Fretting-corrosion of CoCr-alloys against TiAl6V4: The importance of molybdenum in oxidative biological environments.

Periprosthetic fluids often contain reactive oxygen species, including H2O2, that are generated during inflammatory processes. Here, we investigated the fretting-corrosion behavior of CoCrX-alloys (X = Mo, Fe) in a complex protein-containing lubricant, with and without the addition of H2O2. Given the known protective role of molybdenum as an alloying element in metal degradation, we considered its effects by designing a two-way factorial experiment. The aim of the study was to investigate tribocorrosive mechanisms in modular joints of knee and hip prostheses. A previously described test-rig was used to run fretting corrosion tests of CoCrX-alloys with (X=Mo) and without (X=Fe) molybdenum against TiAl6V4 in bovine calf serum (BCS) with and without a physiological relevant H2O2 level (3 mM) in gross slip mode (4 Hz, ±50 µm, pmax=0.18 GPa, 37 °C, 50,000 cycles). Two CoCr-pins were pressed against a cylindrical TiAl6V4-rod, forming a line contact. Normal and frictional forces, the displacement, and the open circuit potential (OCP) were measured and recorded continuously. The dissipated frictional work was independent of alloy composition. The addition of H2O2 lowered the dissipated frictional work and increased wear, and this was significant in the absence of Mo. The mean OCP value was lower with Mo-containing than with Mo-free alloy in both pure BCS (p = .042), and BCS ± H2O2 (p < .0005). The wear scar was deeper for the Mo-free alloy, and this was significant (p = .013) in the presence of H2O2. These findings suggest a marked weakening of the passive film in the presence of H2O2, which is mitigated by the availability of Mo.

The predictive value of ABCB1, ABCG2, CYP3A4/5 and CYP2D6 polymorphisms for risperidone and aripiprazole plasma concentrations and the occurrence of adverse drug reactions.

We investigated in ninety Caucasian pediatric patients the impact of the main polymorphisms occurring in CYP3A, CYP2D6, ABCB1 and ABCG2 genes on second-generation antipsychotics plasma concentrations, and their association with the occurrence of adverse drug reactions. Patients with the CA/AA ABCG2 genotype had a statistically significant lower risperidone plasma concentration/dose ratio (Ct/ds) (P-value: 0.007) and an higher estimated marginal probability of developing metabolism and nutrition disorders as compared to the ABCG2 c.421 non-CA/AA genotypes (P-value: 0.008). Multivariate analysis revealed that the ABCG2 c.421 CA/AA genotype was found associated to a higher hazard (P-value: 0.004) of developing adverse drug reactions classified as metabolism and nutrition disorders. The ABCB1 2677TT/3435TT genotype had a statistically significant lower aripiprazole Ct/ds if compared with patients with others ABCB1 genotypes (P-value: 0.026). Information obtained on ABCB1 and ABCG2 gene variants may result useful to tailor treatments with these drugs in Caucasian pediatric patients.

The role of Toll-like receptor 4 polymorphisms in vaccine immune response.

Toll-like receptors (TLRs) are a class of pattern recognition receptors that are deputed to recognise a range of molecular structures in pathogens. One of the most studied members of this family is the TLR4, which is essential for the signalling of lipopolysaccharide. The gene encoding for TLR4 is highly polymorphic and this genetic variability may explain in part the interindividual variability observed in several clinical setting, including the response to vaccination. Herein, we review and systematise the available scientific evidence about the effect of TLR4 polymorphisms on vaccine response, including approved prophylactic, new therapeutic cancer vaccines and recently approved vaccine adjuvants. Data reviewed in this analysis indicate that TLR4 polymorphisms significantly affect vaccine response. If these results are confirmed by further analyses, the use of these genetic biomarkers may become a useful tool to tailor vaccination in specific subsets of patients.

A case of dysgraphia induced by sertraline and a review of official spontaneous adverse reaction databases.

WHAT IS KNOWN AND OBJECTIVES: The occurrence of dysgraphia after sertraline intake has never been reported. The objective was to describe a case of this adverse drug reaction and present a review of similar cases held in international databases with a discussion of the possible pharmacological mechanisms. CASE SUMMARY: We observed a 60-year-old man who experienced resting tremors, dyskinesia and dysgraphia 2 months after a stepwise increase in sertraline dosing from 50 to 200 mg/day. WHAT IS NEW AND CONCLUSION: Dysgraphia is a possible adverse drug reaction to sertraline, and we suggest that inhibition of extrapyramidal dopaminergic activity might be the pharmacological mechanism.

The first steps towards the era of personalised vaccinology: predicting adverse reactions.

Until now, the occurrence of adverse reactions among individuals inoculated with identical vaccines has been ascribed to unpredictable stochastic processes. Recent advances in pharmacogenomics indicate that some features of host response to immunisation are influenced by genetic traits, henceforth predictable. The ability to predict the adverse reaction to vaccination would represent an important step towards the development of personalised vaccinology and could enhance public confidence in the safety of vaccines. Herein, we have reviewed all the available information on the association between genetic variants and the risk for healthy subjects to develop adverse reactions.

Throbbing headache associated with enoxaparin administration: a case report, a review of pharmacovigilance databases for similar cases and possible mechanisms.

WHAT IS KNOWN AND OBJECTIVES: To date, no case of headache has been reported with enoxaparin. We present the case of a 60-years-old man, who developed enoxaparin-induced throbbing headache and discuss the possible pharmacological mechanisms. We provide an analysis of enoxaparin-induced headache in three international databases. CASE SUMMARY: A few hours after the subcutaneous administration of this drug at therapeutic dose, the patient experienced throbbing headache. Rechallenge on two other separate occasions separated by several days produced the same effect although with reduced intensity when the dose was lowered. The Naranjo Algorithm indicated a 'certain' relationship. WHAT IS NEW AND CONCLUSION: We report a case of throbbing headache associated with the use of enoxaparin; with the increasing use of enoxaparin, physicians who prescribe this drug should be aware of this potential ADR. We suggest that it is a heparin class-effect, and therefore, a more general caution is also appropriate.

Epidemiological analysis on two decades of hospitalisations for meningitis in the United States.

Bacterial meningitis is an important source of mortality and morbidity worldwide. Data exist on specific vaccines against Streptococcus pneumoniae and Neisseria meningitidis indicating that they reduce the incidence of meningitis, yet comprehensive information on the trend of bacterial meningitis is still lacking. We analysed the Kids' Inpatient Database and the National Inpatient Database considering all bacterial meningitides in the United States, excluding cases of tuberculosis and sexually transmitted diseases. We analysed the trend of meningitis incidence from 1993 to 2011 and in specific age groups before and after the introduction of the pneumococcal conjugate vaccine 7 (PCV-7) and the meningococcal conjugate vaccine 4 (MCV-4). Moreover, we analysed the prevalence of aetiological agents to assess their changes. We estimated 295,706 cases of meningitis having occurred in the United States and a reduction of the discharge rate of 21 %. We observed a significant reduction in cases of meningitis in children and elderly patients following the introduction of the PCV-7. We also found a reduction in subjects aged 10-14 years, an age span consistent with the introduction of MCV-4, although further analyses based on serotypes data are required to confirm this observation. By contrast, we observed an increased prevalence of cases of staphylococcal and streptococcal meningitides. The introduction of PCV-7 has reduced the incidence and changed significantly the aetiology of bacterial meningitis in the United States during the last two decades.

Pharyngeal spasticity due to dantrolene.

WHAT IS KNOWN AND OBJECTIVE: Dantrolene can be combined with baclofen to better treat spasticity, but may cause muscular weakness and dysphagia. We instead describe a pharyngeal spasm due to dantrolene. CASE SUMMARY: A 12-year-old male received dantrolene 3 mg/kg/day in adjunct to baclofen 2 mg/kg/day, to improve spasticity. After 5 days of full-dose dantrolene, his dysphagia worsened and he developed pharyngeal spasm. Dantrolene was suspected for an adverse reaction and removed. The patient subsequently improved. WHAT IS NEW AND CONCLUSION: Causality analysis determined a probable relationship between dantrolene and pharyngeal spasm. This may be due to direct muscle contraction by dantrolene, an effect seen previously in vitro.

Neurological and psychiatric adverse events with prucalopride: case report and possible mechanisms.

WHAT IS KNOWN AND OBJECTIVE: Chronic constipation is very frequent in the general population. Although usually considered banal, this disorder has considerable personal, social and healthcare impact. Several studies have shown that the psychological impact exceeds that caused by rheumatoid arthritis or haemodialysis. Recently, prucalopride, a highly selective 5-HT4 receptor agonist has been shown to improve the symptoms of chronic constipation and to have a beneficial effect on social and healthcare impact. The drug was approved by the European Medicine Agency, in 2009 at a dose of 2 mg/day, 'for symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief'. Neurological side effects or psychiatric disorders have not been reported previously with prucalopride. We present the case of a 61-year-old woman, who developed such adverse effects when given prucalopride for the treatment for chronic constipation. CASE SUMMARY: A few hours after oral administration of this drug at therapeutic dose (2 mg/day), the patient experienced life-threatening neurological effects that included visual hallucination, loss of balance and memory, disorientation, exhaustion and suicidal ideation. Analysis with the Naranjo algorithm indicated a 'possible' relationship between prucalopride and these disorders. WHAT IS NEW AND CONCLUSION: This is the first report of prucalopride-induced neurological side effects and psychiatric disorders with prucalopride. The absence of other similar reports suggests that prucalopride rarely causes these adverse effects.

A case of urinary incontinence by hydroxychloroquine in a geriatric patient.

WHAT IS KNOWN AND OBJECTIVE: Rheumatoid arthritis is an autoimmune disorder characterized by persistent synovitis and systemic inflammation. Genetic factors account for approximately 50% of cases of rheumatoid arthritis and environmental factors include smoking. Urinary incontinence may occur as a medication adverse effect. We present the first report of a case of hydroxychloroquine-induced urinary incontinence in rheumatoid arthritis. DETAILS OF THE CASE: A 71-year-old female with a history of rheumatoid arthritis developed urinary incontinence as an adverse drug reaction to hydroxychloroquine administered at therapeutic doses. Urinary incontinence remitted with drug withdrawal and reappeared on rechallenge. The Naranjo's algorithm indicated that hydroxychloroquine was a probable cause of this adverse drug reaction. The likely mechanism of this adverse drug is a direct action of the quinolone on the urinary system. WHAT IS NEW AND CONCLUSION: This is the first report of hydroxychloroquine-induced urinary incontinence. The absence of previous reports suggest that the drug rarely causes this adverse effect. Methotrexate is most often used as first-line treatment, and several other drugs are now available to act as Disease-Modifying Antirheumatic Drugs (DMARDs). These drugs may be used alone or combined with methotrexate, most often to increase efficacy and reduce toxicity. The introduction of new biological agents, such as abatacept, rituximab, tocilizumab and inhibitors of tumour necrosis factor, has opened new therapeutic perspectives but are restricted by high costs and risk of infections. Thus, antimalarial drugs, especially the quinolones chloroquine (CQ) and hydroxychloroquine (HCQ), are still in use, and the latter is very efficacious. An advantage of HCQ is its low toxicity compared with other antimalarial drugs. Common side-effects of HCQ and the other antimalarial drugs include gastrointestinal effects such as nausea and vomiting, as well as skin rashes and headache, whereas their most common and severe side-effect is retinopathy. No case of urinopathy has been reported previously with HCQ.

Impact of age on postsurgical outcomes of nonfunctioning pituitary adenomas.

PURPOSE: The management of pituitary adenomas in the elderly has become a relevant clinical issue, in relationship with improved life expectancy and spreading use of imaging techniques. In this single-center and retrospective study, we investigated the impact of age on peri- and postsurgical outcomes in patients undergoing transnasal sphenoidal (TNS) surgery for pituitary adenomas. METHODS: One-hundred-sixty-nine patients (62% males) undergoing endoscopic transphenoidal (TNS) surgery for nonfunctioning pituitary adenomas (NFPAs) were enrolled. Patients were subdivided into three groups according to age tertiles: ≤56 (group 1), 57-69 (group 2), and ≥70 (group 3) years. Postsurgical and endocrinological outcomes were evaluated and compared among the three age groups. RESULTS: 37/169 patients (21.9%) developed at least one perisurgical complication, without significant association with the patients' age (P = 0.838), Charlson co-morbidity score (P = 0.326), and American Society of Anesthesiologist score (P = 0.616). In the multivariate regression analysis, the adenoma size resulted the only determinant of perisurgical complication (odds ratio [OR] 1.07, 95% confidence interval [C.I.] 1.00-1.13; P = 0.044). The development and the recovery of at least one pituitary hormone deficiency were observed in 12.2% and 14.2% of patients, respectively. The risk of developing new pituitary hormone deficiencies was correlated with cavernous sinus invasion as evaluated by magnetic resonance imaging (hazard ratio [HR] 4.19, 95% C.I. 1.39-12.66; P = 0.010), whereas the probability to normalize at least one pituitary hormone deficiency was significantly correlated with younger age of patients (HR 0.27, 95% CI 0.12-0.61; P = 0.002). CONCLUSIONS: The results of this study reinforce the concept that endoscopic TNS surgery is a safe therapeutic option in the elderly patients with NFPA, even in presence of comorbidities and high anesthetic risk.

Anomalous electrical conduction and negative temperature coefficient of resistance in nanostructured gold resistive switching films.

We report the observation of non-metallic electrical conduction, resistive switching, and a negative temperature coefficient of resistance in nanostructured gold films above the electrical percolation and in strong-coupling regime, from room down to cryogenic temperatures (24 K). Nanostructured continuous gold films are assembled by supersonic cluster beam deposition of Au aggregates formed in the gas phase. The structure of the cluster-assembled films is characterized by an extremely high density of randomly oriented crystalline nanodomains, separated by grain boundaries and with a large number of lattice defects. Our data indicates that space charge limited conduction and Coulomb blockade are at the origin of the anomalous electrical behavior. The high density of extended defects and grain boundaries causes the localization of conduction electrons over the entire investigated temperature range.

In-vitro studies on cells and tissues in tribocorrosion processes: A systematic scoping review.

Tribocorrosion of implants has been widely addressed in the orthopedic and dental research fields. This study is a systematic scoping review about research methods that combine tribocorrosion tests with cells/tissues cultures, aimed to identify related current problems and future challenges. We used 4 different databases to identify 1022 records responding to an articulated keywords search-strategy. After removing the duplicates and the articles that didn't meet the search-criteria, we assessed 20 full-text articles for eligibility. Of the 20 eligible articles, we charted 8 records on cell cultures combined with tribocorrosion tests on implant materials (titanium, CoCrMo, and/or stainless steel). The year of publication ranged from 1991 to 2019. The cell line used was mostly murine. Two records used fretting tests, while 6 used reciprocating sliding with pin-on-disc tribometers. An electrochemical three-electrode setup was used in 4 records. We identified overall two experimental approaches: cells cultured on the metal (5 records), and cells cultured near the metal (3 records). Research activities on tribocorrosion processes in the presence of cells have been undertaken worldwide by a few groups. After a limited initial interest on this topic in the 1990's, research activities have restarted in the last decade, renewing the topic with technologically more advanced setups and analytical tools. We identified the main problems to be the lack of test reproducibility and wear particle characterization. We believe that the main challenges lay in the interdisciplinary approach, the inter-laboratory validation of experiments, and the interpretation of results, particularly in relation to potential clinical significance.

The effect of hyaluronic acid on the corrosion of an orthopedic CoCrMo-alloy in simulated inflammatory conditions.

During joint inflammation, various reactive oxygen species (ROS) are present in the surrounding tissue and joint fluid. In the laboratory, hydrogen peroxide (H2O2) is typically used to simulate inflammatory conditions, and media containing proteins and hyaluronic acid (HA) are employed to simulate joint synovial fluid. Electrochemical interactions between H2O2 and HA in the presence of a CoCrMo surface are expected, since HA molecules contain redox-active moieties. We hypothesized that any redox reactions of these moieties with ROS will mitigate the oxidizing effect of H2O2 on the CoCrMo surface, limiting the corrosion rate of the metal. Non-destructive electrochemical measurements (open circuit potential, linear polarization resistance and electrochemical impedance spectroscopy) were used to investigate the corrosion response of CoCrMo in synovial model fluid containing physiologically relevant concentrations of albumin proteins and hyaluronic acid, with and without H2O2. Two different molarities of H2O2, 3 mM and 30 mM, were tested. While both molarities are within physiological limits, 3mM is well within the range HA could mitigate, whereas 30 mM is not. Contrary to our hypothesis, HA did not alleviate corrosion in 3 mM H2O2 and even caused a corrosion increase in the case of 30 mM H2O2. The decrease in corrosion resistance of the alloy may be attributed to the complexation of degenerated HA molecular chains with chromium ions released from the metallic surface, which are necessary to build a protective oxide film. This finding has clinical implications, suggesting that HA accelerates corrosion of CoCrMo implants in the presence of strong inflammation.

Effects of bovine serum albumin and hyaluronic acid on the electrochemical response of a CoCrMo alloy to cathodic and anodic excursions.

The problem of wear and corrosion of CoCrMo-implant surfaces in the human body following total joint replacement has been commonly investigated with tribocorrosion tests, using different lubricants meant to simulate the pseudo-synovial fluid. While results considering the synovial fluid components separately have highlighted their individual influence on the tribological performance of CoCrMo-alloy, an understanding about the influence of the synovial fluid components under the electrochemical point of view is missing. This work aims to investigate the effect of bovine serum albumin (BSA) and hyaluronic acid (HA) on electrochemical potential variations of CoCrMo alloys tested in a model synovial fluid. To simulate the environment inside the synovial capsule, the tests were performed inside a CO2 incubator at 37°C. Open circuit potential, electrochemical impedance spectroscopy, cathodic and anodic potentiodynamic measurements were performed with different electrolytes, prepared with cell culture medium (RMPI-1640), BSA and HA. The final CoCrMo-surface was analyzed by SEM/EDS and infrared spectroscopy. The influence of HA on the corrosion of the CoCrMo-alloy depended on the presence of BSA proteins adsorbed on the CoCrMo-surface: EIS and anodic polarization results showed a corrosive action of HA in the absence of adsorbed proteins. In the presence of both BSA and HA, organometallic precipitates were found on the CoCrMo surface following reverse anodic polarization, which remind of corrosion products found in-vivo. These results indicate that HA affects the interaction of CoCrMo implant alloys with protein-containing model synovial fluids, and suggest that HA needs to be considered in tribocorrosion studies for more clinically relevant outcomes.

Investigation of CoCrMo material loss in a novel bio-tribometer designed to study direct cell reaction to wear and corrosion products.

Wear and corrosion in total hip replacement negatively impact implant service-life and patient well-being. The aim of this study was to generate a statistical response surface of material loss using an apparatus, capable of testing the effect of wear and corrosion products in situ on cells, such as macrophages. The test chamber of a ball-on-flat tribometer operating inside a CO2 incubator was integrated with an electrochemical setup and adapted for cell culture work. A 20-test series, following a 2-level 3-factor design of experiments, was performed with a ceramic head in reciprocating rotational motion against a CoCrMo-alloy disc, under constant load. The lubricant was cell culture medium (RPMI-1640+10vol% bovine serum). Response surfaces were generated, which statistically showed the influence of motion amplitude, load, and potential on the total mass loss and wear scar volume of the metallic discs. Potential had the highest impact on the total mass loss, while motion amplitude and load significantly influenced the wear scar volume. The concentrations of the alloy elements found in the lubricants reflected the bulk-alloy stoichiometry. The total concentration of Co released into the lubricant (2.3-63 ppm by total mass loss, 1.5 to 62 ppm by ICP-MS) corresponded well with the known range to trigger cell response. Tribocorrosion tests in the presence of cells and tissues, such as macrophages, lymphocytes and/or synovium, will be carried out in the future.

Methods for functionalization of microsized polystyrene beads with titania nanoparticles for cathodic electrophoretic deposition.

Functionalization of colloidal particles based on the use of polyelectrolytes and heterocoagulation was combined with electrophoretic deposition (EPD), with the aim of depositing titania-polystyrene (TiO(2)-PS) composite particles on Ti6Al4V substrates. The composite particles were obtained by heterocoagulation of TiO(2) nanoparticles on the surface of monosized polystyrene beads of 4.6 microm in diameter. Two alternative methods were developed for the preparation of the TiO(2)-PS suspensions in organic fluids for cathodic electrodeposition. The first method was carried out in alkaline aqueous medium with the use of polyelectrolytes and intermediate control measurements of zeta potential, conductivity, and pH; the second one was carried out directly in the organic solvent used for EPD, typically isopropanol. Examples of deposits obtained by EPD in both suspensions and a comparative analysis between the two methods are presented.

Electrophoretic deposition of zirconia-Bioglass composite coatings for biomedical implants.

Composite bilayer coatings on Ti6Al4V substrates were prepared by electrophoretic deposition, a simple and fast low temperature coating technique. Biocompatible yttrium-stabilized zirconia (YSZ) in the form of nanoparticles and bioactive Bioglass (45S5) in the form of microparticles were chosen as coating materials. The first layer consisted of 5 microm of YSZ, deposited with the intention to avoid any metal tissue contact. The second layer consisted of 15-microm thick 45S5-YSZ composite, supposed to react with the surrounding bone tissue and to enhance implant fixation. The adsorption of YSZ nanoparticles on 45S5 microparticles in organic suspension was found to invert the surface charge of the 45S5 particles from negative to positive. This enabled cathodic electrophoretic deposition of 45S5, avoiding uncontrolled anodization (oxidation) of the substrate. The coatings were sintered at 900 degrees C for 2 h under argon flow. The characterization was performed using SEM, EDX, and nanoindentation (cross section). Potential applications in the orthopedics field are discussed.

A family with an unusual myotonic and myopathic phenotype and no CTG expansion (proximal myotonic myopathy syndrome): a challenge for future molecular studies.

Myotonic dystrophy (DM) is a well-defined autosomal dominant disorder characterized by myotonia, muscle weakness, cardiac conduction defects, cataracts, and endocrine abnormalities. Recently a newly recognized disorder, similar to but distinct from DM, has been observed with multisystem findings including intermittent myotonia, proximal myopathy, and occasional cardiac conduction disturbances. This disorder has been called proximal myotonic myopathy (PROMM). No history of anticipation is present and there is no linkage to the gene locus for DM or to the loci for the muscle sodium or chloride channels. This report describes a family with a normal size of the CTG trinucleotide repeat expansion of the DM gene in which affected individuals have myotonia (intermittent, exacerbated by cold), bilateral cataracts, mild hypogonadism and mild temporal atrophy. Affected individuals also have proximal muscle weakness, facial involvement, nonspecific abnormalities on muscle biopsy, normal cardiac conduction, and no glucose intolerance. The absence of trinucleotide repeat expansion in the DM gene is consistent with this family being affected by a disorder distinct from DM, possibly a form of PROMM.

Hyperbaric oxygen increases plasma exudation in rat trachea: involvement of nitric oxide.

This study investigates the microvascular permeability changes in tracheal tissue of rats exposed to hyperbaric oxygen (HBO). Rats, following exposure to HBO or ambient air (control animals) for 1.5, 3 and 6 h, were prepared for recording of nitric oxide exhaled (FENO) in air using a chemiluminescence analyser. The level of FENO was not statistically different in the two groups. Plasma exudation, evaluated by measuring the leakage of Evans blue (EB) dye into the tracheal tissue, was significantly elevated (48, 86 and 105% at 1.5, 3 and 6 h, respectively) in HBO-treated rats. Plasma exudation in the trachea of control rats was significantly increased (42%, P<0.05) by NG-nitro-L-arginine methyl ester (L-NAME), whereas it was significantly reduced (31%, P<0.05) in rats exposed to HBO for 3 h. N-acetylcysteine (NAC) and flunisolide significantly prevented the increase in plasma leakage in HBO-treated rats. In contrast, indomethacin was devoid of anti-exudative activity in these experiments. Western immunoblot showed a significant increase in the level of inducible nitric oxide synthase (iNOS) protein in the tracheal homogenates of HBO-treated rats, as compared to basal levels. These results indicate that nitric oxide (NO) is involved in the maintenance of microvascular permeability in tracheal tissue of rats. The protective effect observed with the steroid seems to support this hypothesis. Furthermore, the beneficial action of NAC underlines that reactive oxygen species participate in the microvascular permeability changes observed in tracheal tissue of rats exposed to HBO.