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Summary: Background: The pathogenesis of malaria is the result of complex interactions between parasites, host and environment. Several studies have assessed the role of genetic characteristics of Plasmodium falciparum infection in the clinical severity of malaria infection comparing different genotypic determinants in mild and severe cases. The genes encoding the polymorphic merozoite surface proteins 1 (msp-1) and 2 (msp-2) and the dihydrofolate reductase (dhfr) of malaria parasites have been extensively used as markers to investigate the genetic diversity and the population structure of P. falciparum. The aim of this study was to assess the epidemiological, clinical, host- and parasite-related determinant factor of the genetic diversity of P. falciparum infections in travellers returning to Italy. Methods: Between 1998 and 2001, we have retrospectively studied 64 inpatients all returning from African malaria-endemic countries. Designation of severe malaria was determined by using the World Health Organization (WHO) definition. P. falciparum infections detected by species-specific PCR were genotyped at the msp-1 and msp-2 loci and clones were determined. PCR and enzyme-digestion methods were used to screen the mutation occurring at codon 108. Results: Multiple P. falciparum genotypes were detected in 32 patients (50%). The number of genotypes was correlated to different host characteristics. No association was found between allelic number of msp-1 or msp-2 and season of travel, absence of antimalarial prophylaxis, length of stay or blood parasitemia. At multiple analysis adjusted for few confounding variables, two variables showed a significant association with multiplicity of P. falciparum genotypes: male gender (p=0.018) and severity of disease (p=0.044). Conclusion: In our study all but one patients with severe malaria had a infection with a multiplicity of P. falciparum clones. At multivariate analysis the male gender, and the occurrence of severe malaria were significanly more commonly detected in patients affected by imported malaria with multiple clones. [Copyright &y& Elsevier]

Abstract Numerous studies have shown a strong correlation between the number of neurofibrillary tangles of the tau protein and Alzheimer's disease progression, making the quantitative detection of tau very promising from a clinical point of view. However, the lack of highly reliable fluorescent probes for selective imaging of tau neurofibrillary tangles is a major challenge due to sharing similar β–sheet motifs with homologous Amyloid-β fibrils. In the current work, we describe the rational design and the in silico evaluation of a small-size focused library of fluorescent probes, consisting of a BODIPY core (electron acceptor) featuring highly conjugated systems (electron donor) with a length in the range 13–19 Å at C3. Among the most promising probes in terms of binding mode, theoretical affinity and polarity, BT1 has been synthesized and tested in vitro onto human induced pluripotent stem cells derived neuronal cell cultures. The probe showed excellent photophysical properties and high selectivity allowing in vitro imaging of hyperphosphorylated tau protein filaments with minimal background noise. Our findings offer new insight into the structure-activity relationship of this class of tau selective fluorophores, paving the way for boosting tau tangle detection in patients possibly through retinal spectral scans.

Abstract Background Multidrug-resistant tuberculosis (MDR-TB) requires lengthy use of second-line drugs, burdened by many side effects. Hepatitis C virus (HCV) chronic infection increases risk of drug-induced liver injury (DILI) in these patients. Data on MDR-TB patients with concurrent HCV chronic infection treated at the same time with second-line antitubercular drugs and new direct-acting antivirals (DAAs) are lacking. We evaluate if treating at the same time HCV infection and pulmonary MDR-TB is feasible and effective. Cases presentation In this study, we described two cases of patients with pulmonary MDR-TB and concurrent HCV chronic infection cured with DAAs at a Tertiary Infectious Diseases Hospital in Italy. During antitubercular treatment, both patients experienced a DILI before treating HCV infection. After DAAs liver enzymes normalized and HCV RNA was undetectable. Then antitubercular regimen was started according to the institutional protocol, drawn up following WHO MDR-TB guidelines. It was completed without further liver side effects and patients were declared cured from both HCV infection and MDR-TB. Conclusions We suggest to consider treatment of chronic hepatitis C with DAAs as a useful intervention for reintroduction of second-line antitubercular agents in those patients who developed DILI, reducing the risk of treatment interruption when re-exposed to these drugs.

Abstract Background Chagas disease (CD) is a systemic parasitic infection caused by the protozoan Trypanosoma cruzi, whose chronic phase may lead to cardiac and intestinal disorders. Endemic in Latin America where it is transmitted mainly by vectors, large-scale migrations to other countries have turned CD into a global health problem because of its alternative transmission routes through blood transfusion, tissue transplantation, or congenital. Aim of this study was to compare the performance of two commercially available tests for serological diagnosis of CD in a group of Latin American migrants living in a non-endemic setting (Rome, Italy). The study was based on a cross-sectional analysis of seroprevalence in this group. Epidemiological risk factors associated to CD were also evaluated in this study population. Methods The present study was conducted on 368 subjects from the Latin American community resident in Rome. Following WHO guidelines, we employed a diagnostic strategy based on two tests to detect IgG antibodies against T. cruzi in the blood (a lysate antigen-based ELISA and a chemiluminescent microparticle CMIA composed of multiple recombinant antigens), followed by a third test (an immunochromatographic assay) on discordant samples. Results Our diagnostic approach produced 319/368 (86.7%) concordant negative and 30/368 (8.1%) concordant positive results after the first screening. Discrepancies were obtained for 19/368 (5.2%) samples that were tested using the third assay, obtaining 2 more positive and 17 negative results. The final count of positive samples was 32/368 (8.7% of the tested population). Increasing age, birth in Bolivia, and previous residence in a mud house were independent factors associated with T. cruzi positive serology. Conclusions Serological diagnosis of CD is still challenging, because of the lack of a reference standard serological assay for diagnosis. Our results reaffirm the importance of performing CD screening in non-endemic countries; employing a fully automated and highly sensitive CMIA assay first could be a cost- and resource-effective strategy for mass screening of low-risk patients. However, our results also suggest that the WHO strategy of using two different serological assays, combined with epidemiological information, remains the best approach for patients coming from endemic countries.

This work aims at elucidating the mechanism and kinetics of hydrolysis of GANT61, the first and most-widely used inhibitor of the Hedgehog (Hh) signalling pathway that targets Glioma-associated oncogene homologue (Gli) proteins, and at confirming the chemical nature of its bioactive form. GANT61 is poorly stable under physiological conditions and rapidly hydrolyses into an aldehyde species (GANT61-A), which is devoid of the biological activity against Hh signalling, and a diamine derivative (GANT61-D), which has shown inhibition of Gli-mediated transcription. Here, we combined chemical synthesis, NMR spectroscopy, analytical studies, molecular modelling and functional cell assays to characterise the GANT61 hydrolysis pathway. Our results show that GANT61-D is the bioactive form of GANT61 in NIH3T3 Shh-Light II cells and SuFu−/− mouse embryonic fibroblasts, and clarify the structural requirements for GANT61-D binding to Gli1. This study paves the way to the design of GANT61 derivatives with improved potency and chemical stability.

The cell division cycle 25 phosphatases (CDC25A, B, and C; E.C. 3.1.3.48) are key regulator of the cell cycle in human cells. Their aberrant expression has been associated with the insurgence and development of various types of cancer, and with a poor clinical prognosis. Therefore, CDC25 phosphatases are a valuable target for the development of small molecule inhibitors of therapeutic relevance. Here, we used an integrated strategy mixing organic chemistry with biological investigation and molecular modeling to study novel quinonoid derivatives as CDC25 inhibitors. The most promising molecules proved to inhibit CDC25 isoforms at single digit micromolar concentration, becoming valuable tools in chemical biology investigations and profitable leads for further optimization.

Antibiotic resistance is now considered a worldwide problem that puts public health at risk. The onset of bacterial strains resistant to conventional antibiotics and the scarcity of new drugs have prompted scientific research to re-evaluate natural products as molecules with high biological and chemical potential. A class of natural compounds of significant importance is represented by alkaloids derived from higher plants. In this review, we have collected data obtained from various research groups on the antimicrobial activities of these alkaloids against conventional antibiotic-resistant strains. In addition, the structure–function relationship was described and commented on, highlighting the high potential of alkaloids as antimicrobials.

The discovery of antibiotics has revolutionized the medicine and treatment of microbial infections. However, the current scenario has highlighted the difficulties in marketing new antibiotics and an exponential increase in the appearance of resistant strains. On the other hand, research in the field of drug-discovery has revaluated the potential of natural products as a unique source for new biologically active molecules and scaffolds for the medicinal chemistry. In this review, we first contextualized the worldwide problem of antibiotic resistance and the importance that natural products of plant origin acquire as a source of new lead compounds. We then focused on terpenes and their potential development as antimicrobials, highlighting those studies that showed an activity against conventional antibiotic-resistant strains.

The chemical composition of the inflorescences from four Cannabis sativa L. monoecious cultivars (Ferimon, Uso-31, Felina 32 and Fedora 17), recently introduced in the Lazio Region, was monitored over the season from June to September giving indications on their sensorial, pharmaceutical/nutraceutical proprieties. Both untargeted (NMR) and targeted (GC/MS, UHPLC, HPLC-PDA/FD and spectrophotometry) analyses were carried out to identify and quantify compounds of different classes (sugars, organic acids, amino acids, cannabinoids, terpenoids, phenols, tannins, flavonoids and biogenic amines). All cultivars in each harvesting period showed a THC content below the Italian legal limit, although in general THC content increased over the season. Citric acid, malic acid and glucose showed the highest content in the late flowering period, whereas the content of proline drastically decreased after June in all cultivars. Neophytadiene, nerolidol and chlorogenic acid were quantified only in Felina 32 cultivar, characterized also by a very high content of flavonoids, whereas alloaromadendrene and trans-cinnamic acid were detected only in Uso-31 cultivar. Naringenin and naringin were present only in Fedora 17 and Ferimon cultivars, respectively. Moreover, Ferimon had the highest concentration of biogenic amines, especially in July and August. Cadaverine was present in all cultivars but only in September. These results suggest that the chemical composition of Cannabis sativa L. inflorescences depends on the cultivar and on the harvesting period. Producers can use this information as a guide to obtain inflorescences with peculiar chemical characteristics according to the specific use.

Abstract Introduction In this short essay, we would like to address a severe divergence observed in Italy between Life Expectancy (LE) and Healthy Life Expectancy (Healthy LE) and a unique trend of worsening in Healthy LE, compared to the other European countries. Both issues emerge in recent data by EUROSTAT Report. Methods The analysis used by the authors of the EUROSTAT report is based on Sullivan method which combines 2 type of variables: mortality and morbidity data. Results While several European countries started to deal with comparable data about LE since 1960, in Italy, analogous data were available for the first time in EUROSTAT Report only in 1985. In Italy, in the period 1985-2008, there was a good progressive increase in L.E., following the best European values. Nevertheless, while until 2004 Italy was among the European best countries in terms of both LE and Healthy LE at birth, four years later in 2008 there was a shocking loss of 10 years of Healthy LE at birth in newborn girls. In the process, they lost their 2-years previous advantage with respect to males (the latter lost only 6 years of Healthy LE, in the same time span). Looking at healthy LE at age 65 in respect to 2004, Italian women in 2008 could expect to live healthy only about 7 years (as much as men) versus the almost 15 years of the European best values (14 years for men). Conclusions It is legitimate to wonder why no one official comment has been produced as a reaction after the first year of spectacular decline in Healthy Life Years in Italy: in counter-tendency with European values, from 2004 to 2008 there is a clear evidence of a 10 years drop in Healthy LE among newborn girls. The problem has not been taken into consideration even when the situation clearly appeared to worsen in the following years, dropping 4-6 more years for males and females in 2006 (for newborn babies); two more years of healthy life expectancy have been lost between 2006 and 2007 for each gender. One more year of Healthy Life Expectancy is lost in 2008. And data have not been made available any more, since then, from Italy.

Abstract Background Global warming and the established responsibility of the anthropogenic emissions of greenhouse gases represent a strong push towards the construction of new nuclear power plants (NPPs) to cope with the growing energy needs. The toxicity of nuclear waste associated with the extreme difficulty of their disposal and increase in cancer mortality and incidence following occupational radiation exposure are considered the only health problems. Methods A search of scientific articles and government documents published since January 1, 1980 to July 1, 2010 was performed to evaluate cancer rate and mortality in residents, particularly children, in the vicinity of NPPs. Results A recent well conducted state-of-the-art case-control study of childhood cancers in the areas around German NPPs (KiKK study) showed a statistically significant cancers (2.2-fold increase in leukemia and a 1.6-fold increase in solid tumor) among children under five years of age living in the inner 5 km circle around NPPs when compared to residence outside this area. These findings have been confirmed by two meta-analyses. Nevertheless, other UK, France, Spain and Finland studies did not find cancer incidence and/or death increase near NPPs. Conclusions Increased cancer risk near NPPs remains in fact an open question. The stronger evidence from the KiKK study suggests there may well be such increases at least in children regardless of the country in which nuclear reactors are located. In fact, few months ago the U.S. Nuclear Regulatory Commission has asked the National Academy of Sciences (NAS) to perform a state-of-the-art study on cancer risk for populations surrounding NPPs.

This review article is aimed at providing a monographic overview on (S)-norcoclaurine (NC) alkaloid from three diverse points of view, collected all together for the first time: 1) the synthetic one, where the compound is seen as a target chiral molecule to be obtained in the highest optical purity and as a starting point for the development of biocatalytic asymmetric syntheses of tetrahydroisoquinoline alkaloids; 2) the chromatographic one, which addresses the HPLC separation of the two NC enantiomers; and 3) the biochemical one, for which a thorough understanding of the topology and mechanism of action of norcoclaurine synthase (NCS) enzyme is still a matter of debate. Special emphasis on the most recent studies in the field is given by discussing the results published by the main research groups who are working on NC and NCS., (© 2016 Wiley Periodicals, Inc.)

Background: In recent years, Nocardia farcinica has been reported to be an increasingly frequent cause of localized and disseminated infections in the immunocompromised patient. However, recent literature is limited. We report a case of left thigh phlegmon caused by N. farcinica that occurred in a patient with leprosy undergoing treatment with prednisone for leprosy reaction., Case Presentation: We describe the case of left thigh phlegmon caused by Nocardia farcinica in a 54-year-old Italian man affected by multi-bacillary leprosy. The patient had worked in South America for 11 years. Seven months after his return to Italy, he was diagnosed with leprosy and started multi-drug antibiotic therapy plus thalidomide and steroids. Then, during therapy with rifampicin monthly, minocycline 100 mg daily, moxifloxacin 400 mg daily, and prednisone (the latter to treat type 2 leprosy reaction), the patient complained of high fever associated with erythema, swelling, and pain in the left thigh. Therefore, he was admitted to our hospital with the clinical suspicion of cellulitis. Ultrasound examination and Magnetic Resonance Imaging showed left thigh phlegmon. He was treated with drainage and antibiotic therapy (meropenem and vancomycin replaced by daptomycin). The responsible organism, Nocardia farcinica, was identified by 16S rRNA sequencing in the purulent fluid taken out by aspiration. The patient continued treatment with intravenous trimethoprim/sulfamethoxazole and imipenem followed by oral trimethoprim/sulfamethoxazole and moxifloxacin. A whole-body computed tomography did not reveal dissemination to other organs like the lung or brain.The patient was discharged after complete remission. Oral therapy with trimethoprim/sulfamethoxazole, moxifloxacin, rifampicin monthly, clofazimine and thalidomide was prescribed to be taken at home. One month after discharge from the hospital the patient is in good clinical condition with complete resolution of the phlegmon., Conclusion: N. farcinica is a rare infectious agent that mainly affects immunocompromised patients. Presentation of phlegmon only without disseminated infection is unusual, even in these kinds of patients. In any case, a higher index of suspicion is needed, as diagnosis can easily be missed due to the absence of characteristic symptoms and the several difficulties usually encountered in identifying the pathogen.

A new seminested polymerase chain reaction (sn-PCR)-based protocol was developed and used to detect and identify Plasmodium species in 1226 whole-blood samples from patients (872 Italians and 354 foreigners) with at least 1 symptom compatible with clinical malaria. The results were compared with those obtained by microscopy: 187 samples were positive by microscopy for malaria parasites and 196 were positive by sn-PCR. When compared to microscopy, the sn-PCR detected different malaria parasite species in 11 cases. In 4 of 11 cases, the sn-PCR identified 1 additional malaria parasite species not observed microscopically, suggesting increased sensitivity. In 4 samples with levels of parasitemia too low for accurate identification of species by microscopy, the sn-PCR detected 2 P. falciparum, 1 P. ovale, and 1 P. falciparum plus P. ovale. Moreover, 9 negative samples by microscopy were positive by sn-PCR. Follow-up analysis demonstrated a parasite clearance of P. falciparum DNA up to 3 days after the disappearance of parasitemia at microscopy. In conclusion, sn-PCR-based diagnosis of malaria appears to be a useful tool when the results of conventional techniques are negative in the presence of a syndrome consistent with malaria, yielding accurate species identification and consequential correct treatment., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We describe one case of eosinophilic meningitis (EM) in a traveler returning from Santo Domingo, presumably caused by Angiostrongylus cantonensis. Treatment with mebendazole and steroids was effective. The presence of persistent headache, fever, and eosinophilia in travelers who return from developing countries should alert clinicians to the possibility of EM.

Background: The number of leishmaniasis cases associated with immunosuppression has increased regularly over the past 20 years. Immunosuppression related to HIV infection, immunosuppressive treatment, organ transplantation, and neoplastic diseases increases the risk for Leishmania-infected people to develop visceral illness., Case Presentation: Three cases of Leishmania infantum leishmaniasis in corticosteroid (CS)-treated patients are reported: an isolated lingual leishmaniasis in a farmer treated with CS for asthma, a severe visceral leishmaniasis associated with cutaneous lesions in a woman with myasthenia gravis, and a visceral involvement after cutaneous leishmaniasis in a man receiving CS., Conclusion: Physicians should recognise CS-treated patients as a population likely to be immune-suppressed. In immunodeficiency conditions, unusual forms of leishmaniasis can develop and foster the risk of a diagnostic delay and of poor response to therapy.

Background: To investigate if high dose inhaled beclomethasone dipropionate started early after upper respiratory tract infection (URTI) could reduce recurrent wheezing in infants., Methods: Twenty-six ambulatory infants, 7-12 months of age, with recurrent wheezing during upper respiratory tract infection participated. All experienced at least three wheezing attacks. Those with underlying lung or systemic disease were excluded. Infants were divided into two groups in an open unblinded manner, until 13 patients had been recruited for each group. The groups were similar in risk factors for recurrent wheezing. Four treatment periods of 5 days were planned for group 1. The dose regimen was nebulized beclomethasone 400 mg by mask tid for 5 days. Treatment was started at the very first sign of URTI prior to any sign of wheezing. Group 2 did not receive any preventive treatment and constituted the control group. Symptoms scores were recorded. The number of emergency room visits, hospital admissions and short courses with oral steroids was also noted., Results: Twelve infants completed 48 treatment periods. Five visited the emergency room, only one during beclomethasone therapy. Six received oral steroids, two receiving beclomethasone. No patient was admitted to the hospital. Symptom scores were significantly lower during beclomethasone treatment (p<0.05). No apparent adverse events were reported., Conclusions: The infant with recurrent wheezing during URTI is a therapeutic challenge. Most of these infants have prodromal symptoms for about 24 hours before wheezing starts. In the present study we observed favorable results, decrease in the number the child wheezed and the number of acute attacks, when high dose inhaled beclomethasone is administered during this critical time.

The Authors describe the intraosseous administration of drugs and fluids in two patients: a preterm infant (gestational age 26 weeks, weight 850 g) with severe cardiopulmonary depression just after delivery, and a 15-day-old newborn with bronchopneumonia. The intraosseous infusion is safe and effective. At present, mainly in United States, it has an important role in pediatric emergency. It is indicated in all emergency situations where a vascular access must be rapidly obtained and in whom other methods of access to the vascular system have failed. After a short review on the history of this old procedure, used for the first time in 1922 for blood transfusions, the Authors describe its physiology, technique, complications, and contraindications.

We report the results of a study held between 1986 and 1988 on a population constituted by 493 subjects (425 of Mozambican nationality) all living in the camp organized for the building of the dam in Corumana (Sabiè district, Maputo). We found five subjects, all of them from Mozambique, seropositive for HIV-1 antibodies (ELISA and WB) with a prevalence of 1.2%. Four of the positive samples came from female subjects (1.7% of 239 females tested); one positive sample came from a male subject (0.5% of 186 tested).