Maturitas - Articles in Press

Magnetic nanovectors for drug delivery - Uncorrected Proof

Jim Klostergaard, Charles E. Seeney — 2012-02-20

Abstract: Nanotechnology holds the promise of novel and more effective treatments for vexing human health issues. Among these are the use of nanoparticle platforms for site-specific delivery of therapeutics to tumors, both by passive and active mechanisms; the latter includes magnetic vectoring of magnetically responsive nanoparticles (MNP) that are functionalized to carry a drug payload that is released at the tumor. The conceptual basis, which actually dates back a number of decades, resides in physical (magnetic) enhancement, with magnetic field gradients aligned non-parallel to the direction of flow in the tumor vasculature, of existing passive mechanisms for extravasation and accumulation of MNP in the tumor interstitial fluid, followed by MNP internalization. In this review, we will assess the most recent developments and current status of this approach, considering MNP that are composed of one or more of the three elements that are ferromagnetic at physiological temperature: nickel, cobalt and iron. The effects on cellular functions in vitro, the ability to successfully vector the platform in vivo, the anti-tumor effects of such localized nano-vectors, and any associated toxicities for these MNP will be presented. The merits and shortcomings of nanomaterials made of each of the three elements will be highlighted, and a roadmap for moving this long-established approach forward to clinical evaluation will be put forth.

Life satisfaction, loneliness and related factors during female midlife - Uncorrected Proof

2012-02-20

Abstract: Background: Studies assessing life satisfaction and feelings of loneliness in mid-aged women are scarce.Objective: To assess loneliness, life satisfaction and related factors in mid-aged Spanish women.Method: This was a cross sectional study in which 182 women aged 40 to 65 completed the menopause rating scale (MRS), the University of California at Los Angeles loneliness scale (UCLA-LS), the life satisfaction index A (LSI-A), and a general socio-demographic questionnaire containing personal/partner data. Internal consistency of each tool was also computed.Results: Median [interquartile range] age of the sample was 51 [9.0] years. A 55.5% were postmenopausal, 47.3% had increased body mass index (BMI) values, 57.7% were abdominally obese, 1.6% had hypertension and 86.3% had a stable partner. In addition, 4.9% used hormone therapy and 19.2% psychotropic drugs. Multiple linear regression analysis found that higher UCLA-LS scores (more loneliness) correlated with MRS psychological scores, partner alcohol abuse, living in urban areas, lower LSI-A scores (less life satisfaction) and not having a stable partner. Lower LSI-A scores (worse life satisfaction) correlated with severe female economical problems, BMI values and UCLA-LS and MRS psychological scores.Conclusion: Loneliness and life satisfaction in this mid-aged female sample was influenced by personal and partner issues which seem to play a much more relevant role than biological aspects. More research is warranted in this regard.

Increased 2-hydroxylation of estrogen is associated with lower body fat and increased lean body mass in postmenopausal women - Uncorrected Proof

2012-02-20

Abstract: Menopause is associated with changes in bone, muscle and fat mass. The importance of postmenopausal estrogen metabolism in bone health has been established. However, its relationship to body composition in postmenopausal women remains undetermined. The objective of this study is to determine the association between estrogen metabolism and body composition in postmenopausal women.This is a cross sectional study of 97 postmenopausal Caucasian women, 49–80 y.o., ≥1 year from the last normal menstrual period or those who have had oophorectomy. Inactive [2-hydroxyestrone (2OHE1)] and active [16α-hydroxyestrone (16α-OHE1)] urinary metabolites of estrogen were measured by ELISA. The whole and regional body composition was measured by DXA.We have found that both 2OHE1, and 2OHE1/16α-OHE1 ratio were negatively correlated with % total fat, and % truncal fat but positively correlated with % total lean mass. Comparing the fat and lean parameters of body composition according to tertiles of 2OHE1 and 2OHE1/16αOHE1 ratio showed that subjects in the lowest tertiles, had the highest % total fat, and % truncal fat and the lowest % total lean mass. Multiple regression analysis also showed 2OHE1 and calcium intake as statistically significant predictors of all body composition parameters.In conclusion, in postmenopausal women, an increase in the metabolism of estrogen towards the inactive metabolites is associated with lower body fat and higher lean mass than those with predominance of the metabolism towards the active metabolites.

Nanoparticle delivery for metastatic breast cancer - Uncorrected Proof

2012-02-20

Abstract: Breast cancer represents a major ongoing public health problem as the most common non-cutaneous malignancy among U.S. women. While significant progress has been made in improving loco-regional treatments for breast cancer, relatively little progress has been made in diagnosing and treating patients with metastatic breast cancer. At present, there are no curative options for most patients with breast cancer metastatic beyond regional nodes. Emerging nanotechnologies promise new approaches to early detection and treatment of metastatic breast cancer. Fulfilling the promise of nanotechnologies for patients with metastatic breast cancer will require delivery of nanomaterials to sites of metastatic disease. Future translational approaches will rely on an ever increasing understanding of the biology of breast cancer subtypes and their metastases. These important concepts will be highlighted and elucidated in this manuscript.

Dose-dependent effect of Resveratrol on bladder cancer cells: Chemoprevention and oxidative stress - Uncorrected Proof

2012-02-20

Abstract: Background: Over 6 million people die annually in the world because of cancer. Several groups are focused on studying cancer chemoprevention approaches. Resveratrol, a polyphenol, at high dosages, has been reported as antitumor and chemopreventive. However, it has a dose-dependent effect on cell death, even on some cancer cells.Objectives: Our aim was to investigate this dose-dependent effect on human bladder carcinoma ECV304 cells during oxidative stress condition.Methods: For this purpose, ECV304 cells incubated with different Resveratrol concentrations were analyzed as for their metabolic rate, membrane permeability, DNA fragmentation, anti/proapoptotic protein levels and phosphatidylserine exposure after oxidative stress.Results: Resveratrol induced cell death at high concentrations (>20μM), but not at low ones (0.1–20μM). Pretreatment with 2.5μM protected the cells from oxidative damage, whereas 50μM intensified the cell death and significantly increased Bad/Bcl-2 ratio (proapoptotic/antiapoptotic proteins). Resveratrol was able to modulate NO and PGE2 secretion and performed an anti-adhesion activity of neutrophils on PMA-activated ECV304 cells.Conclusions: Resveratrol at high doses induces cell death of ECV304 cells whereas low doses induce protection. Modulation of Bcl-2 protein induced by Resveratrol could be mediating this effect. This information about the role of Resveratrol on cancer alerts us about its dose-dependent effects and could lead the design of future chemoprevention strategies.

How the Newcastle Thousand Families birth cohort study has contributed to the understanding of the impact of birth weight and early life socioeconomic position on disease in later life - Uncorrected Proof

2012-02-20

Abstract: Much has been made of the potential influence of birth weight and early socioeconomic disadvantage in influencing adult health, but little has been published in terms of how important these associations may be with respect to exposures throughout the lifecourse. The objective of this review is to describe the contributions of the Newcastle Thousand Families Study in understanding the relative impacts of factors in early life, particularly birth weight and socio-economic position at birth, in influencing health in later life.The Newcastle Thousand Families Study is a prospective birth cohort established in 1947. It originally included all births to mothers resident in Newcastle upon Tyne, in northern England, in May and June of that year. Study members were followed extensively throughout childhood and intermittently in adulthood. At the age of 49–51 years, study members underwent a large-scale follow-up phase enabling an assessment of how early life may influence their later health, and also incorporating adult risk factors which enabled the relative contributions of factors at different stages of life to be assessed.While some findings from the study do support birth weight and early socio-economic position having influences on adult health status, the associations are generally small when compared to risk factors later in life. Using path analyses on longitudinal data of this nature enables mediating pathways between early life and later health to be assessed and if more studies were to take this approach, the relative importance of early life on adult disease risk could be better understood.

Effective and clinically meaningful non-hormonal hot flash therapies - Uncorrected Proof

Thomas Guttuso — 2012-02-15

Abstract: Although many non-hormonal compounds have shown statistically significant benefit over placebo in hot flash randomized controlled trials (RCTs), these studies have varied considerably in basic methodology making it challenging to deduce which compounds have the greatest potential to provide clinically meaningful benefit. This review used evidence-based methodology closely mirroring the FDA and EMEA guidelines as a template to identify “well-designed” RCTs from which effective and clinically meaningful non-hormonal hot flash therapies could be identified. In addition, pertinent safety information was reviewed. Out of 3548 MEDLINE citations and abstracts, 51 well-designed hot flash RCTs were identified. From these trials, gabapentin, oxybutynin ER, desvenlafaxine, soy-derived isoflavones and black cohosh each showed a clinically meaningful treatment effect in at least 1 RCT. Among these 5 compounds, only gabapentin demonstrated consistent and statistically significant benefit over placebo in all of its well-designed RCTs. Desvenlafaxine, soy-derived isoflavones, and black cohosh demonstrated statistically significant benefit over placebo in 75%, 21%, and 17% of the well-designed RCTs for each compound, respectively. There was only 1 well-designed RCT using oxybutynin ER, which showed it to have a robust and clinically meaningful benefit. In terms of safety, there have been cardiovascular risks associated with desvenlafaxine use in postmenopausal women with hot flashes. The use of anticonvulsants, in general, has been associated with an absolute 0.21% increase in suicidal thoughts and behavior. Further research is needed with several of these nonhormonal compounds to replicate these findings and to also directly compare their efficacy and tolerability with those of hormone replacement therapy.

The pharmacology of nomegestrol acetate - Uncorrected Proof

Xiangyan Ruan, H. Seeger, A.O. Mueck — 2012-02-13

Abstract: Nomegestrol acetate (NOMAC) is a 19-norprogesterone derivative with high biological activity at the progesterone receptor, a weak anti-androgenic effect, but with no binding to estrogen, glucocorticoid or mineralocorticoid receptors. At dosages of 1.5mg/day or more, NOMAC effectively suppresses gonadotropic activity and ovulation in women of reproductive age. Hemostasis, lipids and carbohydrate metabolism remain largely unchanged. In normal and cancerous human breast cells, NOMAC has shown favorable effects on estrogen metabolism. Like natural progesterone (but in contrast to some other synthetic progestogens), it does not appear stimulate the proliferation of cancerous breast cells.While there has been some experience of the use of NOMAC in combination with estrogens as a hormone replacement therapy, most of the data on the compound are reported in the context of its inclusion as a component of a new contraceptive pill comprising 2.5mg NOMAC combined with 1.5mg estradiol. Because of its strong endometrial efficacy, and due to its high antigonadotropic activity and long elimination half-life (about 50h), the contraceptive efficacy of the new pill is maintained even when dosages are missed. Furthermore, for the first time with a monophasic 24/4 regimen containing estradiol, cyclical stability can be achieved comparable with that obtained using pills containing ethinyl estradiol and progestogens like levonorgestrel or drospirenone.The addition of NOMAC to estradiol means that the beneficial effects of estrogen are not lost, which is of especial importance in relation to the cardiovascular system. On the basis both of its pharmacology and of studies performed during the development of the NOMAC/estradiol pill, involving some 4000 women in total, good long-term tolerability can be expected for NOMAC, although its safety profile is still to be fully ascertained, as the clinical endpoint studies are yet to be completed.

Incidence of uterine leiomyosarcoma and endometrial stromal sarcoma in Nordic countries: Results from NORDCAN and NOCCA databases - Uncorrected Proof

R. Koivisto-Korander, J.I. Martinsen, E. Weiderpass, A. Leminen, E. Pukkala — 2012-02-13

Abstract: Objectives and study design: Uterine sarcomas are an uncommon and heterogeneous group of malignancies. Their etiology is mainly unknown. Here, we analyzed trends in incidence and occupational variation in risk of uterine leiomyosarcomas (LMS) and endometrial stromal sarcomas (ESS) in the Nordic countries aided by NORDCAN and NOCCA (Nordic Occupational Cancer) databases.Main outcome measures: Incidence rates per 100,000 and Standardized incidences rates (SIR) obtained from NORDCAN and NOCCA databases.Results: The incidence rates were about 0.3 per 100,000 for ESS and about 0.4 per 100,000 for LMS in Denmark, Finland, Iceland, and Norway. During the study-period (1978–2007), the incidence rates in each country were quite similar and constant. The age-specific incidence of LMS showed a peak around menopause. Significantly increased risk for LMS occurred in shoe and leather workers, farmers and teachers, whereas significantly low risk was detected with packers in the NOCCA data from Finland, Norway, and Sweden. For ESS no occupations showed either increased or decreased incidences.Conclusions: The incidence trends of LMS and ESS in our study were constant in four Nordic countries over time. The elevated risk for LMS with women exposed to leather work and animal dust indicates further exploration.

Preventing weight gain through exercise and physical activity in the elderly: A systematic review - Uncorrected Proof

Mareike D. Stehr, Thomas von Lengerke — 2012-02-13

Abstract: This review examines the role of exercise and physical activity for preventing weight gain in older people. A structured search using MeSH-vocabulary and Title/Abstract-searches was conducted in PubMed for January 2000 to June 2011, identifying weight gain and exercise or physical activity as study topics, and aged adults as target group. In study selection, all types of exercise and physical activity and any measure of weight change in aged adults (≥65 years) or postmenopausal women were considered. N=9 primary studies were identified. All were conducted in the US, with one study additionally including samples from Canada and the UK. Three studies focused on aged adults, while six concentrated specifically on postmenopausal women. Forms of exercise or physical activity comprised self-reported exercise history in four studies and low, moderate or high intensity exercise interventions in five studies. Four studies combined exercise with a hypocaloric diet and included comparison groups receiving either diet only, health education, stretching or a delayed intervention (one study each). Exercise was associated with weight loss (1.1–6kg) in all intervention studies, all of which studied an overweight sample, and with weight maintenance in most observational studies, all of which studied a general population or otherwise overweight-unspecific sample. In sum, exercise and physical activity can effectively prevent weight gain in older adults and postmenopausal women either in terms of weight loss or maintenance. They can preserve lean body mass and thus are important for the balance between potentially positive and negative effects of weight reduction in later life. In addition, since all intervention studies were conducted with an overweight sample, it seems that primordial prevention (in terms of preventing the development of risk factors such as excess weight in the first place) might be a neglected issue in geriatric and postmenopausal prevention.

Nanoparticle therapeutics for prostate cancer treatment - Corrected Proof

Vanna Sanna, Mario Sechi — 2012-02-10

Abstract: The application of nanotechnology in medicine is offering many exciting possibilities in healthcare. Engineered nanoparticles have the potential to revolutionize the diagnosis and the therapy of several diseases, particularly by targeted delivery of anticancer drugs and imaging contrast agents. Prostate cancer, the second most common cancer in men, represents one of the major epidemiological problems, especially for patients in the advanced age. There is a substantial interest in developing therapeutic options for treatment of prostate cancer based on use of nanodevices, to overcome the lack of specificity of conventional chemotherapeutic agents as well as for the early detection of precancerous and malignant lesions. Herein, we highlight on the recent development of nanotechnology strategies adopted for the management of prostate cancer. In particular, the combination of targeted and controlled-release polymer nanotechnologies has recently resulted in the clinical development of BIND-014, a promising targeted Docetaxel-loaded nanoprototype, which can be validated for use in the prostate cancer therapy. However, several limitations facing nanoparticle delivery to solid tumours, such as heterogeneity of intratumoural barriers and vasculature, cytotoxicity and/or hypersensitivity reactions to currently available cancer nanomedicines, and the difficult in developing targeted nanoparticles with optimal biophysicochemical properties, should be still addressed for a successful tumour eradication.

Effect of one-month treatment with vaginal promestriene on serum estrone sulfate levels in cancer patients: A pilot study - Corrected Proof

L. Del Pup, D. Postruznik, G. Corona — 2012-02-10

Abstract: Vaginal promestriene was tested in gynecological cancer patients who suffered from severe vaginal dryness and dyspareunia. This form of estrogen has a low level of vaginal absorption and proved to be effective for vaginal atrophy.Method: 17 patients were treated with a 10mg soft vaginal suppository daily for one month. Plasma levels of estrone sulfate (E1S), used as the marker of overall estrogenicity, were measured by liquid chromatography in combination with mass spectrometry.Results: Mean E1S levels changed from 533 (22–2920) to 374 (81–856) pg/ml (p=0.39).Conclusion: In highly symptomatic gynecological cancer patients the level of circulating estrone sulfate was not significantly affected by vaginal promestriene treatment overall, but a wide range of levels was noted pre and post treatment in individual patients.

The pharmacology of dienogest - Uncorrected Proof

Xiangyan Ruan, H. Seeger, A.O. Mueck — 2012-02-10

Abstract: Dienogest (DNG) is a 19-nortestosterone derivative (a C-19 progestogen) with a cyanomethyl instead of an ethinyl group at the C-17 position, which may make the compound elicit fewer hepatic effects than other C-19 nortestosterone derivatives. Its similarity to norethisterone is reflected in its high endometrial efficacy, which could explain the high stability of the menstrual cycle women achieve when they use DNG in combination with ethinyl estradiol (EE) or with estradiol valerate (E2V). Its strong endometrial efficacy underlies the use of DNG (on its own) to treat endometriosis, and gives it antiproliferative and anti-inflammatory effects in the treatment of endometriotic lesions. Properties derived from its C-19 derivative structure include its short plasma half-life, of about 10h (which means the drug is not accumulated), and its high oral bioavailability, of more than 90%. However, DNG also has some of the properties of typical of progesterone derivatives, including a lack of effect on the metabolic and cardiovascular systems, and considerable antiandrogenic activity, the latter increased by its lack of affinity to the sex-hormone binding globulin (SHBG), in contrast to other C-19 progestogens.DNG has no glucocorticoid and no antimineralocorticoid activity. It also has no antiestrogenic activity, which suggests that it should not antagonize estradiol's beneficial effects. This is important for its use in the treatment of endometriosis, because, due to DNG's low gonadotropic activity, E2 levels are not decreased to zero, in contrast to treatments with gonadotropin-releasing hormone (GnRH) analogues. This maintenance beneficial E2 effects is of particular importance for the general tolerability of the first contraceptive pill to use E2V instead of EE, although clinical endpoint studies are still ongoing. These studies are expected, on the basis of its pharmacology, to demonstrate the cardiovascular safety of the new pill.

Smoking, nicotine and dementia - Uncorrected Proof

Louise Grayson, Alan J. Thomas — 2012-02-10

Twenty to thirty years ago cross-sectional studies reported the intriguing possibility that smoking was actually beneficial in dementia and Alzheimer's disease . Such findings shone as an encouraging exception in the gloom of the grim and growing catalogue of harm that smoking causes. However, it subsequently became clear that, as with cancers and heart disease, smoking is harmful to cognitive health and is associated with an increase in dementia . But some neurochemists and clinicians detected a signal in the evidence that, whatever harms smoking may cause, nicotine itself might benefit cognition in general and Alzheimer's disease in particular . Such findings have led to clinical trials investigating this exciting possibility and Dr Newhouse and colleagues have now reported a randomised study in mild cognitive impairment (MCI), a pre-dementia condition.

Corticotropin releasing factor (CRF) and obesity - Uncorrected Proof

Rajeev Sharma, Mary Ann Banerji — 2012-02-06

Nearly 1 billion people around the world are obese and this number is ever increasing . Obesity ranks among the most pressing issues of our times, akin to syphilis and clean water and represents imbalances in energy metabolism and an overall excess storage of nutrients. In our increasingly complex world, obesity, metabolic syndrome, anxiety and depression are intertwined with stressors including lack of sleep, fetal malnutrition and socio-economic inequities . Allostasis is the adaptation to acute stress involving integrated responses of the nervous and endocrine systems which restore homeostasis. The “allostatic load” is the prolonged activation of these systems, including the HPA axis and output of stress hormones, to adapt to chronic stress; this may change the nervous and endocrine systems and includes obesity, metabolic syndrome and type 2 diabetes . To better understand the pathophysiological mechanisms that underlie obesity, increasing attention is being paid to central regulatory element in energy homeostasis, including food intake and energy expenditure. The corticotropin releasing factor (CRF) system interacting with other neuro-peptides is directly implicated in the regulation of energy balance and may participate in the pathophysiology of obesity . Alterations in the interaction of the CRF system with other neuro-peptides, modified in part by external stimuli such as stress, lead to alteration of the neuro-hormonal system and abnormal eating behaviors.

Giving female genital cosmetic surgery a facelift - Corrected Proof

Alexandra M. McPencow, Marsha K. Guess — 2012-02-03

The “designer vagina” sounds like the name of a “Sex in the City” episode, and may evoke a variety of responses, from enthusiasm for anything that can make the vagina more modern and user-friendly, to mistrust for unproven treatments for conditions that have not been clearly defined. Regardless of one's response, the definition of the “designer vagina” is elusive and must be comprehensible before any discussion can ensue. In a committee opinion in 2007, the American College of Obstetricians and Gynecologists , stated that terms such as “designer vaginoplasty” or “vaginal rejuvenation” are not standard medical nomenclature. As such, procedures using these non-specific definitions cannot be appropriately studied for safety and efficacy. Four years later, Mirzabeigi et al., proposed, in a letter to the American Society for Aesthetic Plastic Surgery in 2011, that terminology be standardized in an effort to avoid ambiguity and inconsistency. In this editorial, we refer to techniques employed to modify the physical appearance (shape, caliber or length) of the vagina and external genitalia for aesthetic purposes as “female genital cosmetic surgery” (FGCS) .

Assessment of sexual function of mid-aged Ecuadorian women with the 6-item Female Sexual Function Index - Corrected Proof

2012-02-03

Abstract: Background: Assessing sexuality is a difficult task, hence used tools should be straight forward and easy to use.Objective: To assess sexual function in mid-aged Ecuadorian women.Method: In this cross sectional study, 904 otherwise healthy women 40–59 years completed the short 6-item Female Sexual Function Index (FSFI-6) and a general socio-demographic questionnaire containing personal/partner data. Internal consistency of the tool was also assessed.Results: Median age of the whole sample was 49 years, 51.1% were postmenopausal, 43.8% lived at high altitude, 12.6% used hormone therapy (HT), 58.5% presented hot flushes, 43.5% were abdominally obese and 80.8% had a partner. Overall, 72.4% of surveyed women reported sexual activity (n=655/904) with 65% of these presenting total FSFI-6 scores equal or below 20 the calculated median (lower sexual function). A 10.2% of those having a partner were sexually inactive. Internal consistency of tool was high (Cronbach's alpha=0.91). Total FSFI-6 scores positively correlated with coital frequency and female and partner educational level and inversely with female age, waist circumference, hot flush intensity and partner age (bivariate analysis). Multiple linear regression analysis determined that lower scores (lower sexual function) were related to high altitude, history of sexual abuse, sedentarism, hot flush intensity, partner age and sexual dysfunction whereas partner educational level, coital frequency and female parity were significantly related to higher scores (better sexual function).Conclusion: As assessed with a consistent, short, and easy to use tool lower sexual function of this mid-aged series was related to several female and partner factors. More research with this tool is warranted.

Associations between anxiety, depression and insomnia in peri- and post-menopausal women - Corrected Proof

2012-02-03

Abstract: Objectives: To determine the correlation between somatic and psychological symptoms and insomnia and the contribution of depression and anxiety to insomnia in a sample of peri- and post-menopausal women in a clinical setting.Study design: The responses of 237 peri- and post-menopausal women enrolled in the Systematic Health and Nutrition Education Program (SHNEP) at the Menopause Clinic of the Tokyo Medical and Dental University Hospital between November 2007 and December 2010 to the Menopausal Health-Related Quality of Life (MHR-QOL) and Hospital Anxiety and Depression Scale (HADS) questionnaires were subjected to Spearman's rank correlation and logistic regression analyses.Results: The analysis revealed that (1) insomnia is highly prevalent, (2) the symptoms of difficulty in initiating sleep (DIS) and experiencing non-restorative sleep (NRS) are more strongly correlated with psychological than somatic symptoms, and (3) DIS is strongly associated with anxiety while NRS is strongly associated with depression in the population studied.Conclusions: Insomnia is highly prevalent among peri- and post-menopausal female patients in a clinical setting and more closely associated with psychological than somatic symptoms. DIS is strongly correlated with anxiety while NRS is strongly correlated with depression.

The association of chronic kidney disease with brain lesions on MRI or CT: A systematic review - Corrected Proof

2012-01-30

Abstract: Background and purpose: This review reports on the association between chronic kidney disease (CKD) established with glomerular filtration rate (GFR) and brain lesions established with MRI or CT.Methods: Literature was searched combining synonyms of kidney function, brain lesions and terms for the definitions thereof, and MRI or CT. This resulted in 1507 articles, of which 20 were finally included.Results: Cross-sectional studies found an association between GFR and white matter lesions (WML) with 7 out of 11 associations significant (odds ratios (OR) GFR, continuous variable: 0.84–0.89 per 10ml/min/1.73m2). Most significant results were found in studies including subjects from the general population. GFR was associated with silent cerebral infarcts (SCI) with 9 out of 12 associations significant (OR GFR, continuous variable: 0.96–0.99perml/min/1.73m2). Brain atrophy was reported significant 4 out of 5 associations (OR GFR, continuous variable: 0.64 per 10ml/min/1.73m2). Additionally, 2 follow up studies were included. One established that serum creatinine at baseline is a significant predictor of the presence of SCI; the other that the presence of SCI at baseline is a significant predictor of a decrease in GFR.Conclusion: The results from this review show that CKD is associated with brain lesions. These brain lesions include WML, SCI and brain atrophy. This finding is of clinical importance because these brain lesions are predictive of stroke, cognitive decline and dementia. Additional follow up studies should be performed to better understand the causative pathway and to establish whether screening and preventive programs are beneficial.

Olfactory impairment is associated with functional disability and reduced independence among older adults - Corrected Proof

Bamini Gopinath, Kaarin J. Anstey, Annette Kifley, Paul Mitchell — 2012-01-30

Abstract: Objectives: Despite its relatively high prevalence, population-based data are lacking on whether olfactory impairment influences the functional status and independence of older adults. We assessed associations between olfactory impairment with activities of daily living (ADL) measures and the likelihood of using community support services and/or reliance on non-spouse family/friend support among older adults.Study design: Olfaction was measured using the San Diego Odor Identification Test (SDOIT) among 1636 participants of the Blue Mountains Eye Study (2002–4). Functional status was determined by the Older Americans Resources and Services ADL scale. Use of services and non-spouse family/friend support was self-reported.Results: Use of community support services was reported by 15.2% and 5.2% of persons with and without olfactory impairment, respectively. After multivariable adjustment including for cognitive function, participants with compared to those without olfactory impairment were more likely to use community support services and non-spouse family/friend support, odds ratio, OR, 1.82 (95% confidence intervals, CI 1.16–2.86) and OR 1.62 (95% CI 1.14–2.32), respectively. ADL difficulty was reported by 16.9% (n=57) and 4.4% (n=45) of participants with and without olfactory loss, respectively. Olfactory impairment was associated with increased likelihood of experiencing ADL difficulty, multivariable-adjusted OR 1.98 (95% CI 1.10–3.57). Olfactory loss was significantly associated with impaired basic ADL, OR 1.57 (95% CI 1.12–2.20).Conclusions: The functional ability and independence of older adults is significantly impaired in the presence of olfactory impairment. Early diagnosis of olfactory loss by primary physicians and geriatricians could facilitate timely interventions assisting the maintenance of functional independence in later life.

Endothelial aging and gender - Corrected Proof

A. Virdis, S. Taddei. — 2012-01-30

Abstract: The endothelium plays a pivotal role in maintaining vascular homeostasis, mainly by the production of the relaxing factor nitric oxide, which protects the vessel wall from the development of atherosclerosis.Aging is a powerful cardiovascular risk factor, associated with endothelial dysfunction both in normotensive subjects and in hypertensive patients. Premenopausal normotensive women are protected against the deleterious effect of aging on endothelial function, and age-related impairment of endothelial function is attenuated in premenopausal hypertensive women. This protective effect on endothelium seems to be mediated by endogenous estrogen, which preserves nitric oxide availability by activating the l-arginine-NO pathway in normotensive women and by inhibiting reactive oxygen species generation.Whether endogenous androgen may modulate endothelial function and the mechanisms involved are still unsolved issues, since data concerning the effect of testosterone on endothelium are scanty and contradictory.

LAMC1 gene is associated with premature ovarian failure - Corrected Proof

Jung-A Pyun, Dong Hyun Cha, KyuBum Kwack — 2012-01-30

Abstract: Objectives: Common variations with modest effect in complex and polygenic disease such as premature ovarian failure (POF) can be detected by a genome wide association study. We performed a genome wide association study to identify predisposing genes associated with an increased risk of POF.Study design: In stage I, genome wide association study was performed using 24 POF patients and 24 matched controls. A strongly associated region was re-tested to confirm the association with POF in stage II using 98 patients and 218 matched controls.Results: In the stage I, we found a strongly associated region that was located on chromosome 1q31 and encoded the laminin gamma 1 (LAMC1) gene. All 22 single nucleotide polymorphisms (SNPs) in the LAMC1 formed a linkage disequilibrium block and two haplotypes were significantly associated with POF. In the stage II, 14 SNPs, the majority of which were SNPs located in coding region and tagging SNPs, were genotyped. Distributions of 9 SNPs of them including one nonsynonymous SNP (rs20558) and one haplotype (HT1, C-C-T-G-C-C-A-T-T-C) were significantly higher in POF patients than in control group (86.6% and 74.5%, respectively, OR=2.209, CI: 1.139–4.284, P=0.017).Conclusions: We showed for the first time that LAMC1 is significantly associated with POF, and specifically, possession of at least one HT1 was associated with susceptibility to POF. This result means that HT1 may co-exist with causative variant for susceptibility to POF in linkage disequilibrium and that the LAMC1 may be involved in POF pathogenesis.

Testosterone pellet implants and migraine headaches: A pilot study - Corrected Proof

Rebecca Glaser, Constantine Dimitrakakis, Nancy Trimble, Vincent Martin — 2012-01-25

Abstract: The purpose of this prospective pilot study was to determine the therapeutic effect of continuous testosterone, delivered as a subcutaneous implant, on the severity of migraine headaches in pre- and post-menopausal patients. Twenty-seven women with a history of documented migraine headache were asked to rate their headache severity using a five-point scale at baseline (prior to therapy); and again, 3months following treatment with testosterone implants. Improvement in headache severity was noted by 92% of patients and the mean level of improvement was statistically significant (3.3 on a 5 point scale). In addition, there was no difference in the level of improvement between pre- and post-menopausal cohorts. Seventy-four percent of patients reported a headache severity score of ‘0’ (none) on testosterone implant therapy for the 3-month treatment period. Continuous testosterone was effective therapy in reducing the severity of migraine headaches in both pre- and post-menopausal women.

Impact of testosterone on the expression of organic anion transporting polypeptides (OATP-1A2, OATP-2B1, OATP-3A1) in malignant and non-malignant human breast cells in vitro - Corrected Proof

Petra Stute, Anne Reichenbach, Thomas Szuwart, Ludwig Kiesel, Martin Götte — 2012-01-24

Abstract: Objectives: Postmenopausal hormone therapy (HT) increases local estrogen formation in breast tissue. The enzymatic substrates depend on transmembrane anion transporting polypeptides (OATPs) to reach intracellular enzymes. The aim of this study was to investigate the effect of testosterone (T) on the expression of OATP-1A2, OATP-2B1, and OATP-3A1 in malignant (MCF-7, BT-474) and non-malignant (HBL-100) breast cells in vitro.Study design: Cells were incubated in RPMI 1640 medium containing 5% steroid-depleted fetal calf serum for 3d, and subsequently incubated in the absence or presence of T, anastrozole (A), and T+A (10−6M) for 24h at 37°C.Main outcome measures: OATP expression was determined by immunocytochemical staining. Expression intensity was graded as low, moderate, or strong. Hormone receptor (AR, PR, ESR1, ESR2) expression was investigated by qPCR and Western blotting. Rank variance analysis was performed for statistical analysis (p≤0.05).Results: OATP-1A2, OATP-2B1, and OATP-3A1 expression was present in all untreated breast cell lines examined, with OATP-1A2 and OATP-3A1 being the predominant ones. There was a trend for a higher baseline expression in untreated HBL-100 and BT-474 in comparison to MCF-7 cells, which was significant for OATP-2B1. T treatment led to decreased OATP-1A2, -2B1, and -3A1 expression in BT-474 and HBL-100 cells, respectively. In contrast, in MCF-7 cells, OATP-2B1 expression was significantly increased. T-induced upregulation of AR and PR protein expression in BT-474 and MCF-7 cells was reduced by A treatment.Conclusions: T may constitute a signal for differential regulation of mammary OATP expression. In non-malignant breast cells T seems to have a beneficial effect by reducing the availability of substrates for the intracellular formation of potent estrogens.

Laboratory values in a Spanish population of older adults: A comparison with reference values from younger adults - Corrected Proof

José Carlos Millán-Calenti, Alba Sánchez, Laura Lorenzo-López, Ana Maseda — 2012-01-24

Abstract: Objective: To examine the laboratory indices in a population aged 65 years or more and compare them with the reference values used for young adults.Study design: Distribution patterns of frequently used biochemical and hematological indices were examined in a sample (N=600) of non-institutionalized adults aged over 65.Outcome measures: The obtained values were compared with the reference intervals for young adults.Results: On some of the indices analyzed, large proportions of the participants had values above the upper limit of the reference interval: glucose, 25.0%; urea, 26.6%; creatinine, 27.2% of males; total cholesterol, 54.6%; and low-density lipoprotein cholesterol, 35.8%. Of the participants who met the World Health Organization's diagnostic criteria for diabetes, 31.8% said they had not been previously diagnosed. Similarly, 74.9% of subjects with total cholesterol values above the reference value indicated in the European guidelines on cardiovascular disease said they had not been diagnosed with dyslipidemia, as did 75.5% of those with low-density lipoprotein cholesterol values above the European reference value. The proportion of participants who were not aware that they might be suffering from those disorders was significantly higher among those who reported not having visited their doctor within the last 6 months.Conclusion: Further studies should examine whether the use of adapted, more appropriate reference values for elderly populations will help physicians to make early and correct diagnoses and to decide when medical intervention is required.

Primary ovarian insufficiency: Relation to changes in body composition and adiposity - Corrected Proof

Konstantinos Michalakis, Simon W. Coppack — 2012-01-24

Abstract: There are several causes of primary ovarian insufficiency (POI) but all result in a premature cessation of female reproductive potential, mimicking the normal menopause. In normal menopause, there is increased cardiovascular risk associated with changes in body composition (specifically increasing adiposity). We sought to review the literature on POI in relation to changes in adiposity and related cardiometabolic risk factors. We conclude that POI patients are usually less obese than reference groups.

Stopping menopausal hormone therapy: If breast cancer really decreased, why did colorectal cancer not increase? - Corrected Proof

Gerard G. Nahum, Harold Stanislaw, James A. Simon — 2012-01-20

Abstract: Objective: The Women's Health Initiative (WHI) study of postmenopausal hormone therapy (HT) found that estrogen plus progestogen therapy (EPT) decreased colorectal cancer risk. Thus, the decline in EPT use from 2002 to 2003 should have precipitated an increase in the incidence of colorectal cancer. We tested this prediction using the SEER 9 epidemiologic database.Methods: We analyzed WHI data concerning the effects of EPT and estrogen therapy (ET) on colorectal cancer risks. We also examined HT prescription sales data, as well as SEER 9 colorectal cancer incidences from 2001 to 2004.Results: In the WHI study, the incidence of colorectal cancer was comparable in EPT placebo-users, ET users, and ET placebo-users, but significantly lower in EPT users. Assuming that 30% of eligible women used HT in 2001, the decline in EPT sales from 2002 to 2003 of 63% should have increased the incidence of colorectal cancer by 2.8% in the overall population at risk. However, the SEER 9 colorectal cancer incidence fell by 5.9% in this population, which is comparable to the 6.7% decrease observed for invasive breast cancer from 2002 to 2003.Conclusions: Declining EPT use from 2002 to 2003 should have precipitated an increase in the incidence of colorectal cancer, but the opposite trend was seen in the SEER 9 database during this time. The incidences of invasive breast cancer and colorectal cancer both declined by a similar amount from 2002 to 2003, despite the results of the WHI study predicting opposing trends for the two different types of cancer. Thus, the SEER 9 findings are fundamentally incompatible with expectations from the WHI findings. This implies that reductions in HT use from 2002 to 2003 cannot account for the contemporaneous changes in invasive breast cancer and colorectal cancer incidences. Alternative explanations must be found.

Commentary on the Editorial “Music therapy for dementia” - Corrected Proof

Alfredo Raglio, Giuseppe Bellelli, Marco Trabucchi — 2012-01-20

We read with interest the Editorial by Ahn and Ashida and we would like to comment on the relevant conclusions suggested by the Authors. We agree with the need of more robust evidence on the efficacy of music therapy (MT) as a basis for a further diffusion of this technique. However, we like to stress the fact that MT has reached a good level of evidence in the field of dementia, as indicated also by the recent updating of the Cochrane review . Furthermore in this moment of difficulties in the management of dementia patients, due to the lack of drugs able to prevent the disease and to the poor financial support in this area, MT approach, inexpensive and without side effects, should be considered among the different therapeutical approaches. We suggest also the importance of further randomized controlled trials, to define relevant aspects, such as the intensity and duration of MT, the symptoms target of the intervention and the outcomes, the level of cognitive decline, the quality of BPSD and their phenomenology, the multimorbidity of the patients, their living conditions. The final goal of these studies should be drafting a guideline to support the large number of therapists already utilizing MT in different settings and improve the results of their work . In the mean time we remain convinced of the usefulness of MT in dementia, and we hope its diffusion as a mean to reduce the suffering of persons affected by cognitive impairment.

Short-term hormone therapy improves sCD40L and endothelial function in early menopausal women: Potential role of estrogen receptor polymorphisms - Corrected Proof

2012-01-18

Abstract: Objective: Hormone therapy (HT) has been suggested to improve vascular function and inflammation in menopausal women, although not consistently. We aimed to investigate the effects of HT on endothelial function and inflammation, especially sCD40L, in early menopausal women, and the effect of common estrogen receptor (ER) polymorphisms on vascular responses to HT.Study design: Eighty-four early menopausal women (<3 years in menopause) with menopausal complaints eligible for HT. Forty women received transdermal 17β-estradiol plus cyclical micronized progesterone for 3 months while 44 did not (controls).Main outcome measures: Brachial artery flow-mediated dilation (FMD) and vascular inflammation markers (sICAM, sP-Selectin and sCD40L). Genetic polymorphisms of ERα (PvuII 454-397T>C and XbaI 454-351A>G) and ERβ (AluI 1730A>G) were also assessed.Results: The two groups did not differ at baseline. Following HT, vasomotor complaints’ severity, blood pressure, LDL, sCD40L, sICAM and sP-Selectin decreased and FMD increased compared to controls (P<0.05 for all). ERβ AluI A allele presence was the most important independent predictor of HT-induced increase in FMD while ERα XbaI A allele was the only independent predictor of decrease in sCD40L.Conclusions: Short-term HT in early menopausal women improved endothelial function and inflammation. Specific ER polymorphisms that were found to be main determinants of HT-induced effects on endothelium could identify subgroups of women who may benefit the most from HT.

Can we live longer by eating less? A review of caloric restriction and longevity - Corrected Proof

Lauren W. Roth, Alex J. Polotsky — 2012-01-16

Abstract: Caloric restriction, decreasing caloric intake by 20–30%, was first shown to extend life in rats nearly 80 years ago. Since that time, limiting food intake for longevity has been investigated in species from yeast to humans. In yeast and lower animals, caloric restriction has repeatedly been demonstrated to lengthen the life span. Studies of caloric restriction in non-human primates and in humans are ongoing and initial results suggest prolongation of life as well as prevention of age-related disease. There is also data in rodents suggesting that short term caloric restriction has beneficial effects on fertility. Although caloric restriction has many positive effects on health and longevity, quality of life on a restricted diet as well as the ability to maintain that diet long term are concerns that must be considered in humans.

Nanoparticle delivery for transdermal HRT - Corrected Proof

Pilar Valenzuela, James A. Simon — 2012-01-16

Abstract: Nanomedicine is an emerging technology and the first nano-engineered medical products have come to light in the last decade. Transdermal drug delivery has significant advantages compared to other routes of drug administration. Nanoparticles unique physical and chemical properties enable transport of substances directly into the skin. The objective of this paper is to review different aspects of nanoparticle delivery, generally, and discuss its current use for transdermal hormone therapy. Transdermal estrogen therapy remains the most effective treatment for bothersome menopausal symptoms, particularly in those women for whom the potential adverse effects associated with “first pass” hepatic metabolism are to be avoided. Available alternatives for transdermal estrogen delivery include patches, gels, sprays and lotions. Other non-oral therapies which likewise avoid “first pass” hepatic metabolism include: subcutaneous implants and vaginal rings. Some of the transdermal products are associated with mild adverse skin effects such as redness and irritation, but more severe and bothersome consequences include blistering and tattooing. Even the mild adverse skin effects are frequently cited as reasons for discontinuation. Micellar nanoparticle estradiol emulsion (MNPEE) is a lotion-like therapy which constitutes an alternative transdermal delivery system not requiring the permeation enhancers or temporary skin digestion, both of which increase the possibility of irritation. MNPEE's advantages include low fluctuation of plasma estradiol concentrations, infrequent skin related adverse effects, and pleasant cosmetic-like moisturizing properties. The efficacy of MNPEE for management of menopausal vasomotor symptoms has been demonstrated in a randomized placebo controlled trial , and the product is FDA approved for management of moderate to severe vasomotor symptoms. None of the observed adverse effects in the MNPEE group were statistically different from the placebo group . Studies addressing inadvertent transference of estradiol to the male partners of menopausal women using this delivery technology have demonstrated small, but real amounts of transference, which do not exceed the normal physiological male estradiol range. MNPEE is safe and effective for treatment of vasomotor symptoms and represents the commercial validation of nanoparticle technology for transdermal delivery of estrogen therapy (ET) for postmenopausal women with vasomotor symptoms.

Gene variants in PPARD and PPARGC1A are associated with timing of natural menopause in the general Japanese population - Corrected Proof

2012-01-16

Abstract: Objectives: Timing of menopause affects postmenopausal health risks. The objective of this study was to evaluate the associations of the single nucleotide polymorphisms (SNPs) in peroxisome proliferator-activated receptor (PPAR)-related genes (PPARD, PPARG, and PPARGC1A) and environmental factors with timing of natural menopause among the general Japanese population.Study design: We analyzed cross-sectional data from 1758 women aged 40–69 years who were enrolled in the baseline surveys of the Japan Multi-institutional Collaborative Cohort (J-MICC) Study.Main outcome measures: Associations of timing of natural menopause with its probable covariates and with target gene variants were evaluated by univariate and multivariate Cox proportional hazards models.Results: Lower body mass index and later age at menarche were significantly associated with earlier natural menopause. Women with minor alleles at T-48444C in PPARD showed a significantly higher adjusted hazard ratio of 1.57 (95% confidence interval: 1.18–2.10) for earlier natural menopause. In contrast, women with minor alleles at Thr394Thr in PPARGC1A showed a significantly lower adjusted hazard ratio of 0.86 (0.76–0.97) for earlier natural menopause. These associations did not substantially alter when re-analyzed after excluding the subjects who self-reported a history of diabetes or the subjects whose age was more than 65 years.Conclusions: Gene variants in PPARD and PPARGC1A might be associated with timing of natural menopause, probably through direct actions on the ovaries, among the general Japanese population.

Low dose estriol pessaries for the treatment of vaginal atrophy: A double-blind placebo-controlled trial investigating the efficacy of pessaries containing 0.2mg and 0.03mg estriol - Corrected Proof

2012-01-13

Abstract: Objective: The aim of the study was to confirm the superior efficacy of estriol containing pessaries compared to placebo in the treatment of vaginal atrophy.Study design: In a prospective, multicenter, randomized, placebo-controlled, double-blind study, 436 postmenopausal women with vaginal atrophy (vaginal maturation index, VMI<40%; vaginal pH>5; most bothersome symptom, MBS≥65 on visual analogue scale, VAS) were treated with pessaries containing either 0.2mg estriol (N=142) or 0.03mg estriol (N=147) or with a matching placebo (N=147) for 12 weeks.Main outcome measures: Primary efficacy endpoints included increase in VMI, decrease of the vaginal pH value and decrease in intensity of MBS after 12 weeks of treatment.Results: The increase in VMI was significantly greater under 0.2mg estriol and 0.03mg estriol (46.3±17.0 and 38.4±19.4, respectively) compared to placebo (23.9±21.5; p values<0.001), vaginal pH decreased significantly more (−1.6±0.8 and −1.4±0.9, respectively) compared to placebo (−0.6±0.8; p values<0.001) and MBS intensity (VAS) declined significantly more (−52.2±23.7 and −47.1±23.4, respectively) compared to placebo (−31.8±26.3; p values<0.001). Adverse events were rare and occurred at similar rates in all three groups.Conclusions: Superiority of estriol containing pessaries over placebo was shown in the local treatment of vaginal atrophy. Even a very low dose of 0.03mg estriol proved sufficient for local treatment of vaginal atrophy with excellent tolerability.

Nanomedicine for the prevention, treatment and imaging of atherosclerosis - Corrected Proof

Costas Psarros, Regent Lee, Marios Margaritis, Charalambos Antoniades — 2012-01-09

Abstract: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in developed countries, with an increasing prevalence due to an aging population. The pathology underpinning CVD is atherosclerosis, a chronic inflammatory state involving the arterial wall. Accumulation of low density lipoprotein (LDL) laden macrophages in the arterial wall and their subsequent transformation into foam cells lead to atherosclerotic plaque formation. Progression of atherosclerotic lesions may gradually lead to plaque related complications and clinically manifest as acute vascular syndromes including acute myocardial or cerebral ischemia. Nanotechnology offers emerging therapeutic strategies, which may have advantage overclassical treatments for atherosclerosis. In this review, we present the potential applications of nanotechnology toward prevention, identification and treatment of atherosclerosis.

Nanotechnology for neurodegenerative disorders - Corrected Proof

Francesca Re, Maria Gregori, Massimo Masserini — 2012-01-09

Abstract: The efficacy, cellular uptake and specific transport of drugs and/or imaging agents to target organs, tissues and cells are common issues in the diagnosis and treatment of different disorders. In the case of neurodegenerative diseases, they represent complex problems, since brain targeting remains a still unsolved challenge in pharmacology, due to the presence of the blood–brain barrier, a tightly packed layer of endothelial cells that prevents unwanted substances to enter the brain. Engineered nanomaterials, objects with dimensions of 1–100nm, are providing interesting biomedical tools potentially able to solve these problems, thanks to their physico-chemical features and to the possibility of multi-functionalization, allowing to confer them different features at the same time, including the ability to cross the blood–brain barrier. This review focuses on the state-of-the-art of nanomaterials suitable for therapy and diagnostic imaging of the most common neurodegenerative disorders, as well as for neuroprotection and neuronal tissue regeneration. Finally, their potential neurotoxicity is discussed, and future nanotechnological approaches are described.

Nanomedicine for treatment of diabetes in an aging population: State-of-the-art and future developments - Corrected Proof

Silke Krol, Rutledge Ellis-Behnke, Piero Marchetti — 2011-12-21

Abstract: Nowadays diabetes, especially type 2 diabetes (which is strongly related to the Western diet and life-style), has developed worldwide into an epidemic disease. Nanomedicine aims to provide novel tools for diagnosis, therapy and point-of-care management of patients.Several nanotechnological approaches were developed to improve life quality for patients with insulin-dependent diabetes. They facilitate blood glucose management by non-invasive glucose measurement as well as insulin administration mainly by delivering the fragile protein as protected and targeted formulation via nasal or oral route.In the present review the oral or nasal insulin delivery by polymeric nanoparticles is discussed with focus on physiological change either related to the disease, diabetes or age-related metabolic variations influencing insulin release and bioavailability. One critical point is that new generations of targeted nanoparticle based drugs are developed and optimized for certain metabolic conditions. These conditions may change with age or disease. The influence of age-related factors such as immaturity in very young age, metabolic and physiologic changes in old age or insufficient animal models are still under-investigated not only in nanomedicine but also generally in pharmacology.Summarizing it can be noted that the bioavailability of insulin administered via routes others than subcutaneously is comparably low (max. 60%). Moreover factors like changed gut permeability as described for diabetes type 1 or other metabolic peculiarities such as insulin resistance in case of type 2 diabetes also play a role in affecting the development of novel nanoparticulated drug preparations and can be responsible for unsuccessful translation of promising animal results into human therapy.In future insulin nanoparticle development for diabetes must consider not only requirements imposed by the drug but also metabolic changes inflicted by disease or by age. Moreover new approaches are required for prevention of the disease.

Nanomedicines for chronic non-infectious arthritis: The clinician's perspective - Corrected Proof

Israel Rubinstein, Guy L. Weinberg — 2011-12-16

Abstract: Rheumatoid arthritis (RA) and osteoarthritis (OA) are prevalent chronic health conditions. However, despite recent advances in medical therapeutics, their treatment still represents an unmet medical need because of safety and efficacy concerns with currently prescribed drugs. Accordingly, there is an urgent need to develop and test new drugs for RA and OA that selectively target inflamed joints thereby mitigating damage to healthy tissues.Conceivably, biocompatible, biodegradable, disease-modifying antirheumatic nanomedicines (DMARNs) could represent a promising therapeutic approach for RA and OA. To this end, the unique physicochemical properties of drug-loaded nanocarriers coupled with pathophysiological characteristics of inflamed joints amplify bioavailability and bioactivity of DMARNs and promote their selective targeting to inflamed joints. This, in turn, minimizes the amount of drug required to control articular inflammation and circumvents collateral damage to healthy tissues. Thus, nanomedicine could provide selective control both in space and time of the inflammatory process in affected joints.However, bringing safe and efficacious DMARNs for RA and OA to the marketplace is challenging because regulatory agencies have no official definition of nanotechnology, and rules and definitions for nanomedicines are still being developed. Although existing toxicology tests may be adequate for most DMARNs, as new toxicity risks and adverse health effects derived from novel nanomaterials with intended use in humans are identified, additional toxicology tests would be required. Hence, we propose that detailed pre-clinical in vivo safety assessment of promising DMARNs leads for RA and OA, including risks to the general population, must be conducted before clinical trials begin.