Efficacies of caspofungin and a combination of caspofungin and meropenem in the treatment of murine disseminated candidiasis

Disseminated candidiasis is relatively common in immunocompromised patients. The treatment protocol of these patients usually includes broad-spectrum antibiotics and also emprical antifungals initiated due to unresponsiveness to antibiotics. In this study the efficacies of caspofungin and meropenem - separately and together - in mice with disseminated candidiasis were studied. Immunocompetent mice were infected intravenously with 2x10(6) CFU of Candida albicans. At 24 h postinfection, intraperitoneal therapy was initiated and was continued for 7 days. Therapy groups included those given caspofungin (0.5, 1.25, 5 mg/kg/day), meropenem (20 mg/kg/day), and a combination of the two drugs. The outcome of therapy was evaluated by kidney tissue burden studies and histologic examination. In vitro, drug susceptibilities were tested by checkerboard analysis. Kidney CFU counts showed that mice that had received both drugs had lower residual burdens. Caspofungin was effective at doses of 0.5, 1.25, 5 mg/kg compared to infected untreated controls. In vitro, MICs of caspofungin and meropenem were <0.075 micro g/ml and >64 micro g/ml, respectively. Synergism was observed with the combination. Histopathology showed that the degree of inflammation was 25% less and tubular necrosis was more restricted in combined therapy than monotherapy. The results indicate that concurrent caspofungin and meropenem therapy may be beneficial.     

Synthesis,Cytotoxicity, and Pro‐Apoptosis Activity of Etodolac Hydrazide Derivatives as Anticancer Agents

Etodolac hydrazide and a novel series of etodolac hydrazide‐hydrazones 3 – 15 and etodolac 4‐thiazolidinones 16 – 26 were synthesized in this study. The structures of the new compounds were determined by spectral (FT‐IR, ¹H NMR, ¹³C NMR, HREI‐MS) methods. Some selected compounds were determined at one dose toward the full panel of 60 human cancer cell lines by the National Cancer Institute (NCI, Bethesda, USA). 2‐(1,8‐Diethyl‐1,3,4,9‐tetrahydropyrano[3,4‐b]indole‐1‐yl)acetic acid[(4‐chlorophenyl)methylene]hydrazide 9 demonstrated the most marked effect on the prostate cancer cell line PC‐3, with 58.24% growth inhibition at 10^?5 M (10 µM). Using the MTT colorimetric method, compound 9 was evaluated in vitro against the prostate cell line PC‐3 and the rat fibroblast cell line L‐929, for cell viability and growth inhibition at different doses. Compound 9 exhibited anticancer activity with an IC₅₀ value of 54 µM (22.842 µg/mL) against the PC‐3 cells and did not display any cytotoxicity toward the L‐929 rat fibroblasts, compared to etodolac. In addition, this compound was evaluated for caspase‐3 and Bcl‐2 activation in the apoptosis pathway, which plays a key role in the treatment of cancer.     

Synthesis and characterization of flurbiprofen hydrazide derivatives as potential anti-HCV, anticancer and antimicrobial agents

A novel series of new flurbiprofen hydrazide derivatives 2-(2-fluorobiphenyl-4-yl)-N′-[(substituted phenyl/5-nitro-2-furyl)methylene]propanehydrazide (3a–k), 2-(2-fluorobiphenyl-4-yl)-N-(2-substituted-4-oxo-1,3-thiazolidine-3-yl)propanamide (4a–b, 4d–k), 2-[2-(2-fluorobiphenyl-4-yl) propanoyl]-N-substituted hydrazinecarbothioamide (5a–h) and 2-(2-fluorobiphenyl-4-yl)-N′-[(3-methyl-4-oxo-1,3-thiazolidin-2-ylidene]propanehydrazide (6a–b, 6e and 6g) has been synthesized in this study. All synthesized compounds were screened for antimicrobial activity against various bacterial and fungal strains. Additionally, compounds were evaluated for the ability to inhibit Hepatitis C virus NS5B polymerase. The most active 4-thiazolidinone compound was 4k (SGK119) with 67.0 % and thiosemicarbazide compound was 5d (SGK123) with 69.50 % inhibition at 200 μM against hepatitis C virus NS5B RNA polymerase. Anticancer activity of the selected compounds (3i, 3j, 3h, 4d, 4i and 6b) was determined at a single dose towards the full panel of 60 human cancer cell lines by the National Cancer Institute (NCI). 2-(2-Fluoro-4-biphenylyl)-N-[2-[4-(trifluoromethyl)phenyl]-4-oxo-1,3-thiazolidine-3-yl]propanamide 4d, containing thiazolidinone ring, demonstrated the most marked effect with 20.80 % growth percent on leukaemia cancer cell line SR at 10^?5 M. The results demonstrated that none of the compounds tested have anticandidal and antifungal activities, but two of them (4a and 4i) showed antibacterial inhibition against Micrococcus luteus, and Staphylococcus cohnii and Staphylococcus aureus, respectively.     

Identification of a founder mutation in TPM3 in nemaline myopathy patients of Turkish origin

To date, six genes are known to cause nemaline (rod) myopathy (NM), a rare congenital neuromuscular disorder. In an attempt to find a seventh gene, we performed linkage and subsequent sequence analyses in 12 Turkish families with recessive NM. We found homozygosity in two of the families at 1q12-21.2, a region encompassing the gamma-tropomyosin gene (TPM3) encoding slow skeletal muscle alpha-tropomyosin, a known NM gene. Sequencing revealed homozygous deletion of the first nucleotide of the last exon, c.913delA of TPM3 in both families. The mutation removes the last nucleotide before the stop codon, causing a frameshift and readthrough across the termination signal. The encoded alphaTm(slow) protein is predicted to be 73 amino acids longer than normal, and the extension to the protein is hypothesised to be unable to form a coiled coil. The resulting tropomyosin protein may therefore be non-functional. The affected children in both families were homozygous for the mutation, while the healthy parents were mutation carriers. Both of the patients in Family 1 had the severe form of NM, and also an unusual chest deformity. The affected children in Family 2 had the intermediate form of NM. Muscle biopsies showed type 1 (slow) fibres to be markedly smaller than type 2 (fast) fibres. Previously, there had been five reports, only, of NM caused by mutations in TPM3. The mutation reported here is the first deletion to be identified in TPM3, and it is likely to be a founder mutation in the Turkish population.European Journal of Human Genetics (2008) 16, 1055-1061; doi:10.1038/ejhg.2008.60; published online 2 April 2008.     

Neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole augment the effects of antidepressants acting via serotonergic system in the forced swimming test in rats

Treatment-resistant depression has necessitated new therapeutic strategies in augmenting the therapeutic actions of currently existing antidepressant drugs. The aim of this study was to investigate the possibility of synergistic interaction between 1-(2-trifluoromethylphenyl)-imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor and conventional antidepressants of different classes in the forced swimming test (FST) in rats. TRIM decreased the immobility time at 50 mg/kg doses in the FST in rats. Treatment with a behaviourally subeffective dose of TRIM (20 mg/kg) augmented the behavioural effect of tricyclic antidepressant imipramine, selective serotonin re-uptake inhibitor (SSRI) citalopram and fluoxetine or selective serotonin reuptake enhancer tianeptine but failed to augment the antidepressant effect of reboxetine, a noradrenaline re-uptake inhibitor, in this test. Therefore inhibition of NOS augments the effects of antidepressants acting on serotonergic system in the FST. Neither TRIM (10–50 mg/kg) nor other drug treatments affected the locomotor activity of animals. These findings are in agreement with the view that antidepressant effects or augmentation of these effects in the FST may be explained with inhibition of NOS activity and this may be a new approach in offering greater therapeutic efficacy of antidepressants acting via serotonergic system.     

The characteristics and occurrence of the talon cusps in Turkish population: a retrospective sample study

Purpose

The purpose of this study was to figure out the characteristics and occurrence of talon cusps in a sample of Turkish population.

Methods

In this retrospective study, talon cusps in permanent dentition were evaluated on radiographs and intraoral photographs which were obtained from patients who were referred to Oral and Maxillofacial Radiology Department, Faculty of Dentistry, Adnan Menderes University, Ayd?n, Turkey between January 2013 and January 2014.

Results

Talon cusps were observed in 365 of 4116 patients, with a frequency of 8.86 %. There were 208 (57 %) females and 157 (43 %) males with this variation. Maxillary canines were the most affected anterior teeth (40.83 %), followed by lateral incisors (39.60 %) and central incisors (19.55 %). Of the patients, 81 (22.19 %) had type I talon cusp with two periapical pathologies, 114 (31.23 %) had type II talon cusp with four periapical pathologies and 226 (61.91 %) had type III talon cusp with also four periapical pathologies.

Conclusions

The occurrence of talon cusps was higher than other studies reported in the literature, with an exception of the study in Alaskan Eskimos. The most commonly detected type of talon cusp was type III (61.91 %), and dens invaginatus was the most frequent variation observed with talon cusps.

     

Intrafamilial variability of XYLT2-related spondyloocular syndrome

Spondyloocular syndrome is characterized by generalized osteoporosis, multiple fractures and severe ocular findings. The causative XYLT2 mutations have recently been identified with the use of whole exome sequencing. We report on two siblings with spondyloocular syndrome who presented with varying clinical severity. A novel XYLT2 missense mutation was detected in a region evolutionary conserved across the species. This report along with the previous reports demonstrates that variable expressivity may be possible even within the same family. These two siblings with a novel mutation further expand the clinical and mutational spectrum of spondyloocular syndrome.     

Expression of vascular endothelial growth factor in human periodontal tissues: comparison of healthy and diabetic patients

BACKGROUND: Vascular endothelial growth factor (VEGF) induces proliferation of endothelial cells, stimulates angiogenesis, and increases vascular permeability, but information about its role in periodontal lesions is limited. The aim of this study is to determine the association between VEGF expression in healthy and periodontally diseased tissues of healthy and diabetic patients. METHODS: Ten systemically healthy and 10 Type 2 diabetic patients (DM) all diagnosed with periodontitis were enrolled into the study. Gingival samples were collected from both periodontal and healthy sites in all patients. Each patient served as his/her own control. Additionally, 10 people without any systemic or periodontal diseases were enrolled as a negative control group. RESULTS: In the negative control group tissue samples, no VEGF expression was observed. Among the 10 systemically healthy people, no evidence of VEGF was observed in healthy gingival samples, but was found in diseased tissues in 2 cases. In the diabetic patients, VEGF was observed in 4 healthy gingival tissues and in 6 periodontal sites. VEGF was intensely present in monocytes and macrophages. CONCLUSION: The results of this study show that VEGF is increased in gingival tissues of diabetic patients, especially those with periodontal disease.