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Six cyclodextrin (CD) complexes of the antiepileptic drug valproic acid (VAL) were prepared by kneading and/or co-precipitation methods and characterized by thermal analysis, powder X-ray diffraction and spectroscopic (1H NMR and FT-IR) techniques. The complexes (with host–guest stoichiometries in parentheses) included α-CD·VAL (2 : 1), β-CD·VAL (1 : 1), γ-CD·VAL (3 : 4), DMB·VAL (1 : 1), TMB·VAL (1 : 1) and TMA·VAL (1 : 1). Single crystal X-ray structures of four of the complexes were determined, those with β-CD and γ-CD featuring severely disordered guest molecules. Instead, the VAL molecules in the complexes with dimethylated β-CD (DMB) and permethylated α-CD (TMA) could be modelled, revealing modes of inclusion of valproic acid in CDs for the first time. The aqueous solubility values at 27 °C for VAL in the form of the solid complexes α-CD·VAL, β-CD·VAL and γ-CD·VAL were in the range 0.26–0.58 times that of the pure liquid phase of VAL. The merits of CD inclusion of VAL (e.g. transformation of the liquid guest into a solid, potential for reduction of adverse side effects) are discussed. [ABSTRACT FROM AUTHOR]

The authors comment on the steps taken by the U.S. Department of Health and Human Services (HSS) in favor of women's health on the basis of a report of the U.S. Public Health Service (USPHS) Task Force which was published in Public Health Reports in 1985. Topics discussed include effects of social environment on the health of women, prevention of chronic disease and health care access for women supported by federal policies and research funded by HSS.

Invasive fungal infections ( IFIs) represent important complications in patients with haematological malignancies. Chemoprevention of IFIs may play an important role in this setting, but in the past decades the majority of antifungal drugs utilized demonstrated poor efficacy, particularly in the prevention of invasive aspergillosis. The new triazoles are very useful antifungal drugs, more suitable for prophylaxis of IFIs than amphotericin B and echinocandins. In this review, the main clinical data about antifungal prophylaxis with fluconazole, itraconazole, voriconazole and posaconazole are analysed. At present, posaconazole appears to be the most efficacious azole in antifungal prophylaxis, particularly in patients with acute myeloid leukaemia. [ABSTRACT FROM AUTHOR]

This multicentre observational study evaluated the feasibility, efficacy and toxicity of antifungal combination therapy (combo) as treatment of proven or probable invasive fungal diseases ( IFDs) in patients with haematological malignancies. Between January 2005 and January 2010, 84 cases of IFDs (39 proven and 45 probable) treated with combo were collected in 20 Hematological Italian Centres, in patients who underwent chemotherapy or allogeneic haematopoietic stem cell transplantation for haematological diseases. Median age of patients was 34 years (range 1-73) and 37% had less than 18 years. Acute leukaemia was the most common underlying haematological disease (68/84; 81%). The phase of treatment was as follows: first induction in 21/84 (25%), consolidation phase in 18/84 (21%) and reinduction/salvage in 45/84 (54%). The main site of infection was lung with or without other sites. The principal fungal pathogens were as follows: Aspergillus sp. 68 cases (81%), Candida sp. six cases (8%), Zygomycetes four cases (5%) and Fusarium sp. four cases (5%). The most used combo was caspofungin+voriconazole 35/84 (42%), caspofungin + liposomal amphotericin B (L-AmB) 20/84 (24%) and L-AmB+voriconazole 15/84 (18%). The median duration of combo was 19 days (range 3-180). The overall response rate ( ORR) was 73% (61/84 responders) without significant differences between the combo regimens. The most important factor that significantly influenced the response was granulocyte ( PMN) recovery ( P 0.009). Only one patient discontinued therapy (voriconazole-related neurotoxicity) and 22% experienced mild and reversible adverse events (hypokalaemia, ALT/ AST increase and creatinine increase). The IFDs-attributable mortality was 17%. This study indicates that combo was both well tolerated and effective in haematological patients. The most used combo regimens were caspofungin + voriconazole ( ORR 80%) and caspofungin + L-AmB ( ORR 70%). The ORR was 73% and the mortality IFD related was 17%. PMN recovery during combo predicts a favourable outcome. Clinical Trials Registration: NCT00906633. [ABSTRACT FROM AUTHOR]

This article discusses how the Affordable Care Act 2010 are improving the health of women in the U.S. The law expands the availability of coverage outside of employer-sponsored insurance, providing a larger range of insurance options and more security for women. It also protects women's access to quality healthcare as well as requires most health plans and insurance policies to cover preventive services at no additional cost to the beneficiary.

Clin Microbiol Infect Abstract The electronic surveillance system Hema e-Chart allowed us to prospectively collect data and to perform an analysis of invasive fungal infections (IFI) diagnosed in febrile patients as well as the procedures allowing their diagnosis and outcome according to the treatment given. Every patient admitted to 26 Italian Haematology Units with a new diagnosis of haematological malignancy and who was a candidate for chemotherapy was consecutively registered between March 2007 and March 2009. In all, 147 haematological patients with mycoses were identified. Yeasts were found in 23 infections; moulds were diagnosed in 17 proven, 35 probable and 72 possible mycoses. Galactomannan (GM) antigen was the most important test to diagnose probable mould infection; it was positive (cut-off >0.5) in 27 (77%) probable and in nine (53%) proven mould infections. Among patients with probable/proven mould infection who received no prophylaxis or non-mould-active prophylaxis with fluconazole, more patients ( n = 26, 78.8%) had GM antigen positivity compared with patients ( n = 10, 52.6%) given prophylaxis with mould-active drugs (p <0.05). First-line antifungal therapy was effective in 11/23 (48%) yeast infections and in 37/52 (71.2%) proven/probable mould infections. Twenty patients (14%) died within 12 weeks. The fungal attributable mortality was 30.4% and 17.3% in yeast and proven/probable mould infections, respectively. Among risk factors only age was independently associated (p 0.013) with mortality; sex, underlying haematological malignancy, previous prophylaxis and presence of neutropenia at diagnosis were not significant. A diagnosis of mould infection seemed to have a trend for a better outcome than the diagnosis of yeast infection (p 0.064). [ABSTRACT FROM AUTHOR]

The Hema e-Chart prospectively collected data on febrile events (FEs) in hematological malignancy patients (HMs). The aim of the study was to assess the number, causes and outcome of HM-related FEs. Data were collected in a computerized registry that systematically approached the study and the evolution of FEs developing in a cohort of adult HMs who were admitted to 19 hematology departments in Italy from March 2007 to December 2008. A total of 869 FEs in 3,197 patients with newly diagnosed HMs were recorded. Fever of unidentified origin (FUO) was observed in 386 cases (44.4%). The other causes of FE were identified as noninfectious in 48 cases (5.5%) and infectious in 435 cases (50.1%). Bacteria were the most common cause of infectious FEs (301 cases), followed by fungi (95 cases), and viruses (7 cases). Mixed agents were isolated in 32 episodes. The attributable mortality rate was 6.7% (58 FEs). No deaths were observed in viral infection or in the noninfectious groups, while 25 deaths were due to FUO, 16 to bacterial infections, 14 to fungal infections, and three to mixed infections. The Hema e-Chart provided a complete system for the epidemiological study of infectious complications in HMs. [ABSTRACT FROM AUTHOR]

Background. The purpose of our study was to evaluate the incidence and outcome of invasive fungal infection (IFI) among patients who underwent autologous or allogeneic hematopoietic stem cell transplantation (HSCT) at 11 Italian transplantation centers. Methods. This cohort-retrospective study, conducted during 1999-2003, involved HSCT patients admitted to 11 tertiary care centers or university hospitals in Italy, who developed IFIs (proven or probable). Results. Among 3228 patients who underwent HSCT (1249 allogeneic HSCT recipients and 1979 autologous HSCT recipients), IFI occurred in 121 patients (overall incidence, 3.7%). Ninety-one episodes (2.8% of all patients) were due to molds, and 30 (0.9%) were due to yeasts. Ninety-eight episodes (7.8%) occurred among the 1249 allogeneic HSCT recipients, and 23 (1.2%) occurred among the 1979 autologous HSCT recipients. The most frequent etiological agents were Aspergillus species (86 episodes) and Candida species (30 episodes). The overall mortality rate was 5.7% among allogeneic HSCT recipients and 0.4% among autologous HSCT recipients, whereas the attributable mortality rate registered in our population was 65.3% (72.4% for allogeneic HSCT recipients and 34.7% for autologous HSCT recipients). Etiology influenced the patients' outcomes: the attributable mortality rate for aspergillosis was 72.1% (77.2% and 14.3% for allogeneic and autologous HSCT recipients, respectively), and the rate for Candida IFI was 50% (57.1% and 43.8% for allogeneic and autologous HSCT recipients, respectively). Conclusions. IFI represents a common complication for allogeneic HSCT recipients. Aspergillus species is the most frequently detected agent in these patients, and aspergillosis is characterized by a high mortality rate. Conversely, autologous HSCT recipients rarely develop aspergillosis, and the attributable mortality rate is markedly lower. Candidemia was observed less often than aspergillosis among both allogeneic and autologous HSCT recipients; furthermore, there was no difference in either the incidence of or the attributable mortality rate for candidemia among recipients of the 2 transplant types. [ABSTRACT FROM AUTHOR]

Two polymorphs of the bronchodilator tulobuterol (2-chloro-α-[[(1,1-dimethylethyl)- amino]-methyl]benzenemethanol) with melting points differing by ~10 K were isolated and characterized by thermal analysis (HSM, TG, DSC), as well as powder and single crystal X-ray diffraction. Analysis of melting data for Forms 1 and 2 revealed a monotropic relationship, with ΔG0, the Gibbs free energy difference at the melting temperature of the lower melting form, less than 1 kJ mol-1. This small difference is reconciled with known structural features in the crystals of the two forms. The hydrogen bonding capacity of the tulobuterol molecule is fully utilised in both polymorphs in forming a common trimeric unit via three strong O-H···N interactions. Consequently only weak intermolecular forces characterize the packing of the trimers in the monoclinic polymorph (Form 1, P21/n, Z =12) and the triclinic polymorph (Form 2, P(-1), Z =6). [ABSTRACT FROM AUTHOR]

The thermal and structural characteristics of two crystal forms of ambroxol, (trans-((amino-2-dibromo-3,5-benzyl)amino)-4-cyclohexanol), a drug with remarkable mucolytic and expectorant properties marketed in several drug products, were investigated. Form II (m.p. 92.4°C) is obtained by spontaneous cooling from a hot water/ethanol solution while Form I (m.p. 99.5°C) slowly separates from the mother liquor. The two forms can be identified by PXRD and DSC analyses. On the basis of both thermal and structural data the thermodynamic relationship of enantiotropy was deduced. No metastable (Form I)?stable (Form II) conversion was observed upon storage at ambient conditions. Form I crystallizes in the space group P21/n (alternative setting of P21/c) with Z=8. Form II crystallizes in the space group P21/c with Z=4 and a significantly different crystal packing arrangement from that in Form I. A third crystalline modification, Form III (space group P21/c with Z=16) was detected on cooling a single crystal of Form I down to -70°C. On warming to ambient temperature Form III was found to revert to Form I. This reversible single crystal to single crystal transition was structurally characterised and found to involve subtle changes in the types and extent of molecular disorder as well as the hydrogen bonding arrangement. [ABSTRACT FROM AUTHOR]

Isostructural solvates of the 1:1 molecular complex between the antibacterial drugs tetroxoprim (TXP) and sulfametrole (SMTR) with formulae TXP·SMTR·CH3OH (I), TXP·SMTR·C2H5OH (II) and TXP·SMTR·H2O (III), were investigated to establish their propensity for guest exchange. Separate exposure of powdered (I), (II) and (III) to a saturated atmosphere of each solvent of the complementary solvate pair at ambient temperature resulted in reversible solvent exchange in all cases. DSC and TG were the methods of choice for monitoring the exchange processes since (I)-(III) have distinct onset temperatures of desolvation and characteristic mass losses. Interpretation of the results in terms of the known locations of the solvent molecules in crystals of (I)-(III) led to the conclusion that solvent exchange probably proceeds by a co-operative mechanism involving material transport through channels while the common host framework is maintained. [ABSTRACT FROM AUTHOR]

Inclusion compounds were formed with 1,1,6,6-tetraphenylhexa-2,4-diyne-1,6-diol (H) and carbon tetrachloride, chloroform, dichloromethane and acetonitrile. 1 (H·1/2CCl 4 ), 2 (H·1/2CHCl 3 ) and 3 (H·1/2CH 2 Cl 2 ) are true clathrates with the guest molecules situated in cages created by the host. 4 (H·2CH 3 CN) exhibits a different packing arrangement with the guest molecules located in channels. The crystal structures and stability of these inclusion compounds were investigated. [ABSTRACT FROM AUTHOR]

Complexes between members of a homologous series of alkylparabens and b-cyclodextrin (b-CD) have been prepared by both kneading and co-precipitation methods and their behaviour studied by differential scanning calorimetry (DSC), thermogravimetric (TG), infrared (IR) and powder X-ray diffraction (PXRD) techniques. PXRD revealed that complexation did occur by both the kneading and co-precipitation methods. DSC and IR techniques confirmed these results and TG indicated the presence and number of water molecules in each complex. [ABSTRACT FROM AUTHOR]

A small library of unsymmetrical cysteine disulfides as four aliphatic, three aromatic and one heteroaromatic were evaluated for their inhibition of two important carbonic anhydrase (CA) enzymes, namely human carbonic anhydrase isoenzymes I (hCA I) and II (hCA II). IC50 values were recorded in the low nanomolar range (8.6–18.3 nM for hCA I and 42.9–99.9 nM for hCA II). The inhibition activities were significantly superior to those of the clinically available CA inhibitor acetazolamide for hCA I, while only marginally inferior for hCA II. These results highlight the relevance of screening small molecules as potential CA inhibitors (CAIs). [ABSTRACT FROM AUTHOR]

Apolipoprotein E is a monomeric protein secreted by the liver and responsible for the transport of plasma cholesterol and triglycerides. The APOE gene encodes 3 isoforms Ɛ4, Ɛ3 and Ɛ2 with APOE Ɛ4 associated with higher plasma cholesterol levels and increased pathogenesis in several infectious diseases (HIV, HSV). Given that cholesterol is an important nutrient for malaria parasites, we examined whether APOE Ɛ4 was a risk factor for Plasmodium infection, in terms of prevalence or parasite density. A cross sectional survey was performed in 508 children aged 1 to 12 years in Gabon during the wet season. Children were screened for Plasmodium spp. infection, APOE and hemoglobin S (HbS) polymorphisms. Median parasite densities were significantly higher in APOE Ɛ4 children for Plasmodium spp. densities compared to non-APOE Ɛ4 children. When stratified for HbS polymorphisms, median Plasmodium spp. densities were significantly higher in HbAA children if they had an APOE Ɛ4 allele compared to those without an APOE Ɛ4 allele. When considering non-APOE Ɛ4 children, there was no quantitative reduction of Plasmodium spp. parasite densities for HbAS compared to HbAA phenotypes. No influence of APOE Ɛ4 on successful Plasmodium liver cell invasion was detected by multiplicity of infection. These results show that the APOE Ɛ4 allele is associated with higher median malaria parasite densities in children likely due to the importance of cholesterol availability to parasite growth and replication. Results suggest an epistatic interaction between APOE and HbS genes such that sickle cell trait only had an effect on parasite density in APOE Ɛ4 children. This suggests a linked pathway of regulation of parasite density involving expression of these genes. These findings have significance for understanding host determinants of regulation of malaria parasite density, the design of clinical trials as well as studies of co-infection with Plasmodium and other pathogens. [ABSTRACT FROM AUTHOR]

Gemtuzumab Ozogamicin (GO) is an antibody-targeted chemotherapy agent consisting of the humanized murine CD33 antibody (clone P67.6) to which the calicheamicin-g1 derivative is attached via a hydrolysable bifunctional linker. GO is able to induce apoptosis in vitro in CD33-expressing cells and it has been approved in USA and in Europe as monotherapy for the treatment of elderly patients (older than 60 years) with relapsed acute myeloid leukemia (AML). GO administered as a single agent has resulted in overall response rates of about 30% in previously relapsed adults AML patients (including also with incomplete platelet recovery). Preliminary data indicate a potential role for GO also as a component of induction or consolidation regimens in adults and children. As for adverse events, veno-occlusive syndrome characterizes its tolerability profile, but GO is comparatively well tolerated by most patients.Oncogene (2007) 26, 3679–3690. doi:10.1038/sj.onc.1210364 [ABSTRACT FROM AUTHOR]

Polymorphism of the antiviral drug clevudine is addressed here for the first time. Three polymorphs were isolated and investigated in order to establish their structural relationships as well as their aqueous solubilities and thermodynamic stabilities. Forms 1, 2 and 3 crystallize in the monoclinic space group P21 with 4, 2 and 8 molecules per unit cell respectively. Extensive H-bonding occurs in all three crystals, leading to stacked layers in Forms 1 and 3, while Form 2 contains close-packed columns of clevudine molecules. A combination of hot stage microscopy, differential scanning calorimetry, variable-temperature PXRD and the observation of solvent-mediated transformations, enabled assignment of relevant phase transitions as well as the construction of a schematic energy-temperature diagram, which reflects enantiotropic relationships, with Form 2 as the stable form below ∼175 °C. Possible implications of the results in the context of further development and expected widespread use of this antiviral are discussed. [ABSTRACT FROM AUTHOR]

Epithelium of oviductal ampulla was studied in normal and in superovulated sheep using morphologic analysis and lectin glycohistochemistry. The lining epithelium consisted of two types of cells, ciliated and nonciliated cells. Unlike superovulated samples, the nonciliated cells from control ewes showed apical protrusions indicating an apocrine secretory activity. The ciliated cells showed lectin-binding sites mainly at the level of the cilia which bound all the used lectins except Peanut agglutinin, suggesting the lack of glycans terminating with Galβ1,3GalNAc. In superovulated specimens, the ciliated cells with high mannosylated glycans Concanavalin A (Con A) and GlcNAc and GalNac termini Griffonia simplicifolia agglutinin II (GSA II) and Dolicurus biflorus agglutinin (DBA) decreased. The luminal surface of nonciliated cells showed all investigated sugar residues in controls, whereas it was lacking in high mannosylated (Con A) and terminal GalNAcα1,3(LFucα1,2)Galβ1,3/4GlcNAcβ1 sequence (DBA) in superovulated ewes. Apical protrusions from control ampullae nonciliated cells showed glycans containing mannose, GlcNac, GalNAc, galactose, and α2,3-linked sialic acid (Con A, KOH-sialidase- Wheat germ agglutnin [WGA], GSA II, SBA, Griffonia simplicifolia agglutinin-isolectin B 4 [GSA I-B 4 ], Maackia amurensis agglutinin II [MAL II]). The supranuclear cytoplasm of nonciliated cells expressed terminal GlcNAc (GSA II) in all specimens, also O-linked glycans (mucin-type glycans) with GalNAc and sialic acid termini ( Helix pomatia agglutinin [HPA] and MAL II) in control animals, and also N-linked glycans with fucose, galactose, lactosamine, and α2,3-linked sialic acid termini ( Ulex europaeus agglutinin I [UEA I], GSA I-B 4 , Ricinus communis agglutinin 120 [RCA 120 ], and Sambucus nigra agglutinin [SNA] ) in superovulated ewes. These results report for the first time that the superovulation treatment affects the secretory activity and the glycan pattern of the epithelium lining the sheep oviductal ampulla. [ABSTRACT FROM AUTHOR]

A prospective cohort study was conducted in nine hematology wards at tertiary care centres or at university hospitals located throughout Italy from January 2009 to December 2012. All of the cases of bacterial bloodstream infection (BBSI) occurring in adult patients with hematologic malignancies were included. A total of 668 bacterial isolates were recovered in 575 BBSI episodes. Overall, the susceptibility rates of Gram-negative bacteria were 59.1% to ceftazidime, 20.1% to ciprofloxacin, 79.1% to meropenem, 85.2% to amikacin, 69.2% to gentamicin and 69.8% to piperacillin/tazobactam. Resistance to third-generation cephalosporins was found in 98/265 (36.9%) of Enterobacteriaceae isolates. Among Klebsiella pneumoniae strains, 15/43 (34.9%) were resistant to carbapenems. Of 66 Pseudomonas aeruginosa isolates, 46 (69.7%) were multidrug resistant. Overall, the susceptibility rates of Gram-positive bacteria were 97.4% to vancomycin and 94.2% to teicoplanin. Among the monomicrobial cases of BBSI, the 21-day mortality rate was significantly higher for those caused by Gram-negative bacteria compared to those caused by Gram-positive bacteria (47/278, 16.9% vs. 12/212, 5.6%; p < 0.001). Among Gram-negative bacteria, the mortality rate was significantly higher for BBSI caused by K. pneumoniae, P. aeruginosa, and Acinetobacter baumannii. Our results confirm the recently reported shift of prevalence from Gram-positive to Gram-negative bacteria as causative agents of BBSIs among patients with hematologic malignancies and highlight a worrisome increasing frequency in antimicrobial resistance among Gram-negative bacteria. [ABSTRACT FROM AUTHOR]

In order to better understand the epidemiology of fusariosis in Europe, a survey collecting information on the clinical characteristics of the patients infected by Fusarium as well as on the infecting isolates was launched. A total of 76 cases of invasive fusariosis occurring from January 2007 to June 2012 were collected and Fusarium isolates were identified by sequencing the translation elongation factor 1α (TEF) gene. Also, antifungal susceptibility was tested by broth microdilution according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Etest. Disseminated disease was considered proven in 46 cases and probable in 17 cases. Localised infection was seen in 13 cases. Gibberella fujikuroi species complex (SC), including Fusarium verticillioides and F. proliferatum, and F. solani SC were the most frequent aetiology of disseminated and localised infections, respectively. The crude mortality rate was 46 %, the highest associated with F. solani SC (67 %) and F. proliferatum (62.5 %). A wide range of antifungal susceptibilities was observed. Amphotericin B was the most potent antifungal in vitro, and itraconazole the least effective. The azoles exhibited lower minimum inhibitory concentrations (MICs) against F. verticillioides strains, with posaconazole having a slightly better performance, while F. solani SC isolates were resistant to all three azoles tested. The essential agreement between the Etest and the EUCAST method was 100 % for itraconazole and voriconazole, and 96 % for amphotericin B and posaconazole. In conclusion, we confirm that fusariosis is a rare but severe event in Europe, that G. fujikuroi SC is the predominant cause of deep infections and that different species have different antifungal in vitro susceptibility patterns. [ABSTRACT FROM AUTHOR]

Mycoses summarized in the hyalohyphomycosis group are heterogeneous, defined by the presence of hyaline (non-dematiaceous) hyphae. The number of organisms implicated in hyalohyphomycosis is increasing and the most clinically important species belong to the genera Fusarium, Scedosporium, Acremonium, Scopulariopsis, Purpureocillium and Paecilomyces. Severely immunocompromised patients are particularly vulnerable to infection, and clinical manifestations range from colonization to chronic localized lesions to acute invasive and/or disseminated diseases. Diagnosis usually requires isolation and identification of the infecting pathogen. A poor prognosis is associated with fusariosis and early therapy of localized disease is important to prevent progression to a more aggressive or disseminated infection. Therapy should include voriconazole and surgical debridement where possible or posaconazole as salvage treatment. Voriconazole represents the first-line treatment of infections due to members of the genus Scedosporium. For Acremonium spp., Scopulariopsis spp., Purpureocillium spp. and Paecilomyces spp. the optimal antifungal treatment has not been established. Management usually consists of surgery and antifungal treatment, depending on the clinical presentation. [ABSTRACT FROM AUTHOR]

The aetiological agents of many invasive fungal infections are saprobes and opportunistic pathogens. Some of these fungi are darkly pigmented due to melanin production and traditionally have been named 'dematiaceous'. The melanized fungi cause a wide array of clinical syndromes ranging from superficial to deep-seated infections. Diagnosis relies on histopathological examination of clinical specimens and on examination of cultures. Sequencing is recommended for accurate species identification, especially for unusual or newly described pathogens. In cases of mycetoma and chromoblastomycosis, pathognomonic histological findings are useful and the Fontana–Masson stain, specific for melanin, usually confirms the diagnosis. There are no standardized therapies but voriconazole, posaconazole and itraconazole demonstrate the most consistent in vitro activity against this group of fungi. Oral itraconazole has been considered the drug of choice, given the extensive clinical experience with this drug. However, voriconazole may presumably be superior for central nervous system infections because of its ability to achieve good levels in the cerebrospinal fluid. Posaconazole is a well-tolerated alternative drug, backed by less clinical experience but with excellent salvage treatment results after failure of other antifungals. Amphotericin B has been useful as alternative therapy in some cases. Combination antifungal therapy is recommended for cerebral abscesses when surgery is not possible and for disseminated infections in immunocompromised patients. [ABSTRACT FROM AUTHOR]

Summary: Objectives: To describe the clinical characteristics and prognostic factors of hematological patients affected by Nocardia spp infections. Methods: We retrospectively evaluated all the cases diagnosed in four Italian institutions. Results: Between 2002 and 2012, 10 cases of nocardiosis were recorded. The median age of the patients was 66 years (range 24–85 years). The underlying hematological disease was a lymphoproliferative disorder in all but two patients. Eight patients (80%) showed active underlying hematological disease, relapsed or refractory in five (50%); one patient had a history of previous allogeneic bone marrow transplantation. Eight patients (80%) were on steroid therapy; lymphopenia was present in 8/10 (80%) patients. All patients showed lung involvement. Six patients were affected by disseminated nocardiosis. Three patients (30%) were nocardemic and three (30%) showed central nervous system involvement. Skin, lymph nodes, and bone were involved in one patient each. The median overall survival was 65 days. Older age, a longer period between hematological diagnosis and Nocardia spp infection, and relapsed/refractory hematological disease were associated with a worse prognosis. Conclusions: Although rare, nocardiosis should be considered in the differential diagnosis of pulmonary and central nervous system lesions among hematological patients. Lymphoproliferative disorders, prolonged steroid treatment, lymphopenia, and active hematological disease are the conditions that are worth considering as predisposing factors for the development of this disease. [Copyright &y& Elsevier]

Clin Microbiol Infect 2010; 16: 298–301 This study was prospectively conducted in 11 haematology divisions over a 2-year period to evaluate the efficacy of caspofungin in 24 neutropenic patients with haematological malignancies (HM) and candidaemia. These patients had received chemotherapy for HM and were neutropenic (PNN < 0.5 × 109/L) for a median of 12 days (2–41) before candidaemia. The patients received caspofungin for a median duration of 12 days (range 6–26), obtaining a favourable overall response of 58%. At 30 days, 11 patients had died (46%); candidaemia was responsible for mortality in six patients (25%). These results suggest that treatment of candidaemia with caspofungin in neutropenic HM was efficacious, as it is in non-haematological subgroups. [ABSTRACT FROM AUTHOR]

A hydrated form of theophylline-7-acetic acid obtained by recrystallization from water is described and characterized in terms of thermal properties, physical stability with respect to relative humidity and dehydration kinetics. The hydrate resulted to be stable at ambient conditions. Fitting of experimental dehydration data to solid state reaction equations suggests a three dimensional phase boundary reaction proceeding from the surface of the crystal inward along three dimensions. The relevant activation energy calculated from the Arrhenius plot is 173 kJ/mol. [ABSTRACT FROM AUTHOR]

We report two cases of invasive zygomycoses occurring in severely immunocompromised patients with haematological malignancies that were successfully treated with liposomal amphotericin B and surgical debridement, followed by oral administration of posaconazole. These cases demonstrated that an early instituted, aggressive and combined therapeutic approach results in a recovery from invasive fungal infection, without any relapse of infection, thanks to secondary prophylaxis using posaconazole. [ABSTRACT FROM AUTHOR]

Zygomycosis constitutes the third leading cause of invasive fungal infections following aspergillosis and candidosis. Patients with haematologic malignancies or haematopoietic stem cell transplantation are particularly susceptible to zygomycosis. Neutropenia represents the most important pathogenic mechanism influencing the onset and outcome of zygomycosis. Neutrophils cause a lesion of the fungal wall with subsequent destruction by macrophages. They also enhance the activity of antifungal drugs against Zygomycetes. Strategies that aim to increase neutrophil count and function, such as granulocyte colony stimulating factor and granulocyte transfusion, could play an important role in the management of this life-threatening infectious complication. [ABSTRACT FROM AUTHOR]

Contents The μ-opioid receptor (MOR) is expressed in bovine, human, equine and canine oocytes, and in seasonal breeders, it is expressed with higher intensity during the anoestrous phase. Supplementation of in vitro maturation (IVM) medium with opioid agents, agonists or antagonists, was shown to affect oocyte maturation in several species such as rat, bovine and equine. This study reports the effects of supplementing IVM medium with naloxone (Nx), an opioid antagonist, on nuclear and cytoplasmic maturation rate of oocytes recovered from anoestrous bitches. Cytoplasmic maturation was examined in terms of mitochondrial (mt) distribution. In order to confirm the receptor-mediated action of Nx, in oocytes of anoestrous bitches, MOR expression was analyzed by Western blot. Cumulus–oocyte complexes, recovered from the ovaries of bitches in anoestrous, were cultured in vitro and Nx was added at the concentrations of 1 × 10−6, 1 × 10−8 and 1 × 10−10 m. The rate of oocytes resuming meiosis after culture in presence of 1 × 10−6 m Nx (29%) was significantly higher than that of oocytes of control group (12%; p < 0.05). However, treatment with Nx did not affect mt distribution pattern. In denuded oocytes and in corresponding cumulus cells, a doublet of 65 and 50 kDa was observed. We conclude that, in oocytes of anoestrous bitches, MOR is expressed and Nx significantly improves nuclear maturation rate. Further studies should be performed to elucidate the expression of other opioid receptors, such as δ and κ, and possible interactive effects of their antagonists on canine oocyte maturation. [ABSTRACT FROM AUTHOR]

Background: The protection afforded by human erythrocyte polymorphisms against the malaria parasite, Plasmodium falciparum, has been proposed to be due to reduced ability of the parasite to invade or develop in erythrocytes. If this were the case, variable levels of parasitaemia and rates of seroconversion to infected-erythrocyte variant surface antigens (VSA) should be seen in different host genotypes. Methods: To test this hypothesis, P. falciparum parasitaemia and anti-VSA antibody levels were measured in a cohort of 555 asymptomatic children from an area of intense malaria transmission in Papua New Guinea. Linear mixed models were used to investigate the effect of α+-thalassaemia, complement receptor-1 and south-east Asian ovalocytosis, as well as glucose-6-phosphate dehydrogenase deficiency and ABO blood group on parasitaemia and age-specific seroconversion to VSA. Results: No host polymorphism showed a significant association with both parasite prevalence/ density and age-specific seroconversion to VSA. Conclusion: Host erythrocyte polymorphisms commonly found in Papua New Guinea do not effect exposure to blood stage P. falciparum infection. This contrasts with data for sickle cell trait and highlights that the above-mentioned polymorphisms may confer protection against malaria via distinct mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: We reviewed the incidence and the impact of posttransplant lymphoproliferative disorders (PTLDs) on patient survival among a consecutive series of 255 patients. Five cases of PTLD were observed in adults: two cases were early (less than 1 year) and three cases, late lymphomas. The EBV positivity and the degree of immunosuppression were the main risk factors. We labeled cases as early or late according to whether the time elapsed from the transplant to the first clinical evidence of PTLD was less than 12 months. The median time from transplant to diagnosis of PTLD was 8 (early) and 108 (late) months. All cases were treated by reduction in immunosuppressive therapy with conventional chemotherapy and rituximab. The early cases with lymphoma located at the hepatic hilum died due to local complications (biliary sepsis and hemobilia), after an initial partial response to chemotherapy. The three patients with late cases are in remission after a mean follow-up of 23 months. [Copyright &y& Elsevier]

3- and 4-Methylcyclohexanone have been isolated exclusively as their energetically disfavoured axial conformers in the host-guest complexes formed upon recrystallization of the novel optically pure host compound, (+)-(2R,3R)-1,1,4,4-tetraphenylbutane-1,2,3,4-tetraol (TETROL), from these cycloalkanones. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSC) are defined as multipotent stem cells that can differentiate into various cell types in vivoand in vitrounder controlled conditions. These cells express specific markers detectable by analysis at themRNA or protein level. Important sources of MSC could be fetal adnexa, such as amniotic fluid (AF), amnion (AM), and umbilical cord matrix (UCM). Canine MSC should be of use for cell-based therapies and tissue engineering improving treatment of several diseases. Moreover, the dog has been considered an attractive animal model to study human diseases. In the present study, we successfully isolated and molecularly characterised AF-MSC, AM-MSC, and UCM-MSC from dogs. Chromosomal stability and telomerase activity were also investigated. Samples were recovered after elective ovariohysterectomy in 3 bitches 25 to 40 days of gestational age. After isolation, cells were maintained in culture (Bossolasco et al.2006 Cell Res. 16, 329–336) for different passages to perform growth and doubling time (DT) studies. Expression analyses of embryonic (Oct-4, Nanog), mesenchymal (CD44, CD184, CD29), and haematopoietic (CD34, CD45) markers were carried out by RT-PCR. Karyotype analysis was performed by Q banding. Telomerase activity was analysed by TRAPeze Telomerase Detection Kit. In all 3 cell types, the morphology of proliferating cells appeared typically fibroblast-like. In the growth study, cells isolated from AF and AM were cultured until P3, and cells isolated from UCM were maintained until P7. The population DT in AF-MSC was significantly increased (Student’s t-test: P<0.05) when comparing P1 v.P4. In AM-MSC, DT increased significantly in P1 v.P2 (P<0.001), and in UCM-MSC, DT significantly increased in P1 v.P4 (P<0.001). In AF-MSC, cell viability did not change with passages. In AM-MSC, cell viability significantly decreased (P<0.001) between P1 and P4. In UCM-MSC, cell viability remained at approximately constant levels up to P6 and significantly decreased at P7 (P<0.001). Amnion and UCM-MSC expressed Oct-4and CD44, CD184, and CD29, whereas AF-MSC expressed only Oct-4and CD44. Nanog, CD34, and CD45were never found to be expressed in any cell line at any passage. In all cell lines, analysed metaphases at P4 showed normal chromosomal number and structure. Telomerase activity was observed in UCM-MSC, whereas tests on AF and AM-MSC are still on going. We first reported data on isolation, in vitroculture, and characterisation of MSC from AM and UCM in the dog. Cells expressed embryonic and MSC markers beginning at P1 and showed normal karyotype. These data indicated that canine MSC from fetal adnexa could be used to study stem cell biology and their application in therapeutic programs. Financial support was provided by Fondi di Ateneo 2009. University of Bari Aldo Moro (COD. ORBA09UDWX) (Resp. Sci. Maria Elena Dell’Aquila). [ABSTRACT FROM AUTHOR]

The calcium sensing receptor (CaSR) plays a key role in cells involved in calcium (Ca2+) homeostasis by directly sensing changes in extracellular Ca2+concentration ([Ca2+]o), and external Ca2+is a potent mediator of cell proliferation. The present study investigated the effects of high [Ca2+]o and of the CaSR agonist NPS R-467 on growth and proliferation of equine size-sieved umbilical cord matrix mesenchymal stem cells (UCM-MSC). The involvement of CaSR on observed cell response was analysed at themRNA and protein level. Two subpopulations of UCM-MSC, isolated using multi-dishes with transwell inserts of 8-μm pores and expressing MSC markers (CD105, CD44, CD29; Corradetti et al.2010 Reprod. Fertil. Dev. 22, 347–348), were analysed. Cells were cultured in medium containing: (A) low [Ca2+]o (0.37mM), (B) high [Ca2+]o (2.87mM), (C) NPS R-467 (3μm) in the presence of high [Ca2+]o, and (D) the CaSR antagonist NPS 2390 (10μm for 30′) followed by NPS R-467 in the presence of high [Ca2+]o. Growth and proliferation rates were compared among treatments (Student’s t-test). The CaSR expression and subcellular localization were investigated by real-time quantitative RT-PCR, immunofluorescence, and confocal microscopy. In the >8-μm cell line, the addition of NPS R-467, in the presence of [Ca2+]o, significantly increased cell growth after day 7 of culture (C v.A and B; P<0.001). Increasing [Ca2+]o was not effective in this cell line (B v.A; not significant). In the <8-μm cell line, NPS R-467 increased cell growth, even at a lower extent (C v.A; P<0.05), as observed on day 9 of culture. In this cell line, an increased proliferation rate was observed upon [Ca2+]o increase (B v.A; P<0.05). In both cell lines, preincubation with NPS 2390 significantly inhibited the agonistic effect of NPS R-467. In both cell lines, a stimulatory effect of additional calcium and NPS R-467 on cell proliferation, in terms of reduced DT values, was observed. In the 2 cell lines, CaSR expression was down-regulated in the presence of high calcium and in NPS R-467-treated cells compared with controls (B and C v.A cells; P<0.001). Treatment with high calcium or NPS R-467 reduced CaSR labelling in the cytosol and increased it at the cortical level. We found that CaSR is expressed atmRNA and protein levels in equine UCM-MSC, and it is functionally active because the selective CaSR agonist NPS R-467 induced a stimulatory effect on cell growth and proliferation, which was reversed by the CaSR antagonist NPS 2390. The different responses to treatments between the 2 UCM-MSC subpopulations suggest that CaSR could be differentially activated in these cell lines. The calcimimetic NPS R-467 might be useful as an adjunctive component of media for UCM-MSC culture to obtain enough cells for down-stream purposes. Financial support was provided by Fondi di Ateneo 2009; University of Bari Aldo Moro (COD. ORBA09UDWX) (Resp. Sci. Maria Elena Dell’Aquila). [ABSTRACT FROM AUTHOR]

Analyses of energy and redox status parameters are emerging technologies to improve oocyte quality assessment. Mitochondria (mt) play a vital role in the oocyte to support maturation, fertilization, and pre-implantation development. They are the major source of reactive oxygen species (ROS) produced during oxidative phosphorylation, which are not only by-products of cell metabolism but also important molecules for regulation of intracellular cell signaling. The aim of the present study was to test for mt/ROS colocalization in oocytes recovered from superovulated adult ewes and examined after in vivoor in vitromaturation (IVM). Cumulus–oocyte complexes of 8 superovulated (fluorogestone acetate+D-cloprostenol for oestrus synchronization, pFSH/pLH and eCG for superovulation) adult (2 to 8 years of age) ewes were recovered (ovariohysterectomy by midventral laparotomy performed 54h after vaginal sponge removal) either from flushing oviducts (oviducal oocytes) or from ovarian growing follicles (1–5mm in diameter; follicular oocytes). Follicular oocytes were analysed after IVM (Ambruosi et al.2009 Theriogenology 71, 1093–1104). After cumulus cell removal, all oocytes underwent nuclear chromatin, mt, and ROS evaluation. Hoechst 33258 and Mitotracker Orange CMTM Ros were used to label nuclear chromatin and mt (Ambruosi et al.2009) and 2′,7′-dichloro-dihydro-fluorescein diacetate was used for ROS labelling (Hashimoto et al.2000 Mol. Reprod. Dev. 57, 353–360). Oocytes at the metaphase II (MII) stage showing regular ooplasmic size (>130μm in diameter) and morphology were selected for confocal analysis of mt/ROS fluorescence distribution, intensity, and colocalization. Forty oviducal MII oocytes recovered from 8 ewes were analysed. Thirty-two oocytes recovered from the ovaries of 4 ewes underwent IVM, and 23 out of 32 (72%) reached nuclear maturation and were analysed. The rate of oocytes showing perinuclear mt distribution pattern did not differ between oviducal and IVM oocytes (33%, 13/40 v.43%, 10/23; not significant). In these oocytes, fluorescent intensity of mt labelling and intracellular ROS levels did not differ between oviducal and IVM ooocytes (996.27±363.57 v.798.13±275.91; not significant; and 1808.11±442.78 v.1473.29±662.49, for mt and ROS, respectively; not significant), whereas mt/ROS colocalization was significantly higher in ovulated oocytes than in IVM oocytes (Pearson coefficient 0.67±0.11 v.0.39±0.19, respectively; P<0.001). In conclusion, in oocytes of adult ewes, mt aggregation, apparent energy status, and intracellular ROS levels do not differ between ovulated and IVM oocytes, but mt/ROS colocalization differs between the 2 groups. As it was reported for other cell systems that such a difference can be indicative of healthy status of ovulated oocytes, we suggest that mt/ROS colocalization could be considered as a suitable marker of oocyte quality. Financial support was provided by Fondazione Cassa di Risparmio di Puglia 2008. Project: Salvaguardia di razze ovine autoctone pugliesi (R.U. DPA Resp. Sci. Prof. M. E. DellAquila). [ABSTRACT FROM AUTHOR]