Pulegone and Eugenol Oral Supplementation in Laboratory Animals: Results from Acute and Chronic Studies

Essential oils are natural compounds used by humans for scientific purposes due to their wide range of properties. Eugenol is mostly present in clove oil, while pulegone is the main constituent of pennyroyal oil. To guarantee the safe use of eugenol and pulegone for both humans and animals, this study addressed, for the first time, the effects of these compounds, at low doses (chronic toxicity) and high doses (acute toxicity), in laboratory animals. Thirty-five FVB/n female mice were randomly assigned to seven groups (n = 5): group I (control, non-additive diet); group II (2.6 mg of eugenol + 2.6 mg of pulegone); group III (5.2 mg of eugenol + 5.2 mg of pulegone); group IV (7.8 mg of eugenol + 7.8 mg of pulegone); group V (7.8 mg of eugenol); group VI (7.8 mg of pulegone); and group VII (1000 mg of eugenol + 1000 mg of pulegone). The compounds were administered in the food. Groups I to VI were integrated into the chronic toxicity study, lasting 28 days, and group VII was used in the acute toxicity study, lasting 7 days. Animals were monitored to assess their general welfare. Water and food intake, as well as body weight, were recorded. On the 29th day, all animals were euthanized by an overdose of ketamine and xylazine, and a complete necropsy was performed. Blood samples were collected directly from the heart for microhematocrit and serum analysis, as well as for comet assay. Organs were collected, weighed, and fixed in formaldehyde for further histological analysis and enzymatic assay. Eugenol and pulegone induced behavioral changes in the animals, namely in the posture, hair appearance and grooming, and in mental status. These compounds also caused a decrease in the animals’ body weight, as well as in the food and water consumption. A mortality rate of 20% was registered in the acute toxicity group. Both compounds modulated the serum levels of triglycerides and alanine aminotransferase. Eugenol and pulegone induced genetic damage in all animals. Eugenol increased the activity of the CAT enzyme. Both compounds increased the GR enzyme at the highest dose. Moreover, pulegone administered as a single compound increased the activity of the GST enzyme. Histopathological analysis revealed inflammatory infiltrates in the lungs of groups II, III, and IV. The results suggest that eugenol and pulegone may exert beneficial or harmful effects, depending on the dose, and if applied alone or in combination

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012

OBJECTIVE: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. DESIGN: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. RESULTS: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO (2)/FiO (2) ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO (2)/FI O (2) 180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5-10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). CONCLUSIONS: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients

Volcanic-hypabyssal rock geochemistry of a subduction-related marginal basin ophiolite: Southeast Bohol Ophiolite-Cansiwang Mélange Complex, Central Philippines

The Early Cretaceous Southeast Bohol OphioliteCansiwang Mélange Complex and the Alicia Schist form the basement of southeastern Bohol Island in central Philippines. New geochemical data show that four discrete groups constitute the volcanic and associated hypabyssal rocks of the ophiolite-mélange complex: boninitic rocks (BON), enriched and normal mid-ocean ridge basalt-like rocks (E-MORB; NMORB) and high-magnesian andesites (HMA). Of these four groups, the BON are the most depleted in REEs and with the most pronounced negative Nb anomalies. Both MORB-like types exhibit subduction-zone influence as reflected in their slight negative Nb anomalies. Characteristically with flat and LREE-depleted patterns, the HMA samples appear to mimic N-MORB patterns but with lower REE concentrations. This geochemical diversity is best explained by a suprasubduction zone environment of formation as is also evident from field geological information. Formation of the Cansiwang Mélange is believed to have been concurrent with the ophiolite's emplacement by subduction-accretion along a forearc margin. This tectonic boundary was later jammed into inactivity with the entry of the Alicia Schist that most likely was an oceanic bathymetric high. The intercalation of both tuffaceous materials and pelagic chert with the pillow basalts are consistent with a marginal basin tectonic setting.link_to_subscribed_fulltex

Geology of southeast Bohol, central Philippines: Accretion and sedimentation in a marginal basin

Recent field mapping has refined our understanding of the stratigraphy and geology of southeastern Bohol, which is composed of a Cretaceous basement complex subdivided into three distinct formations. The basal unit, a metamorphic complex named the Alicia Schist, is overthrust by the Cansiwang mélange, which is, in turn, structurally overlain by the Southeast Bohol Ophiolite Complex. The entire basement complex is overlain unconformably by a ∼2000 m thick sequence of Lower Miocene to Pleistocene carbonate and elastic sedimentary rocks and igneous units. Newly identified lithostratigraphic units in the area include the Cansiwang mélange, a tectonic mélange interpreted as an accretionary prism, and the Lumbog Volcaniclastic Member of the Lower Miocene Carmen Formation. The Cansiwang mélange is sandwiched between the ophiolite and the metamorphic complex, suggesting that the Alicia Schist was not formed in response to emplacement of the Southeast Bohol Ophiolite Complex. The accretionary prism beneath the ophiolite complex and the presence of boninites suggest that the Southeast Bohol Ophiolite Complex was emplaced in a forearc setting. The Southeast Bohol Ophiolite Complex formed during the Early Cretaceous in a supra-subduction zone environment related to a southeast-facing arc (using present-day geographical references). The accretion of this ophiolite complex was followed by a period of erosion and then later by extensive clastic and carbonate rock deposition (Carmen Formation, Sierra Bullones Limestone and Maribojoc Limestone). The Lumbog Volcaniclastic Member and Jagna Andesite document intermittent Tertiary volcanism in southeastern Bohol.link_to_subscribed_fulltex

Combination of the anti-tumour cell ether lipid edelfosine with sterols abolishes haemolytic side effects of the drug

Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) is an anti-tumour cell ether lipid with surface-active properties. Pure edelfosine can be dispersed in aqueous media in the form of micelles. One important, negative side effect of edelfosine is that it is highly haemolytic. In this paper, we show that edelfosine can be co-dispersed in water with certain lipids (particularly cholesterol, campesterol or β-sitosterol) so that it gives rise to liposomes. Surface pressure measurements demonstrate that edelfosine is slowly released from these liposomes. In liposomal form, edelfosine remains apoptogenic for a variety of leukemia cell lines, while its haemolytic effect is abolished. The phenomenon is explained on the basis of the complementarity of the molecular geometries of sterols and edelfosine