Post-diagnosis serum 25-hydroxyvitamin D concentrations in women treated for breast cancer participating in a lifestyle trial in Italy.

OBJECTIVE: To report cross-sectionally serum levels of 25-hydroxyvitamin D [25(OH)D] in women living in Italy within 12 months from breast cancer (BC) diagnosis. METHODS: Baseline data were obtained from 394 women diagnosed with primary BC, enrolled from 2016 to 2019 in a lifestyle trial conducted in Italy. Subjects' characteristics were compared between two 25(OH)D concentrations (hypovitaminosis D<20 and ≥20 ng/mL) with the Chi-squared test or Fisher's exact test for small-expected counts. Using multiple logistic regression-adjusted models, we estimated odds ratios (ORs) of hypovitaminosis D with 95% confidence intervals (CIs) in the total sample and in the unsupplemented subgroup. RESULTS: Hypovitaminosis D was found in 39% of all subjects, 60% in unsupplemented subjects, and 10% in supplemented subjects. Increasing ORs of hypovitaminosis D were found with increasing body mass index, 25-30, >30, and ≥35 versus <25 kg/m2 (ORs: 2.50, 4.64, and 5.81, respectively, in the total cohort and ORs: 2.68, 5.38, and 7.08 in the unsupplemented); living in the most southern Italian region (OR 2.50, 95%CI 1.22-5.13); and with hypertriglyceridemia (OR 2.46; 95%CI 1.16-5.22), chemotherapy history (OR 1.86, 95%CI 1.03-3.38), and inversely with anti-estrogenic therapy (OR 0.43, 95%CI 0.24-0.75) in the total sample. CONCLUSIONS: Hypovitaminosis D in women recently diagnosed with BC and participating in a lifestyle trial in Italy was widespread and highest with obesity, hypertriglyceridemia, and chemotherapy use. Considering that hypovitaminosis D is a risk factor for lower efficacy of bone density treatments and possibly BC mortality, our results suggest the need to promptly address and treat vitamin D deficiency.

Plasma microglial-derived extracellular vesicles are increased in frail patients with Mild Cognitive Impairment and exert a neurotoxic effect.

Extracellular vesicles (EVs) are mediators of cellular communication that can be released by almost all cell types in both physiological and pathological conditions and are present in most biological fluids. Such characteristics make them attractive in the research of biomarkers for age-related pathological conditions. Based on this, the aim of the present study was to examine the changes in EV concentration and size in the context of frailty, a geriatric syndrome associated with a progressive physical and cognitive decline. Specifically, total EVs and neural and microglial-derived EVs (NDVs and MDVs respectively) were investigated in plasma of frail and non-frail controls (CTRL), mild cognitive impairment (MCI) subjects, and in Alzheimer's disease (AD) patients. Results provided evidence that AD patients displayed diminished NDV concentration (3.61 × 109 ± 1.92 × 109 vs 7.16 × 109 ± 4.3 × 109 particles/ml) and showed high diagnostic performance. They are able to discriminate between AD and CTRL with an area under the curve of 0.80, a sensitivity of 78.95% and a specificity of 85.7%, considering the cut-off of 5.27 × 109 particles/ml. Importantly, we also found that MDV concentration was increased in frail MCI patients compared to CTRL (5.89 × 109 ± 3.98 × 109 vs 3.16 × 109 ± 3.04 × 109 particles/ml, P < 0.05) and showed high neurotoxic effect on neurons. MDV concentration discriminate frail MCI vs non-frail CTRL (AUC = 0.76) with a sensitivity of 80% and a specificity of 70%, considering the cut-off of 2.69 × 109 particles/ml. Altogether, these results demonstrated an alteration in NDV and MDV release during cognitive decline, providing important insight into the role of EVs in frailty status.

Late-onset presentation and phenotypic heterogeneity of the rare R377W PSEN1 mutation.

BACKGROUND AND PURPOSE: Mutations in the PSEN1 gene are the most common cause of autosomal-dominant Alzheimer's disease and have been associated with the earliest disease onset. We describe an unusual presentation of the rare R377W PSEN1 mutation with a late age of onset, and we provide for the first time in vivo pathological evidence for this mutation. METHODS: A 71-year-old female patient with progressive cognitive decline in the past 3 years and positive family history for dementia underwent neurological evaluation, neuropsychological testing, lumbar puncture, conventional brain imaging, amyloid-positron emission tomography (PET) and extensive genetic screening with a next-generation sequencing technique. RESULTS: The diagnostic workup revealed mixed behavioural and amnestic disease features on neuropsychological tests, magnetic resonance imaging, and 18-fluorodeoxyglucose (FDG)-PET. Amyloid-PET detected amyloid deposition in the frontal areas, in the parietal lobes and the precunei. The genetic screening revealed the presence of the rare R377W mutation in the PSEN1 gene. CONCLUSIONS: Extensive genetic screening is also advisable for late-onset presentations of Alzheimer's disease, especially in the presence of a positive family history or atypical clinical features.

Stochastic cell renewal process and lengthening of cell cycle.

Evolution of the stem cell population responsible for homeostatic cell renewal processes is analyzed. We assume that this regime is the product of a delicate balance between symmetric divisions that, after each cell cycle, originates a new stem cell or its disappearance (through cell differentiation). This dynamics leads to a monoclonal population, that is for an initial homogeneous set of stem cells, fixation of each clone is equiprobable. In this work we show that if there is an altered stem cell with a longer cell cycle than the rest, the fixation of this altered clone is more likely. We also study the consequeces of the appearance of successive alterations with these characteristics and their fixations. This effect is purely due to inherent characteristics of the cell renewal dynamics and as time goes by it leads to a quiescence state for stem cells owing to the recurrent fixation of such altered cells. Therefore it would contribute to the aging process.

Neutral dynamics and cell renewal of colonic crypts in homeostatic regime.

The self renewal process in colonic crypts is the object of several studies. We present here a new compartment model with the following characteristics: (a) we distinguish different classes of cells: stem cells, six generations of transit amplifying cells and the differentiated cells; (b) in order to take into account the monoclonal character of crypts in homeostatic regimes we include symmetric divisions of the stem cells. We first consider the dynamic differential equations that describe the evolution of the mean values of the populations, but the small observed value of the total number of cells involved plus the huge dispersion of experimental data found in the literature leads us to study the stochastic discrete process. This analysis allows us to study fluctuations, the neutral drift that leads to monoclonality, and the effects of the fixation of mutant clones.

Inflammatory molecules in Frontotemporal Dementia: cerebrospinal fluid signature of progranulin mutation carriers.

Mutations in progranulin gene (GRN) are one of the major causes of autosomal dominant Frontotemporal Lobar Degeneration (FTLD). Progranulin displays anti-inflammatory properties and is likely a ligand of Tumor Necrosis Factor (TNF) receptor 2, expressed on microglia. A few cytokines and chemokines are altered in cerebrospinal fluid (CSF) from patients with sporadic FTLD, whereas no information is available in familial cases. We evaluated, through BioPlex, levels of 27 inflammatory molecules, including cytokines, chemokines, and related receptors, in CSF and matched serum, from FTLD patients carrying GRN mutations as compared with sporadic FTLD with no GRN mutations and controls. Mean±SD Monocyte Chemoattractant Protein-1 (MCP-1) levels were significantly increased in CSF from sporadic FTLD patients as compared with controls (334.27±151.5 versus 159.7±49pg/ml; P⩽0.05). In GRN mutation carriers versus controls, CSF levels of MCP-1 were unchanged, whereas Interferon-γ-inducible protein-10 (IP-10) levels were increased (809.17±240.0 versus 436.61±202.5pg/ml; P=0.012). In the same group, TNFα and Interleukin (IL)-15 levels were decreased (3.18±1.41 versus 35.68±30.5pg/ml; P=0.013 and 9.34±5.54 versus 19.15±10.03pg/ml; P=0.023, respectively). Conversely, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) levels were decreased in patients, with or without mutations, as compared with controls (4.63±3.30 and 2.58±20 versus 87.57±70pg/ml, respectively; P<0.05). Moreover, IP-10, IL-15 and RANTES CSF levels were not influenced by age, whereas MCP-1 levels increased with age (ρ=0.48; P=0.007). In conclusion, inflammatory de-regulation was observed in both sporadic FTLD and GRN carriers compared to controls, with a specific inflammatory profile for the latter group.

A stochastic model of neurogenesis controlled by a single factor.

The researches on cortical neurogenesis reveal that asymmetric division plays a key role in controlling the balance between the self-renewal of stem cells and the beginning of the neural differentiation. In such a process a neural stem cell divides by mitosis, originating a postmitotic neuron and other pluripotent stem cell available for subsequent differentiation events. In addition, studies of cell lineage trees of cultured neural progenitors reveal tree shapes and subtrees recurrent, consistent with a stochastic model of division symmetrical/asymmetrical. These considerations have led us to develop a stochastic model of neurogenesis in order to explore the possibility that this is controlled primarily by a single factor (i.e. the concentration of mNumb in the cell). We contrast the predictions of our model with experimental data and compare it with other models of neurogenesis.

Straightforward relative quantitation and age-related human standards of N-acetylaspartate at the centrum semiovale level by CSI (1)H-MRS.

1H-MRS was aimed to monitor metabolite concentrations in homogeneous interaxial slices of cerebral matter at the centrum semiovale level in healthy volunteers. NAA (N-acetylaspartate + N-acetylglutamate), Cr (creatine + phosphocreatine), and Cho (choline + acetylcholine) were evaluated by resonance integrations. Using Cr as an internal standard, NAA/Cr ratio was considered as a relative measure of concentration. CSI sequence explored volunteer's interaxial slices of white and gray matter by means of 8 x 8 matrices of (1)H-NMR spectra. NAA/Cr integral ratios were averaged over the whole spectral matrix to obtain the Index of NAA at Centrum Semiovale (INACS) of each individual. Indexes of the sixty-eight healthy volunteers, divided into three groups by age, showed good intraindividual reproducibility, and were virtually unaffected by small shifts or bendings of the interaxial slice analyzed. The INACSs were used to estimate Age-Sectorial INACS Ranges (ASIR), the intervals that, on the basis of a normal statistical distribution, should comprise 95% of the age-matched healthy population. Individual INACSs, compared to accurately defined ASIRs taken as standards, could early detect subtle, diffuse neuronal or axonal damage within centrum semiovale interaxial slices. Periodic inspection of INACS could also allow monitoring of progressive neuronal or axonal degeneration.

Nickel(II) 2,6-diacetylpyridine bis(isonicotinoylhydrazonate) and bis(benzoylhydrazonate) complexes: structure and antimycobacterial evaluation. Part XI.

The reaction of 2,6-diacetylpyridine (dap) and isonicotinoyl- or benzoylhydrazide leads to bishydrazones H(2)dapin (1a) and H(2)dapb (1b), respectively. The condensation can either take place as a bimolecular kinetic process between the two reactants or as a monomolecular metal-templated synthesis in the presence of nickel(II) ions. In the latter case the reaction products are charged 2,6-diacetylpyridine bis(hydrazone) nickel(II) complexes, which can be easily deprotonated to neutral hydrazonates. Diffractometric analysis of one of these [Ni(dapb)](2) (8b) has shown a binuclear structure with two octahedral nickel(II) ions bridged by two helicoidal dap (bishydrazonates) in a spheroidal structure of C(2V) symmetry. The synthesized complexes 8 are promising as antimycobacterial agents against M. tuberculosis H37Rv. In particular, 8b displays significant activity (MIC=0.025 microg/mL) 10-fold higher than rifampin and equal to isoniazid, while its ligand is ineffective. Compound 8b is also capable of reducing HIV-induced cytopathogenic effect in human T(4 )lymphocytes.

Antimycobacterial in vitro activity of cobalt(II) isonicotinoylhydrazone complexes. Part 10.

Octahedral cobalt(II) complexes of isonicotinoylhydrazones, which were obtained from the primary antituberculous agent isoniazid, have been synthesised and characterised. Their antimycobacterial in vitro activity has been evaluated against Mycobacterium tuberculosis H37Rv: they exhibit MIC values ranging from < 0.1 to 0.39 microg/mL, showing them to be generally more active than previously reported analogous Cu(II) and Ni(II) complexes.

Isoniazid-related copper(II) and nickel(II) complexes with antimycobacterial in vitro activity. Part 9.

Isonicotinoylhydrazones 1, obtained by the primary antituberculous agent Isoniazid, have been used as monoanionic ligands (L) to prepare copper(II) 2 and nickel(II) 3 octahedral complexes of stoichiometry [MeL2(H2O)2]. Their antimycobacterial in vitro activity was evaluated against Mycobacterium tuberculosis H37Rv in comparison with the ligands. Complexes 2a, 2b, 2f, 3b, 3d and 3g displayed MIC values < or = 0.2 microg/mL.

Malignant mesothelioma in thermoelectric power plant workers in Italy.

Asbestos has been widely used in Italian thermoelectric power plants and instances of exposure to workers have been documented in a variety of jobs. Preventive measures were put into effect only in the late 1970s. We report here on four mesothelioma cases among workers of three Italian power plants where cohort studies were carried out, and on three additional cases recorded by a systematic survey carried out on this neoplasm in Tuscany. When the data of the cohorts sources are merged, a significant excess of lung cancer is also evident. Even without a quantitative assessment of exposure, this report shows the importance of asbestos risk in thermal power plants. The risk appears not to be restricted to any particular category of workers.

Does the antitumoral activity of platinum (IV) derivatives result from their in vivo reduction?

The antitumoral activity of some octahedral platinum(IV) and square-planar platinum(II) derivatives against Yoshida ascites tumor in the rat is reported. It is shown that only those octahedral platinum(IV) complexes which give active reduction products are active. These results support the hypothesis that the antitumor activity of octahedral complexes involves activation by in vivo reduction. Anticancer drugs functioning by this mechanism may be preferentially toxic to or may localize in hypoxic areas of tumors.