The Role of Perivascular Adipose Tissue in the Pathogenesis of Endothelial Dysfunction in Cardiovascular Diseases and Type 2 Diabetes Mellitus.

Cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM) are two of the four major chronic non-communicable diseases (NCDs) representing the leading cause of death worldwide. Several studies demonstrate that endothelial dysfunction (ED) plays a central role in the pathogenesis of these chronic diseases. Although it is well known that systemic chronic inflammation and oxidative stress are primarily involved in the development of ED, recent studies have shown that perivascular adipose tissue (PVAT) is implicated in its pathogenesis, also contributing to the progression of atherosclerosis and to insulin resistance (IR). In this review, we describe the relationship between PVAT and ED, and we also analyse the role of PVAT in the pathogenesis of CVDs and T2DM, further assessing its potential therapeutic target with the aim of restoring normal ED and reducing global cardiovascular risk.

Magnetic resonance imaging highlights the meningeal involvement in steroid responsive meningitis-arteritis and suggests the inflammation of the surrounding tissues (70 cases).

Introduction: Steroid-responsive meningitis-arteritis (SRMA) is an immune-mediated disorder of young dogs for which there is no definitive ante-mortem diagnostic test. Magnetic Resonance Imaging (MRI) can be used to explore other differentials and extensive reports about its usefulness in the diagnosis of SRMA are lacking. The aims of this study were to retrospectively investigate the characteristics of MRI studies of the cervical spine of dogs diagnosed with SRMA and to compare the diagnostic capability of MRI obtained with low-field and high-field units. Materials and methods: This is a double center, retrospective case series. Databases were searched between 2008 and 2021 for dogs with a diagnosis of SRMA. Dogs were included if the following criteria were fulfilled: a diagnosis of cervical SRMA, results of CSF analysis, and MRI of the cervical spine available for re-evaluation. Results: Seventy cases were selected. MRI abnormalities were found in 69 cases (98.6%). Enhancement of the meninges, nerve roots, synovium of the articular facets and paravertebral muscles was present in 61 (87.1%), 10 (14.3%), 34 (48.6%), and 34 (48.6%) cases, respectively, when considering all MRI. In the low-field MRI, enhancement of these structures was present in 45 (90%), 4 (8%), 21 (42%) and 23 (46%) cases, respectively. In the high-field MRI, enhancement of these structures was present in 16 (80%), 6 (30%), 13 (65%) and 11 (55%) cases, respectively. Fat suppressed T1W images showed meningeal enhancement better than T1W images. When all the MRIs were considered, a significant increase in cell count of the cerebrospinal fluid was found between the three groups based on the meningeal MRI score (p = 0.001). In cases with no meningeal enhancement but enhancement of synovium of the articular facets and/or muscles a significantly lower cerebrospinal fluid cell count was present (p = 0.043), when considering all MRIs. Conclusions: The most frequent detection on cervical MRI of dogs affected by SRMA is meningeal enhancement, often accompanied by enhancement of the synovium of the articular facets and/or muscular enhancement. Both low-field and high-field MRI have good diagnostic capability but the latter enables a more thorough investigation thanks to specific sequences. MRI is useful as a complementary tool to cerebrospinal fluid analysis.

Evaluation of body surface temperature variations in dogs affected by spinal cord injuries during physiotherapy exercise in a water treadmill.

The aim this study was to evaluate variation in body surface temperature (BST) in healthy and spinal cord injured (SCI) dogs, and to outline temperature variation at rest (T0), during (T1) and after (T2) water-treadmill physiotherapy sessions in SCI using infrared thermography (IRT). Sixty-seven dogs of different sex, breed, body weight and age were enrolled: 14 healthy dogs and 53 dogs affected by disc pathologies. The study examined three regions of interest (ROIs): the total image of the spine (IMAGE), the spinal cord area from 1st thoracic vertebra to the last lumbar vertebra (AR01) and the surgery wound or spinal cord lesion area (AR02). Significant BST variations between healthy and SCI were reported in T°max and T°max-min (ΔT) values in IMAGE (P < 0.05). In SCI group, AR01 and AR02 assessment showed an increase in temperature ate the sited of the injured area and adjacent body structures. In SCI, a significant effect of water-treadmill exercise in AR01 and AR02 was reported. In fact, both AR01 and AR02 reported higher BST (T°max, T°mean, T°min and ΔT) during the physical exercise (T1), representing the response to physical activity of the spine vascularization, muscles and column contiguous tissues. Furthermore, in T2, the same areas reported a significant lower BST (T°max, T°mean, and ΔT), related to a decrease in tissue inflammation on the target area of the water treadmill physiotherapy. This study highlights how IRT can detect BST variations associated with injured areas. In addition, IRT revealed a positive effect of water-treadmill exercise on the injured spinal cord areas, thus it could be a viable non-invasive and rapid method to support both clinical examination and assessment of the effectiveness of medical treatment in SCI.

Obesity, vitamin D status and physical activity: 1,25(OH)2D as a potential marker of vitamin D deficiency in obese subjects.

BACKGROUND: Obesity has been regarded to be protective against fracture in spite of its association with low levels of vitamin D. Vitamin D is the key regulator of bone metabolism and its deficiency contributes to higher level of parathyroid hormone (PTH), leading to the activation of bone turnover. METHODS: We studied 161 subjects of which 65 were young healthy subjects and 96 were elderly subjects. We measured creatinine, 25(OH)D, 1,25(OH)2D, PTH, albumin, and calcium plasma levels, we evaluated physical activity, and we calculated BMI. A sub-cohort of elderly subjects also underwent DXA scans. RESULTS: Overweight and obese subjects, as well as underweight ones, had lower levels of vitamin D but normal serum concentrations of 1,25(OH)2D and PTH was higher in underweight and obese subjects. Moreover, we found a nonlinear relationship between body mass index (BMI) and PTH with a significant U-shaped exponential regression. Regardless of BMI, 25(OH)D mean levels were higher in subjects who practice physical activity. CONCLUSIONS: These findings suggest that physical activity and BMI had a significant effect on the metabolism of bone and vitamin D, but the effect of BMI was different in underweight, normal weight or obese subjects. In obesity the real vitamin D deficiency could be estimate by serum 1,25(OH)2D concentrations whose lower levels contribute to the higher PTH production and consequently to bone loss and to a greater fracture risk.

Comparison of the efficacy of two ventilatory strategies in improving arterial oxygen tension and content in anaesthetized sheep.

OBJECTIVE: To compare F-shunt and oxygen content indices in sheep ventilated with a positive end-expiratory pressure (PEEP) of 5 cmH2O alone or preceded by a stepwise alveolar recruitment manoeuvre (ARM). STUDY DESIGN: Randomized crossover design. ANIMALS: A total of six nonpregnant Brogna ewes weighing 34-47 kg, undergoing thoracolumbar magnetic resonance scan. METHODS: In medetomidine-sedated sheep, anaesthesia was induced with propofol and maintained with isoflurane 1.1% ± 0.1% and an inspired oxygen fraction (FiO2) of 0.4. Animals were placed in left lateral recumbency and, after 10 minutes of spontaneous breathing, mechanically ventilated with 5 cmH2O of PEEP with (group ARM) or without (group PEEP) a stepwise recruitment manoeuvre. Maintaining a fixed driving pressure of 15 cmH2O, PEEP was increased from 0 to 20 cmH2O every 3 minutes in 5 cmH2O increments. In each sheep, arterial blood samples were collected to measure arterial gases and to calculate F-shunt, PaO2/alveolar oxygen partial pressure (PAO2) and PaO2/FIO2 during spontaneous breathing before mechanical ventilation (T0), after 20 minutes of ventilation (T20) and during spontaneous breathing at extubation (Text). RESULTS: Both ventilatory strategies improved the arterial oxygen content although four animals in group PEEP showed oxygen content compatible with hypoxia compared with group ARM. F-shunt values were not statistically different at any time point in sheep that underwent only PEEP ventilation while they decreased at T20 and Text compared with T0 in group ARM. At extubation F-shunt was statistically lower in sheep that underwent an ARM. Mechanical ventilation improved PaO2/PAO2 and PaO2/FIO2 but they did not differ between groups. CONCLUSIONS: and clinical relevance The stepwise ARM evaluated in this study improved oxygenation indices and decreased F-shunt. This effect was maintained at extubation compared with sheep that were ventilated with only PEEP 5 cmH2O.

Gut Microbiota and Type 1 Diabetes Mellitus: The Effect of Mediterranean Diet.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease resulting from a complex interplay between genetic susceptibility and environmental factors. Regarding the latter, gut microbiota has a pivotal role in the pathogenesis of T1DM, by affecting intestinal permeability, molecular mimicry, and modulating innate and adaptive immune system, as described in several previous studies. The composition of the gut microbiota is largely influenced by diet. Some observational studies have shown that a low fiber intake is associated with the development of many inflammatory and immune-mediated diseases. In this context, the Mediterranean diet (MD), which is based on high consumption of cereals (preferably as whole grains), legumes, nuts, vegetables, fruits, olive oil, and fish, could play a protective role. Many of the characteristic components of MD have functional characteristics with positive effects on health and well-being. Eating habits are the main significant determinants of the microbial multiplicity of the intestine and the food components influence both microbial populations and their metabolic activities from the early stages of life. Moreover, food metabolites influence the immune response. The intestine is considered the primary site where food metabolites mediate their effects, through epithelial integrity or mucosal immunity. The compromised epithelial integrity allows the translocation of bacteria and/or the diffusion of their products, such as food antigens and lipopolysaccharides, from the intestinal lumen to the tissues, which could enhance the stimulation of immune cells, contributing to the pathogenesis of autoimmune diseases, such as T1DM. The intake of a high amount of fiber and therefore of prebiotics with MD allows the microbiota to have a good microbial balance. Moreover, as more dietary fibers are ingested, a higher amount of short-chain fatty acids (SCFAs) is produced by anaerobic gut microbiota, promoting gut homeostasis, to which also contribute tryptophan metabolites and omega-3-fatty acids. Furthermore, the higher intake of polyunsaturated fatty acids and omega-3-fatty-acids contribute to a better metabolic control. In this review we report the relationship between gut microbiota and T1DM and we explore the effects of Mediterranean diet on microbiota as a potential therapeutic strategy, aimed at preventing or delaying progression of T1DM and its complications.

Osteoprotegerin in diabetic osteopathy.

AIM: The aim of this study is to evaluate the relationship between OPG and the degree of glycaemic control in a population of elderly subjects. METHODS AND RESULTS: Data presented included 172 elderly subjects, of whom 107 were hospitalized for a hip fracture and 65 were non fractured outpatients. All participants received a multidimensional geriatric evaluation and underwent blood sampling. HbA1c, OPG, CTX and OC were measured and DXA scans were performed. Carotid intima-media thickness (IMT) was measured in all outpatients. Diabetic patients had more comorbidities, higher mean values of lumbar spine and femoral neck BMD and T-score, lower circulating levels of OC and CTX, and higher circulating levels of OPG compared to non-diabetic subjects. OPG was directly correlated with HbA1c. This association was most evident in non-fractured elderly subjects. Moreover, diabetic patients with IMT>1.5 mm had greater mean values of OPG than non-diabetic subjects with high IMT and than elderly subjects with IMT < 1.5 mm, with and without T2DM. CONCLUSIONS: Diabetic patients have reduced circulating levels of OC and CTX, and elevated serum levels of OPG, suggesting a state of low bone turnover. Reduced bone turnover causes an increase of BMD and could lead to a poor bone quality. OPG and HbA1c were directly correlated and OPG mean values were higher in diabetic patients with poor glucose control. Diabetic osteopathy could be considered a late complication of T2DM, directly related with the degree of glucose control and the duration of the disease.

Calcification biomarkers and vascular dysfunction in obesity and type 2 diabetes: influence of oral hypoglycemic agents.

Vascular aging in obesity and type 2 diabetes (T2D) is associated with progressive vascular calcification, an independent predictor of morbidity and mortality. Pathways for vascular calcification modulate bone matrix deposition, thus regulating calcium deposits. We investigated the association between biomarkers of vascular calcification and vasodilator function in obesity or T2D, and whether antidiabetic therapies favorably impact those markers. Circulating levels of proteins involved in vascular calcification, such as osteopontin (OPN), osteoprotegerin (OPG), regulated on activation, normal T cell expressed and secreted (RANTES), and fetuin-A were measured in lean subjects, individuals with metabolically healthy obesity (MHO), and patients with metabolically unhealthy obesity (MUO) or T2D. Vasodilator function was assessed by infusion of ACh and sodium nitroprusside (SNP). Circulating levels of OPN were higher in the MUO/T2D group than in lean subjects (P < 0.05); OPG and RANTES were higher in MUO/T2D group than in the other groups (both P < 0.001); fetuin-A was not different between groups (P > 0.05); vasodilator responses to either ACh or SNP were impaired in both MUO/T2D and MHO compared with lean subjects (all P < 0.001). In patients with T2D who were enrolled in the intervention trial, antidiabetic treatment with glyburide, metformin, or pioglitazone resulted in a significant reduction of circulating OPG (P = 0.001), without changes in the other biomarkers and vasodilator responses (all P > 0.05). In conclusion, obese patients with MUO/T2D have elevated circulating OPN, OPG, and RANTES; in these patients, antidiabetic treatment reduces only circulating OPG. Further study is needed to better understand the mechanisms of vascular calcifications in obesity and diabetes.

Osteoprotegerin as a biomarker of geriatric frailty syndrome.

The lack of a univocal definition of frailty, a condition frequently found in the elderly population which is correlated with an increased risk of mortality, has prompted the search for clinical and laboratory parameters associated with this condition. Whereas OPG is a protein involved in different pathophysiological conditions including bone, vascular, immune and tumor disease and studies found a positive linear correlation between OPG and age we hypothesized that it may represent a frailty marker in the elderly.We conducted an observational study of 172 elderly subjects, with and without hip fracture, including a multidimensional geriatric evaluation and a laboratory evaluation, aimed to evaluate the association between OPG and frailty.Frailty Score was associated with FT3 and osteoprotegerin (OPG), regardless of fracture event. Excluding subjects with hip fracture, in whom the acute event had a direct effect on bone production of OPG, the Frailty Score showed a linear correlation with circulating levels of osteoprotegerin.In the elderly, an increase in osteoprotegerin levels may reflect a progressive accumulation of organ damage leading to the development of frailty. The correlation between OPG and Frailty Score found in our study points to its potential use as a biomarker for geriatric frailty syndrome.

FRAX tool in type 2 diabetic subjects: the use of HbA1c in estimating fracture risk.

AIMS: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures, despite having greater bone mineral density (BMD) than non-diabetic subjects. This has led to the hypothesis that the presence of impaired bone quality among diabetics reduces bone strength. The Fracture Risk Assessment Score (FRAX) algorithm, introduced to facilitate the evaluation of fracture risk, underestimates the risk of fracture in diabetic patients. The purpose of this study is to confirm the relationship between the degree of metabolic compensation and the 10-year probability of a major fracture or a hip osteoporotic fracture observed in our previous study and to ascertain whether glycosylated hemoglobin (HbA1c) can improve the predictive value of FRAX in patients with T2DM. METHODS: Our data derive from a retrospective clinical study conducted at the "Tor Vergata" Polyclinic in Rome on 6355 subjects over 50 years of age evaluated for osteoporosis. All available clinical records were examined. HbA1c was available for 242 of these subjects and all had had a Dual-energy X-ray Absorption (DXA) scan of the lumbar spine and femoral neck. The risk of fracture was estimated using the Italian version of the FRAX algorithm. RESULT: Patients with T2DM had BMD and T-scores higher than those of non-diabetic subjects, while FRAX average values were higher in the non-diabetic group. HbA1c and FRAX are inversely correlated with each other: for each incremental percentage point of HbA1c growth, the FRAX major osteoporotic fracture probability is reduced by 0.915 points and the FRAX hip osteoporotic fracture probability by 1.438 points. The introduction of a correction factor derived from HbA1c, resulted in mean FRAX values of diabetic patients equivalent to those of non-diabetic subjects. CONCLUSIONS: We propose a correction factor derived from HbA1c that could enhance the predictive ability of fracture risk estimated by the FRAX algorithm in subjects with T2DM.

Frailty and nutritional status in older people: the Mini Nutritional Assessment as a screening tool for the identification of frail subjects.

INTRODUCTION: Frailty is a condition characterized by reduced resistance to low-level stress events, resulting from the progressive decline of multiple physiological systems observed with aging. Many factors can contribute to the pathogenesis of frailty, and nutritional status appears to play a key role. The objective of the study was to investigate the relationship between nutritional status, evaluated using Mini Nutritional Assessment (MNA), and frailty among older people. PATIENTS AND METHODS: An observational study was carried out at the University Hospital "Tor Vergata" in Rome among patients aged 65 years or older, with or without hip fracture. The study sample included 62 patients hospitalized for a hip fracture and 50 outpatients without fracture. All subjects underwent blood sampling for laboratory assays and received a multidimensional geriatric evaluation comprising Activity of Daily Living (ADL), Instrumental Activity of Daily Living (IADL), Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), and MNA. Comorbidity was assessed using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). Muscle strength was measured by handgrip dynamometry, and frailty score was calculated using the Survey of Health, Ageing and Retirement in Europe-Frailty Index (SHARE-FI). RESULTS: Approximately 38% of the study population was frail, with the prevalence of frailty being greater among hospitalized older patients. Among frail subjects, 65% were at risk of malnutrition (RMN) and 10% were malnourished. The prevalence and RMN progressively diminished in the pre-frail group and not frail group. Nutritional status was closely associated with the degree of frailty, and in a logistic regression, MNA was the best variable predicting both pre-frailty and frailty. DISCUSSION AND CONCLUSION: Malnutrition contributes to the development of frailty. MNA can generate vital information to help identify a substantial part of both frail and pre-frail patients at low cost and care.

Low FT3: a possible marker of frailty in the elderly.

INTRODUCTION: Frailty is associated with a functional decline of multiple physiological systems, of which they may be a cause or consequence. The objective of the study was to evaluate the prevalence of thyroid hormone modifications in elderly frail subjects and its relationship with frailty. STUDY POPULATION AND METHODS: An observational study was carried out at the University Hospital "Tor Vergata" in Rome among ambulatory and hospitalized patients. The study population consisted of 112 elderly subjects: 62 were hospitalized following hip fracture and 50 control subjects were outpatients. Participating patients received a multidimensional geriatric evaluation. The Survey of Health, Ageing and Retirement in Europe Frailty Instrument (SHARE-FI) was used to assess the degree of frailty. Thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) were measured to evaluate thyroid status. RESULTS: FT3, but not FT4, was significantly correlated with Frailty score, both in patients with hip fracture and in patients from the control group. In the entire study population, FT3 under normal limits is effective in discriminating frail/prefrail subjects from nonfrail subjects. DISCUSSION: The reduction in serum concentrations of FT3 is a clear manifestation of stress associated with fractures. Numerous preexisting factors, such as the fracture patients' nutritional status, sarcopenia, disability and comorbidities, which characterize the condition of frailty and influence its pathogenesis, are strongly correlated with FT3 values, suggesting the existence of latent nonthyroidal illness syndrome (NTIS). CONCLUSION: We conclude that measuring FT3 can be a useful laboratory parameter in clinical assessment, which can play an important role in identifying vulnerable elderly subjects and in quantifying the condition of frailty.

Atherosclerosis severity but not undiagnosed diabetes predicts new cardiovascular events of subjects in secondary cardiovascular prevention.

OBJECTIVE: Undiagnosed diabetes (DM2), especially in individuals that have experienced a major atherosclerotic vascular event, could increase the risk of a second major cardiovascular (CV) event. The aim of this study was to evaluate the impact of type 2 diabetes (DM2), diagnosed after a major cardiovascular event, on subsequent CV disease in high risk individuals. METHODS: 411 subjects without known DM2 and with a history of a prior major CV event were followed for a second major CV event (fatal and nonfatal MI, fatal and nonfatal stroke or any arterial revascularization procedure). At baseline, each individual underwent a physical, biochemical examination, an OGTT and dosed A1c. In addition, patients were classified as having monovascular or polyvascular disease. The average follow-up duration was 31 months. RESULTS: The incidence of second CV events was 10.70 per 100 person-years (114 events/1066 person-years). The diagnosis of occult DM2 was not associated with major CV events, either using A1c values ≥6.5%, fasting glucose ≥126 mg/dL or 2 h post-load glucose ≥200 mg/dL. Polyvascular disease was the only significant predictor of a second major CV event (HR 2.60, 95% CI 1.72-3.95) after adjustment for age, BMI, smoking status, systolic blood pressure, high-density and low-density lipoprotein cholesterol and high sensitivity C-reactive protein. CONCLUSION: DM2 that was newly diagnosed after established vascular atherosclerotic disease did not increase the risk of new major CV events. In our population only the polyvascular disease was able to identify the subjects at high risk for a second major cardiovascular event.