Ceramic-on-metal coupling in THA: long term clinical and radiographic outcomes using two different short stems.

BACKGROUND: Hip prosthetic replacement surgery is the gold standard for patients affected by symptomatic osteoarthritis. The ceramic-on-metal hybrid hard-on-hard bearing was initially launched on the market with the purpose of reducing adhesive and corrosion wear, loss of metal debris and ions and risk of fracture and squeaking. However, this bearing was withdrawn from the market, in the apprehension of local and systemic toxicity. The aim of this study is to evaluate the reliability and safety of ceramic-on-metal bearing at long term follow-up. METHODS: From 2 cohorts of patients suffering of hip osteoarthritis who underwent total hip arthroplasty using ceramic-on-metal bearing with two different short stems, 19 of the GROUP A and 25 of the GROUP B were suitable for this study. All patients were compared clinically using the Harris Hip Score (HHS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analogue scale (VAS), 12-item Short Form Health Survey (SF12P/M), and radiographically. Blood samples were collected in order to evaluate chromium and cobalt ions level. The two groups were compared in terms of metal ions blood levels, and finally all the implanted prostheses were compared with a healthy control group. RESULTS: All the implanted stems were well-positioned and osseointegrated at a mean follow-up of 114 months. Improvements were observed for all clinical scores comparing preoperative and postoperative values in both groups. Radiographic evaluation showed a good ability to restore proper articular geometry. Chromium and cobalt ion analysis revealed values below the safety threshold except for 1 case in GROUP A (cup malposition) and 2 cases in GROUP B (6.1%). No revision occurred. CONCLUSIONS: Ceramic-on-metal bearing is safe and reliable at long term follow-up in association to short stems arthroplasty, if the implant is correctly positioned. Chromium and cobalt metal ions blood levels evaluation should be performed annually.

Nutritional Mushroom Treatment in Meniere's Disease with Coriolus versicolor: A Rationale for Therapeutic Intervention in Neuroinflammation and Antineurodegeneration.

Meniere's disease (MD) represents a clinical syndrome characterized by episodes of spontaneous vertigo, associated with fluctuating, low to medium frequencies sensorineural hearing loss (SNHL), tinnitus, and aural fullness affecting one or both ears. To date, the cause of MD remains substantially unknown, despite increasing evidence suggesting that oxidative stress and neuroinflammation may be central to the development of endolymphatic hydrops and consequent otholitic degeneration and displacement in the reuniting duct, thus originating the otolithic crisis from vestibular otolithic organs utricle or saccule. As a starting point to withstand pathological consequences, cellular pathways conferring protection against oxidative stress, such as vitagenes, are also induced, but at a level not sufficient to prevent full neuroprotection, which can be reinforced by exogenous nutritional approaches. One emerging strategy is supplementation with mushrooms. Mushroom preparations, used in traditional medicine for thousands of years, are endowed with various biological actions, including antioxidant, immunostimulatory, hepatoprotective, anticancer, as well as antiviral effects. For example, therapeutic polysaccharopeptides obtained from Coriolus versicolor are commercially well established. In this study, we examined the hypothesis that neurotoxic insult represents a critical primary mediator operating in MD pathogenesis, reflected by quantitative increases of markers of oxidative stress and cellular stress response in the peripheral blood of MD patients. We evaluated systemic oxidative stress and cellular stress response in MD patients in the absence and in the presence of treatment with a biomass preparation from Coriolus. Systemic oxidative stress was estimated by measuring, in plasma, protein carbonyls, hydroxynonenals (HNE), and ultraweak luminescence, as well as by lipidomics analysis of active biolipids, such as lipoxin A4 and F2-isoprostanes, whereas in lymphocytes we determined heat shock proteins 70 (Hsp72), heme oxygenase-1 (HO-1), thioredoxin (Trx), and γ-GC liase to evaluate the systemic cellular stress response. Increased levels of carbonyls, HNE, luminescence, and F2-isoprostanes were found in MD patients with respect to the MD plus Coriolus-treated group. This was paralleled by a significant (p < 0.01) induction, after Coriolus treatment, of vitagenes such as HO-1, Hsp70, Trx, sirtuin-1, and γ-GC liase in lymphocyte and by a significant (p < 0.05) increase in the plasma ratio-reduced glutathione (GSH) vs. oxidized glutathione (GSSG). In conclusion, patients affected by MD are under conditions of systemic oxidative stress, and the induction of vitagenes after mushroom supplementation indicates a maintained response to counteract intracellular pro-oxidant status. The present study also highlights the importance of investigating MD as a convenient model of cochlear neurodegenerative disease. Thus, searching innovative and more potent inducers of the vitagene system can allow the development of pharmacological strategies capable of enhancing the intrinsic reserve of vulnerable neurons, such as ganglion cells to maximize antidegenerative stress responses and thus providing neuroprotection.

Growth of Pseudomonas aeruginosa in zinc poor environments is promoted by a nicotianamine-related metallophore.

Previous studies have suggested that P. aeruginosa possesses redundant zinc uptake systems. To identify uncharacterized zinc transporters, we analyzed the genome-wide transcriptional responses of P. aeruginosa PA14 to zinc restriction. This approach led to the identification of an operon (zrmABCD) regulated by the zinc uptake regulator Zur, that encodes for a metallophore-mediated zinc import system. This operon includes the genes for an uncharacterized TonB-dependent Outer Membrane Protein (ZrmA) and for a putative nicotianamine synthase (ZrmB). The simultaneous inactivation of the ZnuABC transporter and of one of these two genes markedly decreases the ability of P. aeruginosa to grow in zinc-poor media and compromises intracellular zinc accumulation. Our data demonstrate that ZrmB is involved in the synthesis of a metallophore which is released outside the cell and mediates zinc uptake through the ZrmA receptor. We also show that alterations in zinc homeostasis severely affect the ability of P. aeruginosa to cause acute lung and systemic infections in C57BL/6 mice, likely due to the involvement of zinc in the expression of several virulence traits. These findings disclose a hitherto unappreciated role of zinc in P. aeruginosa pathogenicity and reveal that this microorganism can obtain zinc through a strategy resembling siderophore-mediated iron uptake.

Pyruvate prevents the development of age-dependent cognitive deficits in a mouse model of Alzheimer's disease without reducing amyloid and tau pathology.

Amyloid-ß (Aß) deposition and tau-dependent pathology are key features of Alzheimer's disease (AD). However, to date, approaches aimed at counteracting these two pathogenic factors have produced only modest therapeutic outcomes. More effective therapies should therefore consider additional pathogenic factors like energy production failure, hyperexcitability and excitotoxicity, oxidative stress, deregulation of metal ion homeostasis, and neuroinflammation. Pyruvate is an energy substrate associated with neuroprotective properties. In this study, we evaluated protective effects of long-term administration of pyruvate in 3xTg-AD mice, a preclinical AD model that develops amyloid-ß- and tau-dependent pathology. Chronic (9 months) treatment with pyruvate inhibited short and long-term memory deficits in 6 and 12 months old 3xTg-AD mice as assessed with the Morris water maze test. Pyruvate had no effects on intraneuronal amyloid-ß accumulation and, surprisingly, the molecule increased deposition of phosphorylated tau. Pyruvate did not change aerobic or anaerobic metabolisms but decreased lipid peroxidation, counteracted neuronal hyperexcitability, decreased baseline levels of oxidative stress, and also reduced reactive oxygen species-driven elevations of intraneuronal Zn(2+) as well as glutamate receptor-mediated deregulation of intraneuronal Ca(2+). Thus, pyruvate promotes beneficial cognitive effects without affecting Aß and tau pathology. The molecule mainly promotes a reduction of hyperexcitability, oxidative stress while favors the regulation of intraneuronal Ca(2+) and Zn(2+) homeostasis rather than acting as energy substrate. Pyruvate can be therefore a valuable, safe, and affordable pharmacological tool to be associated with classical anti-Aß and tau drugs to counteract the development and progression of AD-related cognitive deficits and neuronal loss.

p63 isoforms regulate metabolism of cancer stem cells.

p63 is an important regulator of epithelial development expressed in different variants containing (TA) or lacking (ΔN) the N-terminal transactivation domain. The different isoforms regulate stem-cell renewal and differentiation as well as cell senescence. Several studies indicate that p63 isoforms also play a role in cancer development; however, very little is known about the role played by p63 in regulating the cancer stem phenotype. Here we investigate the cellular signals regulated by TAp63 and ΔNp63 in a model of epithelial cancer stem cells. To this end, we used colon cancer stem cells, overexpressing either TAp63 or ΔNp63 isoforms, to carry out a proteomic study by chemical-labeling approach coupled to network analysis. Our results indicate that p63 is implicated in a wide range of biological processes, including metabolism. This was further investigated by a targeted strategy at both protein and metabolite levels. The overall data show that TAp63 overexpressing cells are more glycolytic-active than ΔNp63 cells, indicating that the two isoforms may regulate the key steps of glycolysis in an opposite manner. The mass-spectrometry proteomics data of the study have been deposited to the ProteomeXchange Consortium ( http://proteomecentral.proteomexchange.org ) via the PRIDE partner repository with data set identifiers PXD000769 and PXD000768.

Sex-specific adipose tissue's dynamic role in metabolic and inflammatory response following peripheral nerve injury.

Epidemiological data and research highlight increased neuropathy and chronic pain prevalence among females, spanning metabolic and normometabolic contexts, including murine models. Prior findings demonstrated diverse immune and neuroimmune responses between genders in neuropathic pain (NeP), alongside distinct protein expression in sciatic nerves. This study unveils adipose tissue's (AT) role in sex-specific NeP responses after peripheral nerve injury. Metabolic assessments, metabolomics, energy expenditure evaluations, AT proteomic analyses, and adipokine mobilization depict distinct AT reactions to nerve damage. Females exhibit altered lipolysis, fatty acid oxidation, heightened energy expenditure, and augmented steroids secretion affecting glucose and insulin metabolism. Conversely, male neuropathy prompts glycolysis, reduced energy expenditure, and lowered unsaturated fatty acid levels. Males' AT promotes regenerative molecules, oxidative stress defense, and stimulates peroxisome proliferator-activated receptors (PPAR-γ) and adiponectin. This study underscores AT's pivotal role in regulating gender-specific inflammatory and metabolic responses to nerve injuries, shedding light on female NeP susceptibility determinants.

Contribution of vitamin D3 and thiols status to the outcome of COVID-19 disease in Italian pediatric and adult patients.

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), was declared a global pandemic by the World Health Organization (WHO) on March 2020, causing unprecedented disease with million deaths across the globe, mostly adults. Indeed, children accounted for only a few percent of cases. Italy was the first Western country struck by the COVID-19 epidemic. Increasing age, which is one of the principal risk factors for COVID-19 mortality, is associated with declined glutathione (GSH) levels. Over the last decade, several studies demonstrated that both vitamin D (VD) and GSH have immunomodulatory properties. To verify the association between VD, GSH and the outcome of COVID-19 disease, we conducted a multicenter retrospective study in 35 children and 128 adult patients with COVID-19. Our study demonstrated a hypovitaminosis D in COVID-19 patients, suggesting a possible role of low VD status in increasing the risk of COVID-19 infection and subsequent hospitalization. In addition, we find a thiol disturbance with a GSH depletion associated to the disease severity. In children, who fortunately survived, both VD and GSH levels at admission were higher than in adults, suggesting that lower VD and thiols levels upon admission may be a modifiable risk factor for adverse outcomes and mortality in hospitalized patients with COVID-19.

Composition of meat and offal from weaned and fattened rabbits and results of stereospecific analysis of triacylglycerols and phosphatidylcholines.

BACKGROUND: Rabbit meat has excellent nutritive properties. The purpose of this study was to characterize rabbit meat and offal; in particular, the lipid fraction was studied in order to evaluate total and positional fatty acid (FA) compositions of triacylglycerol (TAG) and phosphatidylcholine (PC) fractions. Eight samples of weaned and eight of fattened rabbits were considered. RESULTS: Fattened rabbit meat contained slightly higher protein percentage content (P < 0.05) in comparison to weaned (20.1% versus 18.0%). Calcium content was higher in meat than in offal, unlike sodium, iron, zinc, manganese and copper. The cholesterol content in offal was much higher than in meat. FA profiles of total lipid showed a high percentage of unsaturated fatty acids and an n-6/n-3 ratio of 10.3 for fattened rabbit meat. Stereospecific analysis of TAG and PC was carried out on an eight-sample pool of each meat and offal from weaned and fattened rabbits. In all samples the sn-2-position was prevalently esterified with oleic and linoleic acids in TAG, with polyunsaturated fatty acids in PC. CONCLUSION: Lipids from rabbit meat presented higher content of monounsaturated FA and lower n-6/n-3 ratio in comparison to offal, which was characterized by higher cholesterol and mineral levels.

Confirmation of congenital adrenal hyperplasia by adrenal steroid profiling of filter paper dried blood samples using ultra-performance liquid chromatography-tandem mass spectrometry.

BACKGROUND: The specificity of screening for congenital adrenal hyperplasia by direct measurement of 17-hydroxyprogesterone in filter paper dried blood spot samples by immunoassay is low and has a high false-positive rate. In order to reduce the false-positive rate of this test, we developed a rapid, robust, specific confirmatory procedure in which cortisol, 4-androstene-3,17-dione and 17-hydroxyprogesterone were measured simultaneously by ultra-performance liquid chromatography-tandem mass spectrometry. METHODS: After extraction, samples were analysed by ultra-performance liquid chromatography-tandem mass spectrometry and 17-hydroxyprogesterone was quantified accurately. Other steroids were determined using stable deuterated internal standards. In total, 25 patient blood spot samples and 92 control samples were analysed. RESULTS: The assay was linear for 17-hydroxyprogesterone, with a coefficient of determination >0.997 and imprecision ≤ 6.5%. An upper limit of normal for 17-hydroxyprogester-one of 4.45 nmol/L was established by analysing a cohort of samples from unaffected newborns. In addition, a cut-off of 3.5 for the peak areas ratio (17-hydroxyprogesterone+4-androstene-3,17-dione)/cortisol, allows confirmation of the affected steroidogenic enzyme. CONCLUSIONS: A high throughput method for the detection of steroids related to congenital adrenal hyperplasia has been developed, allowing the false-positive rate associated with screening for 17-hydroxyprogesterone by immunoassay to be determined.

Cerebrospinal Fluid Levels of AFP and hCG: Validation of the Analytical Method and Application in the Diagnosis of Central Nervous System Germ Cell Tumors.

The determination of Human Chorionic Gonadotropin (hCG) and Alpha Fetoprotein (AFP) levels on serum and amniotic fluid plays a fundamental role in the diagnosis and follow-up of specific physiological or pathological conditions (e.g., pregnancy, threat of abortion or germ cell tumors). Recently, the quantification of hCG and AFP in other biological fluids has gained great attention to support the diagnosis, prognosis and follow-up of neoplastic diseases deriving from trophoblastic cells, such as germinomas. Most of the commercial kits for hCG and AFP assays are developed to be used on biological fluids such as serum/plasma and/or urine by manufacturing companies. The aim of this work was to evaluate the suitability of the analytical method certified for the use on serum, and/or amniotic fluid for the quantification of hCG and AFP in cerebrospinal fluid, carrying out an internal validation protocol. The data reported here show that the automated immunochemical method is fit for quantification of hCG and AFP in cerebrospinal fluid (CSF), allowing selective and specific diagnosis of secreting germ cell tumors. This is confirmed by the positive correlation between elevated levels of hCG or AFP and the diagnosis of brain tumors.

Effects of low-dose methylcyclopentadienyl manganese tricarbonyl-derived manganese on the development of diencephalic dopaminergic neurons in zebrafish.

Fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT) is counted as an organic manganese (Mn)-derived compound. The toxic effects of Mn (alone and complexed) on dopaminergic (DA) neurotransmission have been investigated in both cellular and animal models. However, the impact of environmentally relevant Mn exposure on DA neurodevelopment is rather poorly understood. In the present study, the MMT dose of 100 µM (about 5 mg Mn/L) caused up-regulation of DA-related genes in association with cell body swelling and increase in the number of DA neurons of the ventral diencephalon subpopulation DC2. Furthermore, our analysis identified significant brain Mn bioaccumulation and enhancement of total dopamine levels in association with locomotor hyperactivity. Although DA levels were restored at adulthood, we observed a deficit in the acquisition and consolidation of memory. Collectively, these findings suggest that developmental exposure to low-level MMT-derived Mn is responsible for the selective alteration of diencephalic DA neurons and with long-lasting effects on fish explorative behaviour in adulthood.

Cobalt can fully recover the phenotypes related to zinc deficiency in Salmonella Typhimurium.

Cobalt is an essential element for living systems, which, however, make very limited use of this metal, using it mainly in cobalamin-containing enzymes. The reduced use of cobalt compared to other transition metals is generally attributed to the potential toxicity of this element. In this work, we demonstrate that cobalt not only does not have an obvious toxic effect on Salmonella Typhimurium, but that it can efficiently compensate for zinc deficiency in a znuABC deleted strain. In fact, cobalt, but not cobalamin supplementation, rescued all major phenotypic defects of the znuABC strain, including the reduced ability to grow and swim in zinc-deficient media and the high susceptibility to hydrogen peroxide stress. Growth in a cobalt-supplemented defined medium led to the accumulation of large amounts of cobalt both in the wild type and in the znuABC strain. These data suggest that atoms of cobalt may be incorporated in bacterial proteins in place of zinc, ensuring their functionality. In support of this hypothesis we have shown that, in vivo, cobalt can accumulate in ribosomes and replace zinc in a periplasmic Cu,Zn superoxide dismutase (SodCII). Finally, we provide evidence of the ability of cobalt to modulate the intracellular concentration of zinc-regulated proteins (ZnuA, ZinT, and SodCII). Although some observations suggest that in some proteins the replacement of zinc with cobalt can lead to subtle structural changes, the data reported in this study indicate that Salmonella has the ability to use cobalt instead of zinc, without evident harmful effects for cell physiology.

Ceramic-on-metal bearing in short stem total hip arthroplasty: ions, functional and radiographic evaluation at mid-term follow-up.

INTRODUCTION: The aim of this study is to evaluate clinical, radiographic and laboratory results of ceramic-on-metal (CoM) (hybrid hard bearing) in total hip arthroplasty (THA), associated with a short stem implant. METHODS: From a cohort of 37 patients suffering from primary or secondary hip osteoarthritis who underwent THA using CoM bearing, 19 were suitable for this study. All procedures were performed by the same surgeon using a posterior-lateral approach. All patients were compared clinically using the Harris Hip Score (HHS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analogue scale (VAS), 12-item Short Form Health Survey (SF12F/M), and radiographically (offset, CD angle, limb length discrepancy, cup inclination and anteversion, subsidence, osseointegration, heterotopic ossification). Blood samples were collected in order to evaluate chromium (Cr) and cobalt (Co) ions level. Radiographic evaluations were carried out by 3 different blinded surgeons. A statistical analysis was performed. RESULTS: At a mean follow-up of 97 (73-125) months all implanted stems were well-positioned and osseointegrated. Clear improvements were observed for clinical scores comparing preoperative and postoperative values. Radiographic evaluation showed a good ability to restore proper articular geometry. Cr ion analysis revealed values below the safety threshold except for 1 case. Serum levels of Co were below the threshold in all patients. There was a statistically significant correlation only between Cr metal ions and length of follow-up. CONCLUSIONS: CoM bearing has proven to be reliable and safe at a mean 8-year follow-up for patients in whom the components were correctly implanted. The rise of blood metal ions was minimal and involved neither systemic or local toxicity nor influenced clinical results.

Comment on "Shiatsu as an Adjuvant Therapy for Depression in Patients With Alzheimer's Disease: A Pilot Study".

Recently, there has been increasing interest toward nonpharmacological approaches for dementia and associated clinical manifestations, such as depression, with the common goal to improve health and quality of life of both patients and caregivers. In this scenario, the role of Shiatsu is of clinical and research interest, although to date a definitive recommendation on a systematic use in clinical practice cannot be made. To overcome the heterogeneity of the previous studies, we tested Shiatsu as an add-on treatment for late-life depression in a dedicated community of patients with mild-to-moderate Alzheimer's disease. We found a significant adjuvant effect of Shiatsu for depression in these patients and hypothesized a neuroendocrine-mediated action on the neural circuits implicated in mood and affect regulation. However, this finding must be considered preliminary and requires confirmation in larger-scale controlled studies, possibly extending the range of outcome measures and including predictors of response. Future investigations should also include an objective assessment of the hypothalamus-pituitary-adrenocortical axis functioning. Nevertheless, starting from this pilot study, we suggest that a customized protocol applied for an adequate period in a controlled sample will represent a non-invasive and feasible advance for promoting patients' mood and, possibly, slowing cognitive decline.

Aluminum modulates effects of beta amyloid(1-42) on neuronal calcium homeostasis and mitochondria functioning and is altered in a triple transgenic mouse model of Alzheimer's disease.

Recent findings suggest that beta-amyloid (A beta) is more neurotoxic when present in its oligomeric configuration rather than as monomers or fibrils. Previous work from our laboratories has shown that A beta aggregation is strongly influenced by the conjugation of the peptide with metal ions (aluminum A, copper [Cu], zinc [Zn], and iron [Fe]) that are found in high concentrations in the core of senile plaques. Disruption of Ca++ signaling and mitochondrial dysfunction are potent triggers of neuronal death and have been implicated in the neuronal loss that is associated with Alzheimer's disease (AD). In this study, we explored whether A beta-metal complexes can have detrimental effects on intraneuronal Ca++ ([Ca++]i) homeostasis and mitochondrial function in vitro. Results from our experiments indicate that, when conjugated with Al, A beta perturbs neuronal [Ca++]i homeostasis and inhibits mitochondrial respiration. Finally, we analyzed the content of the four metals in the brain of a triple transgenic animal model of AD and found that Al is the only one to be increased in the cortex of these mice.

Shiatsu as an adjuvant therapy for depression in patients with Alzheimer's disease: A pilot study.

OBJECTIVES: Among the complementary and alternative medicine, Shiatsu might represent a feasible option for depression in Alzheimer's disease (AD). We evaluated Shiatsu on mood, cognition, and functional independence in patients undergoing physical activity. DESIGN: Single-blind randomized controlled study. SETTING: Dedicated Community Center for patients with AD. INTERVENTIONS: AD patients with depression were randomly assigned to the "active group" (Shiatsu + physical activity) or the "control group" (physical activity alone). Shiatsu was performed by the same therapist once a week for ten months. MAIN OUTCOME MEASURES: Global cognitive functioning (Mini Mental State Examination - MMSE), depressive symptoms (Geriatric Depression Scale - GDS), and functional status (Activity of Daily Living - ADL, Instrumental ADL - IADL) were assessed before and after the intervention. RESULTS: We found a within-group improvement of MMSE, ADL, and GDS in the active group. However, the analysis of differences before and after the interventions showed a statistically significant decrease of GDS score only in the active group. CONCLUSIONS: The combination of Shiatsu and physical activity improved depression in AD patients compared to physical activity alone. The pathomechanism might involve neuroendocrine-mediated effects of Shiatsu on neural circuits implicated in mood and affect regulation.

Effects of caloric restriction on neuropathic pain, peripheral nerve degeneration and inflammation in normometabolic and autophagy defective prediabetic Ambra1 mice.

There is a growing interest on the role of autophagy in diabetes pathophysiology, where development of neuropathy is one of the most frequent comorbidities. We have previously demonstrated that neuropathic pain after nerve damage is exacerbated in autophagy-defective heterozygous Ambra1 mice. Here, we show the existence of a prediabetic state in Ambra1 mice, characterized by hyperglycemia, intolerance to glucose and insulin resistance. Thus, we further investigate the hypothesis that prediabetes may account for the exacerbation of allodynia and chronic pain and that counteracting the autophagy deficit may relieve the neuropathic condition. We took advantage from caloric restriction (CR) able to exert a double action: a powerful increase of autophagy and a control on the metabolic status. We found that CR ameliorates neuropathy throughout anti-inflammatory and metabolic mechanisms both in Ambra1 and in WT animals subjected to nerve injury. Moreover, we discovered that nerve lesion represents, per se, a metabolic stressor and CR reinstates glucose homeostasis, insulin resistance, incomplete fatty acid oxidation and energy metabolism. As autophagy inducer, CR promotes and anticipates Schwann cell autophagy via AMP-activated protein kinase (AMPK) that facilitates remyelination in peripheral nerve. In summary, we provide new evidence for the role of autophagy in glucose metabolism and identify in energy depletion by dietary restriction a therapeutic approach in the fight against neuropathic pain.

Proteomic and metabolomic characterization of streptozotocin-induced diabetic nephropathy in TIMP3-deficient mice.

AIMS: The tissue inhibitor of metalloproteinase TIMP3 is a stromal protein that restrains the activity of both protease and receptor in the extracellular matrix and has been found to be down-regulated in diabetic nephropathy (DN), the leading cause of end-stage renal disease in developed countries. METHODS: In order to gain deeper insights on the association of loss of TIMP3 and DN, we performed differential proteomic analysis of kidney and blood metabolic profiling of wild-type and Timp3-knockout mice before and after streptozotocin (STZ) treatment, widely used to induce insulin deficiency and hyperglycemia. RESULTS: Kidney proteomic data and blood metabolic profiles suggest significant alterations of peroxisomal and mitochondrial fatty acids ß-oxidation in Timp3-knockout mice compared to wild-type mice under basal condition. These alterations were exacerbated in response to STZ treatment. CONCLUSIONS: Proteomic and metabolomic approaches showed that loss of TIMP3 alone or in combination with STZ treatment results in significant alterations of kidney lipid metabolism and peripheral acylcarnitine levels, supporting the idea that loss of TIMP3 may generate a phenotype more prone to DN.

Influence of APOE and RNF219 on Behavioral and Cognitive Features of Female Patients Affected by Mild Cognitive Impairment or Alzheimer's Disease.

The risk for Alzheimer's disease (AD) is associated with the presence of the 𝜀4 allele of Apolipoprotein E (APOE) gene and, recently, with a novel genetic variant of the RNF219 gene. This study aimed at evaluating interactions between APOE-𝜀4 and RNF219/G variants in the modulation of behavioral and cognitive features of two cohorts of patients suffering from mild cognitive impairment (MCI) or AD. We enrolled a total of 173 female MCI or AD patients (83 MCI; 90 AD). Subjects were screened with a comprehensive set of neuropsychological evaluations and genotyped for the APOE and RNF219 polymorphic variants. Analysis of covariance was performed to assess the main and interaction effects of APOE and RNF219 genotypes on the cognitive and behavioral scores. The analysis revealed that the simultaneous presence of APOE-𝜀4 and RNF219/G variants results in significant effects on specific neuropsychiatric scores in MCI and AD patients. In MCI patients, RNF219 and APOE variants worked together to impact the levels of anxiety negatively. Similarly, in AD patients, the RNF219 variants were found to be associated with increased anxiety levels. Our data indicate a novel synergistic activity APOE and RNF219 in the modulation of behavioral traits of female MCI and AD patients.