From Companion Diagnostics to Theranostics:A New Avenue for Alzheimer's Disease?

The recent literature signals a growing paradigm shift toward integrating therapeutics and diagnostics rather than developing and deploying them separately. In this gradual move toward more effective and personalized medications, companion diagnostics are an intermediate stage. The next step may be "theranostics", in which single chemical entities are developed to deliver therapy and diagnosis simultaneously. This strategy has been successfully exploited in oncology and is now emerging as a possibility for Alzheimer's disease, where its feasibility has caught the attention of researchers from industry and academia. Medicinal chemists do not yet completely understand the nuances of theranostic action and consequently have not yet developed universally validated strategies for developing theranostic clinical applications against Alzheimer's disease. However, given the emerging indications of the potentially enormous benefits that theranostics may bring to the fight against this devastating disease, further rigorous research is warranted

Navigating the Chemical Space of Multitarget-Directed Ligands:From Hybrids to Fragments in Alzheimer's Disease

Multitarget drug discovery is one of the hottest topics and most active fields in the search for new molecules against Alzheimer’s disease (AD). Over the last 20 years, many promising multitarget-directed ligands (MTDLs) have been identified and developed at a pre-clinical level. However, how to design them in a rational way remains the most fundamental challenge of medicinal chemists. This is related to the foundational question of achieving an optimized activity towards multiple targets of interest, while preserving drug-like properties. In this respect, large hybrid molecules and small fragments are poles apart. In this review article, our aim is to appraise what we have accomplished in the development of both hybrid- and fragment-like molecules directed to diverse AD targets (i.e., acetylcholinesterase, NMDA receptors, metal chelation, BACE-1 and GSK-3β). In addition, we attempt to highlight what are the persistent needs that deserve to be improved and cared for, with the ultimate goal of moving an MTDL to AD clinical studies

shoreline detection capability of cosmo skymed and high resolution multispectral images

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Kriteriji za ocjenu sposobnosti za rad u zdravstvenih radnika inficiranih virusima hepatitisa B i C

The aim of this study was to propose a protocol for assessment of markers of infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) in exposed health care professionals and to define criteria for evaluation of fitness for the job of the infected personnel. The study comprised 800 persons involved in operative procedures, including 414 surgeons, 275 nurses, and 111 anaesthetists. A graduated protocol was created for monitoring markers of HBV and HCV infection. A well-defined combination of markers of antigenantibody systems enabled identification of four groups of persons with HBV infection differing in fitness for work: 1) HBsAg-positive, HBeAgpositive, HBV DNA-positive; 2) HBsAg-positive, anti-HBe-positive, HBV DNA-positive; 3) HBsAgpositive, anti-HBe-positive, HBV DNA-negative; and 4) anti-HBs-positive, anti-HBc-positive, anti-HBe-positive group. For HCV infection, two groups with different job fitness were identified: 1) anti-HCV-positive, HCV RNA-negative and 2) anti-HCV-positive, HCV RNA-positive. Screening of hospital personnel at risk to HBV and HCV infection requires a well-defined protocol which may help to evaluate the fitness of the infected personnel for a specific job.U priopćenju je predložen stupnjevani protokol za procjenu pokazatelja infekcije virusom hepatitisa B (HBV) i virusom hepatitisa C (HCV) u profesionalno izloženih zdravstvenih radnika kao i za utvrđivanje kriterija za ocjenu sposobnosti za rad inficiranog osoblja. U istraživanju je obuhvaćeno 800 zdravstvenih radnika koji sudjeluju u operativnim zahvatima: 414 kirurga, 275 medicinskih sestara i 111 anesteziologa. Prema definiranim kombinacijama ispitivanih pokazatelja u sustavima antigen-antitijelo, ispitanici inficirani virusom hepatitisa B razvrstani su u četiri skupine s različitom sposobnošću za rad, prema ovim nalazima: 1) HBsAg pozitivan, HBeAg pozitivan, HBV DNK pozitivan; 2) HBsAg pozitivan, anti-HBe pozitivan, HBV DNK pozitivan; 3) HBsAg pozitivan, anti-HBe pozitivan, HBV DNK negativan; 4) anti-HBs pozitivan, anti-HBc pozitivan, anti-HBe pozitivan. Slično su razvrstane osobe inficirane virusom hepatitisa C u dvije skupine, prema ovim nalazima: 1) anti-HCV pozitivan, HCV RNK negativan; 2) anti-HCV pozitivan, HCV RNK pozitivan. Zaključeno je da, budući da u Italiji Služba medicine rada nema u nadležnosti nadzor medicinskog osoblja koje je u povećanom riziku od infekcije HBV-om i HCV-om, valja usvojiti jasno definirani protokol za utvrđivanje pokazatelja infekcije u profesionalno izloženih osoba. Takav protokol mogao bi poslužiti za donošenje kriterija za ocjenu sposobnosti za rad inficiranog osoblja

Očna hipertonija i zamućenja leće u zdravstvenih radnika izloženih ionizirajućem zračenju

Some activities performed by healthcare workers may still involve total or partial exposure to ionising radiation exceeding the limit values. In addition to the appearance of crystalline lens opacities which may lead to rays-cataract, recent studies have indicated possible induction of ocular hypertonia in occupationally exposed subjects. The aim of this study was to establish the actual prevalence of ocular hypertonia and crystalline lens opacities in a group of healthcare workers exposed to ionising radiation. The collected data failed to show significant risk of ocular hypertonia and suggested that crystalline lens opacity was not an important indicator of exposure. Notwithstanding, preventive and periodic (every 5 years) ophthalmologic control may prove helpful for medicolegal purposes. Namely, such control would record congenital crystalline lens opacities in many individuals and would thus rule out unjustified claims of occupational disease due to exposure to ionising radiation. Additionally, ophthalmologic control should focus on different and probably more important ocular risks for the radiologists such as the ocular fatigue resulting from a prolonged use of a video display terminal or other diagnostic screens or electrodiaphanoscopes.Neke od djelatnosti zdravstvenih radnika još uključuju rizik od potpune ili djelomične izloženosti ionizirajućem zračenju u razinama koje nadilaze granične vrijednosti. Osim različitih stupnjeva od zamućenja leće do katarakte, nova su istraživanja upozorila na mogućnost pojave očne hipertonije i zamućenja leće u profesionalno izloženih osoba. Cilj je ovoga istraživanja bio utvrditi pravu incidenciju očne hipertonije i zamućenja leće u zdravstvenih radnika koji su povremeno izloženi ionizirajućem zračenju. Rezultati pokazuju da nema značajnoga rizika od očne hipertonije u toj populaciji te upućuju na to da zamućenje leće nije značajan pokazatelj izloženosti ionizirajućem zračenju. Bez obzira na to, periodični i preventivni oftalmološki pregledi (svakih pet godina) mogli bi se pokazati korisnima u medicinskom i pravnom pogledu. Naime, ovakva bi kontrola mogla registrirati uro|ena zamućenja leće u mnogih pojedinaca, što bi isključilo mogućnost neopravdanih zahtjeva za odštetu za profesionalnu bolest zbog izloženosti ionizirajućem zračenju. Osim toga, oftalmološki bi pregledi trebali uzeti u obzir i druge, možda i važnije rizike za zdravlje oka u radiologa kao što je umor oka zbog dugotrajnog naprezanja pri uporabi videoterminala ili ostalih ekrana, odnosno elektrodijafanoskopa

Dietary habits in women with recurrent idiopathic calcium nephrolithiasis

Nutrition has been widely recognized to influence the risk of kidney stone formation. Therefore the aim of our study was to assess: a) whether usual diet of women with idiopathic calcium nephrolithiasis (ICN) living in Parma (Northern-Italy) is different compared to healthy controls, b) how their diet differs from Italian National guidelines and c) whether it is related to nephrolithiasis clinical course

Naphthoquinone Derivatives Exert Their Antitrypanosomal Activity via a Multi-Target Mechanism

BACKGROUND AND METHODOLOGY: Recently, we reported on a new class of naphthoquinone derivatives showing a promising anti-trypanosomatid profile in cell-based experiments. The lead of this series (B6, 2-phenoxy-1,4-naphthoquinone) showed an ED(50) of 80 nM against Trypanosoma brucei rhodesiense, and a selectivity index of 74 with respect to mammalian cells. A multitarget profile for this compound is easily conceivable, because quinones, as natural products, serve plants as potent defense chemicals with an intrinsic multifunctional mechanism of action. To disclose such a multitarget profile of B6, we exploited a chemical proteomics approach. PRINCIPAL FINDINGS: A functionalized congener of B6 was immobilized on a solid matrix and used to isolate target proteins from Trypanosoma brucei lysates. Mass analysis delivered two enzymes, i.e. glycosomal glycerol kinase and glycosomal glyceraldehyde-3-phosphate dehydrogenase, as potential molecular targets for B6. Both enzymes were recombinantly expressed and purified, and used for chemical validation. Indeed, B6 was able to inhibit both enzymes with IC(50) values in the micromolar range. The multifunctional profile was further characterized in experiments using permeabilized Trypanosoma brucei cells and mitochondrial cell fractions. It turned out that B6 was also able to generate oxygen radicals, a mechanism that may additionally contribute to its observed potent trypanocidal activity. CONCLUSIONS AND SIGNIFICANCE: Overall, B6 showed a multitarget mechanism of action, which provides a molecular explanation of its promising anti-trypanosomatid activity. Furthermore, the forward chemical genetics approach here applied may be viable in the molecular characterization of novel multitarget ligands

Discovery of sustainable drugs for neglected tropical diseases: cashew nutshell liquid (CNSL)-based hybrids target mitochondrial function and ATP production in Trypanosoma brucei.

In a search for effective and sustainable treatments for trypanosomiasis, we developed a library of hybrid compounds by merging the structural features of a previously synthesized quinone hit (4) with those of long‐chain phenolic constituents from cashew nut shell liquid (CNSL). CNSL is an agro‐waste product from cashew nut processing factories with great potential as a precursor for the production of drugs. The synthesized compounds were tested against Trypanosoma brucei brucei, including three multi‐drug resistant strains (B48, ISMR1, and aqp2/aqp3‐KO), T. congolense, and a human cell line (HFF). The most potent activity was found against T. b. brucei, the causative agent of African trypanosomiasis. Shorter‐chain derivatives were more active than the starting hit in parasite growth inhibition, displaying rapid trypanocidal activity with low micromolar EC50 values, but no discernable toxicity on human cell lines. Preliminary studies probing their mode of action on trypanosomes showed depletion of cellular ATP, followed by the depolarization of the mitochondrial membrane and ultrastructural damage to the mitochondrion. This was accompanied by the production of high levels of reactive oxygen species. We envisage that such hybrid compounds, obtained from renewable and inexpensive material, might be promising bio‐based, sustainable hits for anti‐trypanosomatid drug discovery

Degenerative Jargon Aphasia: Unusual Progression of Logopenic/Phonological Progressive Aphasia?

Primary progressive aphasia (PPA) corresponds to the gradual degeneration of language which can occur as nonfluent/agrammatic PPA, semantic variant PPA or logopenic variant PPA. We describe the clinical evolution of a patient with PPA presenting jargon aphasia as a late feature. At the onset of the disease (ten years ago) the patient showed anomia and executive deficits, followed later on by phonemic paraphasias and neologisms, deficits in verbal short-term memory, naming, verbal and semantic fluency. At recent follow-up the patient developed an unintelligible jargon with both semantic and neologistic errors, as well as with severe deficit of comprehension which precluded any further neuropsychological assessment. Compared to healthy controls, FDG-PET showed a hypometabolism in the left angular and middle temporal gyri, precuneus, caudate, posterior cingulate, middle frontal gyrus, and bilaterally in the superior temporal and inferior frontal gyri. The clinical and neuroimaging profile seems to support the hypothesis that the patient developed a late feature of logopenic variant PPA characterized by jargonaphasia and associated with superior temporal and parietal dysfunction