Design, synthesis, and evaluation of simple phenol amides as ERRγ agonists.

Herein we report the design and synthesis of a series of simple phenol amide ERRγ agonists based on a hydrazone lead molecule. Our structure activity relationship studies in this series revealed the phenol portion of the molecule to be required for activity. Attempts to replace the hydrazone with more suitable chemotypes led to a simple amide as a viable alternative. Differential hydrogen-deuterium exchange experiments were used to help understand the structural basis for binding to ERRγ and aid in the development of more potent ligands.

Hospital sewage in Brazil: a reservoir of multidrug-resistant carbapenemase-producing Enterobacteriaceae.

The One Health concept recognizes that human health is clearly linked to the health of animals and the environment. Infections caused by bacteria resistant to carbapenem antibiotics have become a major challenge in hospitals due to limited therapeutic options and consequent increase in mortality. In this study, we investigated the presence of carbapenem-resistant Enterobacteriaceae in 84 effluent samples (42 from hospital and 42 from non-hospital) from Campo Grande, midwest Brazil. First, sewage samples were inoculated in a selective culture medium. Bacteria with reduced susceptibility to meropenem and ertapenem were then identified and their antimicrobial susceptibility was determined using the Vitek-2 system. The blaKPC genes were detected using PCR and further confirmed by sequencing. Carbapenem-resistant Enterobacteriaceae (CRE) were identified in both hospital (n=32) and non-hospital effluent (n=16), with the most common being Klebsiella pneumoniae and of the Enterobacter cloacae complex species. This is the first study to indicate the presence of the blaKPC-2 gene in carbapenem-resistant Enterobacteriaceae, classified as a critical priority by the WHO, in hospital sewage in this region. The dissemination of carbapenem antibiotic-resistant genes may be associated with clinical pathogens. Under favorable conditions and microbial loads, resistant bacteria and antimicrobial-resistance genes found in hospital sewage can disseminate into the environment, causing health problems. Therefore, sewage treatment regulations should be implemented to minimize the transfer of antimicrobial resistance from hospitals.

Comparability and utility of body composition measurement vs. anthropometric measurement for assessing obesity related health risks in Korean men.

BACKGROUND: Obesity is commonly assessed by body mass index (BMI) of which limitations come from an inability to distinguish body fat mass from lean mass. Several anthropometric measurements, including BMI, waist circumference, waist-to-height ratio and waist-to-hip ratio have been used to predict metabolic syndrome. The purpose of this study was to evaluate the utility of FMI or BF% combined with previous known anthropometric indices to assess the risk of metabolic syndrome in clinical practice. METHODS: In 5534 men visiting a hospital for health check-ups, blood tests, anthropometric measurements and body composition analysis using BIA were performed. Logistic regression analysis was performed to compare the odds ratios for metabolic syndrome and each component of metabolic syndrome among BMI, waist-to-height ratio, waist-to-hip ratio, FMI and BF%. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) for metabolic syndrome was compared between several measurements. The net reclassification improvement with integrated discrimination improvement was used for assessing value of body composition measurement. RESULTS: The adjusted odds ratios of metabolic syndrome was 1.80 (95% CI, 1.71-1.89) for FMI and 1.15 (95% CI, 1.13-1.17) for BF%. Odds ratio of each metabolic component was highest for FMI among several anthropometric and body composition measurements. AUCs using the ROC curve for metabolic syndrome was highest for waist-to-height ratio, 0.823 (95% CI, 0.808-0.837) by National Cholesterol Education Program criteria. FMI caused a mild increase in integrated discrimination improvement when combined with waist-to-height ratio. CONCLUSIONS: Waist-to-height ratio seems to be the best screening tool for evaluating metabolic syndrome in Korean men, and adding FMI could result in a modest increase in integrated discrimination improvement.

Ten-year study of species distribution and antifungal susceptibilities of Candida bloodstream isolates at a Brazilian tertiary hospital.

To describe the incidence and susceptibility profile of Candida bloodstream infections in a tertiary-care hospital, we performed a retrospective observational study from 1998 to 2007. Comorbidities and risk factors were compiled from all cases. In vitro susceptibility testing to fluconazole, itraconazole, voriconazole, and amphotericin B was performed for 100 isolates, and caspofungin was tested for C. parapsilosis complex. In a ten-year evaluation of candidemias, 44 % were caused by C. albicans, and species of the C. parapsilosis complex were the second most frequent agents (37 %). Other species presented lower incidences (C. tropicalis, 13 %, C. glabrata, 5 %, and C. krusei, 1 %). Neither C. dubliniensis nor C. metapsilosis were observed in this study. C. orthopsilosis (3 %) and C. parapsilosis stricto sensu (34 %) were also found. Species distribution was independent of catheterization, mechanical ventilation, or previous use of antifungals or corticoids. Parenteral nutrition administration was strongly related to C. glabrata infection, and the highest mortality (80 %) was observed in patients infected by this species. All C. albicans isolates showed high susceptibility to all tested drugs. However, two C. parapsilosis stricto sensu isolates presented high minimum inhibitory concentration (MIC) (4 mg/L each) to fluconazole, and one exhibited voriconazole MIC of 0.25 mg/L, highlighting the cross-resistance to these azoles. All isolates of C. tropicalis and C. glabrata showed no resistance to any drug tested. No difference was noted between C. parapsilosis and C. orthopsilosis susceptibilities to caspofungin. Our results suggest that resistance to amphotericin B, fluconazole, voriconazole, itraconazole, and caspofungin in Brazilian Candida bloodstream isolates is still uncommon.

Granulomatous tracheitis and dermatitis due to Curvularia sp. in a horse: case report / [Traqueíte e dermatite granulomatosas associadas a Curvularia sp. em um equino: relato de caso]

Tracheal fungal infections in horses are rare. This case report describes surgical and clinical management of a filly with a Curvularia sp. infection within the trachea and skin that caused severe intraluminal granulomas and cutaneous nodules, respectively. The patient was successfully treated with itraconazole and surgical excision.(AU)

Infecções fúngicas traqueais em equinos são raras. Este relato de caso descreve condutas clínicas e cirúrgicas em uma égua com infecção por Curvularia sp. na traqueia e na pele, causando granulomas intraluminais severos e nódulos cutâneos, respectivamente. O animal foi tratado com sucesso com itraconazol e exérese cirúrgica.(AU)

Transcription factor IID probes localize a single gene to the proximal region of mouse chromosome 17.

We have used a 5' fragment of the gene GTF2D, which encodes human transcription factor IID, and Chinese hamster-mouse somatic cell hybrids to map the murine homologue, Gtf2d, to a single locus on mouse chromosome 17 (Chr 17). Linkage analysis of progeny from an interspecific backcross localized the gene near the marker D17Leh66 in the proximal region of Chr 17.

Synthesis and antitumor activity of fused tetracyclic quinoline derivatives. 1.

Several fused tri- and tetracyclic quinolines (I and II) with [2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino or [3-(N,N-dimethylamino)propyl]amino side chains were prepared, and their DNA intercalative properties, KB cytotoxicity, antitumor activity (P388 leukemia), and ability to induce topoisomerase II dependent DNA cleavage were investigated. Some compounds having both intercalative ability and KB cytotoxicity were found to be inactive in vivo. However, a positive correlation was seen between the ability to induce topoisomerase II dependent DNA cleavage and antitumor activity in vivo. The indeno- (13a), benzofuro- (21a), and benzothieno- (22a) quinoline derivatives exhibited potent antitumor activities in vitro and in vivo, comparable to those of m-AMSA. They also intercalate DNA and induce topoisomerase II dependent DNA cleavage. Extended screening of 13a showed it to be active against solid tumors such as M5076 sarcoma, B16 melanoma, and colon 38 carcinoma.

Amphotericin B-metronidazole combination against Candida spp.

Interaction between amphotericin B and metronidazole was studied against Candida albicans, Candida tropicalis, Candida parapsilosis, Candida krusei, and Candida lusitaniae strains. Minimum inhibitory concentrations (MICs) of the drugs alone and in combination were determined by means of the checkerboard method on YNB supplemented agar. Minimum fungicidal concentrations (MFCs) were determined on Sabouraud dextrose agar. Based on the MIC and MFC values, fractionary indices were determined respectively for inhibitory and lethal activities of the amphotericin B-metronidazole combination. These indices showed occurrence of additive and synergistic interactions between the drugs, but the synergysm was predominant against the studied strains.

Basic science and clinical aspects of wound healing in glaucoma filtering surgery.

Success of glaucoma filtration surgery is influenced by the wound healing response. Attention has been focused on pharmacological agents to control a process that leads to excessive scarring and eventual failure of glaucoma filtration surgery. Several agents, including 5-fluorouracil and mitomycin C, as well as other antiproliferative drugs will be discussed. Newer antifibrotic agents and novel drug delivery systems are under development in tissue culture and animal models in an effort to improve efficacy and safety. This article summarizes current treatment modalities and future prospects to prevent excessive wound healing and improve the success of glaucoma filtration surgery.

The effectiveness and safety of dorzolamide 2% in addition to multiple topical antiglaucoma medications.

Dorzolamide is the first commercial topical carbonic anhydrase inhibitor approved by the Food and Drug Administration (FDA) for the treatment of glaucoma. In a prospective, open label, uncontrolled study on 245 glaucoma patients, dorzolamide significantly lowered the intraocular pressure at least 14% when used alone or in combination with one, two, or three other antiglaucoma medications over ten weeks. There were very few adverse reactions to dorzolamide. Dorzolamide is effective and safe when used alone or in combination with other topical antiglaucoma medications for the treatment of glaucoma.

Surveillance of pediatric infections in a teaching hospital in Mato Grosso do Sul, Brazil.

Nosocomial infections (NI) result in considerably high mortality and morbidity rates, especially among pediatric patients. Considering current worldwide changes, information about the occurrence of pathogens and susceptibility tests are now seen as decisive for optimizing treatment. The purpose of this research was to determine the frequency of microorganisms, antimicrobial and genetic profiles, and risk factors associated with nosocomial infections in a teaching hospital in Campo Grande, Mato Grosso do Sul. From January 1998 to December 1999, 108 patients were characterized as having nosocomial infection, from which 137 pathogens were isolated. Identification and antimicrobial susceptibility was determined by conventional and automated techniques. Staphylococcus aureus and Klebsiella pneumoniae strains were characterized by Pulsed Field Gel Electrophoresis (PFGE). Pathogens were most often isolated from infants one-month old or younger, and bloodstream infections were the most frequent. The main isolated agents isolated were: coagulase-negative staphylococci (38), Pseudomonas aeruginosa (19), S. aureus (26), K. pneumoniae (18), and Candida spp. (13). The risk conditions that were most closely related to NI acquisition were: prolonged hospital stays (69.4%), prematurity (60.9%) and exposure to high-risk device procedures (95.4%). Ciprofloxacin and imipenem were the most effective drugs, inhibiting all or almost all of the Enterobacteriaceae, P. aeruginosa and Acinetobacter calcoaceticus isolates. Only 23% of the S. aureus samples were resistant to oxacillin. Genomic typing revealed 10 distinct patterns for S. aureus and 13 for K. pneumoniae, suggesting that most them did not belong to the same clone. PFGE was effective in differentiating the strains.

[Phlebotomines (Diptera: Psychodidae) focusing visceral leishmaniasis in the State of Mato Grosso do Sul, Brazil]. / Estudo de flebotomíneos (Diptera: Psychodidae) em foco de leishmaniose visceral no Estado de Mato Grosso do Sul, Brasil.

INTRODUCTION: In the Americas, Lutzomyia longipalpis has been incriminated as the vector of visceral leishmaniasis in almost all the areas in which this disease has been reported. The notification of human cases of visceral leishmaniasis and the presence of dogs with an appearance suggestive of the disease in the country of Corumbá, Mato Grosso do Sul State, Brazil, led us to undertake an entomological investigation in this area, for the purpose of identifying the phlebotomine vector. MATERIAL AND METHOD: The county of Corumbá is located in the Pantanal region and its urban area is situated at 18 degrees 59' 44" South and 57 degrees 39' 16" West. The research project was carried out in peri and intradomiciliary environments, in three urban districts, one of which was central and the other two on the outskirts, and in a cave situated outside the urban perimeter. Most of the captures were made weekly with light automatic traps, in the period from February 1984 to December 1986. Meteorological data for this period were obtained from the city's meteorological station and those for the period from 1925 to 1982 from the literature. RESULTS: The urban phlebotomine fauna consisted of eight species and was similar to that of the cave, except that in the latter the species were more abundant. Lutzomyia cruzi was predominant in the peri and intradomiciliary environments. Its prevalence in the central district was of 90.3% and lower in the outskirts. Lu. forattinii presented considerable prevalence (39.0%) in one of the outlying districts too. In the cave, Lu. corumbaensis was the predominant species, followed by Lu. sordellii, Lu. forattinii, Lu. peresi and Lu. cruzi. The impact of the climatic condition and the action of insecticides in the urban area on the frequency of the species, as well as the use of the cave as a breeding ground by the phlebotomines, in view of the changes in the sex rate, are commented. Data on anthropophily and captures of Lu. forattinii using dog bait have been added. CONCLUSION: The predominance of Lu. cruzi in the urban area; the great prevalence of Lu. forattinii in most of the outlying areas studied and the anthropophily of this latter species, as well as the strong affinity of these species with Lu. longipalpis, the main vector of visceral leishmaniais in other areas of the Americas, suggest the participation of both in the transmission of the disease in Corumbá.

Action of phosphorylated mannanoligosaccharides on immune and hematological responses and fecal consistency of dogs experimentally infected with enteropathogenic Escherichia coli strains.

The therapeutic action of phosphorylated mannanoligosaccharides (MOS) was investigated regarding its prebiotic activity on enteropathogenic Escherichia coli (EPEC). Diarrhea was induced in dogs by experimental infection with EPEC strains. Then MOS was supplied once a day, in water for 20 days. Immunological (IgA and IgG), hematological (lymphocytes, neutrophils and monocytes) and bacteriological variables (PCR detection of the eae gene of EPEC recovered from stool culture), as well as occurrence of diarrhea were evaluated. All strains caused diarrhea at 24, 48 and 72 h after infection. PCR results indicated that E. coli isolated from stool culture of all infected animals had the eae gene. There was no significant difference among groups as to number of blood cells in the hemogram and IgA and IgG production. MOS was effective in recovering of EPEC-infected dogs since prebiotic-treated animals recovered more rapidly from infection than untreated ones (p < 0.05). This is an important finding since diarrhea causes intense dehydration and nutrient loss. The use of prebiotics for humans and other animals with diarrhea can be an alternative for the treatment and prophylaxis of EPEC infections.

Action of phosphorylated mannanoligosaccharides on immune and hematological responses and fecal consistency of dogs experimentally infected with enteropathogenic Escherichia coli strains

The therapeutic action of phosphorylated mannanoligosaccharides (MOS) was investigated regarding its prebiotic activity on enteropathogenic Escherichia coli (EPEC). Diarrhea was induced in dogs by experimental infection with EPEC strains. Then MOS was supplied once a day, in water for 20 days. Immunological (IgA and IgG), hematological (lymphocytes, neutrophils and monocytes) and bacteriological variables (PCR detection of the eae gene of EPEC recovered from stool culture), as well as occurrence of diarrhea were evaluated. All strains caused diarrhea at 24, 48 and 72 h after infection. PCR results indicated that E. coli isolated from stool culture of all infected animals had the eae gene. There was no significant difference among groups as to number of blood cells in the hemogram and IgA and IgG production. MOS was effective in recovering of EPEC-infected dogs since prebiotic-treated animals recovered more rapidly from infection than untreated ones (p < 0.05). This is an important finding since diarrhea causes intense dehydration and nutrient loss. The use of prebiotics for humans and other animals with diarrhea can be an alternative for the treatment and prophylaxis of EPEC infections.

Nanoparticles in wastewater from a science-based industrial park - coagulation using polyaluminum chloride.

The Hsinchu Science-based Industrial Park (HSIP) is the hi-tech manufacturing hub of Taiwan. Wastewater from the HSIP contains numerous nano-sized silicate particles whose size distributions peak at 2 and 90 nm. A 3-5 mg l(-1) as Al dose of polyaluminum chloride (PACl) was used in the field to coagulate these particles, but the removal efficiency was low. Laboratory scale tests indicated that although PACl coagulation removed 52% of the turbidity and 48% of the chemical oxygen demand (COD) from water, its effect on nano-particle removal was minimal. About 58% of the soluble COD was associated with colloidal Si particles. A light scattering test and transmission electron microscopy (TEM) demonstrated that the nano-particles agglomerated in approximately linear aggregates of sizes 100-300 nm. Prolonged contact between residual PACl and the nano-particles generated large aggregates with sizes of up to 10 microm and a fractal dimension of 2.24-2.63. The results presented herein should be of interest in the processing of "high-tech" wastewater that contains nanosized silica particles.

Synthesis and antitumor activity of 7-(N-glycosylamino)-indolo[3,2-b]quinolines.

Novel indolo[3,2-b]quinolines (1d-g), introduced at the 7-position with an N-glycosylamino group, were prepared and their antitumor activities against leukemia P388 in mice were examined. The N-Galactopyranosylamino derivative (1e) was a much more potent anti-leukemia compound (optimal dose = 25 mg/kg, T/C greater than 333%, cure 5/6) than lead compound 1a.

Synthesis and antitumor activity of fused quinoline derivatives. II. Novel 4- and 7-hydroxyindolo-[3,2-b]quinolines.

Novel indolo[3,2-b]quinoline derivatives (1c--f), which carried a methoxy or a hydroxy group at the 4- or 7-position of the lead compound 1a, were prepared and their antitumor activities against P388 in mice were examined. Except for the 4-hydroxy derivative (1d), these showed remarkably potent activity. Among these compounds, the 7-hydroxy derivative (1f) was the most potent one (optimal dose = 50 mg/kg, the median survival time of treated group/control group (T/C) greater than 330%, cure = 5/6).

Synthesis and antitumor activity of fused quinoline derivatives. III. Novel N-glycosylamino-indolo[3,2-b]quinolines.

Novel indolo[3,2-b]quinolines (1b-k), having a nitro, amino, acetamido, methanesulfonamido, or glycosylamino group at the 2, 7, or 8-position, were prepared and their antitumor activities against P388 leukemia in mice were examined. The 7-galactopyranosylamino derivative (1g) showed the most potent activity (optimal dose = 25 mg/kg, T/C greater than 333%, cure rate 5/6).

Synthesis and antitumor activity of fused quinoline derivatives.

Some tetracyclic quinolines (9 and 14) with a [2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino side chain were prepared and their deoxyribonucleic acid (DNA) intercalative properties, KB cytotoxicity, antitumor activity (P388 leukemia), and ability to induce topoisomerase II dependent DNA cleavage were investigated. The indoloquinoline derivative 9 exhibited the most potent activity (dose = 6.3 mg, T/C% = 300) in this series. The steric structural features of the chromophores of the compounds previously and newly synthesized were studied by a computer-associated molecular graphics technique. Relationships between the steric structural features of the chromophores and biological activities are also discussed.

Synthesis and antitumor activity of fused quinoline derivatives. V. Methylindolo[3,2-b]quinolines.

Indolo[3,2-b]quinoline derivatives (1b-i) with a methyl group at each possible position have been synthesized. The 1-methyl (1b) and 9-methyl (1i) derivatives were inactive, but the 3-methyl (1d), 4-methyl (1e), and 6-methyl (1f) derivatives exhibited high treatment/control (T/C) value and cure rates against leukemia P388 in mice. These results indicated that modification of indolo[3,2-b]quinoline derivatives at 3, 4, and 6 positions may be useful approach for lead optimization.