Bioinversion of R-flurbiprofen to S-flurbiprofen at various dose levels in rat, mouse, and monkey

Information about the potential and extent of bioinversion of chiral drugs in laboratory animal species and humans is critical to the interpretation of preclinical pharm-tox studies with these drugs. Unlike in the dog, guinea pig, and rabbit, in humans the 2-arylpropionic acid (APA) R-flurbiprofen (R-FB) undergoes very little bioinversion to S-flurbiprofen. The primary objective of this research was to identify laboratory animal species with an R- to S-bioinversion profile similar to humans. Detailed evaluations of the pharmacokinetics parameters of R-flurbiprofen in male and female rats and mice, and male nude rats and monkeys demonstrated R- to S-bioinversion of 30% (average) in monkeys, 15-24% in mice, and approximately 4% in rats. To date, no laboratory animal species has been identified with an R-flurbiprofen bioinversion profile identical to humans. However, the rat has a bioinversion profile sufficiently similar to humans to be useful for preclinical.     

Assessment of Carcinogenic Risk and Non-Carcinogenic Health Hazard from Exposure to Toxicants in Water from the Southwestern Coastal River System in Ghana

This study evaluated cancer risk and non-cancer human health hazard from exposure to the toxicants such as As, Cu, Pb, Zn, Mn, and CN in water from a southwestern river system in Ghana that drains through gold mining areas, using 108 water samples collected with random sampling techniques and analyzed in accordance with standard methods of chemical analysis outlined by the U.S. Environmental Protection Agency (USEPA). The concentrations of Cu and Zn were within World Health Organization and USEPA guideline values; Mn, free cyanide, As, and Pb values in most cases either exceeded USEPA and WHO values or both. The concentrations of the toxicants were used as input parameters in the cancer and non-cancer study that was conducted in line with USEPA risk assessment guidelines. The results of As cancer health risk revealed higher risk cases in two locations (Potroase and Dominase); non-cancer health risk for As was higher in 10 of the 14 locations, with other metals being of health concern at few locations in the study area. In conclusion, the findings of this study hold several policy implications as residents of mining communities still depend on these water bodies as their source of drinking water.     

The impact of dance-aerobics training on the morpho-motor status in female high-schoolers

The aim of the study was to analyze the impact of special programmed physical education including dance, aerobics and rhythmic gymnastics on the development of motor and functional abilities and morphological characteristics of female fourth-grade high-schoolers in Zagreb. A total sample of 220 high-schoolers aged 16-18 years were divided into two groups: experimental group of 115 students attending the program composed of dance structures and aerobics, and control group of 105 students attending classic program of physical education. A set of 3 morphological variables, 6 motor variables and one functional variable were applied in both groups on three occasions during an academic year (initial, transient and final measurements). Two-factor analysis of variance (MANOVA repeated measure design) showed the experimental program to significantly influence the development of coordination/agility and specific rhythm coordination, functional aerobic ability, repetitive and explosive strength and flexibility, along with significant reduction of overweight and adipose tissue. Study results clearly indicate that the existing programs of physical education should be revised and replaced by more appropriate ones.     

Newer and select maize,wheat, and rice varieties can help mitigate N footprint while producing more grain

Sustainably feeding the growing population amid a changing climate and dwindling resources is a grand challenge facing mankind. Decades‐long advancement in crop breeding has progressively elevated yield potential, markedly enhancing global food production capacity. However, relevant impact on reactive N (Nr) emissions associated with crop variety improvement has not been explicitly described. Here, we report multitiered evidence that newer and select maize, wheat, and rice varieties developed in China have the capacity to substantially lower Nr losses while producing more grain. First, we pooled studies featuring side‐by‐side comparison of different varieties, totaling 269 paired observations, to demonstrate that collectively, relatively newer varieties of maize, wheat, and rice had less Nr emissions (9.6%–23.5%) while yielding more grains (7.3%–11.2%) compared to older varieties under wide‐ranging conditions. Next, we built an extended database (142 field studies with 833 observations) and comprehensively evaluated the Nr‐loss reduction potential of newer varieties (2000 and after) versus older ones (1985–1999). We found that newer varieties had Nr emission factors (N loss as a percentage of N applied after correcting for background emissions) 18.2%–75.7% less for N₂O, 18.3%–75.7% less for , and ?8.5% to 22.8% less for NH₃, while producing more grains (16.0%–24.4%). Individual varieties differed markedly in yield‐emission scores. A nationwide farmer survey (2.47 million responses) indicated tremendous opportunities for a new way of management intervention. Coupling variety selection with sound N and other agronomic management can help lower N footprint while producing more grain.     

Differential sensitivity to 4-hydroxynonenal for normal and malignant mesenchymal cells

Normal and malignant cells of various origin differ in their sensitivity to oxidative stress. Therefore, we used normal and malignant mesenchymal cells--human osteosarcoma cells (HOS and 143B), human fibroblasts (WI38) and two primary cultures of normal human osteoblasts to test sensitivity to reactive aldehyde 4-hydroxynonenal (HNE), known as a second messenger of free radicals and a signaling molecule. Upon HNE-treatment, decrease in cell viability (by Trypan-blue), apoptosis induction (by TiterTACS TUNEL assay), HNE-protein binding (by HNE-His ELISA) were higher in malignant than in normal cells, while glutathione content was higher in normal cells. These results indicate that HNE affects the growth of malignant mesenchymal cells more than normal and that this effect was mainly related to lower glutathione concentration and higher binding of HNE to the cellular proteins. We thus assume that HNE and GSH homeostasis play an important role in the growth regulation of normal and malignant mesenchymal cells.     

Unacylated Ghrelin Suppresses Ghrelin-Induced Neuronal Activity in the Hypothalamus and Brainstem of Male Rats

Ghrelin, the endogenous growth hormone secretagogue, has an important role in metabolic homeostasis. It exists in two major molecular forms: acylated (AG) and unacylated (UAG). Many studies suggest different roles for these two forms of ghrelin in energy balance regulation. In the present study, we compared the effects of acute intracerebroventricular administration of AG, UAG and their combination (AG+UAG) to young adult Wistar rats on food intake and central melanocortin system modulation. Although UAG did not affect food intake it significantly increased the number of c-Fos positive neurons in the arcuate (ARC), paraventricular (PVN) and solitary tract (NTS) nuclei. In contrast, UAG suppressed AG-induced neuronal activity in PVN and NTS. Central UAG also modulated hypothalamic expression of Mc4r and Bmp8b, which were increased and Mc3r, Pomc, Agrp and Ucp2, which were decreased. Finally, UAG, AG and combination treatments caused activation of c-Fos in POMC expressing neurons in the arcuate, substantiating a physiologic effect of these peptides on the central melanocortin system. Together, these results demonstrate that UAG can act directly to increase neuronal activity in the hypothalamus and is able to counteract AG-induced neuronal activity in the PVN and NTS. UAG also modulates expression of members of the melanocortin signaling system in the hypothalamus. In the absence of an effect on energy intake, these findings indicate that UAG could affect energy homeostasis by modulation of the central melanocortin system.     

War, mental disorder and suicide

War as a human disaster of major significance has led to an increase in the number of suicides committed by people suffering from mental disorders. Considering the results of similar research, we were particularly interested in the effect that war has on the incidence of suicide among of people with mental disorders. The research included 16,362 patients with mental disorders, treated at the Clinic for Psychiatry at the Clinical Hospital Split during the nine-year timeframe which were divided into pre-war (April 6th 1988- April 7rh 1991), wartime (April 6th 1991 -April 7rh 1994) and post-war (April 6th 1997 - April 7th 2000) periods. We studied the effects of how wartime events upon people with mental disorders in terms of their suicide rates, taking into account gender, age group, and the diagnosis under which they were treated. In our research, we found a statistically significant difference in suicide incidence between three observed periods (prewar April 6th 1988 April 7th 1991; wartime April 6th 1991 -April 7th 1994; and postwar April 6th 1997 -April 7th 2000) with the incidence being the highest during the wartime period (chi2 =9.98: p=0.007). Out of 16,362 patients treated at the clinic during the observed timeframe, a total of 78 people committed suicide. Twenty-two patients committed suicide during the first three year pre-war period; 36, during the three year wartime period; and 20, during the third three year post-war period. With this research we intended to offer a better understanding of the complexity of the suicide problem of mental patients as a phenomenon.     

Changes in skill and physical fitness following training in talent-identified volleyball players

This study investigated the effect of a skill-based training program on measurements of skill and physical fitness in talent-identified volleyball players. Twenty-six talented junior volleyball players (mean +/- SE age, 15.5 +/- 0.2 years) participated in an 8-week skill-based training program that included 3 skill-based court sessions per week. Skills sessions were designed to develop passing, setting, serving, spiking, and blocking technique and accuracy as well as game tactics and positioning skills. Coaches used a combination of technical and instructional coaching, coupled with skill-based games to facilitate learning. Subjects performed measurements of skill (passing, setting, serving, and spiking technique and accuracy), standard anthropometry (height, standing-reach height, body mass, and sum of 7 skinfolds), lower-body muscular power (vertical jump, spike jump), upper-body muscular power (overhead medicine-ball throw), speed (5- and 10-m sprint), agility (T-test), and maximal aerobic power (multistage fitness test) before and after training. Training induced significant (p < 0.05) improvements in spiking, setting, and passing accuracy and spiking and passing technique. Compared with pretraining, there were significant (p < 0.05) improvements in 5- and 10-m speed and agility. There were no significant differences between pretraining and posttraining for body mass, skinfold thickness, lower-body muscular power, upper-body muscular power, and maximal aerobic power. These findings demonstrate that skill-based volleyball training improves spiking, setting, and passing accuracy and spiking and passing technique, but has little effect on the physiological and anthropometric characteristics of players.     

New molybdenum(V) complexes based on the {Mo2O4} structural core with esters or anions of malonic and succinic acid

A series of malonato complexes of molybdenum(V) was prepared by reacting (PyH)₅[MoOCl₄(H₂O)]₃Cl₂ or (PyH)_n[MoOBr₄]_n with malonic acid (H₂mal) or a half-neutralized acid, hydrogen malonate (Hmal⁻), at ambient conditions: (PyH)₃[Mo₂O₄Cl₄(μ₂-Hmal)] · CH₃CN (1), (PyH)₃[Mo₂O₄Br₄(μ₂-Hmal)] · CH₃CN (2), (PyH)₂[Mo₂O₄Cl(η²-mal)(μ₂-Hmal)Py] (3), (3,5-LutH)₂(H₃O) [Mo₂O₄(η²-mal)₂(μ₂-Hmal)] (4), (PyH)[Mo₂O₄Cl₂(μ₂-Memal)Py₂] (5), (3,5-LutH)[Mo₂O₄Cl₂(μ₂-Memal)(3,5-Lut)₂] (6), (PyH)[Mo₂O₄Cl₂(μ₂-Etmal)Py₂] (7), (3,5-LutH)[Mo₂O₄Cl₂(μ₂-Prmal)(3,5-Lut)₂] (8) and [{Mo₂O₄(μ₂-Memal)Py₂}₂(μ₂-OCH₃)₂] (9) (where Py = pyridine, C₅H₅N; PyH⁺ = pyridinium cation, C₅H₅NH⁺; 3,5-Lut = 3,5-lutidine, C₇H₉N; 3,5-LutH⁺ = 3,5-lutidinium cation, C₇H₉NH⁺; mal²⁻ = malonate, ⁻OOCCH₂COO⁻; Memal⁻ = monomethyl malonate, ⁻OOCCH₂COOCH₃; Etmal⁻ = monoethyl malonate, ⁻OOCCH₂COOC₂H₅ and Prmal⁻ = monopropyl malonate, ⁻OOCCH₂COOC₃H₇). The complex anions of compounds 1-8 have a common structural feature: a dinuclear, singly metal-metal bonded {Mo₂O₄}²⁺ core with the carboxylate moiety of the malonato ligand coordinated in a syn-syn bidentate bridging manner to the pair of metal atoms. The remaining four coordination sites of the {Mo₂O₄}²⁺ core are occupied with halides in 1 and 2, with halides/pyridine ligands in 5-8, with a pair of bidentate malonate ions in 4 and with the combination of all in 3. The neutral molecules of 9 consist of two {Mo₂O₄}²⁺ cores linked with a pair of methoxide ions into a chain-like, tetranuclear cluster. An esterification of malonic acid was observed to take place in the reaction mixtures containing alcohols. Solvothermal reactions with malonic acid carried out at 115 °C produced anionic acetato complexes as found in (PyH)[Mo₂O₄Cl₂(μ₂-OOCCH₃)Py₂] · Py (10), (PyH)[Mo₂O₄Cl₂(μ₂-OOCCH₃)Py₂] (11), (3,5-LutH)[Mo₂O₄Cl₂(μ₂-OOCCH₃)(3,5-Lut)₂] (12) and (4-MePyH)₃[Mo₂O₄Cl₂(μ₂-OOCCH₃)(4-MePy)₂]₂Cl (13) (4-MePy = 4-methylpyridine, C₆H₇N). The acetate coordinated in the syn-syn bidentate bridging mode in all. Reactions of (PyH)₅[MoOCl₄(H₂O)]₃Cl₂ with succinic acid (H₂suc) at ambient conditions resulted in a complex with a half-neutralized acid, (PyH)[Mo₂O₄Cl₂(μ₂-Hsuc)Py₂] · Py (14) (Hsuc⁻ = hydrogen succinate, ⁻OOC(CH₂)₂COOH), while those carried out at 115 °C in a tetranuclear succinato complex, (4-MePyH)₂[{Mo₂O₄Cl₂(4-MePy)₂}₂(μ₄-suc)] (15) (suc²⁻ = succinate, ⁻OOC(CH₂)₂COO⁻). The tetranuclear anion of 15 consists of two {Mo₂O₄}²⁺ cores covalently linked with a tetradentate succinato ligand. The compounds were fully characterized by infrared vibrational spectroscopy, elemental analyses and X-ray diffraction studies.     

Specific and gender differences between hospitalized and out of hospital mortality due to myocardial infarction

In this paper, the authors evaluate gender related differences of myocardial infarction mortality before and after hospital admittance. Myocardial infarction mortality in the Clinical Hospital Split in the seven years period between 2000 and 2006, have been analyzed together with out of hospital sudden death patients with acute myocardial infarction established during autopsy. During the seven year period between 2000 and 2006, 3434 patients were treated for myocardial infarction in the Split Clinical Hospital, 2336 (68%) males and 1098 (32%) females with a 12% total mortality (427 patients). The annual number of hospitalized persons has been increasing during that period (474 in yr. 2000 us. 547 in yr. 2006), while mortality decreased from 15% in 2000 to 9.6% in 2006. Female patients had significantly higher hospital mortality than male patients, (228 or 21% vs. 202 or 9%, p<0.05). Women also had significantly higher total AMI mortality (23.7% vs. 15,7%, p <0.05). Anterior myocardial infarction with ST elevation in precordial leads had significantly higher mortality (19%) compared to patients with lateral (11%), inferior (10%) myocardial infarction with ST elevation and also NSTEMI (4%) mortality p<0.05. Female patients more frequently die in hospital, 84% (230) than out of hospital 16% (43). From the total number of AMI deaths (388) in male patients, 56% (217) were in hospital and 44% (171) out of hospital (p<0.001). Men had significantly higher prehospital mortality rate than women (81% vs. 19%, p<0.05). Men also more frequently died from ventricular fibrillation (22% vs. 10%, p<0.05), while women died more frequently of heart failure, cardiogenic shock, and myocardial rupture (33% vs. 15% p<0.05). Regarding the total number of deaths from myocardial infarction men had significantly higher prehospital mortality compared to women (178 or 7.3% vs. 43 or 3.7%, p<0.05). Anterior myocardial infarction had a significantly higher rate in patients dying pre-hospital (58%), in contrast to inferior (36%) and lateral myocardial infarction with ST elevation (6%) p<0.05. We have concluded that male patients die more frequently within the first few hours of AMI mostly due to malignant arrhythmias, while female patients died in sub acute stage due to heart failure while being hospitalized. Nevertheless total mortality of AMI remains significantly higher in women.