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Pain, a severe public health problem, can affect patient quality of life when inadequately controlled. Considering that pain pathophysiological mechanisms are complex, combining active pharmaceutical ingredients (APIs) with multiple and synergistic mechanisms of action represents a potentially more effective therapeutic approach than conventional monotherapy treatments. In turn, topical drug delivery has clear advantages over other routes of administration, such as high levels of efficacy, better safety profile and great patient compliance. In this context, the combination of two or more APIs in a single dosage form - fixed-dose combination product (FDC) - for topical administration may represent a promising therapeutic option in the field of pain management. Considering the above mentioned, the purpose of this manuscript is to address an overview of some general aspects regarding pain management and FDCs, as well as the regulatory environment that has to be taken into consideration during their development. Special emphasis will be given to fixed-dose combinations for topical administration with analgesic and/or anti-inflammatory activity. Market drivers of the topical FDC currently approved are ultimately pointed out, and new opportunities in pain management highlighted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Inc.)

The adoption of carbon inventories for dairy farms in tropical countries based on models developed from animals and diets of temperate climates is questionable. Thus, the objectives of this study were to estimate enteric methane (CH4) emissions through the SF6 tracer gas technique and through equations proposed by the Intergovernmental Panel on Climate Change (IPCC) Tier 2 and to calculate the inventory of greenhouse gas (GHG) emissions from two dairy systems. In addition, the carbon balance of these properties was estimated using enteric CH4 emissions obtained using both methodologies. In trial 1, the CH4 emissions were estimated from seven Holstein dairy cattle categories based on the SF6 tracer gas technique and on IPCC equations. The categories used in the study were prepubertal heifers (n=6); pubertal heifers (n=4); pregnant heifers (n=5); high-producing (n=6); medium-producing (n=5); low-producing (n=4) and dry cows (n=5). Enteric methane emission was higher for the category comprising prepubertal heifers when estimated by the equations proposed by the IPCC Tier 2. However, higher CH4 emissions were estimated by the SF6 technique in the categories including medium- and high-producing cows and dry cows. Pubertal heifers, pregnant heifers, and low-producing cows had equal CH4 emissions as estimated by both methods. In trial 2, two dairy farms were monitored for one year to identify all activities that contributed in any way to GHG emissions. The total emission from Farm 1 was 3.21t CO2e/animal/yr, of which 1.63t corresponded to enteric CH4. Farm 2 emitted 3.18t CO2e/animal/yr, with 1.70t of enteric CH4. IPCC estimations can underestimate CH4 emissions from some categories while overestimate others. However, considering the whole property, these discrepancies are offset and we would submit that the equations suggested by the IPCC properly estimate the total CH4 emission and carbon balance of the properties. Thus, the IPCC equations should be utilized with caution, and the herd composition should be analysed at the property level. When the carbon stock in pasture and other crops was considered, the carbon balance suggested that both farms are sustainable for GHG, by both methods. On the other hand, carbon balance without carbon stock, by both methods, suggests that farms emit more carbon than the system is capable of stock., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The aim of this study was to analyze the economic viability of producing dairy goat kids fed liquid diets in alternative of goat milk and slaughtered at two different ages. Forty-eight male newborn Saanen and Alpine kids were selected and allocated to four groups using a completely randomized factorial design: goat milk (GM), cow milk (CM), commercial milk replacer (CMR) and fermented cow colostrum (FC). Each group was then divided into two groups: slaughter at 60 and 90 days of age. The animals received Tifton hay and concentrate ad libitum. The values of total costs of liquid and solid feed plus labor, income and average gross margin were calculated. The data were then analyzed using the Monte Carlo techniques with the @Risk 5.5 software, with 1000 iterations of the variables being studied through the model. The kids fed GM and CMR generated negative profitability values when slaughtered at 60 days (US$ -16.4 and US$ -2.17, respectively) and also at 90 days (US$ -30.8 and US$ -0.18, respectively). The risk analysis showed that there is a 98% probability that profitability would be negative when GM is used. In this regard, CM and FC presented low risk when the kids were slaughtered at 60 days (8.5% and 21.2%, respectively) and an even lower risk when animals were slaughtered at 90 days (5.2% and 3.8%, respectively). The kids fed CM and slaughtered at 90 days presented the highest average gross income (US$ 67.88) and also average gross margin (US$ 18.43/animal). For the 60-day rearing regime to be economically viable, the CMR cost should not exceed 11.47% of the animal-selling price. This implies that the replacer cannot cost more than US$ 0.39 and 0.43/kg for the 60- and 90-day feeding regimes, respectively. The sensitivity analysis showed that the variables with the greatest impact on the final model's results were animal selling price, liquid diet cost, final weight at slaughter and labor. In conclusion, the production of male dairy goat kids can be economically viable when the kids diet consists mainly of either cow milk or fermented colostrum, especially when kids are slaughtered at 90 days of age.

The metabolic and water evaporation strategies in spiders may be part of a set of physiological adaptations to tolerate low or unpredictable food availability, buffering spiders against environmental fluctuations such as those of the high mountains of the central Andes. The aim of this study is to analyze experimentally the variations in metabolic rate and the rate of evaporative water with food and/or water restriction in a high mountain mygalomorph spider population (Paraphysa sp.). We found that the low metabolism of this spider was not affected by water restriction, but its metabolism was depressed after 3 weeks of food deprivation. The spider did not show seasonal metabolic changes but it presented seasonal changes in the rate of evaporative water loss at high temperatures. Females with egg sacs reduced their metabolic rate and evaporative water at high temperatures. These findings constitute a set of possible adaptations to a highly fluctuating Mediterranean environment, which is completely covered with snow for many months and then progresses rapidly to a very dry climate with high temperatures., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Small animals need efficient water conservation mechanisms for survival and reproduction, which is relevant for the spiders that have large book lungs with large respiratory surface. If lung evaporation is relevant to limit water loss, adjustments of the spiracle opening to metabolic demands should be expected. In this study, we measured the metabolic rate and total evaporative water loss mediated by the opening of the spiracles in the migalomorph spider Paraphysa parvula, a resident of fluctuating Mediterranean environments of the mountains of central Chile. We found that the metabolism of P. parvula was similar to other Theraphosidae and low compared to other arthropods. Carbon dioxide production and evaporative water loss increased with temperature, particularly at 40 degrees C. The total evaporative water loss at 40 degrees C increased dramatically to about 10 times that found with the lower temperatures. Thus, 40 degrees C will be the limit temperature for this species after which evaporative water loss starts to become damaging, so it has to avoid it. The exposition to hypercapnic environments had as a consequence an increase in evaporative water loss and the involvement of the book lungs in this loss was about 60%. The possibility of losing water could condition this species to seek temperate and oxygenated shelters under rocks., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Objective: To compare the role of Akt/PKB signaling pathway in the modulation of reactive oxygen species (ROS) production by autologous plasma in peripheral blood mononuclear cells (PBMNC) from type 2 diabetic patients and healthy subjects., Materials and Methods: This study was approved by Santa Casa Ethical Committee and has included patients diagnosed with diabetes type 2 (DM2) and control group (non-diabetic) (ND). PBMNC were purified utilizing Ficoll-hypaque gradient. ROS was quantified by luminol-dependent chemiluminescence. The Akt/PKB phosphorylation was measured using a CASE kit. Statistical analyses were made with t Student test and chi-square (chi(2)). p<0.05 was considered significant., Results: 12, 13-Phorbol dibutyrate (PDB) stimulated the production of higher levels of ROS in PBMNC from type 2 diabetic patients than that from healthy subjects. Autologous plasma, however, inhibited induced or not ROS production in PBMNC in both groups. The inhibition of PBMNC-ROS derived by autologous plasma from healthy subjects was higher than that from type 2 diabetic patients. Plasma phosphorylated (activated) Akt/PKB. The percentage of phosphorylation induced by autologous plasma in PBMNC from patients and healthy control were 14% and 93%, respectively. Inhibition of ROS production in PBMNC from DM2 were similar for PBMNC+plasma; PBMNC+Akti; and PBMNC+plasma+Akti. However, in ND control, plasma showed a higher ROS inhibition than Akti or plasma plus Akti., Conclusions: Our results suggest that the low antioxidant capacity observed in autologous plasma from DM2 patients in conjunction with the decreased activation of PKB may cause an imbalance in the oxidizing/reducing responses, possible inducing an oxidative stress state, which could be associated with tissular damage.

Thirty, 4-month-old entire Santa Ines lambs were grazed on an Andropogon gayanus pasture, during a 34-week period (rainy season weeks 0-20 and dry season weeks 21-34) and allocated in two treatment groups (n = 15) each with different protein supplementation: high protein (HP-19% CP) and low protein (LP-11% CP). These were subdivided into those receiving anthelmintic treatment (c) (n = 7) and without anthelmintic treatment (i) (n = 8). The objective was to evaluate the effects of supplementation with protein on resistance and resilience to natural helminth infection of hair breed lambs. Lamb weight, blood collection and faecal egg counts (FEC) were carried out monthly. The lambs were slaughtered after 34 weeks, when worm burdens, worm length and eosinophil cell counts were taken. The sheep on treatments HPc and HPi were heavier in live weight than those from LPi and LPc (P < 0.05) at the end of the rainy period. The HPc group finished heavier (P < 0.05) than the other groups in the dry season, which had no significant differences between them. The predominant species of nematode found was T. colubriformis followed by H. contortus, Trichuris globulosa and Moniezia expansa. Animals on HPi had lower FEC than LPi (P < 0.05). The number of worms was lower for both HP groups (P < 0.05) with worm length shorter in the HPc group (P < 0.05) compared with all other groups. The number of eosinophils was higher in animals in the LPi group, which also showed anaemia and lower plasma urea at the end of the dry season. Diet supplementation with high protein was able to improve resilience and resistance to natural infection by endoparasites during the rainy season. In the dry season there was a decrease in both of these traits, which were intimately linked to the quality of available forage under tropical conditions.