Hypersensitivity reactions to non-vitamin K oral anticoagulants - a review of literature and diagnostic work-up proposal.

Summary: Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly being used in hospital and outpatient settings as safe alternatives to warfarin. Hypersensitivity reactions have been described for NOACs and can be classified according to Gell and Coombs. We reviewed case reports of possible drug hypersensitivity reactions, noticing a predominance of delayed reactions (both mild and severe) and the absence of cross-reactions to warfarin and low molecu-lar weight heparins. International experience on diagnostic tests is lacking. The vast majority of authors refer to probability scores and rely on biopsy to classify vasculitis and rule out differential diagnoses. We propose to adapt available tests to confirm the patient's reactivity to new anticoagulants. Among in vivo tests, patch testing revealed promising in delayed reactions.

Galactose-α-1,3-galactose syndrome: an Italian survey.

SUMMARY: Background. The term of α-Gal syndrome, which includes the delayed allergy to red meat and the allergic reactions following the administration of cetuximab, is associated to the presence of specific IgE to α-Gal. In Italy, only anecdotal cases were reported so far. The Association of Italian Allergists (AAITO) carried out a survey with the aim of evaluating presence, characteristics, clinical features, and distribution of the syndrome in Italy. Methods. A web structured questionnaire was made available on the website of AAIITO from July 2016 to January 2017. It included 31 multiple-choice questions concerning different items, including the site of physicians, the number of patients diagnosed as having cetuximab allergy and/or delayed red meat allergy, recall of tick bites, symptoms, time to reactions, elicitor foods, reactions with foods other than meat, and in-vivo and in-vitro tests used for the diagnosis. Results. Seventy-nine physicians completed the questionnaire. Nine cases of allergy to cetuximab and 40 cases of delayed red meat allergy were recorded across Italy. 22.5% of patients with cetuximab allergy and 62.5% of those with delayed red meat allergy recalled a tick bite. 75% of patients with delayed red meat allergy experienced symptoms after eating beef (butcher's cut in 72.5%). Urticaria was the most frequent clinical manifestation (65% of cases). In 60.6% of cases symptoms appeared 2 - 4 hours after meat ingestion, while in 7.9% symptoms appeared after > 4 hours. The most used diagnostic methods were the intradermal test for cetuximab allergy (88.9%) and the detection of IgE to α-Gal (55.5%) for red meat allergy. Most case reports came from Northern Italy. Conclusions. α-Gal syndrome is present in Italy and beef is the most frequent offending food. In most cases symptoms were not severe.

An epidemiological survey of Mycoplasma hominis and Ureaplasma urealyticum in gynaecological outpatients, Rome, Italy.

The objective of this study was to assess the prevalence of Ureaplasma urealyticum and Mycoplasma hominis infections and to investigate associations between their presence in the lower female genital tract and lifestyle characteristics. The study was performed on a population of 3115 women, comparing the demographic and behavioural characteristics of 872 women with U. urealyticum infection and 142 women with M. hominis with uninfected women, using univariate and multiple logistic regression analysis. The prevalence of infection with U. urealyticum was 28% and M. hominis was 4.6%. In multivariate logistic regression analysis, intrauterine device, number of sexual partners and age (<35 years) were significantly associated with U. urealyticum while previous induced abortion, condom use and young age at first intercourse (<16 years) were associated with M. hominis infection. U. urealyticum infection presents the same demographic and behavioural characteristics of a sexually transmitted disease. The unprotective role of condom use suggests a non-sexual mode of transmission of M. hominis infection.

Human polyomavirus JC reactivation and pathogenetic mechanisms of progressive multifocal leukoencephalopathy and cancer in the era of monoclonal antibody therapies.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the neurotropic human polyomavirus JC (JCV) lytic infection of oligodendrocytes. PML was first described as a complication of lymphoproliferative disorders more than 50 years ago and emerged as a major complication of human immunodeficiency virus (HIV) infection in the 1980s. Despite the ubiquity of this virus, PML is rare and always seen in association with underlying immunosuppressive condition, such as HIV infection, autoimmune diseases, cancer, and organ transplantation. JCV remains quiescent in the kidneys, where it displays a stable archetypal non-coding control region (NCCR). Conversely, rearranged JCV NCCR, including tandem repeat patterns found in the brain of PML patients, have been associated with neurovirulence. The specific site and mechanism of JCV NCCR transformation is unknown. According to one model, during the course of immunosuppression, JCV departs from its latent state and after entering the brain, productively infects and destroys oligodendrocytes. Although the majority of PML cases occur in severely immunesuppressed individuals, PML has been increasingly diagnosed in patients treated with biological therapies such as monoclonal antibodies (mAbs) that modulate immune system functions: in fact, CD4+ and CD8+ T lymphopenia, resulting from this immunomodulatory therapy, are the primary risk factor. Furthermore, JCV reactivation in nonpermissive cells after treatment with mAbs, such as intestinal epithelial cells in Crohn's disease patients, in association with other host tumor-inducing factors, could provide valid information on the role of JCV in several malignancies, such as colorectal cancer.

Epidemiology of Chlamydia trachomatis endocervical infection in a previously unscreened population in Rome, Italy, 2000 to 2009.

As reliable data on Chlamydia trachomatis infection in Italy are lacking and as there is no Italian screening policy, epidemiological analyses are needed to optimise effective strategies for surveillance of the infection in the country. We collected data from 6,969 sexually active women aged 15 to 55 years who underwent testing for endocervical C. trachomatis infection at the Cervico-Vaginal Pathology Unit in the Department of Gynaecology and Obstetrics of Sapienza University in Rome between 2000 and 2009. The mean prevalence of C. trachomatis endocervical infection during this period was 5.2%. Prevalence over time did not show a linear trend. Univariate analysis demonstrated a significant association of infection with multiple lifetime sexual partners, younger age (<40 years), never having been pregnant, smoking, use of oral contraceptives, and human papillomavirus and Trichomonas vaginalis infections. Multivariate stepwise logistic regression showed that T. vaginalis infection, age under 20 years and more than one lifetime sexual partner remained significantly associated with C. trachomatis infection in the final model. Prevalence of C. trachomatis in this study was high, even among women aged 25­39 years (5.1%): our data would suggest that a C. trachomatis screening policy in Italy is warranted, which could lead to a more extensive testing strategy.

Antibacterial activity of methyl aminolevulinate photodynamic therapy in the treatment of a cutaneous ulcer.

We describe a 79-year-old female with a chronic venous ulceration infected by Staphylococcus aureus and Enterococcus faecalis and not responsive to conventional treatments. The patient was treated with Methyl-Aminolaevulinate Photodynamic Therapy (MAL-PDT). After four weeks the cutaneous swabs become negative and we observed a significant clinical improvement. Therefore we suppose that MALPDT could represent a valid therapeutic option in the treatment of infected chronic ulcers.

JC Viral reactivation in a pediatric patient with Crohn's disease.

This is a report concerning human polyomavirus JC (JCV) reactivation in a pediatric patient with Crohn's disease (CD) during the treatment with 5-aminosalicylic acid (5-ASA), a non-steroidal anti-inflammatory drug (NSAID). We examined 9 bioptic samples from three different bowel districts (ileum, cecum, rectum) of this child. These samples were analyzed by Quantitative PCR (Q-PCR) to investigate the presence of JCV DNA. JCV DNA was detected in one rectum biopsy taken two months after 5-ASA treatment. Although our result must be validated in a larger group of subjects and with a longer follow-up period, it underlines the importance of JVC monitoring in CD patients.

Bromhidrosis induced by sphingomonas paucimobilis: a case report.

Bromhidrosis is a clinical disorder characterized by excessive or abnormal foul axillary odour due to the interaction of apocrine glands with micro-organisms which causes a serious personal and social handicap for affected people. We present the case of a 50-year-old caucasian female with bromhidrosis. The patient referred that this symptom had begun two months previously. Her past treatments included antibacterial soap, topical antibacterial agents and perfumes, but none of these relieved the patient of the odour. A cultural examination of axillary smear was carried out and it revealed the presence of ciprofloxacin sensible Sphingomonas paucimobilis. Therefore the patient was treated with ciprofloxacin and after 1 week the infection resolved completely.

A cutaneous infection caused by Brevundimonas vesicularis: a case report.

Brevundimonas vesicularis is a non-fermenting gram-negative bacillus, aerobic and motile. This microorganism is ubiquitous in the environment and has rarely been implicated in human infections. We present the second case of cutaneous infection caused by B. vesicularis in an immunocompetent patient.

Cutaneous cryptococcosis in a patient affected by chronic lymphocytic leukaemia: a case report.

Cryptococcosis is an opportunistic infection, the incidence of which is increased in the immunocompromised patients. Cryptococcus neoformans is an encapsulated fungus that mainly infects the lungs and the central nervous system, possibly involving different organs. Cutaneous cryptococcosis is classified into localized infection, usually occurring after traumatic inoculation (primary cutaneous cryptococcosis) and cutaneous manifestation due to hematogenous dissemination (secondary cutaneous cryptococcosis), mostly in patients with underlying immunosuppression. We report a case of cutaneous cryptococcosis in a patient affected by chronic lymphocytic leukaemia.

Virulence traits in Escherichia coli strains isolated from outpatients with urinary tract infections.

This study aims to characterize phenotypic and genotypic virulence traits in Escherichia coli strains, isolated from outpatients with urinary tract infections, comparing with those obtained from inpatients. Information on the pathogenic behavior of the uropathogenic strains was obtained by monitoring different biological properties, such as autoagglutination, hemagglutination, adhesiveness to and invasion of human bladder (HT1376) cells, biofilm formation, phylogenetic grouping, and virulence-related genes. The results show similar behavior in the two groups concerning autoagglutination, hemagglutination, and biofilm formation. None of the strains examined was invasive. However, in strains from outpatients there was an increased adhesion to HT1376 cells compared with clinical strains, a significant higher presence of genes codifying for adhesins and cell protection factors, and a lower proportion of strains belonging to B1 group. These findings add further information on the pathogenic traits of community E. coli, since strains isolated from the outpatients' group were differently "armed" in comparison with those of clinical cases, and more suitable to infect healthy individuals.

Therapeutic targeting of CK2 in acute and chronic leukemias.

CK2 is a ubiquitously expressed, constitutively active Ser/Thr protein kinase, which is considered the most pleiotropic protein kinase in the human kinome. Such a pleiotropy explains the involvement of CK2 in many cellular events. However, its predominant roles are stimulation of cell growth and prevention of apoptosis. High levels of CK2 messenger RNA and protein are associated with CK2 pathological functions in human cancers. Over the last decade, basic and translational studies have provided evidence of CK2 as a pivotal molecule driving the growth of different blood malignancies. CK2 overexpression has been demonstrated in nearly all the types of hematological cancers, including acute and chronic leukemias, where CK2 is a key regulator of signaling networks critical for cell proliferation, survival and drug resistance. The findings that emerged from these studies suggest that CK2 could be a valuable therapeutic target in leukemias and supported the initiation of clinical trials using CK2 antagonists. In this review, we summarize the recent advances on the understanding of the signaling pathways involved in CK2 inhibition-mediated effects with a particular emphasis on the combinatorial use of CK2 inhibitors as novel therapeutic strategies for treating both acute and chronic leukemia patients.

Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin module for acute myelogenous leukemia therapy: from bench to bedside.

The phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B, PKB)/mammalian Target Of Rapamycin (mTOR) signaling pathway plays a critical role in many cellular functions which are elicited by extracellular stimuli. However, constitutively active PI3K/Akt/mTOR signaling has also been firmly established as a major determinant for cell growth, proliferation, and survival in an wide array of human cancers. Thus, blocking the PI3K/AKT/mTOR signal transduction network could be an effective new strategy for targeted anticancer therapy. Pharmacological inhibitors of this signaling cascade are powerful antineoplastic agents in vitro and in xenografted models of tumors, and some of them are now being tested in clinical trials. Recent studies showed that PI3K/Akt/mTOR axis is frequently activated in acute myelogenous leukemia (AML) patient blasts and strongly contributes to proliferation, survival, and drug-resistance of these cells. Both the disease-free survival and overall survival are significantly shorter in AML cases with PI3K/Akt/mTOR upregulation. Therefore, this signal transduction cascade may represent a target for innovative therapeutic treatments of AML patients. In this review, we discuss the possible mechanisms of activation of this pathway in AML cells and the downstream molecular targets of the PI3K/Akt/mTOR signaling network which are important for blocking apoptosis, enhancing proliferation, and promoting drug-resistance of leukemic cells. We also highlight several pharmacological inhibitors which have been used to block this pathway for targeted therapy of AML. These small molecules induce apoptosis or sensitize AML cells to existing drugs, and might be used in the future for improving the outcome of this hematological disorder.

Invasive pathway of Listeria ivanovii in human amnion-derived WISH cells.

Among Listeria genus, only two species, Listeria ivanovii and Listeria monocytogenes, are pathogenic. L. ivanovii is almost only associated with infections in animals, mainly sheep and cattle, and has rarely been associated with human infections, whereas L. monocytogenes causes severe illnesses in both humans and animals. To further investigate the pathogenetic features of L. ivanovii in humans, we undertook a study in which the intracellular behaviour of this pathogen was analysed in WISH cells, a cell line derived from human amniotic tissue, and compared to that of L. monocytogenes. Using microbiological, biochemical, and ultrastructural approaches, we demonstrate that L. ivanovii can adhere to and invade human amniotic cells, lyse the phagosomal membrane, polymerize host cell actin, and spread from cell to cell more efficiently than L. monocytogenes. However, although L. ivanovii is capable of specifically infecting and replicating in human amnion cells, its survival in cytoplasm is limited compared to that of L. monocytogenes.

A case of human polyomavirus Bk infection in a patient affected by late stage prostate cancer: could viral infection be correlated with cancer progression?

The basic molecular mechanisms regulating prostate cancer (PCA) development and progression are very poorly understood. Different tumor suppressor genes are implicated in PCA. In particular, since the mutation rate of the p53 gene is also low, researchers have speculated that an infectious agent might play an important role in PCA. Polyomaviruses are candidates for this agent. We selected a patient with a diagnosis of PCA and underwent radical prostatectomy, to investigate the presence of polyomavirus BK (BKV) sequences (urine and neoplastic tissues) and the mutation pattern of p53 gene. The results obtained showed the presence of BKV DNA and of p53 gene mutations in exons 6, 8 and 9. We speculate that BKV might contribute to cellular transformation process, triggered possibly by p53 gene mutations.

Risk assessment of maize damage by wireworms (Coleoptera: Elateridae) as the first step in implementing IPM and in reducing the environmental impact of soil insecticides.

A survey of maize fields was conducted in northeast Italy from 1986 to 2014, resulting in a dataset of 1296 records including information on wireworm damage to maize, plant-attacking species, agronomic characteristics, landscape and climate. Three wireworm species, Agriotes brevis Candeze, A. sordidus Illiger and A. ustulatus Schäller, were identified as the dominant pest species in maize fields. Over the 29-year period surveyed, no yield reduction was observed when wireworm plant damage was below 15 % of the stand. A preliminary univariate analysis of risk assessment was applied to identify the main factors influencing the occurrence of damage. A multifactorial model was then applied by using the significant factors identified. This model allowed the research to highlight the strongest factors and to analyse how the main factors together influenced damage risk. The strongest factors were: A. brevis as prevalent damaging species, soil organic matter content >5 %, rotation including meadows and/or double crops, A. sordidus as prevalent damaging species, and surrounding landscape mainly meadows, uncultivated grass and double crops. The multifactorial model also showed how the simultaneous occurrence of two or more of the aforementioned risk factors can conspicuously increase the risk of wireworm damage to maize crops, while the probability of damage to a field with no-risk factors is always low (<1 %). These results make it possible to draw risk maps to identify low-risk and high-risk areas, a first step in implementing bespoke IPM procedures in an attempt to reduce the impact of soil insecticides significantly.

Listeria monocytogenes in a young patient with non Hodgkins lymphoma: case report.

Listeria monocytogenes is an intracellular food-borne pathogen, widely distributed in the environment, which rarely causes clinical infection in healthy people, but may cause severe disease in immunocompromised patients. A case of listeriosis is certified in an immunocompromised patient, thus confirming this microorganism to be an opportunistic human pathogen.

Encrusted cystitis in an immunocompromised patient: possible coinfection by Corynebacterium urealyticum and E. coli.

Encrusted cystitis is a severe chronic inflammatory disease of the bladder characterized by excessively alkaline urine and calcifications within the bladder wall. A case of a 60 year-old man affected by systemic lupus erythematosus (SLE), which developed encrusted cystitis due to Corynebacterium urealyticum with E. coli co-infection, shows that the treatment of encrusted cystitis with a endoscopic debulking of the encrusted stones and an antimicrobial therapy specific for C. urealyticum often is not sufficient for the complete resolution of symptoms.

Karyotype studies in South American species of Solanum subgen. Leptostemonum (Solanaceae).

Mitotic chromosome numbers and karyotypes of 13 South American species (12 native and one naturalized) from four sections of SOLANUM subgen. LEPTOSTEMONUM were studied. Chromosome numbers of S. ACERIFOLIUM, S. AENICTUM, S. CONDITUM, S. CONSIMILE, S. INCARCERATUM, and S. PLATENSE are reported for the first time. The number 2n = 24 was found in most species, while 2n = 22 was found in S. MAMMOSUM and S. PLATENSE. The latter is the second SOLANUM with this unusual number. Satellites are always present and were visible in more than 50 % of the cells studied. Karyotypes are symmetrical: M and SM chromosomes are common, whereas ST chromosomes are rare. The karyotypes of S. AENICTUM, S. MAMMOSUM, and S. PANICULATUM are comparatively asymmetrical. Species can be distinguished by a combination of chromosome number, karyotype formulae, karyotype length, the position of satellites in a particular chromosome pair, and asymmetry indices. The phenogram obtained does not reflect the sectional arrangements or the systematic affinities of the species studied. In sect. ACANTHOPHORA, increased asymmetry is associated with derived characters (strong andromonoecy, winged seeds, mammiform fruits). Diversification in the subgenus is suggested to be related to visible chromosome rearrangements and cumulative, cryptic structural changes may have also played a relevant evolutionary role.

Therapeutic potential of targeting sphingosine kinases and sphingosine 1-phosphate in hematological malignancies.

Sphingolipids, such as ceramide, sphingosine and sphingosine 1-phosphate (S1P) are bioactive molecules that have important functions in a variety of cellular processes, which include proliferation, survival, differentiation and cellular responses to stress. Sphingolipids have a major impact on the determination of cell fate by contributing to either cell survival or death. Although ceramide and sphingosine are usually considered to induce cell death, S1P promotes survival of cells. Sphingosine kinases (SPHKs) are the enzymes that catalyze the conversion of sphingosine to S1P. There are two isoforms, SPHK1 and SPHK2, which are encoded by different genes. SPHK1 has recently been implicated in contributing to cell transformation, tumor angiogenesis and metastatic spread, as well as cancer cell multidrug-resistance. More recent findings suggest that SPHK2 also has a role in cancer progression. This review is an overview of our understanding of the role of SPHKs and S1P in hematopoietic malignancies and provides information on the current status of SPHK inhibitors with respect to their therapeutic potential in the treatment of hematological cancers.