Gender-Related Approach to Kidney Cancer Management: Moving Forward.

Men are more frequently diagnosed with kidney cancer than women, with a more aggressive histology, larger tumors, a higher grade and stage, and worse oncological outcomes. Smoking habits and sex steroid hormones seem to have a possible role in explaining these gender disparities. Moreover, the expression of genes involved in tumor growth and immune response in kidney cancer varies between men and women, having an impact on the gender-related response to oncological therapy, such as anti-angiogenic drugs and immunotherapy. Recent advances have been made in our understanding of the molecular and genetic mechanisms involved in kidney cancer, which could partially explain the gender differences, and they are summarized in this paper. However, other key mechanisms, which fully clarify the striking clinical gender-related differences observed in kidney cancer, are not completely understood at present. We reviewed and summarized the most relevant publications about the relationship between gender and kidney cancer. Efforts should be made to progress in bench and clinical research on gender-related signatures and disparities, and their impact on the clinical management of kidney cancer.

The effect of childcare activities on cognitive status and depression in older adults: gender differences in a 4.4-year longitudinal study.

OBJECTIVES: Although involvement in childcare activities seems to promote better physical and mental health in older adults, its impact on cognitive status and depression has not yet been fully elucidated. We aimed to analyze the association between engagement in childcare activities and cognitive and psychological status over a 4.4-year period in community-dwelling older adults. METHODS: Two thousand one hundred four subjects older than 65 years without severe cognitive impairment at baseline were categorized according to the frequency of their involvement in childcare activities (everyday, occasionally, never). The participants' cognitive status and depressive symptoms were evaluated at baseline and after 4.4 years. RESULTS: During the follow-up, 269 (12.8%) new cases of cognitive impairment and 229 (10.9%) new cases of depression were registered. Men engaged in childcare showed an almost 20% lower risk of cognitive impairment and cognitive decline. Women demonstrated similar results, except for those occasionally involved in childcare, who had a higher risk of cognitive decline compared with women who never engaged in it. The risk of developing depression was reduced in men involved daily (OR = 0.44, 95% CI: 0.30-0.62, p < 0.0001) and occasionally in childcare, who also demonstrated a lower risk of exacerbating depressive symptoms compared with subjects who never involved in it. The onset of depression was reduced in women occasionally engaged in childcare (OR = 0.68, 95% CI: 0.56-0.82, p < 0.0001), but not significantly in those daily involved in it. CONCLUSIONS: Involvement of older adults in childcare activities seems to lower the risk of cognitive impairment in both genders and to prevent onset or worsening of depression particularly in older men. Copyright © 2017 John Wiley & Sons, Ltd.

Changes in Frailty Status and Risk of Depression: Results From the Progetto Veneto Anziani Longitudinal Study.

OBJECTIVE: To evaluate whether prefrailty was associated with the risk of developing depression and if longitudinal changes in frailty status corresponded to changes in incident depression during follow up. METHODS: A population-based, prospective cohort study was conducted for 4.4 years in two separate geographic areas near the city of Padua in the Veneto Region of Northern Italy. In 891 nondepressed, nonfrail, community-dwelling Italian subjects aged ≥ 65 (46.6% men) belonging to the Progetto Veneto Anziani study, depression was defined according to the Geriatric Depression Scale and was confirmed by geriatricians skilled in psychogeriatric medicine. Prefrailty was defined by the presence of one or two criteria among the Fried criteria. RESULTS: The incidence rate of depression was 13.3% among subjects improving their frailty status at follow-up (N = 15), 15.0% in those who remained stable (N = 79), and 26.7% among worsening participants (N = 67) (p = 0.001). Prefrailty at baseline did not predict the onset of depression (HR: 0.82; 95% CI: 0.55-1.21; Wald χ2 = 0.73; df = 1; p = 0.43), but a deterioration during follow-up in at least one additional frailty criteria was associated with a significantly higher risk (HR: 1.95; 95% CI: 1.32-2.89; Wald χ2 = 5.78; df = 2; p = 0.01). Improvement in frailty status was not associated with the risk of incident depression (HR: 0.71; 95% CI: 0.35-1.42; Wald χ2 = 0.47; df = 2; p = 0.28). CONCLUSION: Our data did not offer evidence that prefrailty per se predisposes to the onset of depression, but worsening in frailty status is associated with an almost twofold increased risk of incident depression, irrespective from the initial level of impairment.

[Gender medicine: a interdisciplinary approach to medicine.] / La Medicina di Genere: un approccio interdisciplinare alla medicina.

OBJECTIVES: From1995 (Beijing Conference) the World Health Organization strongly did call the attention on the need of great attention to women health and on the lack of studies on the differences in medicine between men and women. From the women health attention we arrived to gender medicine that is a transversal dimension of medicine which describes the differences within the same disease of symptoms, clinical evolution, drug therapy as well as prevention between men and women. METHODS: From some real life examples in this article we wish to make it clear that gender medicine is not a separated medical specialty but a dimension which pass through all specialties. RESULTS: Thus we should speak about gender-specific medicine since all medical specialties have to do a medical training on the basis of gender differences. CONCLUSIONS: Lastly it is underlined also the need of a social approach to gender health in order to pick up all social weight factors that influence diseases in the two genders.

Gender, aging and longevity in humans: an update of an intriguing/neglected scenario paving the way to a gender-specific medicine.

Data showing a remarkable gender difference in life expectancy and mortality, including survival to extreme age, are reviewed starting from clinical and demographic data and stressing the importance of a comprehensive historical perspective and a gene-environment/lifestyle interaction. Gender difference regarding prevalence and incidence of the most important age-related diseases, such as cardiovascular and neurodegenerative diseases, cancer, Type 2 diabetes, disability, autoimmunity and infections, are reviewed and updated with particular attention to the role of the immune system and immunosenescence. On the whole, gender differences appear to be pervasive and still poorly considered and investigated despite their biomedical relevance. The basic biological mechanisms responsible for gender differences in aging and longevity are quite complex and still poorly understood. The present review focuses on centenarians and their offspring as a model of healthy aging and summarizes available knowledge on three basic biological phenomena, i.e. age-related X chromosome inactivation skewing, gut microbiome changes and maternally inherited mitochondrial DNA genetic variants. In conclusion, an appropriate gender-specific medicine approach is urgently needed and should be systematically pursued in studies on healthy aging, longevity and age-related diseases, in a globalized world characterized by great gender differences which have a high impact on health and diseases.

Serum dehydroepiandrosterone sulfate and incident depression in the elderly: the Pro.V.A. study.

OBJECTIVE: Dehydroepiandrosterone sulfate (DHEAS) appears to have a protective effect against depression, but contrasting findings are available. Therefore, we investigated whether high serum DHEAS levels were associated with any protective effect on incident depression and incident severe depression in a representative group of elderly men and women. METHODS: In a population-based cohort longitudinal study in the general community, 789 older participants without depression and cognitive impairment at the baseline were included, among 3,099 screened subjects. Serum DHEAS levels were determined based on blood samples; incident depression and severe depression were diagnosed by means of the Geriatric Depression Scale (GDS) and confirmed by geriatricians skilled in psychogeriatric medicine. RESULTS: No baseline differences were found in GDS across age- and gender-specific tertiles of serum DHEAS. Over 4.4 years of follow-up, 137 new cases of depression were recorded. Of them, 35 among men and 64 in women were cases of incident severe depression. Cox's regression analysis, adjusted for potential confounders, revealed that higher DHEAS levels were associated with reduced risk of incident depression irrespective of gender (HR: 0.30; 95% CI: 0.09-0.96; Wald χ(2) = 4.09; df = 1; p = 0.04; women: HR: 0.31; 95% CI: 0.14-0.69; Wald χ(2) = 8.37; df = 1; p = 0.004) and of severe incident depression only in men (HR: 0.25; 95% CI: 0.06-0.99; Wald χ(2) = 4.05; df = 1; p = 0.04). CONCLUSION: Higher serum DHEAS levels were found to be significantly protective for the onset of depression irrespective of gender, whereas only in men was this association found also for incident severe depression.

Sex and Gender in Ageing and Longevity: Highlights From an International Course.

Gender medicine is a multidisciplinary science and represents an important perspective for pathophysiological and clinical studies in the third millennium. Here, it is provided an overview of the topics discussed in a recent course on the Role of Sex and Gender in Ageing and Longevity. The paper highlights three themes discussed in the course, i.e., the interaction of gender/sex with, i) the pathophysiology of age-related diseases; ii), the role of genetics and epigenetics in ageing and longevity and, iii) the immune responses of older people to pathogens, vaccines, autoantigens, and allergens. Although largely unexplored, it is clear that sex and gender are modulators of disease biology and treatment outcomes. It is becoming evident that men and women should no longer be considered as subgroups, but as biologically distinct groups of patients deserving consideration for specific therapeutic approaches.

Pre-analytical stability of the plasma proteomes based on the storage temperature.

BACKGROUND: This study examined the effect of storage temperature on the protein profile of human plasma. Plasma samples were stored for 13 days at -80°C, -20°C, +4°C and room temperature (20-25°C) prior to proteomic analysis. The proteomic comparisons were based on the differences of mean intensity values of protein spots between fresh plasma samples (named "time zero") and plasma samples stored at different temperatures. To better understand the thermally induced biochemical changes that may affect plasma proteins during storage we identified proteins with different expressions with respect to the time zero sample. RESULTS: Using two-dimensional electrophoresis followed by MALDI-TOF MS and /or LC-MS/MS 20 protein spots representing 10 proteins were identified with significant differences in abundance when stored at different temperatures. Our results, in agreement with various authors, indicate that during storage for a short period (13 days) at four different temperatures plasma proteins were more affected by degradation processes at +4°C compared to the other temperatures analysed. However, we founded that numerous protein spots (vitamin D binding protein, alpha-1-antitrypsin, serotransferrin, apoplipoprotein A-I, apolipoprotein E, haptoglobin and complement factor B) decrease in abundance with increasing temperature up to 4°C, but at room temperature their intensity mean values are similar to those of time zero and -80°C. We hypothesize that these proteins are labile at 4°C, but at the same time they are stable at room temperature (20-25°C). Furthermore we have grouped the proteins based on their different sensitivity to the storage temperature. Spots of serum albumin, fibrinogen gamma chain and haptoglobin are more resistant to the higher temperatures tested, as they have undergone changes in abundance only at room temperature; conversely, other spots of serum albumin, fibrinogen beta chain and serotransferrin are more labile as they have undergone changes in abundance at all temperatures except at -80°C. CONCLUSIONS: Although there are many studies concerning protein stability of clinical samples during storage these findings may help to provide a better understanding of the changes of proteins induced by storage temperature.

Gender medicine: a task for the third millennium.

Gender-specific medicine is the study of how diseases differ between men and women in terms of prevention, clinical signs, therapeutic approach, prognosis, psychological and social impact. It is a neglected dimension of medicine. In this review we like to point out some major issues in five enormous fields of medicine: cardiovascular diseases (CVDs), pharmacology, oncology, liver diseases and osteoporosis. CVDs have been studied in the last decades mainly in men, but they are the first cause of mortality and disability in women. Risk factors for CVD have different impacts in men and women; clinical manifestations of CVD and the influence of drugs on CVD have lot of gender differences. Sex-related differences in pharmacokinetics and pharmacodynamics are also emerging. These differences have obvious relevance to the efficacy and side effect profiles of various medications in the two sexes. This evidence should be considered for drug development as well as before starting any therapy. Gender disparity in cancer incidence, aggressiveness and prognosis has been observed for a variety of cancers and, even if partially known, is underestimated in clinical practice for the treatment of the major types of cancer. It is necessary to systematize and encode all the known data for each type of tumor on gender differences, to identify where this variable has to be considered for the purposes of the prognosis, the choice of treatment and possible toxicity. Clinical data suggest that men and women exhibit differences regarding the epidemiology and the progression of certain liver diseases, i.e., autoimmune conditions, genetic hemochromatosis, non-alcoholic steatohepatitis and chronic hepatitis C. Numerous hypotheses have been formulated to justify this sex imbalance including sex hormones, reproductive and genetic factors. Nevertheless, none of these hypothesis has thus far gathered enough convincing evidence and in most cases the evidence is conflicting. Osteoporosis is an important public health problem both in women and men. On the whole, far more epidemiologic, diagnostic and therapeutic studies have been carried out in women than in men. In clinical practice, if this disease remains underestimated in women, patients' and physicians' awareness is even lower for male osteoporosis, for which diagnostic and therapeutic strategies are at present less defined. In conclusion this review emphasizes the urgency of basic science and clinical research to increase our understanding of the gender differences of diseases.

Gender differences in the quality of life of patients with liver cirrhosis related to hepatitis C after liver transplantation.

BACKGROUND: Hepatitis C virus (HCV) infection frequently leads to chronic liver disease, which adversely affects the quality of life (QoL) of the patient. The gender of the patient may be an important variable in the way severity of the disease is perceived. The aim of our study is to evaluate the effect of the gender variable on QoL in HCV-positive patients. METHODS: This study included a total of 52 patients (26 men and 26 women) who completed a 1-year follow-up after liver transplantation. QoL was assessed using the SF-36 questionnaire. RESULTS: Male subjects have significantly higher scores on physical role functioning, bodily pain and physical activity compared with females. Females have a better QoL compared to males with regard to the emotional state and mental health. CONCLUSIONS: These results show a significant effect of the gender variable on QoL in HCV patients.

Frailty and the risk of infection-related hospitalizations in older age: Differences by sex.

OBJECTIVES: To investigate the extent to which frailty is associated with infection-related hospitalizations in older men and women, and to explore whether, among women, previous exposure to endogenous estrogens in terms of age at menopause and number of pregnancies modify such a relationship. STUDY DESIGN: The sample comprised 2784 participants in the Progetto Veneto Anziani aged ≥65 years. At baseline and after 4.4 years, frailty was identified according to the presence of three or more of the following: weakness, exhaustion, weight loss, low physical activity, and low walking speed. A passive follow-up on infection-related hospitalizations and mortality was performed for 10 years of observation through linkage with regional registers. MAIN OUTCOME MEASURES: The association between frailty and infection-related hospitalizations was assessed through mixed-effects Cox regressions. RESULTS: Frailty was significantly associated with a 78 % higher risk of infection-related hospitalization, with stronger results in men (hazard ratio = 2.32, 95 % confidence interval 1.63-3.30) than in women (hazard ratio = 1.54, 95 % confidence interval 1.18-2.02). Focusing on women, we found a possible modifying effect for the number of pregnancies but not menopausal age. Women who had experienced one or no pregnancy demonstrated a higher hazard of infection-related hospitalization as a function of frailty (hazard ratio = 3.00, 95 % confidence interval 1.58-5.71) than women who had experienced two or more pregnancies (hazard ratio = 1.68, 95 % confidence interval 1.18-2.39). CONCLUSION: Frailty in older age increases the risk of infection-related hospitalizations, especially in men. The "immunologic advantage" of the female sex in younger age seems to persist also after menopause as a function of the number of pregnancies a woman has experienced.

Cardiovascular risk profiles and 20-year mortality in older people: gender differences in the Pro.V.A. study.

The age- and gender-related cardio-metabolic changes may limit the applicability of guidelines for the prevention of cardiovascular diseases (CVD) in older people. We investigated the association of cardiovascular risk profile with 20-year all-cause and CVD-mortality in older adults, focusing on age- and gender-specific differences. This prospective study involved 2895 community-dwelling individuals aged ≥65 years who participated in the Pro.V.A study. The sum of achieved target levels (smoking, diet, physical activity, body weight, blood pressure, lipids, and diabetes) recommended by the European Society of Cardiology 2016 guidelines was assessed in each participant. From this sum, cardiovascular risk profile was categorised as very high (0-2), high (3), medium (4), low (5), and very low (6-7 target levels achieved). All-cause and CV mortality data over 20 years were obtained from health registers. At Cox regression, lower cardiovascular risk profile was associated with reduced 20-year all-cause mortality in both genders, with stronger results for women (HR = 0.42 [95%CI:0.25-0.69] and HR = 0.61 [95%CI:0.42-0.89] for very low vs. very high cardiovascular risk profile in women and men, respectively). This trend was more marked for CVD mortality. Lower cardiovascular risk profile was associated with reduced all-cause and CVD mortality only in men < 75 years, while the associations persisted in the oldest old women. A lower cardiovascular risk profile, as defined by current guidelines, may reduce all-cause and CVD mortality in older people, with stronger and longer benefits in women. These findings suggest that personalised and life-course approaches considering gender and age differences may improve the delivery of preventive actions in older people. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10433-021-00620-y.

Association of physical activity trajectories with major cardiovascular diseases in elderly people.

INTRODUCTION: Cardiovascular benefits deriving from physical activity are well known, but it is unclear whether physical activity trajectories in late life are associated with different risks of cardiovascular diseases. METHODS: Progetto Veneto Anziani (Pro.V.A.) is a cohort study of 3099 Italians aged ≥65 years with baseline assessment in 1995-1997 and follow-up visits at 4 and 7 years. Surveillance was extended to 2018 by linkage with hospital and mortality records. Prevalent and incident cardiovascular diseases (coronary heart disease, heart failure and stroke) were identified through clinical examination, questionnaire, or hospital records. Moderate to vigorous physical activity was considered as a time-varying variable. Physical activity trajectories were categorised as: stable-low, high-decreasing, low-increasing and stable-high. Exposure was also assessed at 70, 75, 80 and 85 years. RESULTS: Overall, physical activity was associated with lower rates of incident cardiovascular diseases. A significant risk reduction was present among men and was stronger earlier in late life (70-75 years). Trajectories of stable-high physical activity were associated with a significantly lower risk of cardiovascular outcomes among men (HR 0.48, 95% CI 0.27 to 0.86) compared with those with stable-low trajectories (p for trend 0.002). No significant association was found with stroke. The greatest cardiovascular risk reduction was observed for >20 min/day of physical activity, and was more marked at 70 years. CONCLUSION: Increasingly active trajectories of physical activity were associated with lower rates of cardiovascular diseases and overall mortality. Promoting at least 20 min/day of physical activity early in late life seems to provide the greatest cardiovascular benefits.

The impact of knee and hip chondrocalcinosis on disability in older people: the ProVA Study from northeastern Italy.

OBJECTIVES: Chondrocalcinosis is frequently associated with osteoarthritis. The role of osteoarthritis in the onset and progression of disability is well known. The impact of chondrocalcinosis on disability has never been investigated in epidemiological studies. METHODS: Progetto Veneto Anziani is a survey of 3099 older Italians, focusing on chronic diseases and disability. Assessment was by questionnaires, physical performance tests and clinical evaluations. Chondrocalcinosis was determined by x-ray readings of 1629 consecutive subjects. Knee and hip osteoarthritis severity was evaluated by summing the radiographic features score (RFS) assigned during x-ray reading. SUBJECTS: with chondrocalcinosis were older and more frequently women (age-adjusted p<0.0001). The gender association disappeared following adjustment for osteoarthritis severity. However, at the knee, the prevalence of osteoarthritis was higher in chondrocalcinosis patients independently of age and sex (age-adjusted p<0.0001). No difference was found between chondrocalcinosis and controls in sociodemographic variables and comorbidity. Knee chondrocalcinosis was strongly associated with clinical features of knee osteoarthritis and with disability assessment parameters in the bivariate analysis. Most associations remained after adjusting for age. After further adjustment for RFS, a significant association remained for knee deformity and pain, the need for a cane, difficulty walking 500 m, using a toilet, shopping and repeatedly rising from a chair. CONCLUSIONS: Pain and physical function are the outcome measures of choice for assessing disability in osteoarthritis patients. The presence of chondrocalcinosis contributes to both, independently of age and osteoarthritis severity, thus compromising the quality of life and worsening comorbidity.

Spotlight on gender-specific disparities in bladder cancer.

Men are at a higher risk of developing bladder cancer, but women present with more advanced disease and have more unfavourable outcomes. Although epidemiologic and genetical studies have underlined the multifactorial aetiology and gender-related differences of bladder cancer, there is lack of evidence-based recommendation for gender-specific management of bladder cancer. We summarize the evidence and most recent findings on gender-specific differences in bladder cancer incidence, diagnosis, treatment and outcome, spotlighting the gender disparities in genetic and hormonal risk factors, pelvic anatomy, diagnostic setting and surgical choices. We reviewed the literature published on PubMed between 1981 and 2018. Males have a threefold to fourfold higher risk of bladder cancer as compared to females; however, women have higher stage-for-stage mortality, being diagnosed with more advanced disease, mostly due to a delay in haematuria evaluation. Numerous studies indicate an increased risk of disease recurrence or progression in women with non-muscle-invasive bladder cancer treated with trans-urethral resection, with or without intravesical chemotherapy or immunotherapy, compared to males. In particular, recent molecular evidence show that there is an excess of female Ta mutant tumours. At the time of radical cystectomy, women have a significantly longer length of hospital stay, operative time, higher blood loss and higher 90-day mortality and perioperative complication rate. Moreover, females are less likely to receive a continent diversion. Future research should guarantee greater inclusion of women in trials and focus on improving the effectiveness of therapies in women, perhaps exploring different therapeutic approaches in men and women. Specific data on functional and oncological outcomes can be analysed to define predictive factors able to guide the surgeon in decisions based on evidence. It is urgently needed to limit gender-related discrepancies in early diagnosis and treatment of bladder cancer. Public awareness and bladder cancer female patients' consciousness on gender inequalities must be similarly uprisen.

Human longevity within an evolutionary perspective: the peculiar paradigm of a post-reproductive genetics.

The data we collected on the genetics of human longevity, mostly resulting from studies on centenarians, indicate that: (1) centenarians and long-living sib-pairs are a good choice for the study of human longevity, because they represent an extreme phenotype, i.e., the survival tail of the population who escaped neonatal mortality, pre-antibiotic era illnesses, and fatal outcomes of age-related complex diseases. (2) The model of centenarians is not simply an additional model with respect to well-studied organisms, and the study of humans has revealed characteristics of ageing and longevity (geographical and sex differences, role of antigenic load and inflammation, role of mtDNA variants) which did not emerge from studies in laboratory model systems and organisms. (3) All the phenotypic characteristics of nonagenarians and centenarians fit the hypothesis that ageing is a remodelling process where the body of survivors progressively adapts to internal and external damaging agents they are exposed to during several decades, largely unpredicted by evolution. (4) Such a remodelling process, which can be considered a Darwinian process occurring at the somatic level within the framework of the evolutionary constraints, established by evolution for Homo sapiens as a species, may explain why the same gene polymorphism can have different (beneficial or detrimental) effects at different ages. (5) Geographic and demographic evidence suggest that longevity can be achieved by different combinations of genes, environment, and chance quantitatively and qualitatively different in many geographic areas, and that population-specific genetic factors, play a role on the longevity trait. (6) The concomitant and integrated use of new in silico and high throughput strategies will greatly accelerate the identification of new longevity genes in humans.

Analysis of HLA-DRB1, DQA1, DQB1 haplotypes in Sardinian centenarians.

Some genetic determinants of longevity might reside in those polymorphisms for the immune system genes that regulate immune responses. Many longevity association studies focused their attention on HLA (the human MHC) polymorphisms, but discordant results have been obtained. Sardinians are a relatively isolate population and represent a suitable population for association studies. Some HLA-DR and DQ alleles form very stable haplotypes with a strong linkage disequilibrium. In a previous study on Sardinian centenarians we have suggested that HLA-DRB1 *15 allele might be marginally associated to longevity. HLA-DR,DQ haplotypes are in strong linkage disequilibrium and well conserved playing a role in the association to diseases. Hence, we have evaluated, by amplification refractory mutation system/polymerase chain reaction (ARMS-PCR) the HLADQA1 and HLA-DQB1 allele frequencies in 123 centenarians and 92 controls from Sardinia to assess whether the association to HLA-DRB1 *15 allele may be due to the other genes involved in the HLA-DR,DQ haplotypes. The frequencies of HLA-DQA1, DQB1 haplotypes were not significantly modified in centenarians. Nevertheless by evaluating the frequency of DRB1 *15 linked haplotypes, we observed a not significant increase in centenarians of HLA-DQA1 *01, DQB1 *05 and HLA-DQA1 *01,DQB1 *06 haplotypes. These data suggest that these haplotypes might have a role in determining life span expectancy and longevity.

White matter lesions and the risk of incident hip fracture in older persons: results from the progetto veneto anziani study.

BACKGROUND: White matter lesions (WMLs) are associated with hypertension, an increased risk of falling, and impaired physical and cognitive performance that may affect the mechanical effect of falls. METHODS: We hypothesized that WMLs are a risk factor for hip fracture (HF). We studied a sample of 820 community-dwelling Italian persons 65 years and older from the cohort of the Progetto Veneto Anziani Study who underwent brain magnetic resonance imaging at baseline. Subjects were classified as having no lesions, focal lesions, or diffuse WMLs. RESULTS: Compared with those with no lesions, participants with diffuse WMLs were older, reported more falls, and had worse physical and cognitive performance, all factors implicated in the causal pathway to HF. During 9 years of follow-up, 51 HFs occurred. Hip fracture risk associated with diffuse WMLs markedly differed between participants younger than 80 years vs those 80 years and older. After adjustment among participants younger than 80 years, diffuse WMLs compared with no lesions were associated with a 2.7-fold (95% confidence interval, 1.1-7.1) increase in the risk of HF. Focal lesions were not statistically significantly associated with an increased risk of HF in the same age group (hazard ratio, 2.0; 95% confidence interval, 0.6-7.6). No associations between diffuse WMLs, focal lesions, and HF were evident among participants 80 years and older, possibly because of the limited sample size. CONCLUSIONS: White matter lesions represent an independent risk factor for HF in persons younger than 80 years. Older persons with diffuse WMLs should be considered candidates for multifactorial interventions aimed at reducing the risk of falling and fractures.

Estrogen and thyroid cancer is a stem affair: A preliminary study.

Gender influences Papillary Thyroid Cancer (PTC) with an incidence of 3:1 when comparing women to men with different aggressiveness. This gender discrepancy suggests some role of sex hormones in favoring the malignant progression of thyroid tissue to cancer. Estrogens are known to promote Stem Cell self-renewal and, therefore, may be involved in tumor initiation. The goals of these studies are to investigate the underlying causes of gender differences in PTC by studying the specific role of estrogens on tumor cells and their involvement within the Cancer Stem Cell (CSC) compartment. Exposure to 1nmoll-1 Estradiol for 24h promotes growth and maintenance of PTC Stem Cells, while inducing dose-dependent cellular proliferation and differentiation following Estradiol administration. Whereas mimicking a condition of hormonal imbalance led to an opposite phenotype compared to a continuous treatment. In vivo we find that Estradiol promotes motility and tumorigenicity of CSCs. Estradiol-treated mice inoculated with Thyroid Cancer Stem Cell-enriched cells developed larger tumor masses than control mice. Furthermore, Estradiol-pretreated Cancer Stem cells migrated to distant organs, while untreated cells remained circumscribed. We also find that the biological response elicited by estrogens on Papillary Thyroid Cancer in women differed from men in pathways mediated. This could explain the gender imbalance in tumor incidence and development and could be useful to develop gender specific treatment of (PTC).

Factors Influencing Transitions Between Frailty States in Elderly Adults: The Progetto Veneto Anziani Longitudinal Study.

OBJECTIVES: To investigate frailty state transitions in a cohort of older Italian adults to identify factors exacerbating or improving frailty conditions. DESIGN: Population-based longitudinal study with mean follow-up of 4.4 years. SETTING: Community. PARTICIPANTS: Individuals enrolled in the Progetto Veneto Anziani (Pro.V.A.) (N = 2,925; n = 1,179 male, n = 1,746 female; mean age 74.4 ± 7.3). MEASUREMENTS: Frailty was identified at baseline and follow-up based on the presence of at least three Fried criteria; prefrailty was defined as the presence of one or two Fried criteria. Anthropometric, socioeconomic, and clinical characteristics were assessed at baseline in a personal interview and clinical examination using validated scales and medical history. RESULTS: During the study period, 1,114 (38.1%) subjects retained their baseline frailty status, 1,066 (36.4%) had a transition in frailty status, and the remainder of the sample died. Older age, female sex, obesity, cardiovascular disease, osteoarthritis, smoking, loss of vision, low levels of self-sufficiency and physical performance, cognitive impairment, hypovitaminosis D, hyperuricemia, and polypharmacy were associated with increasing frailty and greater mortality. Conversely, overweight, low to moderate drinking, high educational level, and living alone were associated with decreasing frailty. CONCLUSIONS: Frailty was confirmed as a dynamic syndrome, with socioeconomic and clinical factors that could be targets of preventive actions influencing transitions to better or worse frailty status.