Increased expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and MMP10, MMP23 in inflammatory bowel disease: Cross‐sectional study

It has been reported that EMMPRIN is involved in the regulation of immune response and the induction of MMPs production by fibroblasts. The aim of this study was to describe the intestinal gene expression and protein production of EMMPRIN, MMP23 and MMP10 in patients with ulcerative colitis (UC) and Crohn’s disease (CD) and compared them with a control group. Gene expression of EMMPRIN, MMP10 and MMP23B was measured by RT‐PCR. In order to determine EMMPRIN and MMP protein expression, colonic tissues were immunostained. The results of the study showed EMMPRIN gene expression was upregulated in rectal mucosa from active (a)UC versus aCD patients (P = .045), remission (r)CD group (P = .0009) and controls (P < .0001). We detected differences between rUC and aCD (P = .004), rCD (P < .0001) or control group (P < .0001). EMMPRIN showed a higher expression in mucosa (intraepithelial lymphocytes), submucosa and adventitia (endothelial cells) from aCD patients. MMP23 levels were increased in aUC and aCD compared to rUC and rCD and the control group (P = .0001). EMMPRIN+/MMP23+─expressing cells were localized mainly in mucosa, muscular and adventitia from active UC patients. MMP10 gene expression was increased in aUC versus CD patients and the control group (P = .0001). MMP10 gene expression is associated with inflammation in UC patients (P = .0001, r² = .585). EMMPRIN+/MMP10+─producing cells were found mainly in all intestinal layers and perivascular inflammatory infiltrates from aUC patients. In conclusion, EMMPRIN, MMP23 and MMP10 were upregulated in patients with active UC versus remission UC , CD and control groups suggesting that, they are involved in the inflammatory process.     

New thiazolyl-pyrazoline derivatives bearing nitrogen mustard as potential antimicrobial and antiprotozoal agents

A new series of N-substituted pyrazoline derivatives 6a–g , 7a–g , 8a–g , and 9a–g was synthetized by reaction of hydrazine derivatives and chalcone–thiazole hybrids bearing nitrogen mustard 5a–g . The chalcones 5a–g were obtained by Claisen–Schmidt condensation of thiazole-2-nitrogen mustard 3 and selected acetophenones 4a–g . These new compounds 6/7/8/9a–g were screened for their antifungal activity against Cryptococcus neoformans, with IC₅₀ values of 3.9–7.8 µg/ml for the N-3,5-dichlorophenyl pyrazolines 9e – g . Interestingly, those compounds show low cytotoxic effects toward erythrocytes (RBC). In addition, N-acetyl ( 6a,b ) and N-formyl pyrazolines ( 7a , 7b , 7c , and 7g ) showed inhibitory activity against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, and vancomycin-intermediate S. aureus, with the most important minimum inhibitory concentration values ranging from 31.25 to 125 µg/ml. Regarding the antiprotozoal activity, thiazolyl-pyrazolines 9g , 8f , and 7c display high activity against Plasmodium falciparum, Leishmania (V) panamensis, and Trypanosoma cruzi, with EC₅₀ values of 11.80, 6.46, and 4.98 μM, respectively, and with 7c being approximately 2.6-fold more potent than benznidazole with a selectivity index of 1.61 on U-937 human cells, showing promising potential as a novel antitrypanosomal agent.     

Treatment of a second maxillary molar with six canals

Variations in the dental anatomy are found in all teeth. Knowledge of these variations, particularly concerning the location and treatment of all canals, is very important for the success of the endodontic therapy. The purpose of this study is to present a clinical case of a maxillary second molar with three palatal canals, two mesio-buccal and one disto-buccal canal. This report serves to remind clinicians that such anatomical variations should be taken into account during endodontic treatment of the maxillary molars.     

Very Long-Term Prognostic Role of Admission BNP in Non-ST Segment Elevation Acute Coronary Syndrome

Background

BNP has been extensively evaluated to determine short- and intermediate-term prognosis in patients with acute coronary syndrome, but its role in long-term mortality is not known.

Objective

To determine the very long-term prognostic role of B-type natriuretic peptide (BNP) for all-cause mortality in patients with non-ST segment elevation acute coronary syndrome (NSTEACS).

Methods

A cohort of 224 consecutive patients with NSTEACS, prospectively seen in the Emergency Department, had BNP measured on arrival to establish prognosis, and underwent a median 9.34-year follow-up for all-cause mortality.

Results

Unstable angina was diagnosed in 52.2%, and non-ST segment elevation myocardial infarction, in 47.8%. Median admission BNP was 81.9 pg/mL (IQ range = 22.2; 225) and mortality rate was correlated with increasing BNP quartiles: 14.3; 16.1; 48.2; and 73.2% (p < 0.0001). ROC curve disclosed 100 pg/mL as the best BNP cut-off value for mortality prediction (area under the curve = 0.789, 95% CI= 0.723-0.854), being a strong predictor of late mortality: BNP < 100 = 17.3% vs. BNP ≥ 100 = 65.0%, RR = 3.76 (95% CI = 2.49-5.63, p < 0.001). On logistic regression analysis, age >72 years (OR = 3.79, 95% CI = 1.62-8.86, p = 0.002), BNP ≥ 100 pg/mL (OR = 6.24, 95% CI = 2.95-13.23, p < 0.001) and estimated glomerular filtration rate (OR = 0.98, 95% CI = 0.97-0.99, p = 0.049) were independent late-mortality predictors.

Conclusions

BNP measured at hospital admission in patients with NSTEACS is a strong, independent predictor of very long-term all-cause mortality. This study allows raising the hypothesis that BNP should be measured in all patients with NSTEACS at the index event for long-term risk stratification.     

Anticancer activity of pyrimidodiazepines based on 2-chloro-4-anilinoquinazoline: synthesis,DNA binding and molecular docking

Multidrug resistance to chemotherapy is a critical health problem associated with mutation of the therapeutic target. Therefore, the development of anticancer agents remains a challenge to overcome cancer cell resistance. Herein, a new series of quinazoline-based pyrimidodiazepines 16a–g were synthesized by the cyclocondensation reaction of 2-chloro-4-anilinoquinazoline-chalcones 14a–g with 2,4,5,6-tetraaminopyrimidine. All quinazoline derivatives 14a–g and 16a–g were selected by the U.S. National Cancer Institute (NCI) for testing their anticancer activity against 60 cancer cell lines of different panels of human tumors. Among the tested compounds, quinazoline-chalcone 14g displayed high antiproliferative activity with GI₅₀ values between 0.622–1.81 μM against K-562 (leukemia), RPMI-8226 (leukemia), HCT-116 (colon cancer) LOX IMVI (melanoma), and MCF7 (breast cancer) cancer cell lines. Additionally, the pyrimidodiazepines 16a and 16c exhibited high cytostatic (TGI) and cytotoxic activity (LC₅₀), where 16c showed high cytotoxic activity, which was 10.0-fold higher than the standard anticancer agent adriamycin/doxorubicin against ten cancer cell lines. COMPARE analysis revealed that 16c may possess a mechanism of action through DNA binding that is similar to that of CCNU (lomustine). DNA binding studies indicated that 14g and 16c interact with the calf thymus DNA by intercalation and groove binding, respectively. Compounds 14g, 16c and 16a displayed strong binding affinities to DNA, EGFR and VEGFR-2 receptors. None of the active compounds showed cytotoxicity against human red blood cells.

A new series of quinazoline-based chalcones and pyrimidodiazepines were tested against 60 human tumor cell lines.     

Direct measurements of kinesin torsional properties reveal flexible domains and occasional stalk reversals during stepping

Kinesin is a homodimeric motor with two catalytic heads joined to a stalk via short neck linkers (NLs). We measured the torsional properties of single recombinant molecules by tracking the thermal angular motions of fluorescently labeled beads bound to the C terminus of the stalk. When kinesin heads were immobilized on microtubules (MTs) under varied nucleotide conditions, we observed bounded or unbounded angular diffusion, depending on whether one or both heads were attached to the MT. Free rotation implies that NLs act as swivels. From data on constrained diffusion, we conclude that the coiled-coil stalk domains are ≈30-fold stiffer than its flexible “hinge” regions. Surprisingly, while tracking processive kinesin motion at low ATP concentrations, we observed occasional abrupt reversals in the directional orientations of the stalk. Our results impose constraints on kinesin walking models and suggest a role for rotational freedom in cargo transport.     

Lack of adaptation to severe malnutrition in elderly patients

BACKGROUND & AIMS: Sarcopenia is a common feature in the healthy elderly. However, little is known on age-related modifications of body composition in malnourished patients. The aims of this cross-sectional study were to evaluate the effects of aging per se on body composition and resting energy expenditure (REE) in malnourished patients. METHODS: Ninety-seven non-stressed patients referred for chronic malnutrition (C-reactive protein <5 mg/l) were separated into two groups: middle-aged (26 female, 19 male, 48+/-15 yr), and elderly (26 female, 26 male, 79+/-6 yr). Body composition was assessed by bioelectrical impedance analysis and REE by indirect calorimetry. RESULTS: In middle-aged patients, body composition remained stable between moderate (body-mass index [BMI; in kg/m(2)] 16-18.5) and severe (BMI < 16) malnutrition, with similar values of fat-free mass (FFM), body cell mass (BCM) and fat mass (FM) as percentages of body weight, whereas in elderly patients malnutrition occurred at the expense of FFM and BCM, with unchanged FM absolute values. REE/FFM values remained stable in middle-aged patients at every stage of malnutrition, whereas they increased in elderly patients along with their degree of malnutrition. In multivariate analysis, both body composition and REE/FFM were influenced by sex, age, BMI and mid-arm circumference. CONCLUSION: Compared to younger patients, weight loss in the elderly leads to cachexia, with a preferential loss of FFM and BCM that may participate in the more severe outcomes observed in these patients. They also show elevated REE/FFM values that induce higher energy needs.     

The microbiological transformation of two 15beta-hydroxy-ent-kaurene diterpenes by Gibberella fujikuroi

The incubation of 15beta-hydroxy-3-oxo-ent-kaur-16-ene (1) with the fungus Gibberella fujikuroi afforded 11beta-hydroxy-3,15-dioxo-ent-kaurane (6), 11beta,15beta-dihydroxy-3-oxo-ent-kaur-16-ene (8), 7beta,11beta,15beta-trihydroxy-3-oxo-ent-kaur-16-ene (9), 7alpha,11beta-dihydroxy-3,15-dioxo-ent-kaurane (7), and 7alpha,11beta,15beta-trihydroxy-3-oxo-ent-kaur-16-ene (10). The incubation of 15beta-hydroxy-ent-kaur-2,16-diene (3) with the same fungus yielded 7alpha,11beta-dihydroxy-15-oxo-ent-kaur-2-ene (12), 7alpha,11beta,15beta-trihydroxy-ent-kaur-2,16-diene (13), 7beta,15beta-dihydroxy-ent-kaur-2,16-dien-19,6-olide (14), 1beta,7beta,15beta-trihydroxy-ent-kaur-2,16-dien-19-oic acid (15), 7alpha,11beta,16alpha-trihydroxy-15-oxo-ent-kaur-2-ene (17), and 7alpha,15beta,17-trihydroxy-11beta,16beta-epoxy-ent-kaur-2-ene (19). These results indicated that a 3-oxo group in ent-kaur-16-ene derivatives inhibits the oxidation at C-19, typical of the biosynthetic pathway of gibberellins and kaurenolides, while a 2,3-double bond or a 15beta-OH does not. In both substrates a 15beta-alcohol directs hydroxylations at C-11(beta) and C-7(alpha), while in those with a 2,3-double bond the functionalization of C-1(beta) is favored.