Is the response to antihypertensive drugs heterogeneous? Rationale for personalized approach.

Arterial hypertension represents the most important cardiovascular risk factor with a direct responsibility for a large share of cardiovascular mortality and morbidity in the world. Despite the wide availability of antihypertensive therapies with documented effectiveness, blood pressure control still remains largely unsatisfactory in large segments of the population. Guidelines for the management of arterial hypertension suggest the preferential use of five classes of drugs-angiotensin-converting enzyme inhibitors, angiotensin II type I receptor inhibitors, calcium channel blockers, thiazide/thiazide-like diuretics, and beta-blockers-recommending the use of combination therapy, preferably in pre-established combinations, for the majority of hypertensive patients. The evidence of a non-negligible heterogeneity in the response to different antihypertensive drugs in different patients suggests the opportunity for personalization of treatment. The notable phenotypic heterogeneity of the population of hypertensive patients in terms of genetic structure, behavioural aspects, exposure to environmental factors, and disease history imposes the need to consider all the potential determinants of the response to a specific pharmacological treatment. The progressive digitalization of healthcare systems is making enormous quantities of data available for machine learning systems which will allow the development of management algorithms for truly personalized antihypertensive therapy in the near future.

Serum Uric Acid Levels Are Associated with the Echogenic Features of Carotid Plaque Vulnerability in Elderly Patients with Atherosclerotic Disease.

Uric acid is a marker of inflammation and a risk factor for atherosclerosis that has been suggested to play a role in carotid plaque instability. Reduced atherosclerotic plaque echogenicity at ultrasound examination is associated with alarming histopathological features and inflammation. In this study, we investigated the relationship between serum uric acid (SUA) levels and echogenic patterns of plaque instability in elderly subjects with carotid atherosclerosis. Since uric acid metabolism largely depends on renal function, SUA levels were indexed for serum creatinine levels (SUA/SCr). We enrolled 108 patients aged 65 years or more (72.7 ± 5.9 years; 50 females and 58 males) who underwent carotid duplex ultrasound to evaluate plaque echogenicity by greyscale median (GSM). The regression analysis demonstrated a significant inverse association between the GSM and the SUA/SCr ratio (ß: -0.567; 95% CI -0.751 to -0.384 and p < 0.0001). Stepwise multivariate regression showed that the SUA/SCr ratio explained 30.3% of GSM variability (ß: -0.600; 95% CI -0.777/-0.424, p < 0.0001, and semi-partial correlation 0.303). After a mean period of 3.5 ± 0.5 years, 48 patients were reevaluated according to the same baseline study protocol. The regression analysis demonstrated a still significant inverse association between the GSM and the SUA/SCr ratio (ß: -0.462; 95% CI -0.745 to -0.178 and p = 0.002). Stepwise multivariate regression showed that the SUA/SCr ratio explained 28.0% of GSM variability (coefficient -0.584, 95% CI -0.848/-0.319, p < 0.0001, and semi-partial R2 0.280). In conclusion, this study demonstrates that SUA levels indexed for serum creatinine are associated with the echogenic features of carotid plaque vulnerability in elderly patients with atherosclerotic disease. These data could suggest an influential role for uric acid metabolism in carotid plaque biology.

Enhanced Carotid Plaque Echolucency Is Associated with Reduced Cognitive Performance in Elderly Patients with Atherosclerotic Disease Independently on Metabolic Profile.

Vulnerable carotid atherosclerotic plaques are related to an increased risk of cognitive impairment and dementia in advanced age. In this study, we investigated the relationship between the echogenicity of carotid plaques and cognitive performance in patients with asymptomatic carotid atherosclerotic plaques. We enrolled 113 patients aged 65 years or more (72.4 ± 5.9 years) who underwent carotid duplex ultrasound to evaluate plaque echogenicity by grey-scale median (GSM) and neuropsychological tests to assess cognitive function. The GSM values at baseline were inversely correlated with the number of seconds required to complete Trail Makin Test (TMT) A (rho: -0.442; p < 0.0001), TMT B (rho: -0.460; p < 0.0001) and TMT B-A (rho: -0.333; p < 0.0001) and directly correlated with Mini Mental State Examination (MMSE) and Verbal Fluency Test (VFT) score (rho: 0.217; p = 0.021 and rho: 0.375; p < 0.0001, respectively) and the composite cognitive z-score (rho: 0.464; p < 0.0001). After a mean period of 3.5 ± 0.5 years, 55 patients were reevaluated according to the same baseline study protocol. Patients with baseline GSM value higher than the median value of 29 did not show any significant variation in the z-score. Instead, those with GSM ≤ 29 showed a significant worsening of z-score (-1.2; p = 0.0258). In conclusion, this study demonstrates the existence of an inverse relationship between the echolucency of carotid plaques and cognitive function in elderly patients with atherosclerotic carotid disease. These data suggest that the assessment of plaque echogenicity if used appropriately, might aid in identifying subjects at increased risk for cognitive dysfunction.

The link between influenza and myocardial infarction: vaccination protects.

The association between influenza and cardiovascular disease has been known since the influenza pandemics of the early years of the last century. This association is more consistent and more lasting in the case of particularly severe infections. Several pathogens, including influenza viruses, can modulate the inflammatory response and influence the biology of atherosclerotic plaque to rupture it and cause a Type 1 myocardial infarction. Clinically relevant viral infections can also exacerbate pre-existing cardiovascular disease and contribute to the development of a Type 2 myocardial infarction through an increase in the metabolic demands of the myocardial tissue for fever and tachycardia and the possible induction of hypoxaemia. Evidence of a relevant protective efficacy of influenza vaccination provides further robust and convincing support for a causal link between influenza and myocardial infarction. Consistent cardiovascular protection linked to influenza vaccination has also been demonstrated in patients with recent myocardial infarction to suggest the possibility that this procedure may become an integral part of in-hospital management of acute coronary syndromes. Despite the solidity of these evidences, acknowledged by the guidelines that recommend influenza vaccination in patients at increased cardiovascular risk, still today an unacceptably high proportion of patients at high cardiovascular risk do not receive flu vaccination. Despite some potential limitations of the current flu vaccination, its advantages in terms of reducing cardiovascular events and related mortality are still such as to justify its wide use, especially, but not limited to, in patients with high cardiovascular risk.

Long-Term Adherence to Levothyroxine Replacement Therapy in Thyroidectomized Patients.

(1) Background: We evaluated the long term adherence to two distinct formulations of levothyroxine (L-T4), liquid or solid, which are differently influenced by concomitant food ingestion. (2) Methods: A total of 106 thyroidectomized patients (82 female, mean age 58.2 ± 13.3 years) on L-T4 replacement therapy in either liquid (n = 52) or solid formulation (n = 54) were administered the four-item Medication Adherence Questionnaire (MAQ). (3) Results: The study population had 59.4% adherers and 40.6% non-adherers. The global MAQ score was significantly better in patients under liquid L-T4 in comparison to those under solid L-T4 (0.42 ± 0.82 vs. 0.83 ± 0.95, respectively, p = 0.0085). The patients on tablet L-T4 forgot to take their medication more frequently than those on liquid LT4 treatment (p = 0.0159) and were more often careless at times about taking their medication (p = 0.007), whilst about one in two thyroidectomized patients preferred tablets for lifetime medication therapy. The global MAQ score was directly correlated with the circulating TSH levels in the whole study population (0.700, p < 0.0001) and inversely correlated with both the FT3 (−0.220, p = 0.0232) and FT4 (−0.327, p = 0.0006) serum concentrations. (4) Conclusions: Long-term adherence to L-T4 treatment was globally satisfactory although it was better for the liquid formulation, which appears to represent an easier-to-manage L-T4 replacement therapy for most thyroidectomized patients, particularly for those with difficulties in taking L-T4 while fasting.

Misdiagnosed giant parathyroid cyst: differential diagnosis of a neck mass of the central region.

Parathyroid cysts (PCs) are rare benign lesions representing between the 0.08% and the 0.34% of the neck masses going on surgery. They should be considered in the differential diagnosis of neck masses, especially in the differential diagnosis of the cystic anterior neck masses.Approximately 300 cases of PC are reported within the international literature.The gold standard for diagnosis is the evidence of high-level intact parathyroid hormone in cystic fluid. It is important to diagnose PCs before surgery, not intraoperatively, in order to avoid unnecessary surgeries or superfluous excision of part of the thyroid gland and prevent the patient from iatrogenic hypothyroidism.A surgical approach is required in those patients with large-sized cysts, relapses despite needle aspirations or if it causes hyperparathyroidism.We describe a case report of a patient, initially misdiagnosed with a thyroid cyst swelling, who instead had a giant non-functioning PC, which produced dyspnoea or dysphagia.

Correlation between cardiovascular risk factors and cognitive decline.

The number of people suffering from dementia in the world is progressively increasing due to the expansion of the geriatric population in which this clinical condition is more frequent. The appearance of a variable degree of cognitive decline up to full-blown dementia does not, however, represent the inevitable fate of those who age, as the studies conducted in the centenarians clearly indicate. Indeed, the age-specific incidence of dementia has progressively decreased in many geographical areas, probably due to an improvement in lifestyles and health care. In fact, a growing number of scientific evidence shows how chronic exposure over the course of life, starting from young adulthood, to various risk factors-arterial hypertension, diabetes mellitus, obesity, tobacco smoke, sleep disorders-contribute significantly to the development of cognitive decline and dementia in the course of senescence. These risk factors, in fact, can trigger and amplify the various neuropathological mechanisms underlying the development of decline, progressively reducing the functional reserve of the brain. Although definitive evidence deriving from ad hoc intervention studies is not currently available, it is legitimate to assert that the early control of cardiovascular risk factors can represent today the most effective tool for the prevention of dementia.

Blood Pressure Profiles and Cognitive Function from Adulthood to Old Age: Chasing a Golden Middle Way?

With the demographic shift toward advanced ages, it is imperative to understand the biological mechanisms behind common, disabling age-related diseases such as cognitive impairment in its mild form to overt dementia. Hypertension, a major cardiovascular risk factor, is epidemiologically linked to vascular and Alzheimer-type dementia, with possible mechanisms being atherosclerotic macro- and microvascular damage leading to neuronal cell death, as well as proinflammatory events responsible for neurodegeneration. Nevertheless, there is currently a knowledge gap as to which population to target, what the diagnostics test, and how to manage early pathogenic events in order to prevent such a dramatic and disabling condition. While clinical trials data support the benefit of active BP control with antihypertensive medications on the risk of future cognitive impairment, hypotension appears to be related to accelerated cognitive decline in both the fit and the cognitively frail elderly. Dedicated, technologically advanced studies assessing the relation of BP with dementia are needed to clarify the pathophysiological mechanisms in the association before a tailored preventive, diagnostic, and therapeutic approach to one of the most widespread modern medical challenges becomes a reality.

Improvement of Executive Function after Short-Term Administration of an Antioxidants Mix Containing Bacopa, Lycopene, Astaxanthin and Vitamin B12: The BLAtwelve Study.

During the last few years increasing interest has been focused on antioxidants as potentially useful agents in the prevention of the onset and progression of cognitive dysfunction. In this randomized, double-blind, controlled, parallel arm study, the effects of daily consumption of an antioxidant mix on cognitive function in healthy older adults were evaluated. After a 1 week run-in period, 80 subjects aged 60 years or more, and with no evidence of cognitive dysfunction, were randomly allocated to a mix of four bioactive compounds (bacopa, lycopene, astaxanthin, and vitamin B12) or matched placebo, taken orally once a day for 8 weeks. The primary objective of the study was to evaluate the changes in trial making test (TMT) scores from baseline to 8 weeks of treatment, analyzed in the following hierarchical order: TMT-B, TMT-A, and TMT-B minus TMT-A. TMT-B increased in the control group (+3.46 s) and decreased in the active group (-17.63 s). The treatment difference was -21.01 s in favor of the active group (95% C.I. -26.80 to -15.2, p < 0.0001). The decrease in TMT-A was significantly higher in the active group (-6.86 s) than in the control group (-0.37 s). TMT-B minus TMT-A increased in the control group (+3.84 s) and decreased in the active group (-10.46 s). The increase in letter fluency in the verbal fluency test (VFT) was also significantly higher in the active group and statistically significant (+5.28 vs. +1.07 words; p < 0.001). Our findings provide encouraging evidence that regular dietary supplementation with bacopa, lycopene, astaxanthin, and vitamin B12 may be an effective dietary approach for counteracting cognitive changes associated with brain aging.

Endocrine surgery during COVID-19 pandemic: do we need an update of indications in Italy?

The ongoing spread of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a significant threat to global health. As the coronavirus outbreak began spreading, hospitals were forced to relocate resources to treat the growing number of COVID-19 patients. As a consequence, doctors across the country canceled tens of thousands of nonurgent surgeries. However, recognizing that the COVID-19 situation may be highly variable and fluid in different communities across the country, elective surgery could be still allowed in some centers for patients included in the high-priority class. The majority of endocrine disorders requiring surgical treatment in patients identifiable as first-priority class, or needing hospitalization within 30 days, are generally represented by malignant thyroid tumors, hyperthyroidism, hyperparathyroidism, and some adrenal disorders. The need for urgent intervention is evaluated on a case-by-case basis according to the severity of the symptoms, the likelihood of progression, and global clinical judgment. On the basis of the above indications, during the last 4 weeks, we performed 18 planned surgical treatments in patients with thyroid cancer (total thyroidectomies, plus lymph node dissection if needed) or multinodular toxic goiter. In no case, postoperative ventilatory support was needed, and the average hospital stay was 3 days. The negative COVID-19 status for all the treated patients was appropriately evaluated beforehand. Nobody knows how long the current COVID-19 pandemic will be lasting. Certainly, we will be requested in the next future to incrementally offer surgical services for endocrine disorders that have been deferred for the COVID-19 pandemic.

Is there a relationship between blood pressure values and dementia?

The relationship between arterial hypertension and cognitive decline, two among the conditions with higher prevalence in the elderly population, has gained significant interest, in the scientific community, during the last few years, stemming from the numerous epidemiologic, experimental, and therapeutic evidences suggesting a non-casual correlation between the two conditions. In fact, the brain, for its substantial metabolic and functional complexity, is more susceptible to the harmful effect of high blood pressure than the other target organs. Chronic ischaemic impairment, microvascular damage, and neurodegenerative phenomena are the likely pathophysiologic basis for the correlation between hypertension and cognitive decline. Vascular dementia and Alzheimer's disease, the two prominent forms of senile dementia, seem to represent the end result of the chronic exposure, during the lifetime, to harmful stimuli, among which the most relevant are the cardiovascular risk factors, at least from an epidemiological perspective. Evidences from interventional studies, although limited, seems to support the concept that to limit the spread of senile dementia, the early optimization of the control of cardiovascular risk factors, first and foremost hypertension, is crucial. The occurrence of a variable degree of mental decline, till overt dementia, in the hypertensive patient, represents the final step of a pathophysiologic process that began many years before. There is, then, the clear opportunity to control the pathophysiologic mechanisms leading to cognitive decline in the hypertensive patient.

Thyroid hormones modulate uric acid metabolism in patients with recent onset subclinical hypothyroidism by improving insulin sensitivity.

Some evidence suggests a relationship between thyroid dysfunction and uric acid (UA) metabolism, but the potential influential role of thyroid hormones on UA metabolism is still debated. This report was designed to evaluate the influential role of levothyroxine (L-T4) replacement therapy on circulating levels of UA in patients with recent onset post-thyroidectomy subclinical hypothyroidism. Circulating levels of thyroid hormones, UA and other metabolic parameters were assessed in 155 recently thyroidectomized patients (131 females, mean age 51.1 ± 12.7 years) at baseline (5-7 day after surgery) and after 2 months under replacement therapy with L-T4. At baseline, circulating levels of thyroid hormones were indicative of a subclinical hypothyroidism (TSH 8.2 ± 5.1 mU/mL, FT3 2.1 ± 0.7 pg/mL, FT4 9.2 ± 3.4 pg/mL). The mean serum UA concentration was 5.0 ± 1.3 mg/dL, while the prevalence of hyperuricemia, defined by serum UA levels > 6 mg/dL, was 22.6%. Serum UA levels at baseline were significantly correlated with HOMA-IR index (r = 0.475, p < 0.0001). After 2 months under the replacement therapy with L-T4, both serum UA levels (- 1.2 ± 0.9 mg/dL, p < 0.0001 vs. baseline) and HOMA-IR (- 0.3 ± 1.5 mmol/L, p = 0.0328 vs. baseline) significantly decreased. Multivariate regression analysis revealed that changes in HOMA-IR explained 23% of the variations of serum UA levels under L-T4 replacement therapy (ß = 0.295, p < 0.0001, R2 = 0.230). Our study suggests that thyroid hormones could modulate UA metabolism in patients with recent onset subclinical hypothyroidism likely by improving insulin sensitivity.

Diet and Brain Health: Which Role for Polyphenols?

BACKGROUND: The aging of western societies is leading to a dramatic increase in the prevalence of chronic conditions, threatening the health status and then the sustainability of our healthcare systems. In particular, dementia is being increasingly recognized as a public health priority, given its enormous socioeconomic burdens further amplified by the absence of treatments really effective in improving the clinical course of the disease. METHODS: The question of whether some degree of cognitive deterioration is an inevitable part of aging or should be considered as a pathological pre-stage of dementia is currently debated. This is a field in need of research because accelerated brain aging as well as further decline in cognition might be preventable in the early stages of cognitive impairment. Herein, we discuss evidence from clinical and experimental studies on the role of polyphenols in preserving cognitive performance across life. RESULTS: In recent years, the possibility of favorably influencing the cognitive trajectory through promotion of lifestyle modifications has been increasingly investigated. In particular, the relationship between nutritional habits and brain health has attracted special attention. Dietary polyphenols exhibit a strong potential to promote brain due to their efficacy in protecting neurons against oxidative stress-induced injury, suppressing neuroinflammation and in ameliorating cardiovascular risk factor control and cardiovascular function thus counteracting neurotoxicity and neurodegeneration. CONCLUSION: Emerging evidence suggest that dietary polyphenols, in particular flavonoids, may exert beneficial effects on the central nervous system thus representing a potential tool to preserve cognitive performance throught senescence.

Comparative study between the effects of replacement therapy with liquid and tablet formulations of levothyroxine on mood states, self-perceived psychological well-being and thyroid hormone profile in recently thyroidectomized patients.

Following thyroid surgery, levothyroxine therapy is used to replace deficient thyroid hormones and prevent postoperative thyroid hypofunction. We compared the effects of replacement therapy with either liquid or tablet formulation of levothyroxine on mood states, self-perceived mental well-being and thyroid hormone profile in recently thyroidectomized patients. Profile of mood states, General Heath Questionnaire 12-items and thyroid hormone profile were assessed in recently (5-7 days) thyroidectomized patients at baseline and 2 months after randomization to replacement therapy with either liquid (n = 77) or tablet (n = 78) formulation of levothyroxine. After 2 months under levothyroxine replacement treatment, significant improvements of Positive Affect Scale (p < 0.001) and Negative Affect Scale (p < 0.001) of Profile of mood states, as well as of General Heath Questionnaire 12-items (p < 0.001) were observed in the study population. However, there were greater variations observed in patients assigned to liquid levothyroxine formulation in comparison to those who were assigned to levothyroxine in the form of tablet (time × treatment interaction: Positive Affect Scale of Profile of mood states, p = 0.030; Negative Affect Scale of Profile of mood states, p < 0.0001; General Heath Questionnaire 12-items, p = 0.003). As expected, circulating TSH levels significantly decreased (p <0.001) while FT3 and FT4 levels significantly increased (p < 0.0001 for both) under levothyroxine replacement therapy. These changes were significantly greater in patients treated with liquid levothyroxine formulation (time × treatment interaction: TSH, p = 0.011; FT3, p = 0.016; FT4, p = 0.028). Our data indicate a greater efficacy of liquid formulation of levothyroxine in ameliorating mood states and self-perception of mental well-being and thyroid hormone profile after 2 months of replacement therapy in recently thyroidectomized patients.

Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects: the Cocoa, Cognition, and Aging (CoCoA) Study--a randomized controlled trial.

BACKGROUND: Recent evidence has indicated that flavanol consumption may have many health benefits in humans, including improved cognitive activities. OBJECTIVE: The aim was to evaluate the effect of flavanol consumption on cognitive performance in cognitively intact elderly subjects. DESIGN: This was a double-blind, controlled, parallel-arm study conducted in 90 elderly individuals without clinical evidence of cognitive dysfunction who were randomly assigned to consume daily for 8 wk a drink containing 993 mg [high flavanol (HF)], 520 mg [intermediate flavanol (IF)], or 48 mg [low flavanol (LF)] cocoa flavanols (CFs). Cognitive function was assessed at baseline and after 8 wk by using the Mini-Mental State Examination (MMSE), the Trail Making Test (TMT) A and B, and the Verbal Fluency Test (VFT). RESULTS: The changes in MMSE score in response to the 3 different treatments were not different. In contrast, there was a positive impact of the intervention on specific aspects of cognitive function. Mean changes (±SEs) in the time required to complete the TMT A and B after consumption of the HF (-8.6 ± 0.4 and -16.5 ± 0.8 s, respectively) and IF (-6.7 ± 0.5 and -14.2 ± 0.5 s, respectively) drinks significantly (P < 0.0001) differed from that after consumption of the LF drinks (-0.8 ± 1.6 and -1.1 ± 0.7 s, respectively). Similarly, VFT scores significantly improved among all treatment groups, but the magnitude of improvement in the VFT score was significantly (P < 0.0001) greater in the HF group (7.7 ± 1.1 words/60 s) than in the IF (3.6 ± 1.2 words/60 s) and LF (1.3 ± 0.5 words/60 s) groups. Significantly different improvements in insulin resistance (P < 0.0001), blood pressure (P < 0.0001), and lipid peroxidation (P = 0.001) were also observed for the HF and IF groups in comparison with the LF group. Changes in insulin resistance explained ∼17% of changes in composite z score (partial r² = 0.1703, P < 0.0001). CONCLUSIONS: This dietary intervention study provides evidence that regular CF consumption can reduce some measures of age-related cognitive dysfunction, possibly through an improvement in insulin sensitivity. These data suggest that the habitual intake of flavanols can support healthy cognitive function with age.

Therapeutic approaches to chronic hyperuricemia and gout.

Gout is currently one of the most common causes of inflammatory arthritis in most industrialised countries. Apart from its high frequency, gout is associated with disability, poor quality of life and increased mortality and therefore represents an ever increasing public health concern. Substantial experimental and epidemiological evidence exists supporting the link between elevated levels of serum uric acid and several comorbidities including cardiovascular and kidney diseases. The cornerstone of effective gout management is long-term serum urate lowering below saturation concentrations (<6 mg/dL or <360 µmol/L) in order to promote crystal dissolution and prevent monosodium urate crystals formation. The management of gout includes not only pharmacological approaches, but also a number of nonpharmacologic interventions aiming at lessening attack risk, lowering uric acid levels and promoting general health while preventing the development of comorbidities. It is of great address whether urate lowering strategies can also lower cardiovascular risk and some preliminary studies in both animal and human subjects suggest that they might. Patient education and appropriate lifestyle advice are core aspects of management of hyperuricemia and gout. The two xanthine oxidase inhibitors currently available are effective as long-term urate lowering therapy although the greater efficacy and good tolerability of febuxostat as urate lowering agent has to be adequately considered especially when the reduction of serum uric acid levels to achieve the target is particularly ambitious and/or the presence of comorbidities increases the risk of adverse effects. Associated comorbidities and cardiovascular risk factors should be also addressed as an important part of the management of chronic hyperuricemia and gout.

Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment: the Cocoa, Cognition, and Aging (CoCoA) study.

Flavanol consumption is favorably associated with cognitive function. We tested the hypothesis that dietary flavanols might improve cognitive function in subjects with mild cognitive impairment. We conducted a double-blind, parallel arm study in 90 elderly individuals with mild cognitive impairment randomized to consume once daily for 8 weeks a drink containing ≈990 mg (high flavanols), ≈520 mg (intermediate flavanols), or ≈45 mg (low flavanols) of cocoa flavanols per day. Cognitive function was assessed by Mini Mental State Examination, Trail Making Test A and B, and verbal fluency test. At the end of the follow-up period, Mini Mental State Examination was similar in the 3 treatment groups (P=0.13). The time required to complete Trail Making Test A and Trail Making Test B was significantly (P<0.05) lower in subjects assigned to high flavanols (38.10±10.94 and 104.10±28.73 seconds, respectively) and intermediate flavanols (40.20±11.35 and 115.97±28.35 seconds, respectively) in comparison with those assigned to low flavanols (52.60±17.97 and 139.23±43.02 seconds, respectively). Similarly, verbal fluency test score was significantly (P<0.05) better in subjects assigned to high flavanols in comparison with those assigned to low flavanols (27.50±6.75 versus 22.30±8.09 words per 60 seconds). Insulin resistance, blood pressure, and lipid peroxidation also decreased among subjects in the high-flavanol and intermediate-flavanol groups. Changes of insulin resistance explained ≈40% of composite z score variability through the study period (partial r(2)=0.4013; P<0.0001). To the best of our knowledge, this is the first dietary intervention study demonstrating that the regular consumption of cocoa flavanols might be effective in improving cognitive function in elderly subjects with mild cognitive impairment. This effect appears mediated in part by an improvement in insulin sensitivity.

Enhanced proatherogenic inflammation after recombinant human TSH administration in patients monitored for thyroid cancer remnant.

OBJECTIVE: To evaluate the effect of recombinant human TSH (rhTSH) on biomarkers of vascular endothelial cell and platelet activation in patients monitored for thyroid carcinoma remnant. METHODS: Circulating levels of soluble(s) intercellular adhesion molecule (sICAM)-1 and sE-selectin, as indices of vascular endothelial cell activation, of sP-selectin and sCD40 ligand (sCD40L), as indices of platelet activation, and of 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)), as an index of lipid peroxidation, were evaluated in 20 patients (16 females, 48.0 +/- 13.6 years) at baseline and after intramuscular rhTSH injection (0.9 mg/day on two consecutive days). RESULTS: At baseline, serum TSH values were below normal whereas free T3 and free T4 were within the normal range. After rhTSH injection, serum TSH increased significantly but free T3 and free T4 remained unchanged. Concomitantly, plasma sICAM-1 concentrations increased significantly (from 155.9 +/- 39.1 to 183.6 +/- 38.1 ng/ml, P < 0.03), as did those of sE-selectin (from 74.8 +/- 15.4 to 91.4 +/- 12.2 ng/ml, P < 0.0006), sP-selectin (from 56.4 +/- 13.7 to 72.2 +/- 14.9 ng/ml, P < 0.002), sCD40L (from 2.1 +/- 0.9 to 2.8 +/- 1.1 ng/ml, P < 0.03) and total 8-iso-PGF(2alpha)(from 238.5 +/- 47.0 to 307.8 +/- 41.2 pg/l, P < 0.0001). Changes in circulating levels of sCD40L were directly correlated with changes in levels of plasma total 8-iso-PGF(2alpha) (r = 0.523, P < 0.02) and sP-selectin (r = 0.480, P < 0.03). CONCLUSIONS: Supraphysiological concentrations of rhTSH might exert proatherogenic effects by promoting activation of vascular endothelial cells and platelets probably through enhanced oxidative stress.

Different effects of angiotensin converting enzyme inhibitors on endothelin-1 and nitric oxide balance in human vascular endothelial cells: evidence of an oxidant-sensitive pathway.

Angiotensin converting enzyme inhibitors (ACE-I) are able to reduce the formation of the potent vasoconstrictor endothelin-1 and increase nitric oxide bioavailability in human vascular endothelial cells (HUVECs). We tested the effects of two sulfhydryl-containing ACE-I, zofenoprilat, and captopril, and two nonsulfhydryl containing ACE-I, enalaprilat and lisinopril, on endothelin-1/nitric oxide balance and oxidative stress in HUVECs. All the four tested ACE-I reduced endothelin-1 secretion and increased nitric oxide metabolite production by HUVECs. However, zofenoprilat (-42% after 8 hours of incubation) was more effective (P < .05) than enalaprilat (-25%), lisinopril (-21%), and captopril (-30%) in reducing endothelin-1 secretion. Similarly, zofenoprilat (+110% after 8 hours of incubation) was more effective (P < .05) than enalaprilat (+64%), lisinopril (+63%), and captopril (+65%) in increasing nitric oxide metabolite production. The effect of ACE-I on endothelin-1 and nitric oxide metabolite production is mediated by the activation of bradykinin B(2) receptor being counteracted, at least in part, by a specific antagonist. Zofenoprilat and, to a lesser extent, captopril also reduced oxidative stress in HUVECs. In conclusion, among the four tested ACE-I, zofenoprilat was more effective in improving endothelin-1/nitric oxide balance in HUVECs likely because of its greater antioxidant properties.