The monoclonal gammopathies are a group of disorders associated with monoclonal proliferation of plasma cells. The characterization of specific entities is an area of difficulty in clinical practice. The International Myeloma Working Group has reviewed the criteria for diagnosis and classification with the aim of producing simple, easily used definitions based on routinely available investigations. In monoclonal gammopathy of undetermined significance (MGUS) or monoclonal gammopathy, unattributed/unassociated (MG[u]), the monoclonal protein is < 30 g/l and the bone marrow clonal cells < 10% with no evidence of multiple myeloma, other B-cell proliferative disorders or amyloidosis. In asymptomatic (smouldering) myeloma the M-protein is greater than or equal to 30 g/l and/or bone marrow clonal cells greater than or equal to 10% but no related organ or tissue impairment (ROTI)(end-organ damage), which is typically manifested by increased calcium, renal insufficiency, anaemia, or bone lesions (CRAB) attributed to the plasma cell proliferative process. Symptomatic myeloma requires evidence of ROTI. Non-secretory myeloma is characterized by the absence of an M-protein in the serum and urine, bone marrow plasmacytosis and ROTI. Solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas (+/- recurrent) are also defined as distinct entities. The use of these criteria will facilitate comparison of therapeutic trial data. Evaluation of currently available prognostic factors may allow better definition of prognosis in multiple myeloma.

Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group

Human intervention trials have provided evidence for protective effects of various (poly)phenol-rich foods against chronic disease, including cardiovascular disease, neurodegeneration, and cancer. While there are considerable data suggesting benefits of (poly)phenol intake, conclusions regarding their preventive potential remain unresolved due to several limitations in existing studies. Bioactivity investigations using cell lines have made an extensive use of both (poly)phenolic aglycones and sugar conjugates, these being the typical forms that exist in planta, at concentrations in the low-μM-to-mM range. However, after ingestion, dietary (poly)phenolics appear in the circulatory system not as the parent compounds, but as phase II metabolites, and their presence in plasma after dietary intake rarely exceeds nM concentrations. Substantial quantities of both the parent compounds and their metabolites pass to the colon where they are degraded by the action of the local microbiota, giving rise principally to small phenolic acid and aromatic catabolites that are absorbed into the circulatory system. This comprehensive review describes the different groups of compounds that have been reported to be involved in human nutrition, their fate in the body as they pass through the gastrointestinal tract and are absorbed into the circulatory system, the evidence of their impact on human chronic diseases, and the possible mechanisms of action through which (poly)phenol metabolites and catabolites may exert these protective actions. It is concluded that better performed in vivo intervention and in vitro mechanistic studies are needed to fully understand how these molecules interact with human physiological and pathological processes.

Dietary (Poly)phenolics in Human Health: Structures, Bioavailability, and Evidence of Protective Effects Against Chronic Diseases

Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials

The endothelium can evoke relaxations (dilatations) of the underlying vascular smooth muscle, by releasing vasodilator substances. The best characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO). The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDHF-mediated responses). Endothelium-dependent relaxations involve both pertussis toxin-sensitive G(i) (e.g. responses to serotonin and thrombin) and pertussis toxin-insensitive G(q) (e.g. adenosine diphosphate and bradykinin) coupling proteins. The release of NO by the endothelial cell can be up-regulated (e.g. by oestrogens, exercise and dietary factors) and down-regulated (e.g. oxidative stress, smoking and oxidized low-density lipoproteins). It is reduced in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively loose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and causing endothelium-dependent hyperpolarizations), endothelial cells also can evoke contraction (constriction) of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factor (EDCF). Most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells. EDCF-mediated responses are exacerbated when the production of NO is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive patients.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1748-1716.2009.01964.x

Endothelial dysfunction and vascular disease

Representing the most common flavonoid consumed in the American diet, the flavan-3-ols and their polymeric condensation products, the proanthocyanidins, are regarded as functional ingredients in various beverages, whole and processed foods, herbal remedies and supplements. Their presence in food affects food quality parameters such as astringency, bitterness, sourness, sweetness, salivary viscosity, aroma, and color formation. The ability of flavan-3-ols to aid food functionality has also been established in terms of microbial stability, foamability, oxidative stability, and heat stability. While some foods only contain monomeric flavan-3-ols [(-)-epicatechin predominates] and dimeric proanthocyanidins, most foods contain oligomers of degree of polymerization values ranging from 1-10 or greater than 10. Flavan-3-ols have been reported to exhibit several health beneficial effects by acting as antioxidant, anticarcinogen, cardiopreventive, antimicrobial, anti-viral, and neuro-protective agents. This review summarizes the distribution and health effects of these compounds.

Flavan-3-ols: nature, occurrence and biological activity.

Consumption of flavanol-rich dark chocolate (DC) has been shown to decrease blood pressure (BP) and insulin resistance in healthy subjects, suggesting similar benefits in patients with essential hypertension (EH) Therefore, we tested the effect of DC on 24-hour ambulatory BP, flow-mediated dilation (FMD), and oral glucose tolerance tests (OGTTs) in patients with EH After a 7-day chocolate-free run-in phase, 20 never-treated, grade I patients with EH (10 males; 43778 years) were randomized to receive either 100 g per day DC (containing 88 mg flavanols) or 90 g per day flavanol-free white chocolate (WC) in an isocaloric manner for 15 days After a second 7-day chocolate-free period, patients were crossed over to the other treatment Noninvasive 24-hour ambulatory BP, FMD, OGTT, serum cholesterol, and markers of vascular inflammation were evaluated at the end of each treatment The homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and insulin sensitivity index (ISI) were calculated from OGTT values Ambulatory BP decreased after DC (24-hour systolic BP 11977 mm Hg, P00001; 24-hour diastolic BP 8550 mm Hg, P00001) but not WC DC but not WC decreased HOMA-IR (P00001), but it improved QUICKI, ISI, and FMD DC also decreased serum LDL cholesterol (from 3405 to 3006 mmol/L; P005) In summary, DC decreased BP and serum LDL cholesterol, improved FMD, and ameliorated insulin sensitivity in hypertensives These results suggest that, while balancing total calorie intake, flavanols from cocoa products may provide some cardiovascular benefit if included as part of a healthy diet for patients with EH (Hypertension 2005;46:398-405)

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Cocoa Reduces Blood Pressure and Insulin Resistance and Improves Endothelium-Dependent Vasodilation in Hypertensives

A retrospective study was conducted in 1216 cases to investigate the possible association between tobacco smoking and the risk of haematological malignancies. A small, but not significant, increase in malignancy was observed in smokers. Significant association was demonstrated between tobacco smoking and acute nonlymphoblastic leukaemia, and myelodysplastic syndromes. The duration and amount smoked increased the risk; heavy smokers presented significant positive associations with overall malignancies, acute nonlymphoblastic leukaemia, myelodysplastic syndromes, and monoclonal gammopathy of undetermined significance, whereas light smokers did not present any significant association. These data support a causal relationship between certain haematological malignancies and tobacco smoking. Further research is needed to examine the risk according to dose-response effect, and the variation in risk according to the histological subtype of the malignancy.

Tobacco smoking and risk of haematological malignancies in adults: a case-control study

A retrospective study was undertaken on onset of symptoms in 667 cases of stroke. All strokes occurred out of hospital. There were 382 males and 285 females, observed from 1971-1988. The 667 cases of stroke consisted of 508 cases of cerebral infarction and 159 cases of cerebral hemorrhage. The data, analyzed by the single cosinor method, demonstrate a significant circadian, circaseptan, and circannual rhythmicity in the occurrence of stroke. The peaks occur in the morning hours, in the weekend, and in winter. Cerebral hemorrhages do not have a circadian rhythmicity in their occurrence, while they do present circaseptan and circannual rhythmicity. Cerebral infarctions present circadian, circaseptan, and circannual rhythms. No difference was found between males and females. The possible factors involved in temporal distribution of stroke are discussed. These observations could be useful for a better understanding of the pathogenesis and treatment of stroke.

Epidemiological chronorisk of stroke.

Patients with monoclonal gammopathy of undetermined significance (MGUS) have a serum monoclonal component (M-component), but no evidence of multiple myeloma, macroglobulinaemia, amyloidosis or other p

The natural history of monoclonal gammopathy of undetermined significance. A 5- to 20-year follow-up of 263 cases.

Alterations in hemostatic equilibrium may favor events such as acute myocardial infarction and sudden cardiac death.1 The clinical incidence of these events demonstrates a circadian distribution with maximum occurrence in the morning hours.2,3 Pulmonary thromboembolism is also recognized as one of the diseases favored by alterations in hemostatic equilibrium,4 but it is yet to be proven whether the incidence of pulmonary thromboembolism has a circadian distribution. We investigated the presence of a circadian rhythm in episodes of fatal pulmonary thromboembolism.

Paolo Pasqualetti

Papers

Cocoa Reduces Blood Pressure and Insulin Resistance and Improves Endothelium-Dependent Vasodilation in Hypertensives

Tobacco smoking and risk of haematological malignancies in adults: a case-control study

Epidemiological chronorisk of stroke.

The natural history of monoclonal gammopathy of undetermined significance. A 5- to 20-year follow-up of 263 cases.

Circadian distribution in fatal pulmonary thromboembolism