Psychiatric symptom burden in older people living with HIV with and without cognitive impairment: the UCSF HIV over 60 cohort study

Psychiatric comorbidities are common in people living with HIV (PLWH) and adversely affect life satisfaction, treatment adherence and disease progression. There are few data to inform the burden of psychiatric symptoms in older PLWH, a rapidly growing demographic in the U.S. We performed a cross-sectional analysis to understand the degree to which symptom burden was associated with cognitive disorders in PLWH over age 60. Participants completed a standardized neuropsychological battery and were assigned cognitive diagnoses using Frascati criteria. We captured psychiatric symptom burden using the Geriatric Depression Scale (GDS) and proxy-informed Neuropsychiatric Inventory-Questionnaire (NPI-Q). Those diagnosed with HIV-associated neurocognitive disorders (HAND, n?=?39) were similar to those without HAND (n?=?35) by age (median?=?67 years for each group, p?=?0.696), education (mean?=?16 years vs. 17 years, p?=?0.096), CD4+ T-lymphocyte counts (mean?=?520 vs. 579, p?=?0.240), duration of HIV (median?=?21 years for each group, p?=?0.911) and sex (92% male in HAND vs. 97% in non-HAND, p?=?0.617). Our findings showed similarities in HAND and non-HAND groups on both NPI-Q (items and clusters) and GDS scores. However, there was a greater overall symptom burden in HIV compared to healthy elder controls (n?=?236, p?p?相似文献   

The impact of image reconstruction settings on 18F-FDG PET radiomic features: multi-scanner phantom and patient studies

Objectives

The purpose of this study was to investigate the robustness of different PET/CT image radiomic features over a wide range of different reconstruction settings.

Methods

Phantom and patient studies were conducted, including two PET/CT scanners. Different reconstruction algorithms and parameters including number of sub-iterations, number of subsets, full width at half maximum (FWHM) of Gaussian filter, scan time per bed position and matrix size were studied. Lesions were delineated and one hundred radiomic features were extracted. All radiomics features were categorized based on coefficient of variation (COV).

Results

Forty seven percent features showed COV?≤?5% and 10% of which showed COV?>?20%. All geometry based, 44% and 41% of intensity based and texture based features were found as robust respectively. In regard to matrix size, 56% and 6% of all features were found non-robust (COV?>?20%) and robust (COV?≤?5%) respectively.

Conclusions

Variability and robustness of PET/CT image radiomics in advanced reconstruction settings is feature-dependent, and different settings have different effects on different features. Radiomic features with low COV can be considered as good candidates for reproducible tumour quantification in multi-center studies.

Key Points

? PET/CT image radiomics is a quantitative approach assessing different aspects of tumour uptake. ? Radiomic features robustness is an important issue over different image reconstruction settings. ? Variability and robustness of PET/CT image radiomics in advanced reconstruction settings is feature-dependent. ? Robust radiomic features can be considered as good candidates for tumour quantification

     

Preparation,Physicochemical Characterization and Anti-fungal Evaluation of Nystatin-Loaded PLGA-Glucosamine Nanoparticles

Purpose

Nystatin loaded PLGA and PLGA-Glucosamine nanoparticles were formulated. PLGA were functionalized with Glucosamine (PLGA-GlcN) to enhance the adhesion of nanoparticles to Candida Albicans (C.albicans) cell walls.

Method

Quasi-emulsion solvent diffusion method was employed using PLGA and PLGA-GlcN with various drug–polymer ratios for the preparation of nanoparticles. The nanoparticles were evaluated for size, zeta potential, polydispersity index, drug crystallinity, loading efficiency and release properties. DSC, SEM, XRPD, ¹H-NMR, and FT-IR were performed to analyze the physicochemical properties of the nanoparticles. Antifungal activity of the nanoparticles was evaluated by determination of MICs against C.albicans.

Results

The spectra of ¹H-NMR and FT-IR analysis ensured GlcN functionalization on PLGA nanoparticles. SEM characterization confirmed that particles were in the nanosize range and the particle size for PLGA and PLGA-GlcN nanoparticles were in the range of 108.63?±?4.5 to 168.8?±?5.65 nm and 208.76?±?16.85 nm, respectively. DSC and XRPD analysis ensured reduction of the drug crystallinity in the nanoparticles. PLGA-GlcN nanoparticles exhibit higher antifungal activity than PLGA nanoparticles.

Conclusion

PLGA-GlcN nanoparticles showed more antifungal activity with appropriate physicochemical properties than pure Nystatin and PLGA nanoparticles.

     

Effect of minocycline on pentylenetetrazol-induced chemical kindled seizures in mice

Inflammation is one of the mechanisms involved in seizure induction. In this study, the effect of minocycline, an anti-inflammatory drug, was investigated on kindling acquisition. Chemical kindling was induced by injection of a subthreshold dose of pentylenetetrazol (PTZ; 37.5 mg/kg) in mice on every other day. Two groups of animals received minocycline (25 mg/kg) at 1 h before or 1 h after PTZ injection. Following the last PTZ injection, the changes in gene expression of TNF-α receptor, γ₂ subunit of GABA_A receptor and NR₂A subunit of NMDA receptor were assessed in the hippocampus and piriform cortex. Injection of minocycline before PTZ increased the latency to stage 4 seizure, and decreased the duration of stages 4 and 5 seizure. It also prevented the increase in the mRNA of NR₂A subunit of NMDA receptor in the hippocampus and removed the PTZ-induced increase in mRNA of γ₂ subunit of GABA_A receptor in piriform cortex of PTZ kindled mice. Minocycline also prevented the increase in TNF-α receptor gene expression in both hippocampus and piriform cortex. Injection of minocycline after PTZ had no significant effect on measured parameters. Therefore, it can be concluded that minocycline may exert an anticonvulsant effect through preventing the increase in GABA_A and NMDA receptor subunits. These effects are accompanied by a reduction in an important inflammation index, TNF-α receptor.     

Reconstruction/segmentation of attenuation map in TOF-PET based on mixture models

Attenuation correction is known as a necessary step in positron emission tomography (PET) system to have accurate and quantitative activity images. Emission-based method is known as a promising approach for attenuation map estimation on TOF-PET scanners. The proposed method in this study imposes additional histogram-based information as a mixture model prior on the emission-based approach using maximum a posteriori (MAP) framework to improve its performance and make such a nearly segmented attenuation map. To eliminate misclassification of histogram modeling, a Median root prior is incorporated on the proposed approach to reduce the noise between neighbor voxels and encourage spatial smoothness in the reconstructed attenuation map. The joint-MAP optimization is carried out as an iterative approach wherein an alteration of the activity and attenuation updates is followed by a mixture decomposition of the attenuation map histogram. Also, the proposed method can segment attenuation map during the reconstruction. The evaluation of the proposed method on the numerical, simulation and real contexts indicate that the presented method has the potential to be used as a stand-alone method or even combined with other methods for attenuation correction on PET/MR systems.     

Iron dysregulation combined with aging prevents sepsis-induced apoptosis

BACKGROUND: Sepsis, iron loading, and aging cause independent increases in gut epithelial and splenic apoptosis. It is unknown how their combination will affect apoptosis and systemic cytokine levels. MATERIALS AND METHODS: Hfe-/- mice (a murine homologue of hemochromatosis) abnormally accumulate iron in their tissues. Aged (24-26 months) or mature (16-18 months) Hfe-/- mice and wild type (WT) littermates were subjected to cecal ligation and puncture (CLP) or sham laparotomy. Intestine, spleen, and blood were harvested 24 h later and assessed for apoptosis and cytokine levels. RESULTS: Gut epithelial and splenic apoptosis were low in both aged septic and sham Hfe-/- mice, regardless of the amount of iron in their diet. Mature septic WT mice had increased apoptosis compared to age-matched sham WT mice. Mature septic Hfe-/- mice had similar levels of intestinal cell death to age-matched septic WT mice but higher levels of splenic apoptosis. Apoptosis was significantly lower in septic aged Hfe-/- mice than septic mature Hfe-/- animals. Interleukin-6 was elevated in septic aged Hfe-/- mice compared to sham mice. CONCLUSIONS: Although sepsis, chronic iron dysregulation, and aging each increase gut and splenic apoptosis, their combination yields cell death levels similar to sham animals despite the fact that aged Hfe-/- mice are able to mount an inflammatory response following CLP and mature Hfe-/- mice have elevated sepsis-induced apoptosis. Combining sepsis with two risk factors that ordinarily increase cell death and increase mortality in CLP yields an apoptotic response that could not have been predicted based upon each element in isolation.     

Enzymatically Inactive Tissue-Type Plasminogen Activator Reverses Disease Progression in the Dextran Sulfate Sodium Mouse Model of Inflammatory Bowel Disease

Enzymatically inactive tissue-type plasminogen activator (EI-tPA) does not activate fibrinolysis, but interacts with the N-methyl-d-aspartate receptor (NMDA-R) and low-density lipoprotein receptor–related protein-1 (LRP1) in macrophages to block innate immune system responses mediated by toll-like receptors. Herein, we examined the ability of EI-tPA to treat colitis in mice, induced by dextran sulfate sodium. In two separate studies, designed to generate colitis of differing severity, a single dose of EI-tPA administered after inflammation established significantly improved disease parameters. EI-tPA–treated mice demonstrated improved weight gain. Stools improved in character and became hemoccult negative. Abdominal tenderness decreased. Colon shortening significantly decreased in EI-tPA–treated mice, suggesting attenuation of irreversible tissue damage and remodeling. Furthermore, histopathologic evidence of disease decreased in the distal 25% of the colon in EI-tPA–treated mice. EI-tPA did not decrease the number of CD45-positive leukocytes or F4/80-positive macrophage-like cells detected in extracts of colons from dextran sulfate sodium–treated mice as assessed by flow cytometry. However, multiple colon cell types expressed the NMDA-R, suggesting the ability of diverse cells, including CD3-positive cells, CD103-positive cells, Ly6G-positive cells, and epithelial cell adhesion molecule–positive epithelial cells to respond to EI-tPA. Mesenchymal cells that line intestinal crypts and provide barrier function expressed LRP1, thereby representing another potential target for EI-tPA. These results demonstrate that the NMDA-R/LRP1 receptor system may be a target for drug development in diseases characterized by tissue damage and chronic inflammation.

The inflammatory bowel diseases (IBDs), such as Crohn disease and ulcerative colitis, are chronic, relapsing diseases of the intestines that eventually compromise tissue structure and function.¹ Disease susceptibility genes such as the pattern recognition receptor, nucleotide-binding oligomerization domain containing 2 (NOD2), have been implicated in Crohn disease.^1,2 Dysbiosis in intestinal microbiomes also has been implicated in the onset of IBD, together with lifestyle choices, such as cigarette smoking.3, 4, 5 Once IBD is established, chronic inflammation and tissue damage dominate the clinical course and are principal targets for therapeutics development.⁶ Despite the availability of numerous drugs, many patients with moderate to severe IBD fail to remain in remission and often experience damaging flares.Tissue-type plasminogen activator (tPA) is a serine protease and major activator of the fibrinolytic system.^7,8 Recombinant tPA is Food and Drug Administration-approved for treating recent-onset stroke.⁹ The structure of tPA includes multiple domains that participate in noncovalent fibrin binding, which is essential for restricting the lytic activity of tPA to fibrin while sparing fibrinogen.10, 11, 12 tPA also binds to cell surface receptors, including the N-methyl-d-aspartate receptor (NMDA-R) and low-density lipoprotein receptor–related protein-1 (LRP1), which function as part of a single system to regulate cell signaling and cell physiology.13, 14, 15, 16, 17 Enzymatically inactive tPA (EI-tPA), in which the enzyme active site serine is mutated to alanine, interacts with the NMDA-R/LRP1 receptor system equivalently to enzymatically active tPA to trigger signal transduction.^16,18,19In mouse macrophages, EI-tPA binding to the NMDA-R/LRP1 receptor system blocks inflammatory cytokine expression elicited by multiple toll-like receptors (TLRs), including TLR4, TLR2, and TLR9.18, 19, 20 EI-tPA also blocks the toxicity of lipopolysaccharide in vivo in mice.¹⁸ These results suggest that EI-tPA and the NMDA-R/LRP1 receptor system constitute a novel pathway for regulating innate immunity and inflammation. EI-tPA does not activate plasminogen, thus avoiding undesirable effects on hemostasis and the possible proinflammatory activity of plasmin.^21,22 Some pattern recognition receptors outside the TLR family, such as NOD1 and NOD2, are not antagonized by EI-tPA in macrophages.¹⁹ Furthermore, because the NMDA-R is expressed by numerous cell types,^17,18,23,24 EI-tPA may regulate inflammation by targeting cells in addition to macrophages. Thus, it is not clear whether EI-tPA would be effective in counteracting pathologic conditions in which diverse pattern recognition receptors function together in diverse cells to stimulate fulminant inflammation.In this study, the dextran sulfate sodium (DSS) preclinical mouse model of colitis was used to test the activity of EI-tPA. DSS causes a chemically-induced form of colitis, in which extensive inflammatory cell infiltrates develop in the mucosa and submucosa.²⁵ Mice were treated systemically with a single dose of EI-tPA after intestinal inflammation was established. EI-tPA rapidly reversed signs and symptoms of the disease and caused significant improvement in disease biomarkers. These results indicate that EI-tPA may be efficacious as a therapeutic for complex inflammatory diseases.