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Atopic dermatitis (AD) therapeutic approach calls for a long-term treatment. Treatment options for AD have recently undergone a revolutionary change by the introduction of the first biologic drug. Availability in daily practice of the last version of international AD guidelines, taking peculiarities of the country into account, can contribute to good clinical practice in Italy. To adapt European Dermatology Forum (EDF) guidelines for AD to the Italian medical–legal context, the EDF guidelines were assessed independently by two independent Italian renowned experts in the field and further integrated with articles published and systematically reviewed before May 2019. The first draft was collegially corrected and updated by the members of the SIDEMAST, ADOI, and SIDAPA. Recommendation levels (A; B; C; D) were graded based on the evidence levels (1–4). The adapted guidelines presented here focus on topical and systemic therapies in AD patients, both children and adults. As opposed to previous Italian guidelines, they include indications about biologics. New relevant evidence available from very recent literature and peculiarities of the Italian medical and legal context have been integrated in the revision process. If compared to general guidelines for AD not adapted to a specific national and cultural context, a revision for specific Italian needs is now available: It comprises the option of implementing the new biologic treatments and is likely to provide an important contribution to the improvement of clinical practice in Italy. Cooperation between patients, dermatologists, allergologists, and pediatricians remains mandatory in AD management. The authors of the present revision recommend an update of the Italian guidelines to be performed at least every second year.

[Image: see text] Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in signaling and repair of DNA single strand breaks. PARP-1 employs NAD(+) to modify substrate proteins via the attachment of poly(ADP-ribose) chains. PARP-1 is a well established target in oncology, as testified by the number of marketed drugs (e.g., Lynparza, Rubraca, Zejula, and Talzenna) used for the treatment of ovarian, breast, and prostate tumors. Efforts in investigating an uncharted region of the previously identified isoindolinone carboxamide series delivered (S)-13 (NMS-P515), a potent inhibitor of PARP-1 both in biochemical (K(d): 0.016 μM) and cellular (IC(50): 0.027 μM) assays. Cocrystal structure allowed explaining NMS-P515 stereospecific inhibition of the target. After having ruled out potential loss of enantiopurity in vitro and in vivo, NMS-P515 was synthesized in an asymmetric fashion. NMS-P515 ADME profile and its antitumor activity in a mouse xenograft cancer model render the compound eligible for further optimization.

Patch testing is the standard procedure used to diagnose allergic contact dermatitis. It is an in-vivo test, which reproduces the reaction to a contact allergen. This in-vivo test aims to reproduce the elicitation phase of allergic contact dermatitis and is performed applying allergens under occlusion on the skin under standardized conditions. These guidelines for the best practice in performing patch test have been developed by an Italian group of experts taking in account the Italian legislation and local pharmacological governance. Guidelines are adapted from the original article under the guidance of the European Society of Contact Dermatitis (ESCD) and on the basis of the SIDAPA guidelines.

Objectives To determine the prevalence of ocular fundus abnormalities in cats with a diagnosis of systemic hypertension, to characterize the abnormalities observed, and to evaluate ophthalmoscopic evolution during treatment with amlodipine besylate. Animals studied Cats diagnosed as affected by SHP in a 2-year period. Procedures Systemic hypertension was assessed by oscillometric blood pressure measurement, and its etiology was also established. All the cats received an ophthalmic examination, and ocular lesions were classified with a score from 0 (no abnormalities) to 4 (severe abnormalities). All cats received amlodipine besylate by mouth, and those that showed fundus abnormalities were regularly rechecked from 7 to 365 days after diagnosis. Data were statistically analyzed to compare Psys and Pdia with all the variables and to correlate Psys and Pdia with the fundus score. Results A total of 225 cats were enrolled in the study, and the prevalence of fundus abnormalities was 58.6% (21.2%: grade 1; 18.2%: grade 2; 36.4%: grade 3; and 24.2%: grade 4). Systemic hypertension was diagnosed concurrently with chronic renal failure (60.4%), hyperthyroidism (28.9%), both chronic renal failure and hyperthyroidism (7.6%), and hypertrophic myocardiopathy (3.1%). A significant effect of Psys values on the fundus score was detected. Amlodipine therapy improved fundus abnormalities in 50% of cases at the 21-day follow-up. Conclusions This study showed that fundus abnormalities are common in hypertensive cats at the time of the systemic diagnosis, and most of the abnormalities are moderate to severe. Treatment with amlodipine appeared to improve ophthalmic lesions over time.

A four-year-old Scottish Shepherd dog was referred for acute onset of disorientation, blindness and chronic diarrhoea. The neurological examination was consistent with a multifocal neurolocalisation involving the prosencephalon and the brainstem. The ophthalmological exam showed bilateral chorioretinitis with retinal detachment. The brain MRI showed periventricular and left caudate nucleus lesions, increased thickness of the left III, IV, VI and opthalmic branch of V cranial nerves and bilateral multifocal lesions in the temporal and masseter muscles. Cerebrospinal fluid examination showed mild mixed pleocytosis. Faecal and urine cultures were positive for Prototheca zopfii genotype 2. Despite starting itraconazole therapy, the dog’s conditions deteriorated and the owner elected euthanasia. Protothecosis should be suspected in young dogs with multifocal neurological signs, blindness and chronic diarrhoea. MRI study of the central nervous system (CNS), together with blood exam, cytology and cultures, is a useful tool to evaluate the CNS in disseminated form of Prototheca infection.

The purpose of this study was to evaluate the diagnostic value of imaging-guided core needle biopsy for canine orbital mass diagnosis. A second excisional biopsy obtained during surgery or necropsy was used as the reference standard. A prospective feasibility study was conducted in 23 canine orbital masses at a single centre. A complete ophthalmic examination was always followed by orbital ultrasound and computed tomography (CT) examination of the head. All masses were sampled with the patient still on the CT table using ultrasound (US) guided automatic tru-cut device. The most suitable sampling approach to the orbit was chosen each time based on the CT image analysis. One of the following different approaches was used: trans-orbital, trans-conjunctival or trans-masseteric. In all cases, the imaging-guided biopsy provided a sufficient amount of tissue for the histopathological diagnosis, which concurred with the biopsies obtained using the excisional technique. CT examination was essential for morphological diagnosis and provided detailed topographic information that allowed us to choose the safest orbital approach for the biopsy. US guided automatic tru-cut biopsy based on CT images, performed with patient still on the CT table, resulted in a minimally invasive, relatively easy, and accurate diagnostic procedure in dogs with orbital masses.Keywords: Computed tomography, Core-needle biopsy, Dogs, Orbital mass, Ultrasound

OBJECTIVES: To validate a retinal imaging software named VAMPIRE® (Vascular Assay and Measurement Platform for Images of the Retina) in feline patients and test the clinical utility in hypertensive cats. ANIMALS STUDIED: One hundred and five healthy cats were enrolled. They represented the normal dataset used in the validation (group 1). Forty‐three hypertensive cats with no noticeable retinal abnormalities were enrolled for the clinical validity of the software (group 2). PROCEDURES: Eleven points (4 veins, 4 arteries, and 3 arterial bifurcations) were measured for each digital image. Repeatability and reproducibility of measurements were assessed using two independent operators. Data were statistically analyzed by the Mann‐Whiney and Tukey box plot. Significance was considered when P

The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.

A case of exophthalmos due to zygomatic mucocele in a puppy with ipsilateral segmental maxillary atrophy is reported. A 7-month-old, mixed breed, male dog suffered the sudden-onset of unilateral painful exophthalmos and a gradual swelling of the right temporal region. A compressing, right retrobulbar mass was observed by ultrasound. Computed tomography revealed a large multiloculated cyst-like lesion of the right zygomatic gland projecting into the orbital space, thus displacing the eyeball. The ipsilateral molar part of the maxillary bone was underdeveloped, besides showing crowded, abnormal, multiple, unerupted maxillary molar teeth in the caudal maxillary region. Modified lateral orbitotomy and a selective caudal maxillary bone access were performed. The cyst-like lesion was removed and the zygomatic gland and the wall was collected for histology, which confirmed the mucocele. Clinical and imaging examinations six months after surgery showed neither recurrence of the mucocele nor ocular abnormalities. A possible common pathogenic mechanism involving these two conditions could be hypothesized.Keywords: Computed tomography, Dog, Exophthalmos, Maxillary atrophy, Zygomatic mucocele

A group of 56 employees exposed to postural risk due to sedentary activity in offices and aged 40 to 60 years underwent a training of ergomotricity. The schedule was based on six simple exercises to be self-managed during the work time. The efficacy was verified by questionnaire before and after 3 months and musculo-skeletal complaints resulted to be improved for 21 out of 56 workers, depending from diligence. The training was realized by an occupational doctor and a physiotherapist; the compliance of this method was good by the trainees, but a recalling intervention was planned to reach better results in the whole group.

Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that is involved in several biological processes and plays a central role in the ubiquitin-mediated degradation of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes associated with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy. In this paper, the discovery and structure-activity relationships of alkylsulfanyl-1,2,4-triazoles, a new class of potent, allosteric VCP inhibitors, are described. Medicinal chemistry manipulation of compound 1, identified via HTS, led to the discovery of potent and selective inhibitors with submicromolar activity in cells and clear mechanism of action at consistent doses. This represents a first step toward a new class of potential anticancer agents.

RET chromosomal rearrangements initially identified in a subset of papillary thyroid cancers, as well as gain-of-function point mutations present in ca. 70% of medullary thyroid carcinomas, are well established as oncogenic events that induce constitutive RET activation. More recently, recurring activating RET gene rearrangements have also been found to be expressed in 1-2% of lung adenocarcinomas and subsets of other solid tumors, including colorectal and salivary gland carcinomas. RET kinase is therefore a validated actionable therapeutic target in multiple tumor types, and several small-molecule inhibitors targeting RET are being explored in clinical settings. A common feature of most advanced agents is their lack of selectivity and in particular their potent cross-reactivity against VEGFR2, a receptor tyrosine kinase whose inhibition has been described to be associated with dose-limiting cardiovascular toxicity. Indeed, the high homology between the two kinases renders identification of ATP competitive compounds that selectively inhibit RET over VEGFR2 a highly challenging task. Here we describe the preclinical activity of NMS-E668, a potent and selective ATP-competitive RET inhibitor characterized by favorable activity, selectivity and ADME profiles. NMS-E668 has low nM potency on RET and excellent biochemical selectivity when tested against a kinome panel, notably including circa 30-fold selectivity over VEGFR2. Importantly, 30-fold selectivity of NMS-E668 for RET vs. VEGFR2 was confirmed at the cellular level using NIH-3T3 cells engineered to express activated forms of the two receptors. NMS-E668 potently and selectively inhibited the proliferation of RET-dependent tumor cells, including TT medullary carcinoma cells harboring a RET C634W activating point mutation and LC-2/ad lung carcinoma cells bearing the oncogenic fusion protein CCDC6-RET. NMS-E668 also potently inhibited IL3-independent growth of Ba/F3 cells expressing KIF5B-RET, the RET rearrangement most commonly found in lung adenocarcinomas. Importantly, the proliferation of circa 100 non-RET-dependent tumor cell lines was not significantly affected by NMS-E668, confirming again its selectivity. Tested in vivo against the TT xenograft tumor model NMS-E668 displayed an excellent tumor growth inhibition with complete tumor regression achieved in all animals treated at the higher dose and with confirmed ex vivo target modulation. Good activity was also observed in additional RET-dependent models following oral administration of the compound. Thus NMS-E668, a potent and VEGFR2-sparing RET inhibitor, is an innovative and highly promising candidate for clinical development. Citation Format: Elena Ardini, Patrizia Banfi, Nilla Avanzi, Marina Ciomei, Paolo Polucci, Alessandra Cirla, Matteo D'Anello, Andrea Lombardi Borgia, Ilaria Motto, Cinzia Cristiani, Dario Ballinari, Eduard Felder, Daniele Donati, Arturo Galvani, Antonella Isacchi, Maria Menichincheri. NMS-E668, a highly potent orally available RET inhibitor with selectivity towards VEGFR2 and demonstrated antitumor efficacy in multiple RET-driven cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4785.

An ultraviolet (UV) spectrophotometric procedure was devised for the determination of polycyclic aromatic compound-oriented organic soluble matter in vapors and particulate collected from emissions of hot asphalt mix. Ultrasonic extraction was carried out with acetonitrile, followed by UV measurements at 254 nm. Polycyclic aromatic compounds (PACs) in volatile and particulate fraction were quantified as phenanthrene or benzo[k]fluoranthene equivalents. A comparison between UV and high-pressure liquid chromatography with fluorescence detection showed that PACs were one to three orders of magnitude higher than the sum of 15 priority polycyclic aromatic hydrocarbons (PAHs); still, significant correlations were found between volatile or particulate PACs and, respectively, total volatile or particulate PAHs. Moreover, in the particulate phase, PACs correlated with total particulate matter quantified by gravimetry. The proposed procedure was employed in a field study for monitoring personal exposure to asphalt emissions of workers engaged in road construction. Observed levels of acetonitrile-soluble PACs in air samples were very low (2-20 microg/m3); however, asphalt pavers were exposed to significantly higher concentrations of volatile PACs than construction workers (geometric mean, 5.9 microg/m3 vs. 4.1 microg/m3). This method for estimating the global content of volatile or particulate PACs in air samples satisfies our requirements of simplicity and is suitable for conducting an initial screening to assess exposure to airborne polyaromatic organics in asphalt pavers.

The work presents a synthetic route to the CD ring of calicheamicin and in the case of neocarzinostatin an approach to a functionalised cyclopentane-1,3-diol containing the naturally occurring naphthoate and a glucosamine motif. In the case of the NCS derivative some biological activity (cytotoxicity) was observed.

RET, a receptor tyrosine kinase (RTK) expressed mainly in neural crest-derived tissues, plays a role in cell growth and differentiation and its physiological activation depends upon binding to the GDNF family. Genetic aberrations leading to constitutive RET activation are well-established as oncogenic events. Activating point mutations of RET, for example, are present in ca. 70% of medullary thyroid carcinoma patients including all hereditary cases, while RET gene rearrangements resulting in production of activated RET fusion proteins occur in approximately 10% of sporadic papillary thyroid carcinomas. More recently, recurring RET gene rearrangements have also been found in 1-2 % of lung adenocarcinomas and subsets of other solid tumors including colorectal and salivary gland carcinomas. Thus RET kinase represents an actionable therapeutic target in multiple clinical settings with high medical need. Consequently several small-molecule inhibitors targeting this kinase have been explored in clinical settings. A common feature of most advanced agents is their lack of selectivity and in particular their potent cross-reactivity against VEGFR2, an RTK whose inhibition is associated with serious, dose-limiting cardiovascular toxicity. Indeed, the high homology between the two kinases renders identification of ATP competitive compounds that selectively inhibit RET over VEGFR2 a highly challenging task. Here we describe the preclinical activity of NMS-E668, a potent and selective ATP-competitive RET inhibitor characterized by favorable activity, selectivity and ADME profiles. Biochemically, NMS-E668 has an excellent selectivity profile against a panel of >50 kinases, notably including >10-fold selectivity over VEGFR2. Selectivity of NMS-E668 for RET vs. VEGFR2 was confirmed in NIH-3T3 cells engineered to express activated forms of these kinases. NMS-E668 potently (IC50 circa 50 nM) and selectively inhibited proliferation of RET-dependent tumor cells, including TT medullary carcinoma cells harboring a RET C634W activating point mutation and LC2/ad lung carcinoma cells bearing the oncogenic fusion protein CCDC6-RET. NMS-E668 also potently inhibited IL3-independent growth of Ba/F3 cells expressing KIF5B-RET, the RET rearrangement that is most commonly found in lung adenocarcinomas. Cellular mechanism studies confirmed that NMS-E668 inhibits RET autophosphorylation and downstream signaling at doses consistent with antiproliferative activity. Tested in vivo against KIF5B-RET-driven Ba/F3 tumors, NMS-E668 displayed >90% tumor growth inhibition accompanied by target modulation following oral administration at 10 and 20 mg/kg, with prolonged tumor regressions observed at the higher dose. Thus NMS-E668, a potent and VEGFR2-sparing RET inhibitor is an innovative and highly promising candidate for further development. Citation Format: Elena Ardini, Patrizia Banfi, Nilla Avanzi, Marina Ciomei, Paolo Polucci, Alessandra Cirla, Antonella Ermoli, Ilaria Motto, Elena Casale, Giulia Canevari, Cinzia Cristiani, Sonia Troiani, Federico Riccardi Sirtori, Nadia Amboldi, Dario Ballinari, Francesco Caprera, Eduard Felder, Arturo Galvani, Daniele Donati, Antonella Isacchi, Maria Menichincheri. NMS-E668, a potent and selective RET kinase inhibitor characterized by specificity towards VEGFR2 and high antitumor efficacy against RET-driven models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2082. doi:10.1158/1538-7445.AM2017-2082

Valosine-containing protein (VCP), also known as p97 or cdc48 in yeast, is a highly abundant protein belonging to the AAA ATPase family involved in a number of essential cellular functions, including ubiquitin–proteasome mediated protein degradation, Golgi reassembly, transcription activation, and cell cycle control. Altered expression of VCP has been detected in many cancer types sometimes associated with poor prognosis. Furthermore, VCP mutations are causative of some neurodegenerative disorders. In this paper we report the discovery, synthesis, and structure–activity relationships of substituted 2-aminopyrimidines, representing a new class of reversible VCP inhibitors. This class of compounds, identified in a HTS campaign against recombinant VCP, has been progressively expanded and manipulated to increase biochemical potency and gain cellular activity.

We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.

Because the widespread use of gloves by health care workers has induced an increase of both irritant and type I or type IV allergic glove-related diseases, the Italian Society of Preventive Medicine for Health Care Workers set up a working group to collect information about glove composition and to standardize procedures for the diagnosis and prevention of glove-related disease and job-fitness evaluation of employees who will be wearing gloves. In addition, the group made recommendations for educational programs focusing not only on users but also on purchasers, who presently favor glove selection for economic reasons. The group's recommendations are summarized in a consensus document, but cannot be considered definitive. More research is needed to achieve answers to questions raised by the working group, indicated in the consensus document. In particular, diagnostic criteria must be standardized to plan multi center studies to verify the real extent of the problem, and further studies are needed ...

Background: The study tests the hypothesis of a reduction of priming due to tree allergy in patients sensitised to both birch/hazel and grass pollen undergoing an associated preseasonal Sublingual/Injective immunotherapy. Methods: 36 out of 49 bisensitized candidates were pair-matched into 18 case-referent couples. During two years all patients were administered preseasonal grass-SIT and one patient in each couple received also birch/hazel-SLIT. Diary cards were fulfilled for three consecutive grass pollen seasons. Specific Nasal Provocation Test (NPT) for grass and aspecific bronchial challenge were done; sera were analyzed for specific IgE and IgG. Results: During the peak of the grass pollen season both groups showed a significant improvement in total symptom-score. Conjunctivitis and cough improved significantly more in patients with associated therapies. While antihistamine score decreased significantly in both groups, antiasthmatics did only in the SLIT-SIT group. The follow-up documented a significant increase in grass- and birch-specific IgG and a decrease in grass-specific IgE. Grass-NPT threshold was clearly higher in SLIT-SIT-group (p = 0.01) and only in this group PD20 methacholine improved significantly (p < 0.05). Conclusions: Combined birch/hazel-SLIT and grass-SIT are safe and improve clinical outcomes of SIT alone in young bisensitized patients. Priming reduction is supported by specific NPT and bronchial hyperresponsiveness.

A double-blind, placebo-controlled study was carried out to test the clinical efficacy and safety of local nasal immunotherapy (LNIT) in powder form. Twenty-two patients suffering from allergic rhinitis strictly associated with early spring symptoms, with positive skin prick tests and RAST for birch-alder, all responders to a specific nasal provocation test (NPT), received randomly active or placebo treatment for 4 months. Immunotherapy consisted of administration of a set of capsules containing progressively increasing amounts of birch (Betula pendula) and speckled alder (Alnus incana) allergens in powder form with controlled granulometry. The active (birch-alder) and placebo (lactose) group completed the treatment according to a similar schedule. During the pollen season (March-April), the patients who took the active treatment reported less sneezing and rhinorrhea than the placebo group, on the basis of a symptoms score, and the differences were statistically significant ; the need for drugs (terfenadine) was also significantly reduced. These findings agreed well with the results of specific NPT after the treatment ; only patients in the active group had a higher threshold dose of nasal specific reactivity to birch-alder allergens than in tests before the LNIT.

Inhibitors of the poly(ADP-ribose) polymerases (PARPs) family of proteins are currently being evaluated as potential anticancer medicines at both preclinical and clinical levels. They have the peculiarity to increase the efficacy of DNA-damaging agents and to selectively target tumor cells with specific DNA repair defects. This later development of these drugs should make it possible, in principle, to selectively target neoplastic vs healthy cells, thus realizing the Ehrlich's magic bullet concept of a personalized and tailored cure of diseases.This review is designed to provide the readers with a brief summary and an update on PARP inhibitors in the oncology field, by covering the recent patent literature (2010 - 2012: and Questel Intellectual Property Portal [QPat] database search).Presently, along with a number of preclinical candidates, there are eight PARP inhibitors in the clinic as either single agents or in combination with various chemotherapy and radiotherapy regimens. The tremendous efforts underneath those results testify the high interest on the target. The investigation and understanding of the cross-reactivity among members of the PARPs family as well as a deeper knowledge of their biological functions may lead to a more profound characterization of the PARP inhibitor's profile. This, in turn, will cast additional light on this exciting approach in treating cancer.

Nickel sensitized patients may suffer of contact dermatitis,but also of urticaria-like, pruritus-erythema and cutaneous rush,sometimes associated with intestinal symptoms.The role of Nickel absorption due to food is still debated, but a clinical framework of Systemic Nickel Allergy Syndrome (SNAS) may be proposed, while a possible induction of oral tolerance deserves to be investigated. In the same Allergy Unit 152 subjects (126 F,26 M) were diagnosed as allergic by positive patch test to Nickel sulphate (class 2-3). All underwent Urinary Nickel determinations (NiU), by AAS with Zeman corrector and results standardized to creatinine concentration. According to single diagnosis patients were selected. Group A (65 pt) with only contact dermatitis. Group B (87 pt) with skin troubles of SNAS. At the first determinationt NiU values in Group B (mean 2,25 mcg/g creatinine) were significantly higher when compared to Group A (mean 0,87 mcg/g creatinine), with p

This 18-week, randomized, flexible-dose, double-blind, double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients. Patients had a DSM-IV diagnosis of schizophrenia, a history of resistance and/or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses, PANSS scoreor= 80, and CGI-S scoreor= 4. Patients were randomized to ziprasidone (80-160 mg/day, n = 73) or clozapine (250-600 mg/day, n = 74). On the primary ITT-LOCF analysis, baseline-to-endpoint decreases in PANSS total scores were similar in the ziprasidone (- 25.0 +/- 22.0, 95% CI - 30.2 to - 19.8) and clozapine (- 24.5 +/- 22.5, 95% CI - 29.7 to - 19.2) groups. A progressive and significant reduction from baseline in PANSS total score was observed from day 11 in both study arms. There were also significant improvements on PANSS subscales, CGI-S, CG-I, CDSS, and GAF, without between-drug differences. The two treatment groups had similar rates of early discontinuations due to AEs. AEs were mostly of similar mild-moderate severity in the two groups. There were also no detrimental effects on prolactin, renal and liver function, hematology, and cardiovascular parameters. However, ziprasidone but not clozapine showed a significant reduction of SAS and AIMS scores. Moreover, when compared with clozapine, ziprasidone also had a more favorable metabolic profile, with significant endpoint differences in weight, fasting glucose, total cholesterol, LDL cholesterol, and triglycerides. In conclusion, this trial indicates that both ziprasidone and clozapine, having comparable efficacy coupled with satisfactory general safety and tolerability, may be regarded as valuable options for the short-term treatment of difficult-to-treat schizophrenia patients with a history of multiple resistance and/or intolerance to antipsychotics. The more favorable metabolic profile of ziprasidone may represent an added value that could guide clinicians, at least in the presence of patients at high risk for metabolic disorders.

PARP-1 and PARP-2 are nuclear enzymes activated by DNA strand breaks and are involved in recruitment of DNA repair proteins to sites of damage. PARP-1 and PARP-2 share partially overlapping functions, as shown by the embryonic lethality of double knockout mice compared to animals with single ablation either gene, which are viable. Despite this partial functional redundancy, PARP-1, but not PARP-2, inhibition has been shown to be synthetically lethal with defects in homologous recombination such as BRCA gene mutations. All PARP inhibitors that are currently under clinical investigation inhibit both PARP-1 and PARP-2, due to the high sequence similarity between the catalytic domains of the two enzymes. A third member of the family, PARP-3, has lower homology with PARP-1 and -2 and is much less well characterized, although it is known that its activity is stimulated by double strand breaks and that it promotes DNA repair through an error prone repair pathway, non-homologous end joining (NHEJ). PARP-3 inhibition is thus presumed to be synthetically lethal with other, alternative DNA repair pathway deficiencies. We report preclinical characterization of NMS-P648, a selective PARP-1/-3 inhibitor, with a dissociation constants (KD), of 0.9 nM on PARP-1 and with greater than four hundred-fold less affinity for PARP-2, as assessed by direct binding assay. In cells, NMS-P648 inhibits hydrogen peroxide induced poly ADP-ribose (PAR) synthesis with an IC50 of 1 nM, confirming expected mechanism of action and indicating that inhibition of PARP-2 is not required for this process. NMS-P648 has favourable ADME properties, including stability in liver microsome incubation assays, low efflux ratio in the CACO2 assay and an excellent pharmacokinetic profile, with complete oral bioavailability and exposure levels that increase proportionally with dose. Testing NMS-P648 on a panel of more than 100 human tumor cell lines using a 2D colony forming assay format revealed that 7 cell lines were highly sensitive to the compound (IC50 Citation Format: Alessia Montagnoli, Gianluca Papeo, Sonia Rainoldi, Alessandra Cirla, Antonella Ciavolella, Clara Albanese, Michele Modugno, Roberta Bosotti, Alessio Somaschini, Giovanni Carapezza, Rosita Lupi, Dario Ballinari, Marina Ciomei, Enrico Pesenti, Daniele Donati, Antonella Isacchi, Arturo Galvani. Preclinical characterization of NMS-P648, a novel and potent PARP-1/-3 inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2851. doi:10.1158/1538-7445.AM2015-2851

The combretastatins are a group of anti-mitotic agents isolated from the bark of the South African tree Combretum caffrum. The most potent member is combretastatin A-4, and this compound together with a phosphate pro-drug form have already progressed through into clinical trails for the treatment of solid tumours. What makes this class of compounds rather more interesting than other anti-mitotic agents is that they are also angiogenesis inhibitors, and are being evaluated for their efficacy in the treatment of diabetic retinopathy which is the biggest single cause of blindness They are thus of considerable contemporary interest.

There is a need for several research centers to carry out coordinated large-scale evaluation of the spread of occupational irritant and allergic dermatitis. The Occupational Health Departments of Bergamo, Brescia, Lecco and Cremona therefore decided to join their experiences and bring together all the cases of occupational irritant and allergic dermatitis diagnosed by these Departments between 1993 and 1998. In this period, 1169 cases of occupational dermatitis were diagnosed, subdivided into 768 cases of allergic contact dermatitis (ACD), 337 of irritant contact dermatitis (ICD), 54 of urticaria and 10 of airborne contact dermatitis, and there has not been a trend towards increase of occupational dermatitis over the years. Our population included 724 males and 445 females and average latency after the beginning of exposure to occupational allergens was 8.01 years for ACD, 6.4 for ICD, 3.22 for urticaria and 5.57 for airborne contact dermatitis. The frequency of atopy was 33.9%, in females and 19.5% in males. The frequency of atopy was particularly high (89%) in subjects with urticaria. Among subjects with allergic dermatitis, 362 had had only one sensitization while 406 had had two or more sensitizations. The working areas where we found the highest number of ACD were metal working industry, building, health care workers and hairdressers and the frequency of ICD was high in metal workers and health care workers. Most of the cases of urticaria were diagnosed in health care workers (68.5%) and the main causing agent was latex. These are only preliminary data but occupations at risk and the substances expected to be the most frequent etiological agents do not differ significantly from those reported in the literature. It is hoped that as a result of this project there will be in the future: standardization of diagnostic procedures, uniform assessment of allergological risk in working environments not yet fully investigated, standardization of preventative measures and proper evaluation of their effectiveness.

Objective: The aim of this study was to eval- uate the outcome of the specific inhalation challenge test (SIC) in 160 subjects with suspected baker's asthma and to assess its relation to total flour dust levels and to personal characteristics such as specific skin sensitisa- tion, non-specific bronchial hyper-responsiveness (NSBH) and atopy. Methods: We investigated the out- come of SIC tests performed with wheat flour in six Italian laboratories. For each subject, data was available regarding skin sensitisation to wheat flour, NSBH, ato- py, forced expiratory volume at 1 s (FEV1) monitoring and airborne flour dust in the challenge chamber mea- sured by the gravimetric method (total dust in mg/m 3 ). Results: The SIC test was positive for early asthma in 42 subjects (26%) and for late/dual asthma in 18 (11%). Positive outcome to SIC was significantly associated with NBSH (odds ratio, OR: 3.5, 95% CI: 1.6-7.7) and skin sensitisation to wheat flour (OR: 3.1, 95% CI: 1.3- 7.0). Exposure level to wheat flour was less than or equal to 10 mg/m 3 in 12% of individuals, ranged between 11 and 30 mg/m 3 in 43% and exceeded 30 mg/m 3 in 45%. The outcome of SIC was always negative among workers not skin sensitised to wheat flour and without NSBH and atopy. An increasing prevalence of positive SIC was observed among workers with one or more of the above-mentioned personal characteristics whose challenge exposure was greater than 10 mg/m 3 (P < 0.001). Conclusion: Procedures currently adopted for wheat flour dust exposure during SIC need to be better standardised in order to avoid excessive airborne dust exposure. Over-exposure seems to be of no use for the diagnosis and risks making the asthmatic reaction worse, particularly in patients who are both sensitised to wheat allergens and have NSBH and/or atopy.

Several clinical and experimental findings point to cobalt as the only sensitizer and causal agent of hard metal asthma. The clinical features have been clearly defined by bronchial provocation tests, with a prevalence of late phase responses. Epidemiology is still insufficient to configure prevalence and incidence rates for cobalt asthma. IgE and IgG antibodies with cobalt specificity have been demonstrated, but T-lymphocytes and eosinophils involvement seem to be important in the mechanism of an allergic inflammation in the airways. Such an immunological pathogenesis links cobalt asthma with other manifestation of hard metal disease.

An occupational type exposure-test to toluene di-isocyanate (TDI) for the diagnosis of specific respiratory sensitization is proposed. The subjects were tested by exposure to a two-pot polyurethane varnish with and without TDI activator, using a paint-spraying system under standard and controlled conditions, so as not to exceed the threshold limit value of TDI. Forced expiratory volume per second and specific airway resistance (plethysmographic method) were measured before each exposure and during the following 24 h. 47 subjects with clinical symptoms of asthma were examined during their hospital care. For the purpose of this study they were divided into two groups: 42 workers exposed to TDI and 5 not exposed. The preliminary control test, using polyurethane varnish without TDI activator, was always negative and no significant changes in ventilatory parameters were recorded. The spray-painting test, with the same varnish and TDI activator, gave positive responses in 35 out of the 42 exposed workers and negative findings in the group not exposed. This method permits to formulate an accurate diagnosis of TDI respiratory sensitization in the majority of cases (83%). Immediate asthmatic reactions were frequently observed in the exposed subjects with high acetylcholine reactivity. Ten subjects showed a late bronchial reaction (3 h or more after TDI exposure).

A group of 182 workers exposed to diisocyanates (varnishers, carpenters, producers of polyurethane resins and expanded plastic) were examined to study the immunogenic capacity of these substances. The skin tests, particularly the intradermal tests, revealed reactions of the immediate, accelerated and/or delayed types due to the presence of IgE and IgG, in addition to responses of the cellular type. This was confirmed by passive transfer in guinea-pigs and man and immunohaematological tests such as passive haemagglutination and lymphocyte transformation. In 4 cases it was possible to demonstrate thermoresistant, homocytotropic immunoglobulins, that were not dependent on complement and behaved like reagins (i.e. short-term anaphylactic IgG). Exposure tests were performed on 45 cases; the results are analyzed and compared with those of the skin tests. It is concluded that both these groups of tests are of value in investigating the aetiopathogenesis of the pathology of the isocyanates: the skin tests for initial screening, and then the exposure tests for resolving doubtful diagnoses. Cross-reactions were also demonstrated between toluene-diisocyanate and methylene-diisocyanate. Two phases could be considered in the pathogenesis; in the first phase, signs of inflammation appeared at the primary sites of contact with the irritant, then the ability of the diisocyanates to form a conjugate with organic proteins results in the production of a complete antigen and consequent sensitization of the exposed person. The appearance of symptoms naturally depends on subsequent exposure and the immunogenic capacity of the patient: the response is mainly of the reagin type in atopic patients and of type 3 in non-atopic patients.

The alterations of lactate dehydrogenase and its isoenzyme fractions, of glucose-6-phosphate dehydrogenase, and of glutamate dehydrogenase were studied in the kidneys of 12 guinea pigs poisoned with a daily dose of 120 mg/kg body weight of lead nitrate given by means of an oesophageal catheter, and in the kidneys of 12 guinea pigs made ischemic by partial constriction of the renal artery. The investigation was made on homogenates of kidney in toto and on homogenates of cortex and medulla separately. In the kidneys of lead-poisoned guinca pigs and in the kidneys with ischemia as a result of stenosis of the renal artery, similar metabolic alterations were observed. In both experimental situations a marked increase in type M isoenzymes of lactate dehydrogenase (LDH 4 and LDH 5 ), an increase in glucose-6-phosphate dehydrogenase up to values twice those found in normal kidneys, and a marked reduction in glutamate dehydrogenase activity were observed. The increase of glucose-6-phosphate dehydrogenase activity was only moderately prevalent in the cortical zone, and the other enzymes examined did not undergo alteration of their percentage distribution between cortex and medulla. These results are interpreted as indicating a metabolic adaptation of the kidney to a condition of tissue hypoxia, in both experimental situations.

17 workers in a thermometer factory exposed to mercury for periods ranging from 1 to 40 years all had high urine and blood mercury levels on undergoing electromyographic examination. All were clinically free from central and peripheral nervous symptoms. 88% had subclinical neuropathy, mainly distal and axonal. There was no correlation between severity of the neuropathy and blood and urine mercury levels or between severity of neuropathy and duration of exposure to mercury. The presence of a subclinical neuropathy in symptomless workers exposed to mercury is perhaps the most reliable index for the detection of the early toxic effects of mercury on the peripheral nerve fiber when it is probably still reversible.

Summary A study was performed on twenty-five workers exposed to polyurethane varnishes exclusively catalysed with TDI, who developed asthma to this substance. The aim of the study was to establish, using bronchial provocation tests, whether a cross-response to MDI exists. The results were positive but no definitive evidence has been reached because there was cross-response in only 48% of cases. It is interesting, however, that cross-responders did not predominate among the subjects with a late reaction to TDI (P= 0.0038), whereas cross-responders were in the majority among the subjects with a dual reaction to TDI (P= 0.0334). It is possible that the pattern of the asthmatic reaction to BPT with TDI influences the cross-reaction to other isocyanates.

Summary Objectives: To evaluate the efficacy of juvenile pubic symphysiodesis (JPS) in a clinical setting for the early treatment of canine hip dysplasia (CHD), and to identify its indications and contraindications. Methods: The final degree of CHD using the FCI (Fédération Cynologique Internationale) CHD classification in 5 Grades (A, B, C, D, E) was assessed at skeletal maturity in two homogeneous groups of dogs assessed at the age of 14 to 22 weeks and selected according to their susceptibility to CHD; one group was treated with JPS and one group was conservatively managed. Two hundred seventeen puppies completed the study; 81 were treated with JPS (group 1) and 76 were conservatively managed (group 2). A third group of 60 puppies with normal hips was followed as a negative control group. Results: In group 1, 43.2% of the puppies had regression or a lack of progression of the disease in the final evaluation (Grade A & B), 25.9% had mild CHD (Grade C) and 30.9% had moderate and severe CHD (Grade D & E). In group 2, 23.6% of the puppies did not show any development of the disease (Grade A & B), 21.1% had mild CHD (Grade C) and 55.3% developed moderate to severe CHD (Grade D & E). Further investigation was done by comparing the severity of early signs of susceptibility to CHD with the final FCI Grades at adulthood in both groups. Clinical significance: The JPS procedure increased the odds of arresting or limiting the progression of CHD in mild to moderate grades of CHD, while it was less effective or ineffective in more severe forms.