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In a search for potent inhibitors of class III histone/protein deacetylases (sirtuins), a series of sirtinol analogues have been synthesized and the degree of inhibition was assessed in vitro using recombinant yeast Sir2, human SIRT1, and human SIRT2 and in vivo with a yeast phenotypic assay. Two analogues, namely, 3- and 4-[(2-hydroxy-1-naphthalenylmethylene)amino]-N-(1-phenylethyl)benzamide (i.e., m- and p-sirtinol), were 2- to 10-fold more potent than sirtinol against human SIRT1 and SIRT2 enzymes. In yeast in vivo assay, these two small molecules were as potent as sirtinol. Compounds lacking the 2-hydroxy group at the naphthalene moiety or bearing several modifications at the benzene 2‘-position of the aniline portion (carbethoxy, carboxy, and cyano) were 1.3−13 times less potent than sirtinol, whereas the 2‘-carboxamido analogue was totally inactive. Both (R)- and (S)-sirtinol had similar inhibitory effects on the yeast and human enzymes, demonstrating no enantioselective inhibitory effect.

Chemical manipulations performed on aroyl-pyrrolyl-hydroxyamides (APHAs) led to (aryloxopropenyl)pyrrolyl hydroxamates 2a−w, and their inhibition against maize HDACs and their class I or class II HDAC selectivity were determined. In particular, from these studies some benzene meta-substituted compounds emerged as highly class II (IIa)-selective HDAC inhibitors, the most selective being the 3-chloro- and 3-fluoro-substituted compounds 2c (SI = 71.4) and 2f (SI = 176.4). The replacement of benzene with a 1-naphthyl ring afforded 2s, highly active against the class II homologue HD1-A (IC50 = 10 nM) but less class II-selective than 2c,f. When tested against human HDAC1 and HDAC4, 2f showed no inhibitory activity against HDAC1 but was able to inhibit HDAC4. Moreover, in human U937 acute myeloid leukaemia cells 2f did not produce any effect on apoptosis, granulocytic differentiation, and the cell cycle, whereas 2s (that retain class I HDAC inhibitory activity) was 2-fold less potent than SAHA used as reference.

Spinobulbar muscular atrophy (SBMA) is a late-onset disorder characterized by progressive muscle loss, degeneration of motoneurons in the spinal cord and brainstem, and partial androgen insensitivity. SBMA is directly correlated with the expansion of CAG repeats encoding a polyglutamine tract (polyQ) of extended length. The identification of polyQ expansion in SBMA led to the discovery of an entire class of neurodegenerative disorders. In fact, at least eight different diseases, including Huntington’s disease, share a common molecular mechanism involving an expansion of a polyQ tract within different proteins. The elongated polyQ tract causes a toxic gain of function in the mutant protein and is associated with the formation of intracellular aggregates, whose pathogenetic role has not been fully established yet. Our observations in a motoneuron cell line (NSC34), indicate that the expression of the androgen receptor (AR) carrying the elongated polyQ tract (AR-Q48) has a toxic effect in aggregate-independent manner. In fact, in basal condition, AR-Q48 shows a cytoplasmic diffuse distribution, yet it reduces the viability of transfected NSC34. In contrast, testosterone treatment, while inducing aggregation of the mutant AR, also increases cell viability. Aggregates in NSC34 are localized mainly in the perinuclear region and occasionally in the neuropil, whereas no nuclear aggregate has ever been found. Further observations of the minor subset of cells showing neuropil aggregates, reveal an alteration of the neurite morphology, suggesting a different role of the two types of cytoplasmic aggregates.

A new find of the mineral palygorskite from Bolca, Vicenza, Italy is described. The mineral occurs in association with calcite and diaspore along the shear fractures and in the veins of secondary minerals in the Eocene marls of the Bolca quarry, a locality known for its well-preserved fossil specimens. Selected regions of the X-ray powder diffraction spectra (XRPD) were collected using X-ray synchrotron radiation and high-resolution parallel-beam geometry. The data are interpreted by comparison with the computer-simulated powder diffraction patterns relative to the proposed strcture models for palygorskite. Cell parameters and relative phase weight evaluation were obtained by model-constrained Rietveld refinement. The sample was also investigated by electron probe micro-analysis (EPMA), TGA and DTG analysis, and SEM imaging. The average material is a mixture containing about 60% orthorhombic palygorskite, 30% monoclinic palygorskite, and less than 10% calcite and diaspore impurities. The association of the two different varieties of palygorskite is in agreement with recent reevaluation studies of the mineral from different localities, showing the ubiquitous presence of the two forms.

Monochromatic X-ray beam produced by synchrotron radiation may be considered an ideal probe in some fields of diagnostic radiology. In this paper the potential of monochromatic synchrotron radiation X-ray beam in mammography is analyzed. The image quality of four different phantom radiographs, obtained using two different energies equal to 17 and 18 keV, respectively, and a mammographic film/screen system, is assessed. The doses have been determined for both energies by using thermoluminescent dosimeters and a 5-cm thick phantom having a composition of 50% water and 50% fat. The results have been compared with those obtained in the same manner using a mammographic unit equipped with a molybdenum anode, molybdenum filter tube and antiscanner grid. The radiographs obtained with synchrotron radiation show higher contrast and less blur than those obtained with a conventional mammographic system. The average breast doses, 1.55 and 0.80 mGy at 17 and 18 keV, respectively, are comparable with the dose (1.51 mGy) of the conventional technique.

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ObjectivesSacral Tarlov cysts (TC) are frequent incidental findings on spinal MRI. Controversy remains regarding their ability to cause nerve root compression. Pelvic neurophysiological and urodynamics testing provides information about sacral nerve root involvement.DesignCase seriesSubjectsPatients with MRI evidence of sacral (S1, 2 or 3) TC seen in the Uro-neurology Department between 2011 and 2018.MethodsClinical, neurophysiological and urodynamics data were reviewed.Results13 patients (9 females, mean age54/SD13.1) were included. Symptoms were urgency/incontinence (n=8), hesitancy/urinary retention (n=7), bowel complaints (n=4), sexual complaints (n=3), back pain (n=5), genital/pelvic pain (n=6), genital numbness (n=5), impaired sensation of bladder fullness (n=2), lower limb (LL) pain/hypoesthesia (n=6), LL weakness (n=2). The following neurophysiological abnormalities were seen: anal sphincter EMG (n=10) evidence for reinnervation (n=8), pudendal sensory evoked potentials (SEPs) (n=6) absent response (n=1), S2 and S3 dermatomal SEPs (n=6) absent response (n=2), sympathetic skin response (n=6) absent response (n=3). Findings in cystometry (n=5) were: detrusor underactivity (n=2), detrusor after-contraction (n=1), equivocal obstructed voiding (n=1) and reduced bladder compliance (n=1).ConclusionsAbnormal results in urodynamics and pelvic neurophysiology suggest involvement of the somatic and autonomic sacral innervation. Further studies are required to explore any association between structural changes on MRI and functional changes in urodynamics and neurophysiology.