages of the surface reaction layer formation were similar to those of 45S5 bioactive glass although the kinetics of the reaction layer formation were slower. We combined the bioactive glass fibers with a polymeric matrix to form a fiber-reinforced composite material and observed the formation of a calcium phosphate layer on the surface of the glass fibers within the composite material after immersion in both protein-free and protein-containing simulated body fluids. The rate of reaction layer formation was reduced in the presence of proteins. In both protein-free and protein-containing solutions, a "halo" of bioactivity reactions was observed on the surface of the polymer in regions surrounding the glass fibers. Our results suggest these glass fibers and glass fiber composites will exhibit bioactivity reactions in vivo.

[Effects of simvastatin on plasma levels of lipids, lipoproteins and apolipoproteins in primary hypercholesterolemia]. / Effetti del simvastatin sui livelli plasmatici dei lipidi, delle lipoproteine e delle apolipoproteine nell'ipercolesterolemia primitiva.

To evaluate the effectiveness, tolerance and safety of simvastatin (MK 733), a new HMG-CoA reductase inhibitor, a 28-week, single blind study with placebo was carried out on 10 patients suffering from primary hypercholesterolaemia. All patients followed the AHA Phase 1 or Phase 2 diet and underwent active treatment for 24 weeks with increasing doses of simvastatin from 10 to 40 mg in a single evening administration. A reduction in plasma levels of total cholesterol (-29%, p less than 0.001 and -41%, p less than 0.001), LDL cholesterol (-35%, p less than 0.001 and -49%, p less than 0.001), VLDL cholesterol (-9%, ns and -38%, ns), Apo-B (-27%, p less than 0.005 and -37%, p less than 0.001), Apo-A2 (-3%, ns and -3%, ns), and triglycerides (+2%, ns and -10%, ns), was obtained in the VIth and XXIVth week. There was also an increase in HDL cholesterol (+4%, ns and +17%, p less than 0.05), HDL2 subfractions (+9%, p less than 0.05 and +36%, p less than 0.05), HDL3 (+3%, ns and +11%, ns) and Apo-A1 (+7%, ns and +4%, ns). In all patients, simvastatin was generally tolerated and there were no clinical, laboratory or ophthalmological side-effects related to the drug. If long-term studies confirm its safety, simvastatin will offer excellent prospects for the prevention of ischaemic cardiopathy.

[Bicameral stimulation in a case of corrected transposition of the great vessels]. / Stimolazione bicamerale in un caso di trasposizione corretta dei grossi vasi.

A patient with Corrected Transposition of the Great Arteries (CTGA), mild incompetence of left A-V valve, complete atrioventricular block without associated anatomic lesions, in whom a bicameral permanent pace maker has been implanted, is described. The procedure of implantation did not present any particular problem; the stability of the electrocatheters was good. The exercise tolerance with DDD mode stimulation was normal and definitively better as compared to that achieved with ventricular stimulation at progressively higher stimulation frequency. The patient is now well and attending a normal physical activity.