Prevalence of contraindications and prescription of pharmacologic therapies for gout

Background

Patients with gout have comorbidities, but the impact of these comorbidities on treatment has not been studied.

Methods

A total of 575 patients with gout were stratified according to certainty of diagnosis according to International Classification of Diseases, 9th Revision, Clinical Modification code alone (cohort I), American College of Radiology criteria (cohort II), and crystal diagnosis (cohort III). Comorbid conditions were defined according to International Classification of Diseases, 9th Revision, Clinical Modification codes, and stratified as either moderate or severe. Drug contraindications were defined as moderate or strong, based on Food and Drug Administration criteria and severity of disease.

Results

The most common comorbidity was hypertension (prevalence 0.89). The presence of comorbidities resulted in a high frequency of contraindications to approved gout medications. More than 90% of patients had at least 1 contraindication to nonsteroidal anti-inflammatory drugs. Many patients demonstrated multiple contraindications to 1 or more gout medications. Frequently, patients were prescribed medications to which they harbored contraindications. The prevalence of patients prescribed colchicine despite having at least 1 strong contraindication was 30% (cohort I), 37% (cohort II), and 39.6% (cohort III).

Conclusion

Patients with gout typically harbor multiple comorbidities that result in contraindications to many of the medications available to treat gout. Frequently, despite contraindications to gout therapies, patients are frequently prescribed these medications.     

The neurophysiological balance in Chiari type 1 malformation (CM1), tethered cord and related syndromes

The Chiari malformation (CM) is a syndrome embodied in heterogeneous groups of malformations, spanning from the more benign and known, the CM1, to more complex syndromes such as the rare association with the tethered cord, as spinal lipomas, and the CM2, associated to open spina bifida. The clinical picture may be well expressed and detected at birth or even during intrauterine life, as for CM2, but in the other cases they may run a rather subtle clinical course. The diagnosis of these syndromes is driven by clinical examination and MRI, and it usually requires a multidisciplinary approach in order to plan the therapeutic strategies, such as surgery. Among the diagnostic investigations, the imaging techniques represent the most useful, for their capabilities to detect subclinical lesions, such as syringomyielia and lipoma; the urological investigation is useful to evaluate the urogenital dysfunctions. The neurophysiological investigations represent a non invasive diagnostic procedure to investigate the peripheral nerve, the spinal cord, the brainstem functionalities and more higher brain functions; the nerve conduction studies and the cranial reflexes, the brainstem (BAEP) and the somatosensory (SEPs) evoked potentials (EPs), alone or in combination, can be used for the diagnosis, follow-up and intraoperative monitoring. The most useful diagnostic tools in CM1 are likely represented by the brainstem auditory evoked potentials (BAEPs) and the blink-reflex (BR), while the usefulness of SEPs is still doubtful and debated; in CM2 and tethered cord the neurophysiological techniques can be combined in different ways in order to make a functional balance and to answer specific questions. BAEPs and BR can be useful to investigate the brain stem functionality and SEP to evaluate whether the ascending sensory pathway to the cortex can be hampered at some level; the visual EPs are particularly useful to evaluate the integrity of posterior visual pathway and visual cortex in the case of associated hydrocephalus. In the tethered cord, both nerve conduction study and somatosensory evoked potentials (SEPs) are useful to evaluate motor and sensory dysfunction of the lombosacral roots and nerves and spinal cord for their capability to detect subclinical impairment of conduction along the sensory and motor pathway. Finally, last but not the least, the neurophysiological techniques are remarkably useful during surgery; the intraoperative monitoring (IOM) by means of electromyography and direct nerve stimulation and recordings are able to detect early nerve damage, minimize nerve lesions and optimise the surgical techniques. In the operated children with incomplete removal of lipoma and/or persistent tethering, the recordings of SEP and BAEP are useful to demonstrate a conduction deterioration along the ascending sensory pathway due to increasing tethering of the spinal cord due to somatic growth.     

Neurological pictures in paediatric Chiari I malformation

The clinical features of Chiari I Malformation (CIM) may be related to the compression of dural and/or neural structures at the craniocervical junction or to the associated syringomyelia. Additionally, patients may exhibit symptoms and signs of associated disorders. CIM is a heterogeneous and multifactorial disorder including congenital and acquired forms; it can also be found as an isolated malformation or in association with many clinical conditions. We analyse the clinical features in a series of 65 children with CIM, focusing on the high frequency of associated clinical disorders. We emphasise the importance of a careful clinical and neurological assessment for a proper diagnosis and a correct management of these patients.     

Neurological pictures in Paediatric Chiari I malformation

At the end of 2006, a pharmacovigilance program on natalizumab was settled by the Italian Pharmaceutical Agency, and on January 2007, multiple sclerosis patients poorly responding to the immunomodulating therapies or with an aggressive clinical form of disease from onset initiated to be registered and to receive the medication. On February 2010, almost 3,000 cases have been treated with natalizumab. The drop-out rate is 10%. Almost 800 cases received cycles of natalizumab for more than 18 months. One case of PML was reported and other adverse events are similar to those described in phase III studies. The majority of cases remained stable, while in 25% of cases, an improvement of disability was documented.     

Behavioral change with influenza vaccination: factors influencing increased uptake of the pandemic H1N1 versus seasonal influenza vaccine in health care personnel

Background

Many health care personnel (HCP) choose not to get vaccinated against influenza despite recommendations to do so. The pH1N1 epidemic gave a unique opportunity to evaluate the attitudes to influenza vaccination of a group of HCP who routinely choose not to get vaccinated, but accepted the pH1N1 vaccine.

Methods

HCP employed at a tertiary care hospital in Winnipeg, Canada who received the pH1N1 vaccine were invited to participate in an online survey asking about attitudes and experiences regarding seasonal and pH1N1 influenza and vaccination. Those eligible included primarily nurses, other clinical staff, and support staff, as few physicians work as employees.

Results

Of the 684 respondents (29% return rate), 504 reported routinely getting vaccinated (RV) for seasonal influenza and 180 reported routinely not getting vaccinated (NRV). These two groups had different attitude towards the two strains of influenza, with markedly lower level of concern about seasonal influenza than pH1N1 for the NRV group. The contrast was especially notable regarding the NRV's view of the seriousness of the illness, their sense of exposure risk, and their confidence in the vaccine effectiveness (for all, seasonal < pH1N1, p < 0.001). The most common motivators for getting vaccinated for both NRV and RV groups related to concerns about personal or family safety, while the choice to decline seasonal vaccination related primarily to lack concern about the illness and concerns about vaccine effectiveness and safety. Coworkers were influential in the decision to get the pH1N1 vaccine for the NRV group.

Conclusion

For HCP who do not routinely get the seasonal vaccination, perception of risk outweighing side effect concerns appeared to be a major influence in going ahead with the pH1N1 vaccine. Educational campaigns that focus on personal benefit, engage peer champions, and address concerns about the vaccine may improve influenza vaccine uptake among health care personnel.     

The GAS6-AXL signaling pathway triggers actin remodeling that drives membrane ruffling,macropinocytosis, and cancer-cell invasion

AXL, a member of the TAM (TYRO3, AXL, MER) receptor tyrosine kinase family, and its ligand, GAS6, are implicated in oncogenesis and metastasis of many cancer types. However, the exact cellular processes activated by GAS6-AXL remain largely unexplored. Here, we identified an interactome of AXL and revealed its associations with proteins regulating actin dynamics. Consistently, GAS6-mediated AXL activation triggered actin remodeling manifested by peripheral membrane ruffling and circular dorsal ruffles (CDRs). This further promoted macropinocytosis that mediated the internalization of GAS6-AXL complexes and sustained survival of glioblastoma cells grown under glutamine-deprived conditions. GAS6-induced CDRs contributed to focal adhesion turnover, cell spreading, and elongation. Consequently, AXL activation by GAS6 drove invasion of cancer cells in a spheroid model. All these processes required the kinase activity of AXL, but not TYRO3, and downstream activation of PI3K and RAC1. We propose that GAS6-AXL signaling induces multiple actin-driven cytoskeletal rearrangements that contribute to cancer-cell invasion.

Metastasis, the ability of cancer cells to spread from the primary tumor and invade distant secondary sites, makes cancer incurable. Despite much progress in oncology in the last decades, metastasis still causes ∼90% of cancer-related deaths. To initiate metastasis, cancer cells need first to disassemble cell–cell and cell–substrate adhesion sites and prepare for migration and invasion through the extracellular matrix (ECM), vessels, and tissues. This requires, among other things, a significant remodeling of the plasma membrane and actin cytoskeleton (1, 2).During migration and invasion, cancer cells form various actin-based protrusions such as lamellipodia, filopodia, invadopodia, peripheral ruffles (PRs), and circular dorsal ruffles (CDRs) (3–5). CDRs are enigmatic actin-rich, ring-shaped structures formed transiently on the dorsal surface of cells in response to certain growth factors. To date, it was demonstrated that CDRs are formed upon stimulation with platelet-derived growth factor (PDGF) in fibroblasts, hepatocyte growth factor (HGF) in HeLa and polarized epithelial Madin-Darby Canine Kidney (MDCK) cells, and epidermal growth factor (EGF) in fibroblasts and liver-derived epithelial cells (6–10). The functions of these structures are still not fully explored, but they have been postulated to play a role in the preparation of cells for motility, mesenchymal migration through ECM, and macropinocytosis (9). Additionally, CDRs have recently been proposed to amplify AKT activation (11).Macropinocytosis is an evolutionarily conserved, actin-dependent form of endocytosis that mediates nonselective uptake of a large amount of extracellular fluid into cells. During macropinocytosis, PRs collapse inward to create large plasma membrane–derived vesicles, termed macropinosomes, which contain extracellular fluid and solutes (12, 13). Macropinosomes may also form concomitantly with the contraction and closure of CDRs (4). Generally, macropinocytosis allows rapid and efficient remodeling of the plasma membrane and its composition. Another proposed function of macropinocytosis is to support cellular metabolism, particularly of cancer cells in which macropinocytosis is constitutively activated by mutated RAS, PTEN, or PI3K (14–17). Up-regulated macropinocytosis enables cancer cells to acquire extracellular macromolecules which, upon lysosomal degradation, provide nutrients for the metabolism and cell growth. In this way, macropinocytosis allows cancer cells to survive in a nutrient-poor tumor microenvironment (14–20). Moreover, growth factor–induced macropinocytosis has been shown to increase cell growth and proliferation by the delivery of amino acids into endolysosomes that subsequently activate mTORC1 (21).AXL is a receptor tyrosine kinase (RTK) implicated in oncogenesis. Together with TYRO3 and MER, it belongs to the TAM family. TAM receptors are dispensable for embryonic development but participate in phagocytic clearance of apoptotic cells (efferocytosis) in adult organisms (22–25). Two known TAM ligands are vitamin K–dependent proteins: growth arrest–specific 6 (GAS6) and anticoagulant protein S (PROS1). GAS6 appears to bind all three TAMs, with the highest affinity for AXL, whereas PROS1 predominantly binds TYRO3 and MER (26, 27).AXL is associated with the pathogenesis of a wide array of human cancers including gliomas, melanomas, breast, lung, and ovarian cancer (28–31). Overexpression of AXL and/or GAS6 has been shown to correlate with a poorer prognosis and increased cancer invasiveness—for example, in glioblastoma patients (32). Inhibition of AXL reduced glioma-cell migration, invasion, and proliferation in vitro and prolonged the survival of mice after intracerebral implantation of glioma cells (33, 34). An increased expression of AXL in highly metastatic breast cancer was found to be essential for all steps of the metastatic process, starting with intravasation of cancer cells (35, 36). Consistent with the association of AXL with cancer invasion and metastasis, a recent study by Revach et al. (37) reported that AXL may regulate the formation of invadopodia in melanoma cells. Furthermore, AXL has been linked to epithelial-to-mesenchymal transition (EMT) that is associated with metastasis (36, 38, 39). Several studies showed that AXL activation associated with an EMT-like phenotype conferred resistance to both conventional and targeted anticancer therapies (28, 29). Thus, AXL inhibition constitutes a promising therapeutic strategy (28, 40). Accordingly, R428, a first-in-class AXL kinase inhibitor, is being tested in the second phase of clinical trials for metastatic lung and triple-negative breast cancer, glioblastoma, and acute myeloid leukemia (41, 42).Despite the multiple roles of AXL in cancer invasion and metastasis, the molecular mechanisms underlying its action in cancer cells are not fully characterized. Here, we identified an interactome of AXL using a proximity-dependent biotin identification (BioID) assay. Our results reveal intracellular processes induced by GAS6-AXL signaling and mechanisms underlying GAS6-AXL–driven cell invasion.