Accumulating evidence identifies diet and inflammation as potential mechanisms contributing to cardiometabolic risk. However, inconsistent reports regarding dietary inflammatory potential, biomarkers ...of cardiometabolic health and metabolic syndrome (MetS) risk exist. Our objective was to examine the relationships between a food frequency questionnaire (FFQ)-derived dietary inflammatory index (DII
), biomarkers of lipoprotein metabolism, inflammation and glucose homeostasis and MetS risk in a cross-sectional sample of 1992 adults. Energy-adjusted DII (E-DII) scores derived from an FFQ were calculated. Lipoprotein particle size and subclass concentrations were measured using nuclear magnetic resonance (NMR) spectroscopy. Serum acute-phase reactants, adipocytokines, pro-inflammatory cytokines and white blood cell (WBC) counts were determined. Insulin resistance was calculated by homeostasis model assessment (HOMA-IR). Our data indicate that a more pro-inflammatory diet, reflected by higher E-DII scores, was associated with potentially pro-atherogenic lipoprotein profiles characterised by increased numbers of large very low density lipoprotein (VLDL), small dense low density lipoprotein (LDL) and high density lipoprotein (HDL) particles and less large LDL and HDL particles (all
< 0.001). Inflammatory profiling identified a range of adverse phenotypes among those with higher E-DII scores, including higher complement component C3 (C3), C-reactive protein (CRP), (both
< 0.05), interleukin 6 (IL-6) and tumour necrosis factor (TNF)-α concentrations, higher WBC counts and neutrophil to lymphocyte ratio (NLR) and lower adiponectin levels (all
< 0.001). MetS risk was increased among those with higher E-DII scores (OR 1.37, 95% CI (1.01, 1.88),
< 0.05), after adjusting for potential confounders. In conclusion, habitual intake of a more pro-inflammatory diet is associated with unfavourable lipoprotein and inflammatory profiles and increased MetS risk.
Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal ...antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian-human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans.
Microglia in neurodegenerative disease Perry, V Hugh; Nicoll, James A R; Holmes, Clive
Nature reviews. Neurology,
04/2010, Letnik:
6, Številka:
4
Journal Article
Recenzirano
Microglia, the resident macrophages of the CNS, are exquisitely sensitive to brain injury and disease, altering their morphology and phenotype to adopt a so-called activated state in response to ...pathophysiological brain insults. Morphologically activated microglia, like other tissue macrophages, exist as many different phenotypes, depending on the nature of the tissue injury. Microglial responsiveness to injury suggests that these cells have the potential to act as diagnostic markers of disease onset or progression, and could contribute to the outcome of neurodegenerative diseases. The persistence of activated microglia long after acute injury and in chronic disease suggests that these cells have an innate immune memory of tissue injury and degeneration. Microglial phenotype is also modified by systemic infection or inflammation. Evidence from some preclinical models shows that systemic manipulations can ameliorate disease progression, although data from other models indicates that systemic inflammation exacerbates disease progression. Systemic inflammation is associated with a decline in function in patients with chronic neurodegenerative disease, both acutely and in the long term. The fact that diseases with a chronic systemic inflammatory component are risk factors for Alzheimer disease implies that crosstalk occurs between systemic inflammation and microglia in the CNS.
Newly diagnosed glioblastoma is now commonly treated with surgery, if feasible, or biopsy, followed by radiation plus concomitant and adjuvant temozolomide. The treatment of recurrent glioblastoma ...continues to be a moving target as new therapeutic principles enrich the standards of care for newly diagnosed disease. We reviewed PubMed and American Society of Clinical Oncology abstracts from January 2006 to January 2012 to identify clinical trials investigating the treatment of recurrent or progressive glioblastoma with nitrosoureas, temozolomide, bevacizumab, and/or combinations of these agents. At recurrence, a minority of patients are eligible for second surgery or reirradiation, based on appropriate patient selection. In temozolomide-pretreated patients, progression-free survival rates at 6 months of 20%-30% may be achieved either with nitrosoureas, temozolomide in various dosing regimens, or bevacizumab. Combination regimens among these agents or with other drugs have not produced evidence for superior activity but commonly produce more toxicity. More research is needed to better define patient profiles that predict benefit from the limited therapeutic options available after the current standard of care has failed.
Venous thromboembolism (VTE) is common throughout the course of disease in high-grade glioma (HGG). The interactions between the coagulation cascade, endothelium, and regulation of angiogenesis are ...complex and drive glioblastoma growth and invasion. We reviewed the incidence of VTE in HGG, the biology of the coagulome as related to glioblastoma progression, prevention and treatment of thrombosis, and the putative role of anticoagulants as anti-cancer therapy. VTE can be significantly reduced during the postoperative period with adherence to the use of mechanical and medical thromboprophylaxis. Activation of the coagulation cascade occurs throughout the course of disease because of a variety of complex interactions, including tumor hypoxia, upregulation of VEGR expression, and increases in both tumor cell-specific tissue factor (TF) expression and inducible TF expression in numerous intrinsic regulatory pathways. Long-term anticoagulation to prevent VTE is an attractive therapy; however, the therapeutic window is narrow and current data do not support its routine use. Most patients with proven symptomatic VTE can be safely anticoagulated, including those receiving anti-VEGF therapy, such as bevacizumab. Initial therapy should include low molecular weight heparin (LMWH), and protracted anticoagulant treatment, perhaps indefinitely, is indicated for patients with HGG because of the ongoing risk of thrombosis. A variety of coagulation- and tumor-related proteins, such as TF and circulating microparticles, may serve as potential disease-specific biomarkers in relation to disease recurrence, monitoring of therapy, and as potential therapeutic targets.
Updates in IDH-Wildtype Glioblastoma Melhem, Jawad M.; Detsky, Jay; Lim-Fat, Mary Jane ...
Neurotherapeutics,
10/2022, Letnik:
19, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Glioblastoma is the most aggressive primary brain tumor with a poor prognosis. The 2021 WHO CNS5 classification has further stressed the importance of molecular signatures in diagnosis although ...therapeutic breakthroughs are still lacking. In this review article, updates on the current and novel therapies in IDH-wildtype GBM will be discussed.
The worldwide diversity of HIV-1 presents an unprecedented challenge for vaccine development. Antigens derived from natural HIV-1 sequences have elicited only a limited breadth of cellular immune ...responses in nonhuman primate studies and clinical trials to date. Polyvalent 'mosaic' antigens, in contrast, are designed to optimize cellular immunologic coverage of global HIV-1 sequence diversity. Here we show that mosaic HIV-1 Gag, Pol and Env antigens expressed by recombinant, replication-incompetent adenovirus serotype 26 vectors markedly augmented both the breadth and depth without compromising the magnitude of antigen-specific T lymphocyte responses as compared with consensus or natural sequence HIV-1 antigens in rhesus monkeys. Polyvalent mosaic antigens therefore represent a promising strategy to expand cellular immunologic vaccine coverage for genetically diverse pathogens such as HIV-1.
Symptomatic epilepsy is a common complication of glioblastoma and requires pharmacotherapy. Several uncontrolled retrospective case series and a post hoc analysis of the registration trial for ...temozolomide indicated an association between valproic acid (VPA) use and improved survival outcomes in patients with newly diagnosed glioblastoma.
To confirm the hypothesis suggested above, a combined analysis of survival association of antiepileptic drug use at the start of chemoradiotherapy with temozolomide was performed in the pooled patient cohort (n = 1,869) of four contemporary randomized clinical trials in newly diagnosed glioblastoma: AVAGlio (Avastin in Glioblastoma; NCT00943826), CENTRIC (Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Methylated Gene Promoter Status; NCT00689221), CORE (Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Unmethylated Gene Promoter Status; NCT00813943), and Radiation Therapy Oncology Group 0825 (NCT00884741). Progression-free survival (PFS) and overall survival (OS) were compared between: (1) any VPA use and no VPA use at baseline or (2) VPA use both at start of and still after chemoradiotherapy. Results of Cox regression models stratified by trial and adjusted for baseline prognostic factors were analyzed. The same analyses were performed with levetiracetam (LEV).
VPA use at start of chemoradiotherapy was not associated with improved PFS or OS compared with all other patients pooled (PFS: hazard ratio HR, 0.91; 95% CI, 0.77 to 1.07; P = .241; OS: HR, 0.96; 95% CI, 0.80 to 1.15; P = .633). Furthermore, PFS and OS of patients taking VPA both at start of and still after chemoradiotherapy were not different from those without antiepileptic drug use at both time points (PFS: HR, 0.92; 95% CI, 0.74 to 1.15; P = .467; OS: HR, 1.10; 95% CI, 0.86 to 1.40; P = .440). Similarly, no association with improved outcomes was observed for LEV use.
The results of this analysis do not justify the use of VPA or LEV for reasons other than seizure control in patients with newly diagnosed glioblastoma outside clinical trials.
Purpose
To assess relationships between the Dietary Approaches to Stop Hypertension (DASH), Mediterranean Diet (MD), Dietary Inflammatory Index (DII
®
) and Energy-adjusted DII (E-DII™) scores and ...pro-inflammatory cytokines, adipocytokines, acute-phase response proteins, coagulation factors and white blood cells.
Methods
This was a cross-sectional study of 1862 men and women aged 46–73 years, randomly selected from a large primary care centre in Ireland. DASH, MD, DII and E-DII scores were derived from validated food frequency questionnaires. Correlation and multivariate-adjusted linear regression analyses with correction for multiple testing were performed to examine dietary score relationships with biomarker concentrations.
Results
In fully adjusted models, higher diet quality or a less pro-inflammatory diet was associated with lower concentrations of c-reactive protein, neutrophils (all dietary scores), complement component 3 C3, interleukin 6 IL-6, tumour necrosis factor-alpha TNF-α, white blood cell count WBC, the neutrophil-to-lymphocyte ratio NLR (DASH, DII and E-DII), monocytes (DASH and DII) and resistin (DII and E-DII). After accounting for multiple testing, relationships with C3 (DASH:
β
= − 2.079
, p
= .011 and DII:
β
= 2.521,
p
= .036), IL-6 (DASH:
β
= − 0.063
, p
= .011), TNF-α (DASH:
β
= − 0.027
, p
= .034), WBC (DASH:
β
= − 0.028
, p
= .001 and DII:
β
= 0.029,
p
= .02), neutrophils (DASH:
β
= − 0.041
, p
= .001; DII:
β
= 0.043,
p
= .007; E-DII:
β
= 0.029,
p
= .009) and the NLR (DASH:
β
= − 0.035
, p
= .011) persisted.
Conclusions
Better diet quality, determined by the DASH score, may be more closely associated with inflammatory biomarkers related to health in middle- to older-aged adults than the MD, DII and E-DII scores.
Background
Detailed recognition of the three-dimensional (3-D) deformity in acetabular dysplasia is important to help guide correction at the time of reorientation during periacetabular osteotomy ...(PAO). Common plain radiographic parameters of acetabular dysplasia are limited in their ability to characterize acetabular deficiency precisely. The 3-D characterization of such deficiencies with low-dose CT may allow for more precise characterization.
Questions/purposes
The purposes of this study were (1) to determine the variability in 3-D acetabular deficiency in acetabular dysplasia; (2) to define subtypes of acetabular dysplasia based on 3-D morphology; (3) to determine the correlation of plain radiographic parameters with 3-D morphology; and (4) to determine the association of acetabular dysplasia subtype with patient clinical characteristics including sex, range of motion, and femoral version.
Methods
Using our hip preservation database, we identified 153 hips (148 patients) that underwent PAO from October 2013 to July 2015. Among those, we noted 103 hips in 100 patients with acetabular dysplasia (lateral center-edge angle < 20°) and who had a Tönnis grade of 0 or 1. Eighty-six patients (86%) underwent preoperative low-dose pelvic CT scans at our institution as part of the preoperative planning for PAO. It is currently our standard to obtain preoperative low-dose pelvic CT scans (0.75–1.25 mSv, equivalent to three to five AP pelvis radiographs) on all patients before undergoing PAO unless a prior CT scan was performed at an outside institution. Hips with a history of a neuromuscular disorder, prior trauma, prior surgery, radiographic evidence of joint degeneration, ischemic necrosis, or Perthes-like deformities were excluded. Fifty hips in 50 patients met inclusion criteria and had CT scans available for review. These low-dose CT scans of 50 patients with symptomatic acetabular dysplasia undergoing evaluation for surgical planning of PAO were then retrospectively studied. CT scans were analyzed quantitatively for acetabular coverage, relative to established normative data for acetabular coverage, as well as measurement of femoral version. The cohort included 45 females and five males with a mean age of 26 years (range, 13–49 years).
Results
Lateral acetabular deficiency was present in all patients, whereas anterior deficiency and posterior deficiency were variable. Three patterns of acetabular deficiency were common: anterosuperior deficiency (15 of 50 30%), global deficiency (18 of 50 36%), and posterosuperior deficiency (17 of 50 34%). The presence of a crossover sign or posterior wall sign was poorly predictive of the dysplasia subtype. With the numbers available, males appeared more likely to have a posterosuperior deficiency pattern (four of five 80%) compared with females (13 of 45 29%, p = 0.040). Hip internal rotation in flexion was significantly greater in anterosuperior deficiency (23° versus 18°, p = 0.05), whereas external rotation in flexion was significantly greater in posterosuperior deficiency (43° versus 34°, p = 0.018). Acetabular deficiency pattern did not correlate with femoral version, which was variable across all subtypes.
Conclusions
Three patterns of acetabular deficiency commonly occur among young adult patients with mild, moderate, and severe acetabular dysplasia. These patterns include anterosuperior, global, and posterosuperior deficiency and are variably observed independent of femoral version. Recognition of these distinct morphologic subtypes is important for diagnostic and surgical treatment considerations in patients with acetabular dysplasia to optimize acetabular correction and avoid femoroacetabular impingement.
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