Osteonecrosis of the jaw (ONJ) is a rare treatment related side effect that was firstly described in 2002 through a case report in metastatic bone cancer patient treated with bisphosphonates (BPs) ...therapy. ONJ is defined as an eight weeks or longer clinical finding of exposed bone in the oral cavity without response to appropriate therapy. The diagnosis is mainly clinical but often requires a radiological confirmation with an orthopantomography. So it must be made by a dental specialist with sufficient experience on ONJ and requires a detailed anamnestic exploration of comorbidities and treatments history. In particular, ONJ affects a wide number of oncologic patients treated with BPs for bone metastatic cancers and, more recently, with anti-angiogenic drugs. The aim of this this paper is to describe diagnosis and classification of this rare but serious side effect and its pathophysiology. In particular, we provide a detailed description of clinical evidences upon the relationship between anti-angiogenic drugs and ONJ. Considering the evolving of cancer epidemiology with a greater number of cancer surviving patients, this side effect always deserves more attention. We conclude that ONJ must be always carefully investigated and prevented with a multidisciplinary approach involving oncologist, radiation oncologist and skilled dental practitioner when a cancer patient must begin a BP or an antiangiogenic treatment.
To report 5-year efficacy and safety in rheumatoid arthritis (RA) patients with active disease treated with tocilizumab.
LITHE was a 2-year, randomised, placebo-controlled study of tocilizumab in RA ...patients (ClinicalTrials.gov, NCT00106535), with an additional 3-year, open-label extension. Patients were randomly assigned to tocilizumab (4 or 8 mg/kg IV) or placebo every 4 weeks + methotrexate. They could receive rescue with tocilizumab from week 16; after week 52, patients could switch to open-label tocilizumab 8 mg/kg. Radiographs were analysed by randomized treatment using the Genant-modified Total Sharp Score (GmTSS). Patients with at least baseline, week 104 and post-week 104 radiographs were included. Clinical and safety data were pooled for all patients who received ≥1 dose of tocilizumab; results are presented from the first tocilizumab dose.
1,149 patients were included with 4,380 patient-years of exposure; 34% received 5 years of treatment. Mean 5-year change in GmTSS revealed greater inhibition of radiographic progression in tocilizumab patients than placebo patients (1.34 vs. 3.02), with the greatest annualised progression rate in year 1. Overall, 53% of tocilizumab and 35% of placebo patients experienced no progression (GmTSS ≤0). Clinical benefit was maintained - determined by ACR response, DAS28-ESR <2.6, EULAR good/moderate response and Boolean remission - as was physical function. The safety profile over 5 years was similar to that over 2 years.
Over 5 years, tocilizumab + MTX inhibited radiographic progression and maintained improvements in signs and symptoms and physical function in MTX-inadequate responders with active disease; no new safety signals occurred.
Aliment Pharmacol Ther 2011; 33: 115–126
Summary
Background Distinct functional subsets of natural killer cells potentially contribute to the pathology of inflammatory bowel disease (IBD).
Aim To ...report the phenotypic and functional characteristics of natural killer cells in blood and lamina propria of IBD patients, and the effect of azathioprine.
Methods Natural killer cells from blood and lamina propria of healthy controls or patients with Crohn’s disease, or ulcerative colitis were studied by flow cytometry. Activation, cytokine production, proliferation and apoptosis of natural killer cell subsets were studied in vitro.
Results CD16+ natural killer cells are increased in frequency in the lamina propria comparing Crohn’s disease or ulcerative colitis with healthy controls. Azathioprine therapy was associated with a reduction in total natural killer cells in blood and lamina propria, preferentially of the CD16+ subset. Azathioprine therapy did not impair natural killer degranulation, but reduced natural and cytokine‐activated cytotoxicity and interferon‐gamma (IFN‐γ) production. Culture of resting peripheral blood mononuclear cells with azathioprine resulted in loss of natural killer cells and inhibition of activation and IFN‐γ production. Azathioprine preferentially inhibited proliferation of CD16+ natural killer cells and induced apoptosis in resting but not in pre‐activated natural killer cells.
Conclusions Natural killer cells with cytolytic potential are enriched in the colonic lamina propria of individuals with IBD. Azathioprine is associated with a reduction in these cells and a normalization of natural killer cell populations.
Abstract Aim Improved survival after cardiac arrest has placed greater emphasis on neurologic resuscitation. The purpose of this pilot study was to evaluate the relationship between cerebrovascular ...autoregulation and neurologic outcomes after pediatric cardiac arrest. Methods Children resuscitated from cardiac arrest had autoregulation monitoring during the first 72 h after return of circulation with an index derived from near-infrared spectroscopy in a pilot study. The range of mean arterial blood pressure (MAP) with optimal vasoreactivity (MAPOPT ) was identified. The area under the curve (AUC) of the time spent with MAP below MAPOPT and MAP deviation below MAPOPT was calculated. Neurologic outcome measures included placement of a new tracheostomy or gastrostomy, death from a primary neurologic etiology (brain death or withdrawal of support for neurologic futility), and change in the Pediatric Cerebral Performance Category score (ΔPCPC). Results Thirty-six children were monitored. Among children who did not require extracorporeal membrane oxygenation (ECMO), children who received a tracheostomy/gastrostomy had greater AUC during the second 24 h after resuscitation than those who did not ( P = 0.04; n = 19). Children without ECMO who died from a neurologic etiology had greater AUC during the first 48 h than did those who lived or died from cardiovascular failure ( P = 0.04; n = 19). AUC below MAPOPT was not associated with ΔPCPC when children with or without ECMO were analyzed separately. Conclusions Deviation from the blood pressure with optimal autoregulatory vasoreactivity may predict poor neurologic outcomes after pediatric cardiac arrest. This experimental autoregulation monitoring technique may help individualize blood pressure management goals after resuscitation.
Methylmercury is a potent toxic present in Amazonian fish species due to gold mining activities. In the present work, we investigated the morphological effects of methylmercury in liver and kidney of
...Hoplias malabaricus feeding contaminated prey fish over 70 days. Two groups of nine mature fish (tested and control) were acclimatized for four weeks to laboratory conditions and then the tested group fed prey fish previously contaminated at an additional level of 0.075
μg MeHg
g
−1 at 5-day intervals and over 14 successive intervals whereas control group fed uncontaminated fish.
H. malabaricus specimens were then dissected for chemical and morphological analyses. The low and realistic level of MeHg in the prey fish induced a low increase of total mercury in liver (1.8-fold) and muscle (2.2-fold). The biomagnification factor (Hg in predator/Hg in prey) reached 142 in liver and 21 in muscle and was indicative of a relatively fast contamination of internal organs by dietary exposure. The liver of exposed individuals presented leukocyte infiltration, increased number of melano-macrophage centers, necrotic areas and lesions in Disse's space. Evident disorder and chaos in cytoskeleton organization suggest a strong toxic effect in hepatocytes, such as organelles positioning and movement, vesicles traffic and secretion. Head kidney showed large necrosis areas, increased number of melano-macrophages centers, phagocytic areas, intercellular space among parenquimal cells and atypical cells. Injuries and damages to tissues suggest too slow defense mechanisms to immobilize or eliminate ingested methylmercury, demonstrating that the sensitivity of fish cells to methylmercury exposure is higher than it has been previously described in the literature.
Summary
Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients treated with lamivudine. Whether HCC rates are comparable in patients treated with the current ...first‐line antivirals remains uncertain. We estimated the incidence and evaluated predictors of HCC in a large nationwide prospective cohort (HepNet.Greece) of HBeAg‐negative CHB patients treated with entecavir. HBeAg‐negative CHB patients from the same cohort who were initially treated with lamivudine were used as controls. We included 321 patients treated with entecavir for a median of 40 months and 818 patients treated initially with lamivudine for a median of 60 months. In the entecavir group, HCC developed in 4 of 321 (1.2%) patients at a median of 1.5 (range: 1.0–4.5) years, while the cumulative HCC incidence was significantly higher in cirrhotics than noncirrhotics (1, 3, 5 years: 0%, 3%, 9% vs 1%, 1%, 1%; P = 0.024) and in older patients (P = 0.026). Entecavir compared with lamivudine group patients had lower HCC incidence (1, 3, 5 years: 0.3%, 1.2%, 2.8% vs 0.7%, 3.8%, 5.6%; P = 0.024). However, in multivariable Cox regression analysis, the HCC risk was independently associated with older age (P < 0.001), male gender (P = 0.011) and cirrhosis (P = 0.025), but not with the initial agent. In conclusion, our large nationwide study indicates that the HCC risk remains increased in entecavir‐treated HBeAg‐negative CHB patients with cirrhosis, particularly of older age, at least for the first 5 years. The HCC risk does not seem to be significantly reduced with entecavir compared with antiviral therapy starting with lamivudine.
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•The retinas of the fish were accessed by silver nanospheres (PVP coated).•Alterations in photoreceptors, hemorrhage and deteriorated pigment epithelium.•Silver nanospheres (PVP ...coated) may be a crosslinking agent.
Nanotechnologies are at the center of societal interest, due to their broad spectrum of application in different industrial products. The current concern about nanomaterials (NMs) is the potential risks they carry for human health and the environment. Considering that NMs can reach bodies of water, there is a need for studying the toxic effects of NMs on aquatic organisms. Among the NMs’ toxic effects on fish, the interactions between NMs and the nervous system are yet to be understood. For this reason, our goal was to assess the neurotoxicity of polyvinylpyrrolidone coated silver nanospheres AgNS (PVP coated) and compare their effects in relation to silver ions (Ag+) in carnivorous Hoplias intermedius fish after acute and subchronic trophic exposure through the analysis of morphological (retina), biochemical (brain) and genetic biomarkers (brain and blood). For morphological biomarkers, damage by AgNS (PVP coated) in retina was found, including morphological changes in rods, cones, hemorrhage and epithelium rupture, and also deposition of AgNS (PVP coated) in retina and sclera. In the brain biomarkers, AgNS (PVP coated) did not disturb acetylcholinesterase activity. However, lowered migration of the DNA tail in the Comet Assay of blood and brain cells was observed for all doses of AgNS (PVP coated), for both acute and subchronic bioassays, and in a dose-dependent manner in acute exposure. Ag+ also reduced the level of DNA damage only under subchronic conditions in the brain cells. In general, the results demonstrated that AgNS (PVP coated) do not cause similar effects in relation to Ag+. Moreover, the lowered level of DNA damage detected by Comet Assay suggests that AgNS (PVP coated) directly interacts with DNA of brain and blood cells, inducing DNA-DNA or DNA-protein crosslinks. Therefore, the AgNS (PVP coated) accumulating, particularly in the retina, can lead to a competitive disadvantage for fish, compromising their survival.
Patient oriented research (POR) is new to the healthcare research landscape in Canada and has not yet been applied to the forensic field. This review begins by introducing POR, the POR Level of ...Engagement Tool, and complimentary approaches used in research with forensic patients. Next, the potential key challenges, paradoxes, and benefits of applying POR to a forensic mental health setting are presented. Drawing on this understanding, a review of our team's experiences applying the POR Level of Engagement Tool at the Regional Psychiatric Center, a Canadian forensic psychiatric facility, is presented as a case study. The research question supported by our patient advisors and addressed with patients and facility staff was: "What topics do you think we need to know more about to benefit patients at the Regional Psychiatric Center?" We conclude this review article with recommendations on how to meaningfully, and practically, involve forensic psychiatric patients diagnosed with mental disorders in POR when initiating a project. Forensic psychiatric patients can provide insightful knowledge based on their experiences of mental illness to improve the prison health care system and practices.
HIV-1 infection is characterized by increase in inhibitory receptors and loss of activating receptors on natural killer (NK) cells, resulting in loss of cell activity. Exceptionally, for an ...inhibitory receptor, the proportion of NK cells bearing CD94-NKG2A decreases during HIV-1 infection. It is not understood whether HIV-1 itself or other concomitant infections drive these changes.
To investigate the relationship between HIV-1 viraemia and changes in C-type lectin-like receptor expression in NK cells and to investigate the effect of highly active antiretroviral therapy (HAART) on these changes.
Three cohorts of patients were studied: (1) before, during and after treatment interruption in aviraemic and viraemic patients receiving HAART (n = 15); (2) HIV-1-positive treatment-naive individuals (n = 13); and (3) HIV-1-positive individuals receiving successful HAART for a minimum of 1 year without interruption (n = 11). Flow cytometry was used to study the expression of NKG2A before and after treatment interruption and to define expanded populations of NK cells in untreated and treated HIV-1-positive individuals. Assays were performed in vitro to assess the cytotoxicity of the expanded populations.
Increases in plasma HIV-1 RNA during treatment interruption in aviraemic HAART-treated individuals did not influence the proportion of NK cells carrying the complex CD94-NKG2A. Loss of NKG2A NK cells corresponded to the dramatic expansion of a distinct population of cells expressing a functional activating CD94-NKG2C receptor with skewed expression of killer cell immunoglobulin-like receptor family and natural cytotoxicity receptors.
Changes in the NK cell repertoire during HIV-1 infection were not a result of HIV-1 viraemia alone but resembled those associated with concomitant infections.
Risk assessment studies on aquatic pollution, a threat to water quality and aquatic biota, often rely on animal capture and experimentation. However, ethical concerns surrounding animal use have ...prompted the development and use of alternative methods. This study investigates the viability of primary hepatocyte cultures from
Oreochromis niloticus
as an in vitro tool for environmental contaminant screening, focusing on cadmium as a pollutant model. Isolated hepatocytes were cultured on plates using a mixture of supplemented L15/F12 media. Freezing conditions were tested for cell stock preservation. The cultured hepatocytes were exposed to 0.5, 5, and 50 µM of cadmium to assess cell viability, reactive oxygen and nitrogen species, and antioxidant molecules. Results demonstrated a concentration and time-dependent decrease in cell viability upon cadmium exposure. Cadmium exposure also induced an imbalance in the antioxidant defense system, leading to increased reactive oxygen species levels and lipid peroxidation. These findings validate the cadmium toxicity to primary hepatocytes and confirm the applicability of commonly used biomarkers in animal-based ecotoxicology and risk assessment studies. The replication of these biomarkers in primary hepatocyte cultures provides an ethical alternative to reduce animal testing in ecotoxicology. Lastly, the study highlights the potential of primary hepatocyte cultures as an in vitro tool for evaluating the toxicity of environmental contaminants and supports the integration of this tool in future environmental risk assessment studies, promoting sustainable water resource management while reducing reliance on animal experimentation.
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