EGFR-Targeted Pentacyclic Triterpene Analogues for Glioma Therapy.

Glioma, particularly its most malignant form, glioblastoma multiforme (GBM), is the most common and aggressive malignant central nervous system tumor. The drawbacks of the current chemotherapy for GBM have aroused curiosity in the search for targeted therapies. Aberrantly overexpressed epidermal growth factor receptor (EGFR) in GBM results in poor prognosis, low survival rates, poor responses to therapy and recurrence, and therefore EGFR-targeted therapy stands out as a promising approach for the treatment of gliomas. In this context, a series of pentacyclic triterpene analogues were subjected to in vitro and in silico assays, which were conducted to assess their potency as EGFR-targeted anti-glioma agents. In particular, compound 10 was the most potent anti-glioma agent with an IC50 value of 5.82 µM towards U251 human glioblastoma cells. Taking into account its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), compound 10 exerts selective antitumor action towards Jurkat human leukemic T-cells. This compound also induced apoptosis and inhibited EGFR with an IC50 value of 9.43 µM compared to erlotinib (IC50 = 0.06 µM). Based on in vitro and in silico data, compound 10 stands out as a potential orally bioavailable EGFR-targeted anti-glioma agent endowed with the ability to cross the blood-brain barrier (BBB).

Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity.

Imatinib, an Abelson (ABL) tyrosine kinase inhibitor, is a lead molecular-targeted drug against chronic myelogenous leukemia (CML). To overcome its resistance and adverse effects, new inhibitors of ABL kinase are needed. Our previous study showed that the benzyl ester of gypsogenin (1c), a pentacyclic triterpene, has anti-ABL kinase and a subsequent anti-CML activity. To optimize its activities, benzyl esters of carefully selected triterpenes (PT1-PT6), from different classes comprising oleanane, ursane and lupane, and new substituted benzyl esters of gypsogenin (GP1-GP5) were synthesized. All of the synthesized compounds were purified and charachterized by different spectroscopic methods. Cytotoxicity of the parent triterpenes and the synthesized compounds against CML cell line K562 was examined; revealing three promising compounds PT5, GP2 and GP5 (IC50 5.46, 4.78 and 3.19 µM, respectively). These compounds were shown to inhibit extracellular signal-regulated kinase (ERK) downstream signaling, and induce apoptosis in K562 cells. Among them, PT5 was identified to have in vitro activity (IC50 = 1.44 µM) against ABL1 kinase, about sixfold of 1c, which was justified by molecular docking. The in vitro activities of GP2 and GP5 are less than PT5, hence they were supposed to possess other more mechanisms of cytotoxicity. In general, our design and derivatizations resulted in enhancing the activity against ABL1 kinase and CML cells.

[Psychosocial burden and strains in geriatric nursing: comparison of nursing personnel with and without migration background]. / Psychosoziale Belastungen und Beanspruchungen in der Altenpflege: Vergleich zwischen Pflegekräften mit und ohne Migrationshintergrund.

BACKGROUND: Because of demographic changes the nursing care sector is faced with a lack of qualified employees in the medium and long term. The shortage in the work force is caused by high workloads and unfavorable working conditions. In response to this shortage, there have been attempts to recruit qualified nursing staff from abroad and also to improve the integration of people with a migration background living in Germany into the job market. METHODOLOGY: Based on a quantitative cross-sectional study of 366 nurses, the psychosocial burden and strains among employees with a migration background (n = 112) and without a migration background (n = 254) were examined. For this purpose, 13 scales of the German version of the Copenhagen Psychosocial Questionnaire (COPSOQ) were used for the assessment of psychosocial factors at work. The results were compared with professional group-specific reference values (geriatric care) from the COPSOQ database. RESULTS: The comparison of nursing staff with and without a migration background revealed that the emotional demands, work-privacy conflict and role conflicts factors received a significantly better rating among nursing staff with a migration background, while development opportunities were rated worse by this population group. The surveyed nursing staff exhibited higher stress values compared to the COPSOQ reference group in almost all scales. CONCLUSION: Nursing staff with a migration background need to be supported with respect to development opportunities. Suitable education and training measures may offer adequate career perspectives and may encourage employees to stay in their jobs.

Effect of mouthwashes on the discolouration of restorative materials commonly used in paediatric dentistry.

AIM: This was to investigate the effects of Klorhex, Tantum Verde, Kloroben, and Listerine on the discolouration of composite resin, compomer, giomer, and resin-modified glass ionomer. METHODS: Fifty disc-shaped specimens from each restorative material (n = 50) were prepared; initial colour values were measured with a spectrophotometer. Forty specimens from each group were placed in the four different types of mouthwashes (n = 10), while the remaining 10 specimens were immersed in distilled water for 2 min, twice a day for a period of 3 weeks. Colour change (ΔE*) values were obtained and the results were evaluated statistically. RESULTS: The ΔE* of composite resin in Klorhex (0.84 ± 0.37) was significantly lower than that of the other mouthwash groups. Moreover, composite resin showed the least colour change when compared with the other materials in all four mouthwashes. Resin-modified glass ionomer values were significantly higher in Tantum Verde (6.36 ± 2.82) when compared with the other mouthwashes (p < 0.05). Clinically appreciable discolourations were observed in the resin-modified glass ionomer specimens placed in Tantum Verde and Listerine. CONCLUSIONS: Nano-filling composite resins are the most successful aesthetic restorative materials, whereas the commonly used resin-modified glass ionomers exhibit more aesthetically divergent results following the use of mouthwashes.

Subjective burden of family caregivers with Turkish immigration background in Germany : Validation of the Turkish version of the Burden Scale for Family Caregivers.

BACKGROUND: Subjective burden is a central variable for describing the situation of family caregivers. Up to now the subjective burden of family caregivers with Turkish immigration background in Germany has not been quantitatively investigated. OBJECTIVES: The aim of this study was the validation of the Turkish version of the Burden Scale for Family Caregivers (BSFCtr). MATERIAL AND METHODS: In order to measure the subjective burden of family caregivers with Turkish immigration background, the BSFC was translated into Turkish. The internal consistency of the 28-item BSFCtr was calculated using Cronbach's alpha. The difficulty indices and discriminating powers of the items were analyzed. The construct validity was examined by using three hypotheses of association. RESULTS: The cross-sectional study was conducted on 49 family caregivers with a Turkish immigration background in Germany who care for older, chronically ill persons. Cronbach's alpha for the total scale was 0.89. The caregiver burden was greater when the care recipient had substantial regular nursing care needs and when the spouse or partner had assumed the care as compared with the children or children-in-law. Caregiver burden significantly increased with the extent of psychosomatic symptoms of the caregiver. CONCLUSION: The Turkish version of the BSFC proved to be a reliable and valid measure for determining the subjective burden of family caregivers.

[Turkish emigrants in Germany. Deficits in home care knowledge and health services - a review]. / Türkische Migranten in Deutschland. Wissens- und Versorgungsdefizite im Bereich häuslicher Pflege - ein Überblick.

Family members caring for relatives at home are often under great stress. Numerous studies have shown that taking care of a chronically ill family member may have negative effects on physical and emotional health. Frequent symptoms observed in family caregivers are insomnia, joint pain, physical exhaustion, and depression. There are, as yet, no definitive empirical studies in Germany on the subjective burden of family caregivers in Turkish families and on their specific needs for help, although their numbers are increasing exponentially. The statement based on the low rate of use of professional care by Turkish families in Germany that there is great willingness among Turkish families to take care of family members at home - a self-evident part of the concept of family - should not lead to the assumption that care causes less stress in this population. There is a great need for research into the way in which the care situation and the changes attendant thereon are experienced by Turkish family caregivers. Recording of subjective burden and individual needs is important to develop accepted strategies to relief Turkish family caregivers.

The risk of malignancy index in discrimination of adnexal masses.

OBJECTIVE: To assess the ability of the risk of malignancy index (RMI) based on a serum CA125 level, ultrasound findings and menopausal status, to discriminate benign from malignant adnexal masses. METHOD: Between September 2002 and November 2004, 296 women with adnexal masses were enrolled. The sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of the CA125 serum level, ultrasound findings and menopausal status in prediction of ovarian cancer were calculated and compared individually or combined into the RMI. RESULTS: The RMI identified malignant cases more accurately than any individual criterion in diagnosing ovarian cancer. Using a cut-off level of 153 to indicate malignancy, the RMI showed a sensitivity of 76.4%, a specificity of 77.9%, a PPV of 65.9%, a NPV of 85.5% with 79.4% correct diagnosis rate. CONCLUSION: The RMI is an appropriate method in diagnosing adnexal masses with high risk of malignancy and forwarding to gynecological oncology centers for suitable surgical operations.

[Name-based identification of cases of Turkish origin in the childhood cancer registry in Mainz]. / Namensbasierte Identifizierung von Fällen mit türkischer Herkunft im Kinderkrebsregister Mainz.

Until now few analyses of routine data relating to the health of migrants have been conducted in Germany. A major obstacle is that most data sources do not provide reliable information on the origin of migrants. While some sources contain the nationality of persons registered, this information does not allow one to identify migrants who have taken up German citizenship, i.e., a substantial part of second-generation migrants. In this paper we demonstrate how a computer-aided, name-based algorithm can be used to identify persons of Turkish origin in the German Childhood Cancer Registry in Mainz, Germany. The performance of the algorithm, as assessed against the gold standard of assessing names manually, was very good (sensitivity and specificity > or = 0.975). In total, we identified 1774 of the 37,259 cases in the registry as being of Turkish origin. The name algorithm proved to be a useful tool to identify Turkish migrants in routine data sources, thus avoiding potential bias due to changes in citizenship. This approach aims at improving migrant-sensitive health reporting and research in Germany. In future, additional information on migrant status should be obtained already during primary data collection so that health data for all migrant groups can be provided.

Inhibition of gastric emptying by acarbose is correlated with GLP-1 response and accompanied by CCK release.

We investigated the effect of acarbose, an alpha-glucosidase and pancreatic alpha-amylase inhibitor, on gastric emptying of solid meals of varying nutrient composition and plasma responses of gut hormones. Gastric emptying was determined with scintigraphy in healthy subjects, and all studies were performed with and without 100 mg of acarbose, in random order, at least 1 wk apart. Acarbose did not alter the emptying of a carbohydrate-free meal, but it delayed emptying of a mixed meal and a carbohydrate-free meal given 2 h after sucrose ingestion. In meal groups with carbohydrates, acarbose attenuated responses of plasma insulin and glucose-dependent insulinotropic polypeptide (GIP) while augmenting responses of CCK, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY). With mixed meal + acarbose, area under the curve (AUC) of gastric emptying was positively correlated with integrated plasma response of GLP-1 (r = 0.68, P < 0.02). With the carbohydrate-free meal after sucrose and acarbose ingestion, AUC of gastric emptying was negatively correlated with integrated plasma response of GIP, implying that prior alteration of carbohydrate absorption modifies gastric emptying of a meal. The results demonstrate that acarbose delays gastric emptying of solid meals and augments release of CCK, GLP-1, and PYY mainly by retarding/inhibiting carbohydrate absorption. Augmented GLP-1 release by acarbose appears to play a major role in the inhibition of gastric emptying of a mixed meal, whereas CCK and PYY may have contributory roles.

Gender influence on jejunal migrating motor complex.

The role of gender and the menstrual cycle in small bowel motility has not been clearly elucidated. Jejunal motility was recorded with a nasojejunal catheter incorporating five solid-state pressure transducers in ambulatory menstruating women and men of comparable age over 24 h. All women were studied twice, in the early follicular (early-F) and midluteal (mid-L) phases of the menstrual cycle, verified by determining serum levels of gonadal steroids and gonadotropins. The propagation velocity of phase III was slow and the contraction amplitude was high in both menstrual cycle phases compared with men, and these parameters were correlated with serum estrogen levels in the mid-L phase. In the early-F phase, migrating motor complex (MMC) cycle duration during sleep was long compared with other groups and positively correlated with estrogen concentrations, whereas in the mid-L phase MMC cycle duration during sleep was negatively correlated with serum progesterone levels. In all groups, the frequency of phase III contractions was low and the intercontractile interval measured from pressure peak to peak was long during sleep compared with the awake state. Postprandial motility did not display gender difference in any parameter examined. The results demonstrate that the majority of patterns of motility are similar in menstruating women and men, whereas certain aspects of the MMC, most conspicuously propagation velocity and phase III contraction amplitude, differ. We have also documented circadian variation of phase III contraction frequency in both women and men.

Synthesis and antimicrobial activity of some 1,2,4-triazole-3-mercaptoacetic acid derivatives.

Ethyl 5-(2-furyl)-4-ethyl-1,2,4-triazole-3-mercaptoacetate (2), 5-(2-furyl)-4-ethyl-1,2,4-triazole-3-mercaptoacetic acid hydrazide (3) and a series of new N-alkylidene/arylidene-5-(2-furyl)-4-ethyl-1,2,4-triazole-3-mercaptoacetic acid hydrazides (4a-f) were synthesized and evaluated for in vitro antibacterial activity against Staphylococcus aureus ATCC 6538. Staphylococcus epidermidis ATCC 12228, Klebsiella pneumoniae ATCC 4352, Pseudomonas aeruginosa ATCC 1539, Escherichia coli ATCC 8739, Shigella flexneri, Salmonella typhi, Proteus mirabilis and antifungal activity against Candida albicans ATCC 10231 using the disk diffusion and microdilution methods. Compound 4f showed antibacterial activity against some bacteria. The in vitro antimycobacterial activity of the new compounds against Mycobacterium tuberculosis H37Rv was evaluated employing the BACTEC 460 radiometric system. The highest inhibition observed was 61% at > 6.25 microg/ml.

Synthesis of some 4-(alkylidene/arylidene)amino-2,4-dihydro-5- (2-thienyl)-3H-1,2,4-triazole-3-thiones tested for antimicrobial activity.

A series of 4-(alkylidene/arylidene)amino-2,4-dihydro-5- (2-thienyl)-3H-1,2,4-triazole-3-thiones (2a-h) were synthesized. The structural elucidation of all the compounds was made on the basis of analytical and spectral data (IR, 1H-NMR and EIMS). All synthesized compounds were evaluated for in vitro antimicrobial activity against various bacteria and fungi. Some of the compounds demonstrated antimicrobial activity against Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, Trichophyton rubrum, Trichophyton mentagrophytes var. erinacei NCPF-375 and Microsporum canis (MIC 50-6.25 mg/ml). The in vitro antimycobacterial activity of the new compounds was also investigated. Some of the compounds showed varying degrees of inhibition (2-40%) against Mycobacterium tuberculosis H37Rv in the primary screen that was conducted at 12.5 mg/ml using the BACTEC 460 radiometric system.

Synthesis and antimicrobial activity of new 6-phenylimidazo[2,1-b]thiazole derivatives.

A series of new N2-substituted-6-phenylimidazo[2,1-b]thiazole-3-acetic acid hydrazides (2a-j) were synthesized and evaluated for in vitro antimicrobial activity against various bacteria and fungi. Some of the compounds showed antimicrobial activity against Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, Trichophyton mentagrophytes var. Erinacei NCPF-375, Trichophyton rubrum and Microsporum audounii (MIC 25-0.24 micrograms/ml). The in vitro antimycobacterial activity of the new compounds was also investigated. The compounds exhibited different degrees of inhibition (17.98%) against Mycobacterium tuberculosis H37Rv in the primary screen that was conducted at 12.5 micrograms/ml using the BACTEC 460 radiometric system.

Glucagon-like peptide (GLP-1) is involved in the central modulation of fecal output in rats.

In addition to its insulinotropic action, exogenously administered glucagon-like peptide (GLP-1) inhibits gastropancreatic motility and secretion via central pathways. The aims of the present study were to evaluate the effects of exogenous GLP-1-(7-36) amide on fecal output and to investigate the role of endogenous GLP-1 on stress-induced colonic activity. With the use of a stereotaxic instrument, adult male Sprague-Dawley rats weighing 200-250 g were fitted with stainless steel cerebroventricular guide cannulas under ketamine anesthesia. A group of rats were placed in Bollman-type cages to induce restraint stress. Fecal output monitored for 2 h was increased significantly by intracerebroventricular GLP-1 to 500, 1, 000, and 3,000 pmol/rat (P < 0.05-0.01), whereas intraperitoneal GLP-1 had no effect. Intracerebroventricular administration of the GLP-1 receptor antagonist exendin-(9-39) (10 nmol/rat) reversed the increases induced by GLP-1 (500 pmol/rat; P<0.01). Similar results were also observed with the injection of corticotropin-releasing factor receptor antagonist astressin (10 microg/rat icv). The significant increase in fecal pellet output induced by restraint stress was also decreased by both intracerebroventricular exendin (10 nmol/rat) and astressin (10 microg/rat; P<0.01-0.001). These results suggest that GLP-1 participates in the central, but not peripheral, regulation of colonic motility via its own receptor and that GLP-1 is likely to be a candidate brain-gut peptide that acts as a physiological modulator of stress-induced colonic motility.

Distinct functional muscarinic receptors in guinea-pig gallbladder, ileum and atria.

OBJECTIVE: The contractile responses of guinea-pig gallbladder smooth muscle cells have been suggested to be mediated by M3 and M4 muscarinic receptors by different research groups. Therefore, in the present study, several pharmacological properties of cholinergic functions in guinea-pig gallbladder, guinea-pig ileum (mediated via M3 receptors), and guinea-pig and rat atria (mediated via M2 receptors) were compared. METHODS: The isometric contractions of isolated guinea-pig ileum, guinea-pig gallbladder, guinea-pig and rat atrial strips in in vitro organ bath were recorded on a polygraph and the effects of carbachol, oxotremorine, McN-A-343, and clozapine have been investigated. RESULTS: Three muscarinic receptor agonists, carbachol, oxotremorine and McN-A-343 showed different order of potencies in their negative inotropic effects and contractile actions in guinea-pig gallbladder suggesting that functional muscarinic receptors in the gallbladder are distinct from those in the atria, and similar to M4-subtypes. Clozapine which was shown to have antagonistic affinity for muscarinic M1, M2, M3 and M5, but partial agonistic affinity for muscarinic M4 receptors, contracted gallbladder concentration-dependently. On the other hand, clozapine antagonised carbachol-induced ileal and gallbladder contractions and negative inotropic effects indicating that it acts like a partial agonist in the gallbladder. CONCLUSION: It was concluded that the contractile muscarinic receptors of guinea-pig gallbladder are distinct from those of atria (M2) and ileum (M3), but seem to be of M4 subtype.

5-Nitroimidazole derivatives as possible antibacterial and antifungal agents.

Some novel 1-[2-[[5-(2-furanyl)-4-substituted 4H-1,2,4-triazol-3-yl[thio[ethyl[-2-methyl-5-nitro-1H-imidazoles (3), 1-[3-[[5-(2-furanyl/2-thienyl)-4-substituted 4H-1,2,4-triazol-3-yl[-thio]-2-hydroxypropyl[-2-methyl-5-nitro-1H- imidazoles (5) and 1-[3-[(N,N-disubstituted thiocarbamoyl)-thio[-2-hydroxypropyl]-2-methyl-5-nitro-1H-imidazoles (7) were synthesized and evaluated for in vitro antibacterial and antifungal activity. Some of 5 were found to be effective against bacteria and fungi (minimum inhibitory concentration (MIC) 7.3-125 micrograms/ml), whereas 7 were found to be effective against fungi (MIC 3-25 micrograms/ml).

Synthesis and preliminary anticonvulsant activity evaluation of new 2-thioxo-4,5-imidazolidinedione derivatives.

A series of 1-substituted benzylideneamino-2-thioxo-3-allyl-4,5-imidazolidinediones (2a-j) were synthesized by the cyclization of 1-substituted benzylidene-4-allylthiosemicarbazides (1a-j) with oxalyl chloride in anhydrous ethereal medium. The structures of 2a-j were confirmed by analytical and spectral data (IR, 1H-NMR and EIMS). All synthesized compounds were evaluated for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazole (ScMet) induced seizures. Among the compounds tested, 2b and 2h exhibited some activity in anticonvulsant identification (Phase I) trials in mice.

Corticosteroid therapy augments gastroduodenal permeability to sucrose.

OBJECTIVE: The aim of the present study was to investigate whether corticosteroid therapy alters gastroduodenal mucosal permeability and whether permeability alteration is associated with macroscopic mucosal damage. METHODS: Eight patients taking oral corticosteroid therapy (total prednisone-equivalent dose, 1.5+/-0.1 g; duration, approximately 30 days), nine patients with multiple sclerosis taking high-dose intravenous methyl-prednisolone therapy (total dose, 11.7+/-0.5 g; duration, approximately 9 days), and 20 age- and gender-matched controls were studied. Gastroduodenal permeability was determined using sucrose as a site-specific permeability probe. Five-hour urine was collected after ingesting 100 g of sucrose and its urinary excretion rate was measured using high-pressure liquid chromatography. Gastroduodenal endoscopy was performed before steroid therapy to exclude subjects with evidence of macroscopic mucosal lesions. The sucrose test and endoscopy were repeated after completion of corticosteroid therapy. RESULTS: The urinary sucrose excretion rates were similar in the control group and in patient groups before corticosteroid therapy. The median excretion rate of sucrose increased four (one to 28)- and eight (two to 35)-fold, respectively, as compared with pretreatment values in patients taking oral steroid and high-dose intravenous methyl-prednisolone therapy (p < 0.01). Considering all patients together, subjects who received a mean prednisone-equivalent dose of 8.4+/-1.5 g exhibited mucosal lesions, whereas patients who received 3.3+/-1.8 g did not (p = 0.06). The post-therapy increments in sucrose excretion rates were associated with neither the presence of macroscopic lesions nor with the total steroid dose received. CONCLUSIONS: Corticosteroid therapy augments gastroduodenal permeability and high doses are associated with macroscopic mucosal lesions. Steroid-induced permeability increase does not appear to be associated with the presence of macroscopic mucosal lesions.

Thrombophilia and inflammatory bowel disease: does factor V mutation have a role?

BACKGROUND: An increased tendency for thromboembolism is a well known problem of inflammatory bowel disease (IBD). Microvascular thrombosis has also been claimed as a pathogenic factor in IBD. Recently a point mutation in the gene coding factor V (FV Leiden) has been identified in various thromboembolic diseases, but the role in IBD is unknown. OBJECTIVE: To determine the frequency of FV Leiden in IBD patients and compare with a group of controls. METHODS: Sixty-three IBD patients [43 ulcerative colitis (UC) patients and 20 Crohn's disease (CD) patients] and 36 healthy controls were included in the study. Only one of the UC patients had a history of cerebral thromboembolism. The extracted DNA from frozen blood was subjected to polymerase chain reaction for the amplification of FV gene. The amplicons were hybridized both with the mutant and wild-type probes to detect FV mutation. Readings of optical density above 0.3 were considered as positive results. According to the patterns of ELISA, heterozygosity and homozygosity for normal and mutant alleles were determined. RESULTS: Eight (18%) of UC patients were heterozygous normal and one (2%) patient had homozygous mutation. Eight (45%) of the 20 CD patients had a heterozygous pattern and one (5%) had a homozygous pattern. In the control group four (11%) subjects showed a heterozygous genotype. FV Leiden was found to be statistically more frequent in CD patients (P < 0.005) (odds ratio 6.5, 95% confidence interval 1.3-18.), but not in the UC patients as compared with controls (P> 0.05). There was no significant correlation between FV Leiden presence and disease activity, gender or disease duration for both UC and CD. CONCLUSION: The results suggest that FV Leiden is more frequent in CD patients, but not in the UC patients as compared with controls. The high rate of factor V mutation in our CD patients suggests the need for further studies to confirm a relationship between this mutation and aetiology of the disease.