Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 197
Filter
1.
Int J Cancer ; 154(5): 863-872, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-37840339

ABSTRACT

Despite molecular selection, patients (pts) with RAS wildtype mCRC represent a heterogeneous population including diversity in metastatic spread. We investigated metastatic patterns for their prognostic and predictive impact on maintenance therapy with 5-fluorouracil/folinic acid ± panitumumab. The study population was stratified according to (1) number of involved metastatic sites (single vs multiple organ metastasis), liver-limited disease vs (2) liver metastasis plus one additional site, and (3) vs liver metastasis plus ≥two additional sites. Kaplan-Meier method and Cox regressions were used to correlate efficacy endpoints. Single organ metastasis was observed in 133 pts (53.6%) with 102 pts (41.1%) presenting with liver-limited disease, while multiple organ metastases were reported in 114 pts (46.0). Multiple compared to single organ metastases were associated with less favorable PFS (HR 1.48, 95% CI 1.13-1.93; P = .004) and OS (HR 1.37, 95% CI 0.98-1.93; P = .068) of maintenance therapy. While metastatic spread involving one additional extrahepatic site was not associated with clearly impaired survival compared to liver-limited disease, pts with liver metastasis plus ≥two additional sites demonstrated less favorable PFS (HR 1.92, 95% CI 1.30-2.83; P < .001), and OS (HR 2.38, 95% CI 1.51-3.76; P < .001) of maintenance therapy. Pmab-containing maintenance therapy appeared active in both pts with multiple (HR 0.58; 95% CI, 0.39-0.86; P = .006) as well as to a lesser numerical extent in pts with single organ metastasis (HR 0.83; 95% CI, 0.57-1.21; P = .332; Interaction P = .183). These data may support clinical decisions when EGFR-based maintenance therapy is considered.


Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Liver Neoplasms , Rectal Neoplasms , Humans , Prognosis , Colorectal Neoplasms/pathology , Panitumumab , Colonic Neoplasms/drug therapy , Fluorouracil/therapeutic use , Rectal Neoplasms/drug therapy , Leucovorin/therapeutic use , Liver Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
2.
J Anat ; 244(1): 22-41, 2024 01.
Article in English | MEDLINE | ID: mdl-37591692

ABSTRACT

Marine amniotes have played many crucial roles in ocean ecosystems since the Triassic, including predation at the highest trophic levels. One genus often placed into this guild is the large Early Jurassic neoichthyosaurian Temnodontosaurus, the only post-Triassic ichthyosaurian known with teeth which bear a distinct cutting edge or carina. This taxonomically problematic genus is currently composed of seven species which show a wide variety of skull and tooth morphologies. Here we assess the craniodental disparity in Temnodontosaurus using a series of functionally informative traits. We describe the range of tooth morphologies in the genus in detail, including the first examples of serrated carinae in ichthyosaurians. These consist of false denticles created by the interaction of enamel ridgelets with the carinal keel, as well as possible cryptic true denticles only visible using scanning electron microscopy. We also find evidence for heterodonty in the species T. platyodon, with unicarinate mesial teeth likely playing a role in prey capture and labiolingually compressed, bicarinate distal teeth likely involved in prey processing. This type of heterodonty appears to be convergent with a series of other marine amniotes including early cetaceans. Overall, the species currently referred to as the genus Temnodontosaurus show a range of craniodental configurations allowing prey to be captured and processed in different ways - for example, T. eurycephalus has a deep snout and relatively small bicarinate teeth likely specialised for increased wound infliction and grip-and-tear feeding, whereas T. platyodon has a more elongate yet robust snout and larger teeth and may be more adapted for grip-and-shear feeding. These results suggest the existence of niche partitioning at higher trophic levels in Early Jurassic ichthyosaurians and have implications for future work on the taxonomy of this wastebasket genus, as well as for research into the ecology of other extinct megapredatory marine tetrapods.


Subject(s)
Coleoptera , Ecosystem , Animals , Head , Skull , Cetacea , Fossils , Biological Evolution
3.
J Cancer Res Clin Oncol ; 149(18): 16575-16587, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37715831

ABSTRACT

BACKGROUND: Cancer patients often use complementary and alternative medicine (CAM), however, standardized assessment in clinical routine is missing. The aim of this study was to evaluate a screening questionnaire on CAM usage that was published in the S3 Guideline Complementary Medicine in the Treatment of Oncological Patients. METHODS: We developed a survey questionnaire to assess the practicability of the guideline questionnaire and communication on CAM between health care providers (HCPs) and patients. We collected 258 guideline questionnaires and 116 survey questionnaires from ten clinics and held twelve semi-structured interviews with HCPs. RESULTS: 85% used at least one of the listed CAM methods, 54 participants (N = 77) never disclosed usage to a physician. The most frequently used CAM methods were physical activity (76.4%) and vitamin D (46.4%). 25.2% used at least one method, that was labeled risky by the guideline. 53.4% did not know of CAM's risk of interactions and side effects. Introducing the guideline questionnaire in routine cancer care increased the rate of patients talking to an HCP regarding CAM significantly from 35.5 to 87.3%. The HCPs stated positive effects as an initiation of conversation, increased safety within CAM usage and patients feeling thankful and taken seriously. However, due to the limited amount of time available for discussions on CAM, generalized distribution to all patients was not feasible. CONCLUSION: Institutions should focus on implementing standard procedures and resources that help HCPs discuss CAM on a regular basis. HCPs should meet the patient's demands for CAM counseling and make sure they are equipped professionally.


Subject(s)
Complementary Therapies , Neoplasms , Physicians , Humans , Physicians/psychology , Surveys and Questionnaires , Health Personnel , Neoplasms/therapy
4.
Eur J Cancer ; 173: 297-306, 2022 09.
Article in English | MEDLINE | ID: mdl-35970102

ABSTRACT

PURPOSE: This trial investigates the addition of panitumumab to chemotherapy with fluorouracil/folinic acid and oxaliplatin (FOLFOX) in a 2:1 randomised, controlled, open-label, phase II trial in RAS wild-type colorectal cancer patients with R0/1-resected liver metastases. EXPERIMENTAL DESIGN: The primary endpoint was progression-free survival (PFS) two years after randomisation. The experimental arm (12 weeks of biweekly mFOLFOX6 plus panitumumab followed by 12 weeks of panitumumab alone) was considered active if the two-year PFS rate was ≥65%. Based on historical data, a two-year PFS rate of 50% was estimated in the control arm (12 weeks of biweekly FOLFOX). The trial was performed with a power of 80% and an alpha of 0.05. Secondary endpoints included overall survival (OS) and toxicity. The trial is registered with ClinicalTrials.gov, NCT01384994. RESULTS: The full analysis set consists of 70 patients (pts) in the experimental arm and 36 pts in the control arm. The primary endpoint was missed with a two-year PFS of 35.7% with FOLFOX plus panitumumab and 30.6% in the control arm. In comparative analyses, trends towards improved PFS (HR 0.83; 95%CI, 0.52-1.33; P = 0.44) and OS (HR 0.70; 95% CI, 0.34-1.46; P = 0.34) were observed in favour of the panitumumab-based study arm. No new or unexpected safety signals were observed with FOLFOX plus panitumumab following liver resection. CONCLUSION: The PARLIM trial failed to demonstrate a two-year PFS rate of 65% after resection of colorectal liver metastases. The positive trends in survival endpoints may support future trials evaluating treatment with anti-EGFR agents after resection of liver metastases.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Colorectal Neoplasms , Liver Neoplasms , Panitumumab , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Fluorouracil/therapeutic use , Humans , Leucovorin/therapeutic use , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Organoplatinum Compounds , Panitumumab/therapeutic use
5.
Aust Dent J ; 67 Suppl 1: S3-S13, 2022 03.
Article in English | MEDLINE | ID: mdl-35735746

ABSTRACT

Anxiety is an adaptive emotional response to potentially threatening or dangerous situations; moderated by the sympathetic nervous system. Dental anxiety is common and presents before, during or after dental treatment. The physiological response includes an increase in heart rate, blood pressure, respiratory rate, and cardiac output. Consequently, extensive distress leads to avoidance of dental treatment and multiple failed appointments, impacting both oral and general health. Dental anxiety can generate a variety of negative consequences for both the dentist and the patient. Evidence-based strategies are essential for mitigating and relieving anxiety in the dental clinic. Psychotherapeutic behavioural strategies can modify the patient's experience through a minimally invasive approach with nil or negligible side effects, depending on patient characteristics, anxiety level and clinical situations. These therapies involve muscle relaxation, guided imagery, physiological monitoring, utilizing biofeedback, hypnosis, acupuncture, distraction and desensitization. Pharmacological intervention utilizes either relative analgesia (nitrous oxide), conscious intravenous sedation or oral sedation, which can have undesirable side effects, risks and contraindications. These modalities increase the cost and availability of dental treatment.


Subject(s)
Anesthesia, Dental , Anesthesia , Adult , Humans , Dental Anxiety/therapy , Dental Clinics , Conscious Sedation
6.
Arq. bras. med. vet. zootec. (Online) ; 73(3): 622-630, May-June 2021. tab
Article in English | LILACS, VETINDEX | ID: biblio-1278347

ABSTRACT

This study aimed to determine the physiological and hematological parameters of sheep in Brazil. Therefore, 5,081 observations were used from previous experiments with animals from different Brazilian regions with the time of day, gender, breed, age, physiological characteristics, hematological and climatic variables. The animals were classified according to their stress level, and only data of non-stressed animals were used to calculate the reference values. Respiratory rate was the parameter that most differed from the normal range, with values ​​above the limits usually reported for the species, being higher in commercial wool sheep. For hematological variables, differences were observed between the present results and the previously reported values in the literature. A higher number of red blood cells (RBC), lower hemoglobin and mean corpuscular hemoglobin concentration (MCHC) were observed in young animals. A higher number of RBC and MCHC were noted in sheep crossed with local breeds. Considering that physiological and hematological parameters are indicators of the animal's pathological or physiological state, for a correct interpretation of the results, the use of reference values based on animals with similar racial characteristics and subjected to similar environmental conditions is recommended.(AU)


O objetivo deste estudo foi determinar parâmetros fisiológicos e hematológicos de ovinos no Brasil. Portanto, foram utilizadas 5.081 observações de experimentos anteriores com animais de diversas regiões do Brasil, com diferentes horário, sexo, raça, idade, características fisiológicas, variáveis ​​hematológicas e climáticas. Os animais foram classificados de acordo com o nível de estresse, e apenas os dados dos animais não estressados ​​foram utilizados para o cálculo dos valores de referência. A frequência respiratória foi o parâmetro que mais diferiu em relação à normalidade, com valores acima dos limites usualmente relatados para a espécie, sendo maior em ovinos de lã comercial. Para as variáveis ​​hematológicas, também foram verificadas diferenças entre os resultados observados e os valores previamente relatados na literatura. Maior número de hemácias, menor hemoglobina e concentração de hemoglobina corpuscular média (CHbCM) foram observados em animais jovens e maior número de hemácias e CHbCM em ovinos cruzados com raças locais. Considerando que os parâmetros fisiológicos e hematológicos são indicadores do estado patológico ou fisiológico do animal, para uma correta interpretação dos resultados recomenda-se a utilização de valores de referência baseados em animais com características raciais semelhantes e submetidos a condições ambientais também semelhantes.(AU)


Subject(s)
Animals , Sheep/physiology , Sheep/blood , Reference Values , Tropical Climate , Body Temperature , Brazil , Respiratory Rate , Hematologic Tests/veterinary
7.
Animal ; 15(2): 100032, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33573969

ABSTRACT

Plant extracts have been recognized as beneficial to human health and have been evaluated as feed additive for domestic and companion animals. This study evaluated oregano and green tea extracts fed to Jersey cows from approximately 21 d before calving to 21 d after calving on milk production, milk composition, and blood metabolites as well as investigated immunological and antioxidant attributes. Twenty-four Jersey cows with 441 ±â€¯27 kg of BW, 3.5 ±â€¯0.3 of body condition score (BCS), and 2.7 ±â€¯1.8 lactations were selected at approximately 28 d before the expected parturition date and were randomly assigned to three treatments with eight cows each: without plant extracts in diet (control - CON), addition of 10 g per day of oregano extract (OR), and addition of 5 g per day of green tea extract (GT). Feed intake, BW, BCS, blood metabolites, hemogram as well as oxidative stress biomarkers were evaluated from approximately 3 weeks prepartum to 3 weeks postpartum (transition period) while milk production and composition were evaluated during the first 3 weeks of lactation. Plant extracts did not change BW, BCS, and DM intake (DMI) throughout the transition period, but OR increased in approximately 20% total digestive nutrients and metabolizable energy intake on days 15 and 16 postpartum compared with CON. In the prepartum, OR increased in 48% platelets count compared to the CON, while GT augmented in 142% eosinophils compared with CON. Oregano extract reduced the levels of reactive species in the erythrocytes in 40% during prepartum and postpartum compared with CON, while GT reduced its levels in 24 and 29% during prepartum and postpartum, respectively, when compared with CON. In the postpartum period, OR increased in 60% the carbonylated protein content compared with CON, while GT reduced in 45% the levels of reactive species in plasma compared with CON. During the postpartum, both extracts increased in 33% the concentration of reduced glutathione when compared with CON. Moreover, GT tended to decrease feed efficiency in 11% when compared with CON; OE reduced milk pH and somatic cell count when compared with CON. In conclusion, OE and GT did not expressively affect immunological attributes in blood but reduce some oxidative stress biomarkers without compromising productive traits of Jersey cows during the transition period.


Subject(s)
Antioxidants , Origanum , Animals , Cattle , Female , Diet/veterinary , Dietary Supplements , Lactation , Milk , Postpartum Period , Tea
8.
Trop Anim Health Prod ; 53(1): 44, 2020 Nov 24.
Article in English | MEDLINE | ID: mdl-33231754

ABSTRACT

Infrared thermography of the lateral side portion of the udder was taken from 38 lactating cows in a 6-day experiment. Thermograms were analyzed using specific software with the use of eight different methods. The experiment was aimed at correlating the different methods with each other and with rectal temperature (RT), in order to suggest a method to assess udder side temperature, and also at creating regression equations to enable RT calculation through the use of thermographic data. All methods of analyzing thermograms were highly correlated; correlations between thermograms and RT were significant (P < 0.01) and above 0.840. The highest correlation was between RT and the maximum temperature obtained using a horizontal rectangle placed within the lateral (side) portion of the udder (maximum temperature in a horizontal rectangle (MHR), 0.897). With the exception of the average temperature of a horizontal rectangle, linear regression coefficients were significant (P < 0.05) and coefficients of determination were higher than 75.51%. We suggest the use of MHR to evaluate udder side temperature. The ease of accessing the side of the udder, the welfare advantages of non-invasive observations, and the high correlation with RT suggest the use of thermograms in the lateral portion of the udder to assess animals' temperature.


Subject(s)
Mammary Glands, Animal/physiology , Skin Temperature , Thermography/veterinary , Animals , Body Temperature , Cattle , Female , Thermography/methods
9.
Biochem Biophys Res Commun ; 503(4): 2678-2684, 2018 09 18.
Article in English | MEDLINE | ID: mdl-30093109

ABSTRACT

Clinical and experimental studies demonstrate the potential of low-magnitude high-frequency vibration (LMHFV) to enhance bone formation in the intact skeleton and during fracture healing. Moreover, it was shown that the effects of vibration therapy during fracture healing are highly dependent on the estrogen status of the vibrated individual and that estrogen receptor (ER) α signaling plays a major role in mechanotransduction of LMHFV. Because it is known that LMHFV can directly act on osteogenic cells, we hypothesize that the differential effects of LMHFV in the presence and absence of estrogen are mediated by ERα signaling in osteoblasts. To prove this hypothesis, we subjected preosteoblastic MC3T3-E1 cells and primary osteoblasts to LMHFV in vitro. We found increased Cox2 gene expression, cell metabolic activity and cell proliferation after LMHFV in the absence of estrogen, whereas the effects were contrary in the presence of estrogen. Blocking of ERα signaling by Esr1-siRNA knockdown or adding the selective ERα antagonist MPP dihydrochloride abolished the effects of LMHFV on osteoblast proliferation and Cox2 expression. Furthermore, primary osteoblasts isolated from ERα-knockout mice did not show a response towards LMHFV in the presence of estrogen. Additionally, blocking of actin cytoskeletal remodeling by adding the p160ROCK inhibitor Y-27632 abolished the effects of LMHFV. In contrast, expression of primary cilium was not necessary for mechanotransduction of LMHFV. These results suggest that direct effects of LMHFV on osteoblasts are dependent on ERα signaling and cytoskeletal remodeling.


Subject(s)
Estradiol/metabolism , Estrogen Receptor alpha/genetics , Fractures, Bone/therapy , Mechanotransduction, Cellular , Osteoblasts/metabolism , Osteogenesis/genetics , Vibration/therapeutic use , Actin Cytoskeleton/drug effects , Actin Cytoskeleton/metabolism , Actin Cytoskeleton/ultrastructure , Amides/pharmacology , Animals , Cell Differentiation , Cell Line , Cell Proliferation , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Estradiol/pharmacology , Estrogen Receptor alpha/antagonists & inhibitors , Estrogen Receptor alpha/deficiency , Female , Fracture Healing/drug effects , Fractures, Bone/genetics , Fractures, Bone/metabolism , Fractures, Bone/pathology , Gene Expression Regulation , Mice , Mice, Inbred C57BL , Osteoblasts/cytology , Osteoblasts/drug effects , Piperidines/pharmacology , Primary Cell Culture , Pyrazoles/pharmacology , Pyridines/pharmacology , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , rho-Associated Kinases/antagonists & inhibitors , rho-Associated Kinases/genetics , rho-Associated Kinases/metabolism
10.
Eur Cell Mater ; 35: 365-385, 2018 06 22.
Article in English | MEDLINE | ID: mdl-29931664

ABSTRACT

Calcium and vitamin D are essential for maintaining bone health. Therefore, deficiencies in calcium and vitamin D are major risk factors for osteoporosis development. Because sufficient amounts of calcium are also required for fracture-callus mineralisation, compromised bone repair that is frequently observed in osteoporotic patients might be attributed to calcium and vitamin D deficiencies. Consequently, calcium and vitamin D supplementation represents a potential strategy for treating compromised fracture healing in osteoporotic patients. Growing clinical evidence suggests that a fracture event may induce post-traumatic bone loss in the non-fractured skeleton, particularly in osteoporotic patients, which might further exacerbate osteoporosis and increase the risk of secondary fractures. Because the skeleton represents the main source of calcium, which is increasingly required during fracture-callus mineralisation, post-traumatic calcium mobilisation might occur under conditions of insufficient calcium and vitamin D status. However, to date, investigations of the roles of calcium and vitamin D in bone repair and post-traumatic bone turnover are very limited. The current review summarises the state of the literature, focusing on the role of calcium and vitamin D in fracture healing and post-traumatic bone turnover, and critically discusses the therapeutic potential of calcium and vitamin D supplementation in this context.


Subject(s)
Bone Remodeling/drug effects , Calcium/pharmacology , Fracture Healing/drug effects , Fractures, Bone/pathology , Fractures, Bone/physiopathology , Vitamin D/pharmacology , Wounds and Injuries/pathology , Wounds and Injuries/physiopathology , Animals , Humans
11.
R Soc Open Sci ; 5(3): 172177, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29657811

ABSTRACT

Polycotylidae is a clade of plesiosaurians that appeared during the Early Cretaceous and became speciose and abundant early in the Late Cretaceous. However, this radiation is poorly understood. Thililua longicollis from the Middle Turonian of Morocco is an enigmatic taxon possessing an atypically long neck and, as originally reported, a series of unusual cranial features that cause unstable phylogenetic relationships for polycotylids. We reinterpret the holotype specimen of Thililua longicollis and clarify its cranial anatomy. Thililua longicollis possesses an extensive, foramina-bearing jugal, a premaxilla-parietal contact and carinated teeth. Phylogenetic analyses of a new cladistic dataset based on first-hand observation of most polycotylids recover Thililua and Mauriciosaurus as successive lineages at the base of the earliest Late Cretaceous polycotyline radiation. A new dataset summarizing the Bauplan of polycotylids reveals that their radiation produced an early burst of disparity during the Cenomanian-Turonian interval, with marked plasticity in relative neck length, but this did not arise as an ecological release following the extinction of ichthyosaurs and pliosaurids. This disparity vanished during and after the Turonian, which is consistent with a model of 'early experimentation/late constraint'. Two polycotylid clades, Occultonectia clade nov. and Polycotylinae, survived up to the Maastrichtian, but with low diversity.

12.
J Dairy Sci ; 101(5): 4221-4234, 2018 May.
Article in English | MEDLINE | ID: mdl-29477520

ABSTRACT

Plant extracts have been proposed as substitutes for chemical feed additives due to their potential as rumen fermentation modifiers and because of their antimicrobial and antioxidant activities, possibly reducing methane emissions. This study aimed to evaluate the use of oregano (OR), green tea extracts (GT), and their association as feed additives on the performance and methane emissions from dairy between 28 and 87 d of lactation. Thirty-two lactating dairy cows, blocked into 2 genetic groups: 16 Holstein cows and 16 crossbred Holstein-Gir, with 522.6 ± 58.3 kg of body weight, 57.2 ± 20.9 d in lactation, producing 27.5 ± 5.0 kg/cow of milk and with 3.1 ± 1.8 lactations were evaluated (means ± standard error of the means). Cows were allocated into 4 treatments: control (CON), without plant extracts in the diet; oregano extract (OR), with the addition of 0.056% of oregano extract in the dry matter (DM) of the diet; green tea (GT), with the addition of 0.028% of green tea extract in the DM of the diet; and mixture, with the addition of 0.056% oregano extract and 0.028% green tea extract in the DM of the diet. The forage-to-concentrate ratio was 60:40. Forage was composed of corn silage (94%) and Tifton hay (6%); concentrate was based on ground corn and soybean meal. Plant extracts were supplied as powder, which was previously added and homogenized into 1 kg of concentrate in natural matter, top-dressed onto the total mixed diet. No treatment by day interaction was observed for any of the evaluated variables, but some block by treatment interactions were significant. In Holstein cows, the mixture treatment decreased gross energy and tended to decrease the total-tract apparent digestibility coefficient for crude protein and total digestible nutrients when compared with OR. During the gas measurement period, GT and OR increased the digestible fraction of the ingested DM and decreased CH4 expressed in grams per kilogram of digestible DMI compared with CON. The use of extracts did not change rumen pH, total volatile fatty acid concentration, milk yield, or most milk traits. Compared with CON, oregano addition decreased fat concentration in milk. The use of plant extracts altered some milk fatty acids but did not change milk fatty acids grouped according to chain length (short or long), saturation (unsaturated or saturated), total conjugated linoleic acids, and n-3 and n-6 contents. Green tea and oregano fed separately reduced gas emission in cows during the first third of lactation and have potential to be used as feed additives for dairy cows.


Subject(s)
Camellia sinensis/chemistry , Cattle/metabolism , Methane/analysis , Origanum/metabolism , Plant Extracts/metabolism , Animal Feed/analysis , Animals , Camellia sinensis/metabolism , Cattle/growth & development , Diet/veterinary , Digestion , Fatty Acids, Volatile/analysis , Fatty Acids, Volatile/metabolism , Female , Food Additives/analysis , Food Additives/metabolism , Lactation , Methane/metabolism , Milk/chemistry , Milk/metabolism , Plant Extracts/analysis , Rumen/metabolism , Silage/analysis , Zea mays/metabolism
13.
Clin Pharmacol Ther ; 102(4): 679-687, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28411400

ABSTRACT

Dasabuvir, a nonnucleoside NS5B polymerase inhibitor, is a sensitive substrate of cytochrome P450 (CYP) 2C8 with a potential for drug-drug interaction (DDI) with clopidogrel. A physiologically based pharmacokinetic (PBPK) model was developed for dasabuvir to evaluate the DDI potential with clopidogrel, the acyl-ß-D glucuronide metabolite of which has been reported as a strong mechanism-based inhibitor of CYP2C8 based on an interaction with repaglinide. In addition, the PBPK model for clopidogrel and its metabolite were updated with additional in vitro data. Sensitivity analyses using these PBPK models suggested that CYP2C8 inhibition by clopidogrel acyl-ß-D glucuronide may not be as potent as previously suggested. The dasabuvir and updated clopidogrel PBPK models predict a moderate increase of 1.5-1.9-fold for Cmax and 1.9-2.8-fold for AUC of dasabuvir when coadministered with clopidogrel. While the PBPK results suggest there is a potential for DDI between dasabuvir and clopidogrel, the magnitude is not expected to be clinically relevant.


Subject(s)
Cytochrome P-450 CYP2C8/metabolism , Models, Biological , Sulfonamides/pharmacokinetics , Ticlopidine/analogs & derivatives , Uracil/analogs & derivatives , 2-Naphthylamine , Antiviral Agents/pharmacokinetics , Area Under Curve , Clopidogrel , Cytochrome P-450 CYP2C8/drug effects , Drug Interactions , Glucuronides , Humans , In Vitro Techniques , Ticlopidine/pharmacokinetics , Ticlopidine/pharmacology , Uracil/pharmacokinetics
14.
Trop Anim Health Prod ; 49(4): 851-856, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28332069

ABSTRACT

Lameness can negatively affect production, but there is still controversy about the perception of pain in dairy cows. This study aimed to verify the effects of hoof affections in dairy cows on locomotion score, physiological attributes, pressure nociceptive threshold, and thermographic variables, as well as assess improvement on these variables after corrective trimming and treatment. Thirty-four lame lactating cows were gait-scored, and all cows with locomotion score ≥4 were retained for this study 1 day before trimming. Lame cows were diagnosed, pressure nociceptive threshold at sound, and affected hooves were measured, thermographic images were recorded, and physiological attributes were evaluated. Hooves with lesions were trimmed and treated and cows were re-evaluated 1 week after such procedures. The experimental design was a completely randomized design. Each cow was considered an experimental unit and traits were analyzed using paired t test, linear correlation, and linear regression. Digital and interdigital dermatitis were classified as infectious diseases while laminitis sequels, sole ulcers, and white line were classified as non-infectious diseases. After 1 week, the locomotion score was reduced on average in 1.5 points. Trimming increased the pressure nociceptive threshold for cows with non-infectious affections while tended to increase the pressure nociceptive threshold for cows with infectious affections. Physiological attributes and thermographic values did not change with trimming. Trimming and treatment have benefic effects on animal welfare as gait is improved and sensitivity to pain is reduced.


Subject(s)
Cattle Diseases/physiopathology , Hoof and Claw/physiopathology , Lameness, Animal , Locomotion , Pain Measurement/methods , Animals , Cattle , Communicable Diseases , Female , Gait , Lactation , Pain , Pain Threshold , Phenotype
15.
Mol Pharm ; 14(4): 1307-1314, 2017 04 03.
Article in English | MEDLINE | ID: mdl-28195732

ABSTRACT

The overall objective of OrBiTo, a project within Innovative Medicines Initiative (IMI), is to streamline and optimize the development of orally administered drug products through the creation and efficient application of biopharmaceutics tools. This toolkit will include both experimental and computational models developed on improved understanding of the highly dynamic gastrointestinal (GI) physiology relevant to the GI absorption of drug products in both fasted and fed states. A part of the annual OrBiTo meeting in 2015 was dedicated to the presentation of the most recent progress in the development of the regulatory use of PBPK in silico modeling, in vivo predictive dissolution (IPD) tests, and their application to biowaivers. There are still several areas for improvement of in vitro dissolution testing by means of generating results relevant for the intraluminal conditions in the GI tract. The major opportunity is probably in combining IPD testing and physiologically based in silico models where the in vitro data provide input to the absorption predictions. The OrBiTo project and other current research projects include definition of test media representative for the more distal parts of the GI tract, models capturing supersaturation and precipitation phenomena, and influence of motility waves on shear and other forces of hydrodynamic origin, addressing the interindividual variability in composition and characteristics of GI fluids, food effects, definition of biorelevant buffer systems, and intestinal water volumes. In conclusion, there is currently a mismatch between the extensive industrial usage of modern in vivo predictive tools and very limited inclusion of such data in regulatory files. However, there is a great interest among all stakeholders to introduce recent progresses in prediction of in vivo GI drug absorption into regulatory context.


Subject(s)
Gastrointestinal Tract/metabolism , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/metabolism , Administration, Oral , Biopharmaceutics/methods , Gastrointestinal Absorption/physiology , Humans , Models, Biological , Solubility
16.
Arq. bras. med. vet. zootec ; 68(2): 506-516, mar.-abr. 2016. tab, graf
Article in Portuguese | LILACS | ID: lil-779785

ABSTRACT

O objetivo do presente estudo foi caracterizar as propriedades leiteiras da região do Vale do Braço do Norte, sul de Santa Catarina, Brasil, quanto à qualidade do leite e ao perfil em infraestrutura, manejo e alimentação dos animais. Foram coletadas informações de 50 propriedades leiteiras, obtidas por meio da aplicação de um questionário estruturado, abrangendo questões socioeconômicas dos produtores, manejo do rebanho, estrutura da propriedade, caracterização dos animais, alimentação das vacas além de manejo e higiene da ordenha. As amostras de leite foram submetidas a análises de composição, contagem bacteriana total, contagem de células somáticas e estabilidade do leite ao teste do álcool. Os dados foram analisados pela análise fatorial, discriminante, canônica, e de agrupamento. As propriedades têm como principal característica a agricultura familiar, com área média de 30 hectares; destes, 15,1 são destinados à pecuária leiteira, com média de 23,1 vacas ordenhadas. Na análise fatorial, o primeiro fator representa as relações entre as práticas de higiene na ordenha e de controle/prevenção de mastite, o segundo fator compreende a infraestrutura da fazenda com o nível de produção e o terceiro fator demonstra a relação entre a suplementação concentrada, a produção e a estabilidade do leite ao teste do álcool. A análise de agrupamento formou três grupos, sendo dois compostos por produtores com maior nível tecnológico e outro constituído por pequenos produtores com menor infraestrutura e nível de tecnologia. As propriedades que apresentam infraestrutura mais adequada para a produção, maior adoção das práticas recomendadas de manejo de ordenha e critérios de alimentação mais adequados produzem leite com melhor qualidade.


The aim of this study was to characterize the dairy farms of the Vale do Braço do Norte region, south of Santa Catarina State, Brazil, regarding milk quality and profile of the farms for infrastructure, management and nutrition of the animals. Information about 50 dairy farms was obtained through a survey regarding socio-economic conditions of the farmers, farm structure, characterization of animals, cow feeding and also milking management and hygiene. The milk samples were analyzed for total bacterial count, somatic cell count and stability of milk to ethanol. The data were analyzed in factorial, discriminant, canonical and cluster analysis. The main characteristic of farms is family farming with an average area of 30 hectares, of which 15.1 are destined for dairy farming, where an average of 23.1 cows are milked. On the factor analysis, the first factor represents the relation between hygiene practices during milking and control / prevention of mastitis, the second factor comprises the infrastructure of the farm with the level of production and the third factor shows the ratio of concentrate supplementation, production and stability of the milk to the ethanol test. The cluster analysis formed three groups, two composed of producers with higher technological level and another by small producers with lower infrastructure and level of technology. The dairy farms that have more adequate infrastructure for production, greater adoption of practices recommended for milking management and more appropriate criteria for cow feeding produce better quality milk.


Subject(s)
Animals , Cattle , Breast-Milk Substitutes , Cattle , Animal Husbandry/organization & administration , Infrastructure , Milk Ejection , Agricultural Zones , Food Quality , Livestock Industry
17.
Animal ; 9(12): 2024-8, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26220469

ABSTRACT

A total of 90 cows from three commercial farms were used to evaluate the relationship between subclinical mastitis and clinical mastitis and thermal nociceptive threshold. Milk strips from all udder quarters were tested for clinical mastitis with visual inspection of milk and udder alterations and for subclinical mastitis using California Mastitis Test. Milk yield was recorded, milk was sampled and further analyzed for somatic cells count (SCC). Cows were considered healthy when SCC200 000 cells/ml and no visual alterations in milk and/or udder, with moderate subclinical mastitis when SCC>500 000 cells/ml and no visual alterations in milk and/or udder and with clinical mastitis when visual alterations in milk and/or udder were detected. Nociceptive threshold was evaluated with the thermal threshold meter apparatus applied to the rear legs. Thermal threshold (TT) decreased when we compared healthy cows with cows presenting clinical mastitis and tended to decrease when we compare healthy cows with those with moderate subclinical mastitis. TT was lower at the ipsilateral rear leg compared with the contralateral leg to the infected mammary gland. TT linearly decreases as log10SCC increased and it showed sharp decrease as log10SCC exceed the value of 6.4. Increase in one unit of log10SCC increased the odds of low thermal threshold (lower than 55.8°C). Subclinical mastitis might be a welfare issue as it tended to decrease nociceptive thermal threshold.


Subject(s)
Animal Welfare , Mastitis, Bovine/complications , Milk/metabolism , Pain Threshold , Pain/veterinary , Animals , Behavior, Animal , Cattle , Cell Count/veterinary , Female , Hindlimb/physiopathology , Mammary Glands, Animal/physiopathology , Milk/cytology , Pain/etiology , Pain Measurement/veterinary , Reaction Time , Stress, Physiological
18.
Animal ; 9(9): 1559-66, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25994200

ABSTRACT

The effect of shade on behavior and physiological attributes of grazing cows in a high altitude subtropical zone is not well established. This work aimed to investigate how social and ingestive behaviors, as well as physiological and other attributes of dairy cows such as milk production, change in a subtropical environment during the hot season either with or without free access to shade. Fourteen lactating cows were kept on pasture either with no shade or with free access to shade for 5 days and their behavior was recorded with instantaneous scan sampled every 10 min, from sunrise, 0530 h (Greenwich mean time, GMT-0200 h) to sunset, 2100 h (GMT-0200 h). Behavior traits included (1) time spent in activities such as grazing, ruminating, resting, lying, standing, walking, seeking shade and staying in the proximity to the water trough and (2) number of events such as water ingestion, aggressive interactions, as well as competition for shade and water. Physiological attributes such as heart and respiratory rates, rectal temperature, number of rumen movements, panting score, as well as milk yield, were evaluated. Time spent in behavioral activities, number of behavioral events and physiological attributes varied between groups (with and without access to shade). Cows with no shade showed increased respiratory and heart rates and panting score at 1300 h, higher values for time of permanence near the water trough, number of competition and aggression events for shade. On the other hand, they showed lower values for time spent resting while lying, ruminating while standing, seeking shade. Access to shade did not change time spent lying, standing, walking with the head up, ruminating while lying, resting while standing, as well as milk yield and number of ruminal movements. Significant interactions between access to shade and days of measurements were detected for time spent walking, ruminating, grazing, resting, number of water ingestion events, competition events near the water trough and for shade, as well as for rectal temperature and panting score measured at 1700 h. In the high altitude subtropical region, access to shade minimizes negative heat stress effects on behavior and physiological aspects of dairy cows.


Subject(s)
Altitude , Behavior, Animal/physiology , Cattle/physiology , Hot Temperature , Milk/metabolism , Seasons , Sunlight , Animals , Body Temperature/physiology , Brazil , Digestion/physiology , Drinking/physiology , Feeding Behavior/physiology , Female , Lactation/physiology , Milk/statistics & numerical data , Observation , Respiratory Rate , Social Behavior
19.
Rofo ; 187(4): 260-8, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25816060

ABSTRACT

PURPOSE: To survey integrative teaching in radiology at German universities. MATERIALS AND METHODS: A questionnaire about radiological education was sent electronically to all 37 chairpersons of university radiology departments in Germany. The questions included the course type, teaching methods, concept, perception, and advantages and disadvantages of integrative teaching. Statistical analysis was performed with nonparametric statistics and chi-square test. RESULTS: The survey was considered representative with a return rate of 68 %. Integrative teaching is established at 4/5 of all departments. Integrative teaching is well accepted with an acceptance rate that is significantly higher in so-called "Modellstudiengängen" [model courses of study] (100 %) compared to conventional courses of study (72 %). The advantages of integrative teaching include linking of content (92 %) and preparation for interdisciplinary work (76 %). The disadvantages include high effort (75 %) and time (67 %) for organization. Furthermore, there is a risk that basic radiological facts and knowledge cannot be conveyed and that the visibility of radiology as an independent discipline is lost. Conventional radiological teaching has a similarly high acceptance (84 %) compared to integrative courses (76 %). CONCLUSION: Integrative teaching has a high acceptance among chairpersons in radiology in Germany despite the greater effort. A good interdisciplinary collaboration is essential for integrative teaching and at the same time this can be conveyed to the students. However, the visibility of radiology as a discipline and the possibility to cover basic radiological content must be ensured. Therefore, both conventional courses and integrative teaching seems reasonable, especially in cross-disciplinary subjects such as radiology. KEY POINTS: Both integrative teaching and conventional radiological teaching are highly accepted. The advantages include the linking of multidisciplinary content and the preparation for interdisciplinary cooperation. The disadvantages include more time and effort for organization and reduced visibility of cross-disciplinary subjects.


Subject(s)
Attitude of Health Personnel , Cooperative Behavior , Education, Medical/trends , Faculty, Medical , Interdisciplinary Communication , Radiology/education , Computer-Assisted Instruction/trends , Curriculum/trends , Data Collection , Forecasting , Germany , Humans , Models, Educational , Schools, Medical/trends , Surveys and Questionnaires
20.
Phys Chem Chem Phys ; 17(10): 6695-9, 2015 Mar 14.
Article in English | MEDLINE | ID: mdl-25679288

ABSTRACT

Small changes make a big difference: we demonstrate how slight changes in the supersaturation have a huge impact on the formed crystal morphology and present a convenient method to monitor the level of local supersaturation on a flat substrate. Further we provide a non-additive based explanation for natural biomineralization processes.


Subject(s)
Biomimetic Materials/chemistry , Carbonates/chemistry , Crystallization , Silicon Dioxide/chemistry , Strontium/chemistry
SELECTION OF CITATIONS
SEARCH DETAIL
...