Manoalide derivatives from a sponge, Luffariella sp.

A new derivative of manoalide, 24-n-propyl-O-manoalide (1) together with manoalide (4) and four known derivatives (2, 3, 5, 6) were isolated from the methanolic extract of a sponge. Their structures were elucidated on the basis of spectroscopic method. All the compounds showed significant cytotoxicity against HCT-116 cell line by MTS assay. Secomanoalide indicated antifungal activity on fungal lines Candida glabrata, Candida krusei and Candida albicans by in vitro antibiotic assay.     

Evaluation of a prototype dengue-1 DNA vaccine in a Phase 1 clinical trial

Candidate dengue DNA vaccine constructs for each dengue serotype were developed by incorporating pre-membrane and envelope genes into a plasmid vector. A Phase 1 clinical trial was performed using the dengue virus serotype-1 (DENV-1) vaccine construct (D1ME¹⁰⁰). The study was an open-label, dose-escalation, safety and immunogenicity trial involving 22 healthy flavivirus-naïve adults assigned to one of two groups. Each group received three intramuscular injections (0, 1, and 5 months) of either a high dose (5.0 mg, n = 12) or a low dose (1.0 mg, n = 10) DNA vaccine using the needle-free Biojector^® 2000. The most commonly reported solicited signs and symptoms were local mild pain or tenderness (10/22, 45%), local mild swelling (6/22, 27%), muscle pain (6/22, 27%) and fatigue (6/22, 27%). Five subjects (41.6%) in the high dose group and none in the low dose group developed detectable anti-dengue neutralizing antibodies. T-cell IFN gamma responses were detected in 50% (4/8) and 83.3% (10/12) of subjects in the low and high dose groups, respectively. The safety profile of the DENV-1 DNA vaccine is acceptable at both doses administered in the study. These results demonstrate a favorable reactogenicity and safety profile of the first in human evaluation of a DENV-1 DNA vaccine.     

Synthesis and biological activity of tricyclic cycloalkylimidazo-, pyrimido- and diazepinopurinediones

Syntheses and physicochemical properties of N-cycloalkyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones are described. These derivatives were synthesized by cyclization of 7-halogenoalkyl-8-bromo-1,3-dimethylxanthine derivatives with aminocycloalkanes. The obtained compounds (1-33) were evaluated for their affinity to rat adenosine A₁ and A_2A receptors. Selected compounds were additionally investigated for affinity to the human A₁, A_2A, A_2B and A₃ receptor subtypes. The results of the radioligand binding assays at adenosine A₁ and A_2A receptors showed that most of the compounds exhibited adenosine A_2A receptor affinity at micromolar or submicromolar concentrations; an annelated pyrimidine ring was beneficial for A_2A affinity. The most potent A_2A ligands of the present series were compounds 6 (K_i 0.33 μM rat A_2A, 0.31 μM human A_2A), 8 (K_i 0.98 μM rat A_2A, 0.42 μM human A_2A) and 15 (K_i 0.24 μM rat A_2A, 0.61 μM human A_2A) with the latter one showing high A_2A selectivity. In NaCl shift assay, 15 was shown to be an antagonist at A_2A receptors. This result was confirmed for the best compounds 6, 8, 15 in cAMP accumulation studies. A 3D-QSAR equation with a good predicting power (q² = 0.88) for A_2A AR affinity was obtained. The compounds were evaluated in vivo as anticonvulsants in MES and ScMet tests and examined for neurotoxicity in mice (i.p.). Most of them showed anticonvulsant activity in chemically induced seizures; among them the diazepinopurinediones were the best (e.g. 31) showing protection in both tests on short time symptoms, without signs of neurotoxicity. Five compounds, 8, 17, 20, 29, and 31, exhibited anticonvulsant activity after peroral application in rats. Structure-activity relationships are discussed including the analysis of lipophilic and spatial properties. The new compounds, which contain a basic nitrogen atom and can therefore be protonated, may be good starting points for obtaining A_2A antagonists with good water-solubility.     

Indicator-based assessment of environmental hazards and health effects in the industrial cities of upper Silesia,Poland

Using an indicator-based approach, we assessed environmental hazards and related health effects in populations of industrial cities with more than 100,000 inhabitants in Upper Silesia, Poland, and analyzed the relationship between environment and health. We adopted the method developed by Dutkiewicz et al. for assessing large geographic areas. Based on routinely collected environmental and health data, two groups of indicators, environmental indicators (EIs) and health status indicators (HSIs), related to environmental contamination were selected. The EI and HSI values were normalized and aggregated into synthetic measures using Strahl's taxonometric method. The synthetic measures indicated the intensity of environmental hazards and health outcomes. We used a three-level index scale to compare and rank the cities under the study and, consequently, to facilitate decision making. Findings of the assessment identified cities where actions aimed at reducing environmental hazards and improving population health status should be established as priorities. These cities included Chorzów, Katowice, Sosnowiec, Bytom, and Zabrze. We found a high correlation between the synthetic measures of environmental indicators and the synthetic measure of health status indicators (r = 0.77), as well as a high level of consistency between environmental hazard indices and environmental-related health status indices (73%). This may indicate the existence of a causal relationship between the environmental contamination within industrial cities and the health status of their inhabitants.     

Improvement in Parameters of Hematologic and Immunologic Function and Patient Well-being in the Phase III RESONATE Study of Ibrutinib Versus Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Background

Ibrutinib compared with ofatumumab significantly improves progression-free and overall survival in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Investigations of anti-inflammatory and analgesic activities of prednisolone solid dispersion prepared with skimmed milk

Prednisolone is an analgesic and anti-inflammatory drug. It possesses poor aqueous solubility and has irritant effects on stomach mucosa. In order to modulate its gastric side effect and increase aqueous solubility, physical mixture and solid dispersion of prednisolone were prepared with skimmed milk. In this study, anti-inflammatory and analgesic effects of these formulations were investigated in comparison to the plain drug itself employing hind paw edema test and Randall's analgesia test. Based on the data, it was determined that the drug maintained its pharmacological activity even after formulating in the form of physical mixture and solid dispersion.     

Hodgkin's type of Richter's syndrome in familial chronic lymphocytic leukemia treated with cladribine and cyclophosphamide

Second malignancies are frequent complications in patients with chronic lymphocytic leukemia (CLL). Hodgkin's disease (HD) has been observed in approximately 0.5% of the patients with CLL and is known as Hodgkin's type Richter's syndrome (H-RS). We present a 64-year-old male patient with a familial history of CLL who developed H-RS in abdominal lymph nodes 6 years after CLL diagnosis and 18 months after treatment with cladribine (2-CdA) and cyclophosphamide. HD was diagnosed by fine needle aspiration. The disease was refractory to treatment with two courses of CHOP and three courses of ABVD chemotherapy. In the current literature we found case reports of only 6 patients with H-RS who were treated with fludarabine (FA) before transformation, and, to our knowledge the presented patient is the first to develop H-RS after treatment with 2-CdA combined with cyclophosphamide. He is also the first published patient with familial CLL in whom this complication developed.     

Evaluation of Certain Risk Factors for Lung Cancer in Cracow (Poland): A Case-Control Study

The relationship of lung cancer risk to cigarette smoking, occupational exposure, air pollution at permanent residence and usual frequency of consumption of fruits and vegetables was analysed in a case-control study in Cracow, Poland. The cases were 176 male lung cancer patients diagnosed in 1992-1994 with histological confirmation of the diagnosis, obtained from the population-based Cracow Cancer Registry, and 341 controls randomly selected from the general population. Classification of exposure to outside air pollution was based on measured level of total suspended particular matter and sulphur dioxide by particular districts of town (from 1973 to 1980). Except calculation of odds ratios for male lung cancer associated with exposures among all study subjects, the association between lung cancer risk and frequency of consumption of fruit and vegetables was examined among drinkers of vodka above average. Risk of lung cancer was increased significantly with increasing number of pack-years of smoking (OR = 18.7 for more than 40 pack-years). The significant inverse association of frequent usual consumption of boiled vegetables was present both among all subjects and among vodka drinkers (OR = 4.6 and 12.5, respectively, for a rare consumption). The risk of male lung cancer was negatively associated with the level of air pollution but positively with the percentage of occupationally exposed. Our study provides no evidence of a significant harmful effect of air pollution and found a strong inverse association between frequent fruit and vegetables consumption and lung cancer risk.     

Mild cerebral hypoxia–ischemia produces a sub-acute transient inflammatory response that is less selective and prolonged after a substantial insult

Cerebral ischemia initiates various injurious processes including neuroinflammatory responses such as activation of microglia and increases in cytokine and nitric oxide release. Evidence primarily from in vitro studies, indicates that neuroinflammatory effects can be either beneficial or harmful, possibly related to stimulus strength. We investigated using in vivo models, the effect of a mild or substantial cerebral hypoxia–ischemia on: cerebral microglial/macrophage activation (ED1), pro-inflammatory cytokines (tumor necrosis factor-alpha), nitrosative stress (nitrotyrosine) and permanent brain damage. A mild insult produced a transient (1–2 days post) increase in activated microglia/macrophages within subcortical white and not gray matter but transiently increased cytokine or nitrotyrosine expression in cortex and not white matter. There was also prolonged scattered cell death in cortex and white matter over weeks along with loss of myelin/axons and cortical atrophy at 4 weeks post-insult. In contrast, a substantial insult produced white and gray matter necrosis, cyst formation and atrophy, along with increases in tumor necrosis factor and nitrotyrosine staining within both white and gray matter starting at 1–2 days post-insult. Microglial/macrophage staining was increased starting at 1-week post a substantial insult and remained elevated for weeks thereafter.Thus, a transient neuroinflammatory response occurs following a mild insult whereas prolonged scattered cell death occurs for weeks, particularly in white matter. Insult severity also affects the progression of the neuroinflammatory response, which is prolonged after a substantial insult. Effective therapy will need to be customized for insult severity and timing; and, monitoring the injury processes with imaging or biomarkers may help guide treatment.