Hypothyroidism in older adults: A narrative review.

INTRODUCTION: The prevalence of hypothyroidism increases along with aging, resulting in one of the most common comorbidities among patients over 75 years. The leading causes of hypothyroidism in older adults are iatrogenic, Hashimoto's thyroiditis, and medications. AIMS: The narrative review aimed to discuss the clinical characteristics of hypothyroidism in older adults and the impact of hormonal replacement therapy on survival rates. RESULTS: Thyroid function declines over time due to physiological changes in the thyroid stimulating hormone signaling, iodine absorption and metabolism, thyroid hormone metabolism, and activity at peripheral sites. A serum TSH value over the upper limit of the normal reference range is not necessarily attributable to hypothyroidism. However, an appropriate diagnostic work-up is required to rule out true hypothyroidism and discriminate the etiology (i.e., thyroid autoimmune diseases, iodine deficiency, drug-induced hypothyroidism). Levothyroxine treatment should be considered in cases of overt hypothyroidism. A complete risk-to-benefit assessment, particularly considering the overall health status, life expectancy, cognitive function, mood, and cardiovascular and neurological background, should be considered before treating subclinical hypothyroidism with more potential benefits in patients under 75 years old. Levothyroxine formulations facilitating hormone absorption and increasing compliance to long-term treatment should be preferred. TSH target should usually be set over 3 mIU/ml. CONCLUSION: Defining optimal diagnostic approaches and targeted therapeutic strategies should be considered in the personalized management of aged patients with hypothyroidism.

Dyslipidemia and Cardiovascular Prevention in the Elderly: A Balance between Benefits and Risks of Statin Treatment in a Specific Population.

INTRODUCTION: Atherosclerotic Cardiovascular Diseases (CVD) are among the most relevant causes of morbidity and mortality worldwide, especially in aged people. Statins are one of the leading pharmacological interventions against atherosclerosis and are widely used to reduce the risk of occurring coronary artery diseases and related outcomes in both primary and secondary prevention. The management of chronic diseases is improved considerably over time, leading to an increase in life expectancy despite heavier comorbidity-related burdens in the elderly. AIMS: The paper focused on the role of statins in the management of atherosclerosis and related burdens in elderly patients. RESULTS: Statins are essential in reducing the risk of CVD in secondary and primary prevention, particularly in high-risk individuals. Guidelines encourage using specific algorithms with age-specific cutoffs to assess individual cardiovascular risk irrespective of baseline age, as the expansion of life expectancy produces favorable effects of statin treatment in those over 70. DISCUSSION: Besides the estimation of baseline CV risk, a specific age-related assessment is also necessary before prescribing statin treatment in aged people focusing on frailty, potential pharmacological interactions due to polypharmacotherapy, cognitive impairment, and background chronic comorbidities, such as diabetes mellitus. Before starting statin therapy, an accurate choice of type and dose of statins is needed as potential adverse events are more prevalent with high-dose than low-to-moderatedose regimens and with lipophile than hydrophile statins (e.g., potential implication on intra-cerebral cholesterol metabolism). CONCLUSION: Despite possible adverse events, elderly patients should receive statins, when appropriate, to avoid the first occurrence of recurrent cardiovascular events and related burdens.

Gonadal Function Recovery and Fertility in Women Treated with Chemo- and/or Radiotherapy for Hodgkin's and Non-Hodgkin Lymphoma.

BACKGROUND: Fertility and gonadal function represent one of the most important aspects for long-term lymphoma survivors. AIMS: The aim of our study was to determine possible risk factors, such as age at treatment, chemotherapeutic regimen, protection with oral contraceptives (OCs), and gonadotropin-releasing hormone (GnRH) analogues in female patients treated for Hodgkin's lymphoma (HL) or non-Hodgkin lymphoma (NHL) at a reproductive age. METHODS: Patients between the age of 16 and 50 years at the time of HL or NHL diagnosis were selected. Eligible patients were requested to respond to a questionnaire by phone interview about fertility, menstrual status, sexual aspects, and treatment with OCs or GnRH analogues during chemotherapy. RESULTS: The resumption of menstrual activity was associated with the use of the OCs and GnRH analogues during chemotherapy (p = 0.008 and 0.034, respectively). At univariate analysis, the use of OCs during chemotherapy was associated with a lower risk of amenorrhea (prevalence ratio [PR] = 0.37; 95% CI 0.17-0.82). A higher age at the time of treatment correlated positively with therapy-induced amenorrhea, with a difference of 12.8 years between the mean age at diagnosis of the women with therapy-induced amenorrhea and those who resumed their menses. Amenorrhea was significantly higher in women receiving R-CHOP than in women treated with ABVD (PR = 6.00; 95% CI 2.32-15.54). Moreover, NHL had an infertility PR of 1.51 (95% CI 0.86-2.45) at multivariate analysis compared to HL. CONCLUSIONS: This study suggests a possible role of pharmacological prophylaxis with OCs and GnRH analogues.

Booster immunizations with DNA plasmids encoding HER-2/neu prevent spontaneous mammary cancer in HER-2/neu transgenic mice over life span.

Cancer vaccines are less effective at old than at young age because of immunosenescence. Besides, in preliminary observations we showed that the immunization with HER-2/neu DNA plasmid in transgenic young mice (standard immunization, SI) delays but not abrogate spontaneous mammary tumours progressively appearing during aging. In this study we evaluated whether booster immunizations (BI) of HER-2/neu transgenic mice with HER-2/neu DNA plasmids every 6 (ECD6), 3 (ECD3), or 1.5 (ECD1.5) months after SI induce a protective immunity that could be maintained over life span. The long term BI significantly improved the effect of SI increasing the number of tumour free mice at 110 weeks of age from 13% (SI) to 58% (BI). Both the number and the volume of tumour masses were reduced in BI than in SI groups. The protective effect of BI was associated with increased antibody production with isotype switching to IgG2a, augmented CD4 T cells, and increased in vivo cytotoxicity of HER-2/neu specific cytotoxic T lymphocytes, mainly in ECD1.5 and ECD3 groups. The transfer of sera from ECD1.5 mice to untreated HER-2/neu mice highly protected against tumour development than sera from SI mice. We conclude that BI induce a protective immunity effective over life span.

Colistin enhances therapeutic efficacy of daptomycin or teicoplanin in a murine model of multiresistant Acinetobacter baumannii sepsis.

We investigated the efficacy of colistin combined with teicoplanin or daptomycin in an experimental mouse model of multiresistant Acinetobacter baumannii infection. Animal received intraperitoneally 1ml saline containing 2×1010CFU of A. baumannii. Colistin, daptomycin, teicoplanin, and colistin plus daptomycin or teicoplanin were given by intraperitoneal administration 2h after bacterial challenge. A control group received sodium chloride solution. In the in vitro study A. baumannii showed to be susceptible only to colistin with MIC of 2mg/l. In the in vivo study, colistin alone showed a good antimicrobial efficacy. When combined with teicoplanin or daptomycin, colistin produced the lowest bacterial and the best survival rates. In immunological studies, when colistin was associated to daptomycin or teicoplanin, both the number and the cytotoxic activity of NK cells increased. In conclusion, colistin combined with teicoplanin or daptomycin may improve the therapy of multiresistant A. baumannii infection.

Enhanced Efficacy of Combinations of Pexiganan with Colistin Versus Acinetobacter Baumannii in Experimental Sepsis.

We investigated the efficacy of colistin combined with pexiganan in experimental mouse models of Acinetobacter baumannii infection.Adult male BALB/c mice received intraperitoneally 1 mL saline containing 2 × 10 CFU of susceptible and multiresistant A. baumannii. Two hours after bacterial challenge, animals received 1 mg/kg of colistin, 1 mg/kg of pexiganan, or 1 mg/kg of colistin plus 1 mg/kg of pexiganan.Blood culture positivity, the quantities of bacteria in the intra-abdominal fluid, the rate of lethality and immunological studies, such as immunophenotyping and NK cytotoxicity, were evaluated.In the in vitro study, A. baumannii showed susceptibility to colistin and pexiganan and a strong synergy was observed by testing colistin combined with pexiganan with fractionary inhibitory concentration index of 0.312 for both strains.In the in vivo study colistin or pexiganan alone showed a good antimicrobial efficacy. When colistin was combined with pexiganan, the positive interaction produced low bacterial counts that were statistically significant versus singly treated groups. For both strains the highest rate of survival was observed in combined-treated groups (90%).Pexiganan increased NK cytotoxic activity over the levels of infected and colistin-treated animals.In conclusion, pexiganan combined with colistin was found to be efficacious against A. baumannii infection.

IB-367 pre-treatment improves the in vivo efficacy of teicoplanin and daptomycin in an animal model of wounds infected with meticillin-resistant Staphylococcus aureus.

Antimicrobial peptides are known as immunomodulators and antibiotic enhancers. We report that administration of an antimicrobial peptide, IB-367, was efficacious in increasing the antimicrobial activity of daptomycin and teicoplanin in a mouse model of wound infection caused by meticillin-resistant Staphylococcus aureus (MRSA). Mice were assigned to seven groups: an IB-367 pre-treated group with no antibiotics given after challenge, two IB-367 pre-treated groups plus daptomycin or teicoplanin given after challenge, two groups treated with daptomycin or teicoplanin only after challenge, and two control groups without infection or that did not receive any treatment. The main outcome measures were quantitative bacterial culture and analysis of natural killer (NK) cytotoxicity and leukocyte phenotype. The wound, established through the panniculus carnosus muscle of mice, was infected by MRSA. Bacterial cultures of mice receiving antibiotics alone showed a -2 log decrease, whilst those for IB-367 plus daptomycin or teicoplanin showed a -4 log decrease. IB-367 plus daptomycin showed the highest efficacy. The higher antimicrobial effect exerted by IB-367 was associated with increased levels of NK cytotoxicity but not of NK cell number. IB-367 increased the number of both CD11b and Gr-1 cells 3 days after MRSA challenge, whereas both of these leukocyte populations were reduced at 10 days after challenge. Our data suggest that a combination of IB-367 with antibiotic exerts a therapeutic effect and may be useful for the management of staphylococcal wounds.

Effect of annatto-tocotrienols supplementation on the development of mammary tumors in HER-2/neu transgenic mice.

Tocotrienols (T3), the lesser known isomers of vitamin E, have been reported to possess anticancer activity both in in vitro and in vivo experimental models of rodents transplanted with parental tumors or treated with carcinogens. We investigated the effects of dietary supplementation with annatto-T3 (90% δ-T3 and 10% γ-T3) on the spontaneous development of mammary tumors in HER-2/neu transgenic mice. Underlying mechanisms of the antitumor effect were evaluated by studying apoptosis, senescent-like growth arrest, immune modulation, oxidative effect and the expression of HER-2/neu in tumoral mammary glands of transgenic mice and in vitro in human and mice tumor cell lines. Annatto-T3 supplementation delayed the development of mammary tumors, reducing the number and size of mammary tumor masses and those of lung metastases. In annatto-T3-supplemented mice, both apoptosis and senescent-like growth arrest of tumor cells were increased in mammary glands while no immune modulation was observed. In vitro, a dose-dependent inhibition of cell growth, increased apoptosis and senescent-like growth arrest and a time-dependent accumulation of reactive oxygen species were observed in tumor cells treated with annatto-T3 or purified δ-T3. Annatto-T3 reduced both HER-2/neu mRNA and p185(HER-2/neu) protein in tumors and in tumor cell lines. The results show that the antitumor effect of annatto-T3 supplementation in HER-2/neu transgenic mice is mainly related to the direct induction of oxidative stress, senescent-like growth arrest and apoptosis of tumor cells rather than to an immune modulation.

In vivo electroporation restores the low effectiveness of DNA vaccination against HER-2/neu in aging.

Experimental evidence has been provided that cancer vaccines are less effective at older age than in young adults. In this study, we evaluated the possibility to recover the low effectiveness of DNA immunization against HER-2/neu increasing plasmid uptake by cells from old mice through electroporation with the aim to enhance the activation of specific immune responses. Young and old Balb/c mice received two immunizations with a pCMV-ECDTM DNA plasmid using plasmid intramuscular injection followed by electroporation (IM + E) or plasmid intramuscular injection alone (IM), and successively, they were challenged with syngeneic HER-2/neu overexpressing TUBO cells. Young mice were completely protected whereas less than 60% protection was observed in old mice after IM immunization. IM + E immunization completely protected old mice against a TUBO cell challenge. The protection was associated with increased transgene expression in the site of immunization and with the induction of both humoral and cell-mediated immunity in old mice. We conclude that the effectiveness of anticancer DNA vaccination in old ages may be improved increasing plasmid uptake and transgene expression through electroporation, suggesting the relevant role of the first steps of the immunization process in the success of cancer vaccines at older age.

Vitamin E improves the in vivo efficacy of tigecycline and daptomycin in an animal model of wounds infected with meticillin-resistant Staphylococcus aureus.

A relevant bacterial load in cutaneous wounds significantly interferes with the normal process of healing. Vitamin E (VE) is a known immunomodulator and immune enhancer. Here, it was shown that administration of VE before infection was effective at increasing the antimicrobial activity of daptomycin (DAP) or tigecycline (TIG) in a mouse model of wound infection caused by meticillin-resistant Staphylococcus aureus (MRSA). A wound was established through the panniculus carnosus of mice and inoculated with MRSA. Mice were assigned to six groups: a VE pre-treated group with no antibiotics given after MRSA challenge; two VE pre-treated groups with DAP or TIG given after MRSA challenge; two groups treated with DAP or TIG only after MRSA challenge; and a control group that did not receive any treatment. Mice receiving each antibiotic alone showed a 3 log decrease in the number of c.f.u. recovered compared with the control group, mice treated with VE plus TIG had a 4 log decrease, whilst mice treated with VE plus DAP had the largest decrease in c.f.u. recovered (5 logs). The increased antimicrobial effect seen from treatment with VE plus antibiotics was associated with increased levels of natural killer cell cytotoxicity, with a more pronounced increase in leukocyte populations in mice treated with VE plus DAP. These data suggest that treatment with VE prior to infection and subsequent antibiotic treatment act in synergy.

Inflammation, aging, and cancer vaccines.

Immunosenescence is characterized by a series of changes of immune pathways, including a chronic state of low-grade inflammation. Mounting evidence from experimental and clinical studies suggests that persistent inflammation increases the risk of cancer and the progression of the disease. Cancer vaccination, which came into view in the last years as the most intriguing means of activating an immune response capable of effectively hampering the progression of the preclinical stages of a tumour, has been shown to be less effective in older age than in young adults. Available evidence on the use of inhibitors of inflammation has indicated their potential enhancement of cancer vaccines, suggesting the possibility to improve the low effectiveness of cancer vaccines in old age employing pharmacological or natural compounds-based anti-inflammatory intervention. This review addresses the effects of age and inflammation on cancer development and progression, and speculates as to whether the modulation of inflammation may influence the response to cancer immunization.

Tumor endothelial marker 8 expression levels in dendritic cell-based cancer vaccines are related to clinical outcome.

Previous studies have shown that tumor endothelial markers (TEMs 1-9) are up modulated in immunosuppressive, pro-angiogenic dendritic cells (DCs) found in tumor microenvironments. We recently reported that monocyte-derived DCs used for vaccination trials may accumulate high levels of TEM8 gene transcripts. Here, we investigate whether TEM8 expression in DC preparations represents a specific tumor-associated change of potential clinical relevance. TEM8 expression at the mRNA and protein level was evaluated by quantitative real-time RT-PCR and cytofluorimetric analysis in human clinical grade DCs utilized for the therapeutic vaccination of 17 advanced cancer patients (13 melanoma and 4 renal cell carcinoma). The analyses revealed that DCs from patients markedly differ in their ability to up-modulate TEM8. Indeed, mDCs from eight non-progressing patients [median overall survival (OS) = 32 months, all positive to the delayed-type hypersensitivity test (DTH)], had similar TEM8 mRNA expression levels [mDCs vs. immature iDCs; mean fold increase (mfi) = 1.97] to those found in healthy donors (mfi = 2.7). Conversely, mDCs from nine progressing patients (OS < 5 months, all but one with negative DTH) showed an increase in TEM8 mRNA levels (mfi = 12.88, p = 0.0018). The present observations suggest that TEM8 expression levels in DC-based therapeutic vaccines would allow the selection of a subgroup of patients who are most likely to benefit from therapeutic vaccination.

Unfaithful association of FCGR2B genetic polymorphisms with susceptibility to SLE.

Correcting errors and proofreading are crucial in a post-genomic era, when DNA sequences are already part of an effective medical screening and treatments. SNPs genotyping of complex human genes can lead to questionable associations if not properly handled. Here, we report about a spurious (reitered) association between FCGR2B genetic polymorphisms and systemic lupus erythematosus.

Molecular stability of DNA typing short tandem repeats in the mammary tree of patients with breast cancer.

Archival pathologic specimens are a rich source for the studies of hereditary diseases, cancer genetics, and identification cases in forensic science. In this study, the intraindividual consistency of eight identifying microsatellite polymorphisms (i.e., HMTH01, vWFA31, F13A, MITMH26, FES-FPS, CD4, TPOX, CSF1PO)in a cohort of 40 patients with invasive breast carcinoma were analyzed. Nests of cancer and adjacent morphologically normal ductal-lobular structures (TDLUs) were microdissected as discrete regions from hematoxylin-eosin-stained slides. As controls for each case, DNA templates were prepared from TDLUs located in nontumor quadrants and from unaffected breast skin. Over 1,400 carefully controlled PCR reactions were reviewed, and no evidence was found for microsatellite mismatches among intraindividual cancer and control DNAs. The negative results, supported by validation experiments, strongly argue that alterations of simple repeats are rare somatic events during the onset and progression of breast cancer. This study suggests that PCR artifacts may be a relevant cause of misdiagnosis of microsatellite instability in human sporadic cancer.