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The heliospheric magnetic field (HMF) is controlled by solar activity, as established by measurements over the last few decades, but its characteristics when the sun was quiet for prolonged periods, such as during Gleissberg or Maunder minima, are not known. Titanium-44, produced in meteorites, provides a monitor of the galactic cosmic ray (GCR) flux and allows estimation of the modulation effect of the sun for the period 1883 to 1992. The titanium-44 activity is consistent with the expected value, but the increase, due to the last Gleissberg minimum, is four times greater than expected for a GCR modulation based solely on sunspot numbers. This result implies that the HMF was weaker than at present and as a result the GCR flux (for energy greater than 1 gigaelectron volt) was higher between 2.2 to 3.6 protons per square centimeter per second per 4π steradians at 1 to 3 astronomical units in solar cycles 12 to 15., Production of cosmogenic radioisotopes in meteorites depends on the GCR flux, which is controlled by the HMF which, in turn, depends on solar activity. GCR flux is inversely correlated with [...]

Abstract: The δ 13C profile of Globigerinoides ruber, measured in the GT90/3 shallow-water Ionian sea core and dated with high precision, is presented and analyzed using the Singular Spectrum Analysis and the Wavelet Transform. This time series covers the period 200–1979 AD, with a resolution of 3.87 years. The δ 13C of foraminifera depends on the photosynthetic activity of the symbiontic algae living on the shells, strictly related to the illumination of the sea-surface. Both spectral methods, besides an 11-years oscillation in phase with the Schwabe cycle of the solar activity, show the presence of a centennial cycle that is in phase with the amplitude modulation of the sunspot number series in the last 300 years. Moreover, another climatic record, the tree ring δ 13C of a Japanese cedar covering the time interval 125–1952 AD, shows a similar centennial oscillation and therefore suggests that this climatic variation is global and in phase with the solar activity. [Copyright &y& Elsevier]

We show the δ13C profile of Globigerinoides ruber measured in the GT90/3 shallow-water Ionian sea core. This core is dated with high accuracy (better than 1%) using radiometric and tephroanalysis methods, for the last 2000 years. The core, extracted from the Gallipoli platform, was sampled at contiguous steps of thickness 2.5 mm, corresponding to 3.87 years. The δ13C profile covers the period 1147–1975 AD. During the first seven centuries it appears fairly flat, while it shows a steep increase between 1760 and 1950 of ∼0.3‰. The analysis of the time series performed using different methods shows a dominant decadal periodicity throughout the record. The 11-year component is identified at high significance level by Monte Carlo singular spectrum analysis (MC-SSA); the SSA-reconstructed-11-year component is in phase with the sunspot solar cycle. The average amplitude of this component is A11y=0.04‰. It is commonly accepted that δ13C variations in symbiontic foraminifera mainly record the effects of symbiont density and of photosynthetic activity, varying with ambient light level. The δ13C peak-to-trough 11-year variation (0.08‰) can be related to solar irradiance variation of 0.1% on decadal time scale, like that measured in space in the last 20 years. By supposing that the observed δ13C modern increase of ∼0.3‰ is also produced by a solar irradiance variability on a longer time scale, through the same mechanisms, we estimate a secular increase of the total solar irradiance between 1760 and 1950 of (0.3/0.08)*0.1% ≅ 0.37%. This value is at the higher limit of the long term variability estimates (0.25%–0.35%) that are currently proposed.Finally, in the light of the available experimental evidences, we discuss possible ways in which direct solar forcing can be modified by atmospheric processes in order to give the observed δ13C signal. [Copyright &y& Elsevier]

This study aims to investigate the sensitivity of microscopy, culture and polymerase chain reaction on three gastric aspirates (GAs) in the microbiological confirmation of active pulmonary tuberculosis (TB) and to identify possible changes in sensitivity derived from the collection of a different number of aspirates. Children with clinical and radiological diagnoses of active pulmonary TB who underwent three GAs between March 2007 and June 2019 were retrospectively evaluated. Clinical, radiological, and microbiological data were collected. The sensitivity of microbiological tests on GAs was calculated. Moreover, differences in sensitivity according to age and radiological pattern were investigated. Overall, 156 children with active pulmonary TB were enrolled with a median age of 51.5 (IQR: 25.2-113.2) months. Microbiological investigations on the first GA showed a sensitivity of 34% (95%CI 26.7, 42), the cumulative sensitivity of first and second GAs was 40.4% (95%CI 32.7, 48.5) and of the three GAs was 47.4% (95%CI 39.8, 55.2). The collection of three GAs leads to an overall increase in sensitivity of the first GA by 13.4% (95%CI 2.8, 24.1%; p=0.014). Moreover, the increase in sensitivity was significantly higher in children ≤ 4 years of age and in those with uncomplicated TB (p=0.008).Conclusions: Performing a higher number of GAs increases the sensitivity of microbiological confirmation of active pulmonary TB, particularly in children ≤ 4 years and with an uncomplicated radiological pattern. What is known: • The diagnosis of paediatric tuberculosis is a challenge for paediatricians • Despite their low sensitivity gastric aspirates represent the standard sample for microbiological confirmation of active pulmonary tuberculosis in children • Most international guidelines recommend performing three sequential gastric aspirates on three consecutive days What is new: • A significant increase in global sensitivity by 13.4% was found by the collection of three gastric aspirates compared to the first one • Performing a higher number of gastric aspirates increases the sensitivity of microbiological confirmation, particularly in children ≤ 4 years and with an uncomplicated radiological pattern., (© 2023. The Author(s).)

(1) Background: MLH1 hypermethylation is an epigenetic alteration in the tumorigenesis of colorectal cancer (CRC) and endometrial cancer (EC), causing gene silencing, and, as a consequence, microsatellite instability. Commonly, MLH1 hypermethylation is considered a somatic and sporadic event in cancer, and its detection is recognized as a useful tool to distinguish sporadic from inherited conditions (such as, Lynch syndrome (LS)). However, MLH1 hypermethylation has been described in rare cases of CRC and EC in LS patients. (2) Methods: A total of 61 cancers (31 CRCs, 27 ECs, 2 ovarian cancers, and 1 stomach cancer) from 56 patients referred to cancer genetic counselling were selected for loss of MLH1 protein expression and microsatellite instability. All cases were investigated for MLH1 promoter methylation and MLH1/PMS2 germline variants. (3) Results: Somatic MLH1 promoter hypermethylation was identified in 16.7% of CRC and in 40% of EC carriers of MLH1 germline pathogenic variants. In two families, primary and secondary MLH1 epimutations were demonstrated. (4) Conclusions: MLH1 hypermethylation should not be exclusively considered as a sporadic cancer mechanism, as a non-negligible number of LS-related cancers are MLH1 hypermethylated. Current flow charts for universal LS screening, which include MLH1 methylation, should be applied, paying attention to a patient's family and personal history.

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers., Methods: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk., Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions., Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management., (© The Author(s) 2021. Published by Oxford University Press.)

Backgrounds: MUTYH-associated polyposis (MAP) is an autosomal recessive disease caused by biallelic pathogenic variants (PV) of the MUTYH gene. The aim of this study was to investigate the genetic causes of unexplained polyposis patients with monoallelic MUTYH PV. The analysis focused on 26 patients with suspected MAP, belonging to 23 families. Ten probands carried also one or more additional MUTYH variants of unknown significance., Methods: Based on variant type and on the collected clinical and molecular data, these variants were reinterpreted by applying the ACMG/AMP rules. Moreover, supplementary analyses were carried out to investigate the presence of other variants and copy number variations in the coding and promoter regions of MUTYH, as well as other polyposis genes (APC, NTHL1, POLE, POLD1, MSH3, RNF43, and MCM9)., Results: We reclassified 4 out of 10 MUTYH variants as pathogenic or likely pathogenic, thus supporting the diagnosis of MAP in only four cases. Two other patients belonging to the same family showed a previously undetected deletion of the APC gene promoter. No PVs were found in the other investigated genes. However, 6 out of the 18 remaining families are still interesting MAP candidates, due to the co-presence of a class 3 MUTYH variant that could be reinterpreted in the next future., Conclusion: Several efforts are necessary to fully elucidate the genetic etiology of suspected MAP patients, especially those with the most severe polyposis/tumor phenotype. Clinical data, tumor molecular profile, family history, and polyposis inheritance mode may guide variant interpretation and address supplementary studies., (© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

A MSH6 3'UTR variant (c.*23_26dup) was found in 13 unrelated families consulted for Lynch/Muir-Torre Syndrome. This variant, which is very rare in the genomic databases, was absent in healthy controls and strongly segregated with the disease in the studied pedigrees. All tumors were defective for MSH2/MSH6/MSH3 proteins expression, but only MSH2 somatic pathogenic mutations were found in 5 of the 12 sequenced tumors. Moreover, we had no evidence of MSH6 transcript decrease in carriers, whereas MSH2 transcript was downregulated. Additional evaluations performed in representative carriers, including karyotype, arrayCGH and Linked-Reads whole genome sequencing, failed to evidence any MSH2 germline pathogenic variant. Posterior probability of pathogenicity for MSH6 c.*23_26dup was obtained from a multifactorial analysis incorporating segregation and phenotypic data and resulted >0.999, allowing to classify the variant as pathogenic (InSiGHT Class 5). Carriers shared a common haplotype involving MSH2/MSH6 loci, then a cryptic disease-associated variant, linked with MSH6 c.*23_26dup, cannot be completely excluded. Even if it is not clear whether the MSH6 variant is pathogenic per se or simply a marker of a disease-associated MSH2/MSH6 haplotype, all data collected on patients and pedigrees prompted us to manage the variant as pathogenic and to offer predictive testing within these families., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification., (© 2019 Wiley Periodicals, Inc.)

Background: Inherited epimutations of Mismatch Repair (MMR) genes are responsible for Lynch Syndrome (LS) in a small, but well defined, subset of patients. Methylation of the MSH2 promoter consequent to the deletion of the upstream EPCAM gene is found in about 1%-3% of the LS patients and represents a classical secondary, constitutional and tissue-specific epimutation. Several different EPCAM deletions have been reported worldwide, for the most part representing private variants caused by an Alu-mediated recombination., Methods: 712 patients with suspected LS were tested for MMR mutation in our Institute. EPCAM deletions were detected by multiplex ligation-dependent probe amplification (MLPA) and then defined by Long-Range polymerase chain reaction (PCR)/Sanger sequencing. A comprehensive molecular characterization of colorectal cancer (CRC) tissues was carried out by immunohistochemistry of MMR proteins, Microsatellite Instability (MSI) assay, methylation specific MLPA and transcript analyses. In addition, somatic deletions and/or variants were investigated by MLPA and next generation sequencing (NGS)., Results: An EPCAM deletion was found in five unrelated probands in Italy: variants c.556-490_*8438del and c.858+1193_*5826del are novel; c.859-1430_*2033del and c.859-670_*530del were previously reported. All probands were affected by CRC at young age; tumors showed MSI and abnormal MSH2/MSH6 proteins expression. MSH2 promoter methylation, as well as aberrant in-frame or out-of-frame EPCAM/MSH2 fusion transcripts, were detected in CRCs and normal mucosae., Conclusion: An EPCAM deletion was the causative variant in about 2% of our institutional series of 224 LS patients, consistent with previously estimated frequencies. Early age and multiple CRCs was the main clinical feature of this subset of patients., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Objective: Recent data from the literature indicate gynecological cancers (GCs) as sentinel cancers for a diagnosis of Lynch syndrome (LS). Clinical approaches to identifying LS have low sensitivity, whereas somatic tests on GCs may be a more sensitive and cost-effective strategy., Methods: A series of 78 GCs belonging to 74 patients sent to the Genetic Counselling Service were investigated using microsatellite instability, immunohistochemical expression of mismatch repair (MMR) genes, and MLH1 promoter methylation., Results: The presence of microsatellite instability was observed in 67.5% of GCs, and the absence of immunohistochemical expression of at least 1 of the 4 MMR proteins was observed in 71.4% of GCs, showing 96.1% concordance between the methods. Methylation analysis using methylation specific multiplex ligation-dependent probe amplification performed on 35 samples revealed MLH1 promoter hypermethylation in 18 cases (54%). Molecular analysis identified 36 LS carriers of MMR variants (27 pathogenetic and 9 variants of uncertain significance), and, interestingly, 3 LS patients had MLH1 methylated GC.With regard to histological features, LS-related GCs included endocervical cancers and also histological types different from the endometrioid cancers. The presence of peritumoral lymphocytes in GCs was statistically associated with LS tumors., Conclusions: Somatic analysis is a useful strategy to distinguish sporadic from LS GC. Our data allow the identification of a subset of LS patients otherwise unrecognized on the basis of clinical or family history alone. In addition, our results indicate that some clinicopathological features including age of GC diagnosis; presence of peritumoral lymphocytes; isthmic, endocervical sites, and body mass index value could be useful criteria to select patients for genetic counseling.

Background: About 20 % of hereditary breast cancers are caused by mutations in BRCA1 and BRCA2 genes. Since BRCA1 and BRCA2 mutations may be spread throughout the gene, genetic testing is usually performed by direct sequencing of entire coding regions. In some populations, especially if relatively isolated, a few number of recurrent mutations is reported, sometimes caused by founder effect., Methods: BRCA1 and BRCA2 screening for mutations was carried out on 1114 breast and/or ovarian cancer patients complying with the eligibility criteria for BRCA testing. Haplotype analysis was performed on the probands carrying recurrent mutations and their relatives, using two sets of microsatellite markers covering the BRCA1 (D17S588, D17S806, D17S902, D17S1325, D17S855, D17S1328, D17S800, and D17S250) and BRCA2 (D13S220, D13S267, D13S171, D13S1701, D13S1698, D13S260, D13S290, D13S1246) loci. The DMLE + 2.2 software was used to estimate the age of BRCA1 c.676delT and BRCA2 c.7806-2A > G. A multiplex PCR and two different primer extension assays were optimized and used for genotyping the recurrent mutations of the two genes., Results: In the time frame of almost 20 years of genetic testing, we have found that five BRCA1 and three BRCA2 mutations are recurrent in a substantial subset of carriers from North-East Italy and neighboring Istria, where they represent more than 50 % of all mutations. Microsatellite analyses identified a common haplotype of different length for each mutation. Age estimation of BRCA1 c.676delT and BRCA2 c.7806-2A > G mutations revealed that they arose in the Friuli Venezia Giulia area about 86 and 94 generations ago, respectively. Suggestion of an association between BRCA2 c.7806-2A > G and risk of breast cancer in males has emerged. Finally, we developed a simple and efficient pre-screening test, performing an in-house primer extension SNaPshot® assay for the rapid identification of the eight recurrent mutations., Conclusions: Proofs of common ancestry has been obtained for the eight recurrent mutations. The observed genotype-phenotype correlation and the proposed rapid mutation detection strategy could improve the clinical management of breast and ovarian patients in North-East of Italy and neighboring geographic areas.

Numerous genetic factors that influence breast cancer risk are known. However, approximately two-thirds of the overall familial risk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p.Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk [odds ratio (OR) = 3.93 (95% confidence interval (CI) = 1.28-12.11; P = 0.017)]. Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls and of all available data. These analyses showed breast cancer associations with OR = 3.67 (95% CI = 1.04-12.87; P = 0.043) and OR = 3.33 (95% CI = 1.09-13.62; P = 0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p.Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Lynch syndrome (LS) is an inherited predisposition cancer syndrome, typically caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 and PMS2. In the last years, a role for epimutations of the same genes has also been reported. MLH1 promoter methylation is a well known mechanism of somatic inactivation in tumors, and more recently, several cases of constitutional methylation have been identified. In four subjects affected by multiple tumors and belonging to a suspected LS family, we detected a novel secondary MLH1 gene epimutation. The methylation of MLH1 promoter was always linked in cis with a 997 bp-deletion (c.-168_c.116+713del), that removed exon 1 and partially involved the promoter of the same gene. Differently from cases with constitutional primary MLH1 inactivation, this secondary methylation was allele-specific and CpGs of the residual promoter region were totally methylated, leading to complete allele silencing. In the colon tumor of the proband, MLH1 and PMS2 expression was completely lost as a consequence of a pathogenic somatic point mutation (MLH1 c.199G>A, p.Gly67Arg) that also abrogated local methylation by destroying a CpG site. The evidences obtained highlight how MLH1 mutations and epimutations can reciprocally influence each other and suggest that an altered structure of the MLH1 locus results in epigenetic alteration., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Male breast cancer (MBC) is rare and poorly understood. Like female breast cancer (FBC), MBCs are highly sensitive to hormonal changes, and hyperestrogenism, specifically, represents a major risk factor for MBC. MBC is considered similar to late-onset, post-menopausal estrogen/progesteron receptors positive FBC (ER+/PR+). Sulfotransferase 1A1 (SULT1A1) is an enzyme involved in the metabolism of estrogens. Recently, SULT1A1 common functional polymorphism Arg(213)His (638G>A) variant has been found to be associated with increased breast cancer (BC) risk, particularly in post-menopausal women. For this reason, we decided to explore whether SULT1A1 Arg(213)His could exert an effect on MBC development. The primary aim of this study was to evaluate the influence of the SULT1A1 Arg(213)His polymorphism on MBC risk. The secondary aim was to investigate possible associations with relevant clinical-pathologic features of MBC. A total of 394 MBC cases and 786 healthy male controls were genotyped for SULT1A1 Arg(213)His polymorphism by PCR-RFLP and high-resolution melting analysis. All MBC cases were characterized for relevant clinical-pathologic features. A significant difference in the distribution of SULT1A1 Arg(213)His genotypes was found between MBC cases and controls (P < 0.0001). The analysis of genotype-specific risk showed a significant increased MBC risk in individuals with G/A (OR 1.97, 95% CI 1.50-2.59; P < 0.0001) and A/A (OR 3.09, 95% CI 1.83-5.23; P < 0.0001) genotypes in comparison to wild-type genotype, under co-dominant model. A significant association between SULT1A1 risk genotypes and HER2 status emerged. Results indicate that SULT1A1 Arg(213)His may act as a low-penetrance risk allele for developing MBC and could be associated with a specific tumor subtype associated with HER2 overexpression.

Subclinical hyperthyroidism (SH) has been reported associated with atrial fibrillation (AF), heart failure (HF) and coronary heart disease events, including mortality. An expert opinion indicates that AF is the possible link between SH and the other important cardiovascular (CV) manifestations. We analyzed the data of three recent studies including 60,883 subjects of whom 2,284 SH patients. In these subjects, the ratio between the AF events and each of the other above reported CV events varied from 0.14 to 0.4 in SH and from 0.2 to 2.4 in euthyroidism (ET). The general pattern of this ratio in 6 comparisons performed was not significantly higher for SH than ET. This data suggest that AF is not the major link between SH and the related CV manifestations. We suggest that a further link to be considered is the higher frequency of the early atherosclerosis manifestations such as carotid intima media thickness or carotid integrated back scatter, observed in SH. This atherogenic effect of SH can affect the occurrence of all the above clinical CV manifestations.

We review podocyte molecular structure and function, consider the underlying mechanisms related to podocyte dysfunction and propose that podocyte dysfunction be considered in the evaluation and management of age-associated glomerulosclerosis. With aging, progressive sympathetic activation, increased intrarenal renin-angiotensin system (RAS) activity, endothelin system and oxidative stress and reduced nitric oxide (NO)-availability can damage podocytes. Apoptosis and proliferation are the principal podocyte changes following injury with the latter leading to sclerosis and loss of nephrons. Podocyte loss can be evaluated by either determining their average number in biopsed glomeruli or by estimating podocyte number or their associated molecules in urine sediment. Podocyturia may be considered a marker of active glomerular disease. Preliminary data suggest that antiadrenergic drugs, angiotensin converting enzyme (ACE) inhibitors, RAS blocking drugs, endothelin system inhibitors and reduced oxidative stress can protect podocytes. Thus podocytes appear to play an important role in the pathogenesis, evaluation and therapy of age related glomerulosclerosis.

Unlabelled: The aim of the present study was to evaluate the effect of subclinical hyperthyroidism (SHT) on cardiovascular autonomic function and ventricular repolarization., Methods: Thirty subjects (25 females; mean age 49.6 ± 9.8 years) with SHT, as judged by reduced TSH serum levels and normal free T4 and T3 serum levels, and 30 age and sex-matched control subjects underwent standard 12-lead ECG, and 24h ambulatory ECG monitoring. The dispersion of the QT interval, an index of inhomogeneity of repolarization, and the heart rate variability (HRV), a measure of cardiac autonomic modulation, were studied., Results: Patients with SHT showed higher QT dispersion (p<0.001) and lower HRV measures (0.01>p<0.001) than controls. In SHT patients, QT dispersion was inversely related to HRV (r=-0.47, p<0.01)., Conclusion: The results of the present study demonstrated that SHT is associated with a sympathovagal imbalance, characterized by increased sympathetic activity in the presence of diminished vagal tone, and with an increased inhomogeneity of ventricular recovery times. The assessment of HRV and QT dispersion in patients with SHT may represent a useful tool in monitoring the cardiovascular risk of this condition., (Copyright © 2009 Elsevier Masson SAS. All rights reserved.)

Phaeochromocytomas are rare neuroendocrine tumours secreting high levels of catecholamines, able to exert serious metabolic and cardiovascular effects. The serious and potentially lethal cardiovascular complications of these tumours are due to the potent effects of secreted catecholamines, especially noradrenaline, the main transmitter released from sympathetic nerve terminals. Hypertension, tachycardia, pallor, headache and anxiety, usually dominate the clinical presentation. Occasionally, patients with predominantly epinephrine-secreting tumours present hypotension or even shock. Other cardiovascular complications of pheochromocytoma include ischaemic heart disease, acute myocardial infarction, cardiac arrhythmias, heart failure due to toxic cardiomyopathy, or pulmonary edema. Catecholamines have been shown to influence the extracellular matrix with collagen deposition and subsequent fibrosis in the arterial wall and in the myocardium. These morphofunctional changes of the myocardium and of arterial wall can be emphasized by ultrasound imaging. Indeed, ultrasound imaging of the myocardium and arterial wall not only identifies wall thickness but also contains information on texture that may be revealed by acoustic tissue characterization. The latter can be quantified through videodensitometric analysis of echographic images or through ultrasonic integrated backscatter signal analysis. This paper reviews cardiovascular complications in patients with pheochromocytoma and utility of the new ultrasound technique as backscatter signal. It is useful for evaluating preclinical pathological morphofunctional changes of the myocardium and arterial wall, characterized by increased collagen content in pheochromocytoma patients. The recognition of early catecholamine-induced alterations in patients with pheochromocytoma, is important to prevent at least morbidity and mortality, before surgical treatment., (2009 Elsevier Masson SAS. All rights reserved.)

Thyroid dysfunction, however mild, can significantly affect the cardiovascular (CV) system. The effects of thyroid hormones may be viewed as genomic and non-genomic, with the former occurring over a longer time scale and both affecting structural and functional proteins in CV tissue. As the interplay between thyroid function and the CV system becomes elucidated, particularly in the context of a system biology approach, the heart failure phenotype is better understood. Symptomatology is related to disturbance in inotropic and chronotropic function. Moreover, biochemical changes reflected by thyroid function testing with the non-thyroidal illness syndrome can prognosticate and guide therapy in heart failure. In addition, empiric treatment with thyroid hormone analogues or T3 represent emergent and highly controversial interventions.

Melatonin is endowed with a growth inhibitory effect in MCF-7 breast cancer cells whose mechanism has been related to an antiestrogenic activity exerted by inhibition of binding of the estradiol-estrogen receptor complex to its DNA responsive element. Looking for downstream gene determinants of this effect, we performed a transcriptome profiling by high-density microarrays of estrogen-treated MCF-7 cells exposed or not to melatonin. We found that cyclin D1 was one of the main downregulated genes by melatonin. Validation experiments clearly confirm that in MCF-7 cells the estrogen-induced growth inhibitory activity of melatonin is consistently associated with inhibition of estrogen-elicited cyclin D1 induction. This effect is almost purely transcriptional. Reporter gene assays indicate that the same portion of the cyclin D1 promoter which confers estrogen sensitivity, encompassing a potential cAMP responsive element binding site, is repressed by melatonin. Transcriptional downregulation of cyclin D1 is the key molecular event for melatonin's antiproliferative activity, as this activity can be completely and selectively rescued by transient cyclin D1 overexpression. Finally, we provide indirect evidence that the effect of melatonin on the cyclin D1 promoter is mediated by the c-jun and ATF-2 proteins, known to bind the minimal estrogen-sensitive cyclin D1 promoter element. These findings establish for the first time a molecular link between melatonin and its effects on the cell cycle, providing at the same time a rationale for its use in adjuvant chemotherapy.