The role of L-carnitine in bovine embryo metabolism. A review of the effect of supplementation with a metabolic modulator on in vitro embryo production.

Early embryo development is driven first by the maternal RNAs and proteins accumulated during the oocyte's cytoplasmic maturation and then after the embryo genome activation. In mammalian cells, ATP generation occurs via oxidative pathways or by glycolysis, whereas in embryonic stem cells, the consumption of glucose, pyruvate, lipids, and amino acids results in ATP synthesis. Although the bovine embryo has energy reserves in glycogen and lipids, the glycogen concentration is deficient. Conversely, lipids represent the most abundant energy reservoir of bovine embryos, where lipid droplets-containing triacylglycerols are the main fatty acid stores. Oocytes of many mammalian species contain comparatively high amounts of lipids stored as droplets in the ooplasm. L-carnitine has been described as a cofactor that facilitates the mobilization of fatty acids present in the oocyte's cytoplasm into the mitochondria to facilitate ß-oxidation processes. However, the L-carnitine effects by addition to media in the in vitro produced embryos on the quality are highly disputed and contradictory by different researchers. This review's objective was to explore the effect that the addition of L-carnitine on culture media could have on the overall bovine embryo production in vitro, from the oocyte metabolism to the modulation of gene expression in the developing embryos.

Regional Changes in Patterns of Stroke Presentation During the COVID-19 Pandemic.

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l-Carnitine Supplementation during In Vitro Maturation and In Vitro Culture Does not Affect the Survival Rates after Vitrification and Warming but Alters Inf-T and ptgs2 Gene Expression.

l-carnitine is a potent antioxidant used for in vitro culture systems. Controversial results have been reported using l-carnitine in culture medium at different stages of in vitro bovine embryo production. Cumulus-oocyte complexes (n = 843) were in vitro-fertilized and cultured and added (treatment group) or not added (control group) with l-carnitine. At day three of culture, each group was subdivided into two subgroups receiving no l-carnitine (group 1), 3.8 mM l-carnitine added during in vitro maturation (group 2), 1.5 mM added during the in vitro culture (group 3), and 3.8 mM and 1.5 mM added during the maturation and culture, respectively (group 4). At day 8, blastocyst embryos were examined for mitochondrial activity, the presence of lipid droplets, total cell number, gene expression, and cryotolerance by vitrification. The data were analyzed with a one-way analysis of variance. l-carnitine added in the late in vitro culture significantly reduced mitochondrial activity and lipid content, and upregulated ifn-τ and ptgs2 gene expression compared to controls (p < 0.05). l-carnitine supplementation did not significantly affect the embryo rate production or survival rate after vitrification and warming (p > 0.05). l-carnitine supplementation significantly improved embryo potential to develop viable pregnancies in agreement with a study reporting improved pregnancy rates.

L-carnitine supplementation in culture media improves the pregnancy rate of in vitro produced embryos with sexed semen from Bos taurus indicus cows.

The in vitro embryo production industry in the actual world presents some difficulties related to low embryonic production rates, a problem that could be associated with in vitro culture conditions that differed from the in vivo (oviductal) conditions, mainly related to cytoplasmic lipid accumulation. L-carnitine is known as a modulator of ß-oxidation in the developing embryo, as it has been demonstrated that it improves embryo quality without affecting the in vitro embryo production rate. The aim of the present work was to evaluate the effect of L-carnitine supplemented during the in vitro maturation and culture processes on the implantation rate of in vitro produced embryos. Supplementation with 3.8 mM of L-carnitine was used during in vitro maturation, and later, during late in vitro culture, it was added at 1.5 mM. A control group contained no L-carnitine supplementation. Bovine oocytes obtained by ultrasound-guided follicle aspiration from healthy Bos taurus indicus cows were matured, fertilized and cultured in vitro. Multiparous F1 (Bos taurus taurus × Bos taurus indicus) cows were used as recipients. Overall, 460 oocytes were processed in three independent replicates from in vitro maturation until day 8 of the in vitro culture. No significant difference was found between treatments of in vitro embryo production. However, pregnancy rate at days 45 and 72 was significantly higher in blastocysts derived from L-carnitine treatment (31.55 ± 9.78%) compared to the control group (18.68 ± 6.31%). In conclusion, addition of L-carnitine at 3.8 mM and 1.5 mM in the maturation, and culture medium after day 3 of in vitro production process, significantly improved pregnancy rate after embryo transfer.

Trends in Telestroke Care Delivery: A 15-Year Experience of an Academic Hub and Its Network of Spokes.

BACKGROUND: Telestroke provides access to vascular neurology expertise for hospitals lacking stroke coverage, and its use has risen rapidly in the past decade. We aim to characterize consultations, spoke behavior, and the relationship between spoke telestroke utilization (number of telestroke consults per year) and spoke alteplase treatment metrics in an academic telestroke network. METHODS AND RESULTS: We analyzed prospectively collected data on all telestroke consults from 2003 to 2018. Trends in network performance and spoke characteristics were analyzed using generalized estimating equations and Kendall τß nonparametric tests as appropriate. Unadjusted and adjusted linear regression models determined associations between telestroke utilization and treatment metrics. The network included 2 hubs and 43 spokes with 12 803 consults performed during the study period. Network growth overall was +1.8 spokes per year, and median duration of spoke participation was 7.9 years. The numbers of consults and alteplase-treated patients increased annually, even after adjusting for the number of spokes in the network (P<0.01 for both). Although times from last seen well to spoke emergency department arrival and to consult request increased, door-to-needle time, time from teleconsult request to callback, and time from teleconsult to alteplase administration all decreased (all P<0.01). With time, the network included more spokes without a Primary Stroke Center designation. In adjusted analyses, for every 10 telestroke consults requested by a spoke, the spoke door-to-needle decreased by 1.8 minutes (P=0.02), number of patients treated with alteplase was an additional 1.7 (P<0.01), and the percent of eligible patients treated with alteplase increased by 8% (P=0.03). CONCLUSIONS: Telestroke network size and utilization increased over time. Increased use of teleconsults was associated with increased and timely use of alteplase. Over time, the delivery of timely emergency care has improved significantly among emergency departments participating in this telestroke network. Replication of these findings in other networks is warranted.

Falla ovárica en una yegua de paso fi no colombiano:tratamiento combinado homeopático antihomotóxicoy hormonal: reporte de un caso / Fracasso ovário em uma égua de passo colombiano: manipulação homeopática antihomotoxicae hormonal combinada: reporte de um caso / Ovulation failure in a Colombian Paso fino Mare: A combined antihomotoxic homeopathic therapy and hormonal treatment: a case report

La falla ovulatoria es una de las principales causas de infertilidad en yeguas cíclicas. En el presentecaso, se describe el seguimiento de una yegua nulípara de paso fino colombiano de seis años que ingresóa consulta para ser sometida a reproducción. Al examen ecográfico se le halló el ovario izquierdo de 15x 13 cm con una estructura patológica de aspecto anecóico y contenido líquido de 13 x 11 cm, el ovarioderecho sin estructuras y el útero flácido. La yegua fue sometida a tratamiento con antihomotóxicos deltipo Ovarium compositum®, Damiana injeel®, Cerebrum compositum®, y Phosphor hommacord® durante1½ mes, y terapia FK (terapia neural, dos en 15 días), lo cual disminuyó el tamaño del folículo y delovario, indujo ablandamiento de la pared folicular y leve respuesta uterina. Un mes y medio después,el ovario izquierdo tenía 13 x 11 cm y un folículo de 9 x 8 cm, y el ovario derecho estaba multifolicular.Las concentraciones de progesterona, estradiol y testosterona eran características de anestro. La yeguafue tratada con eCG (3.000 UI/3 días, i.v.), cuatro días después la progesterona ascendió a 14.91 ng/dl, el examen ecográfico reveló un cuerpo lúteo en el ovario izquierdo y a los siete días fue tratada conPGF2α (9 μg/kg/2 días) intramuscular. Cinco días después la yegua presentó estro, fue inseminada y tuvouna gestación que perdió a los 40 días; luego presentó un nuevo estro a los 20 días, fue inseminada, sele confirmó gestación a los 20 días y tuvo una gestación a término con un potro viable al momento del parto. Este caso sugiere la posibilidad de combinar terapia hormonal con medicina alternativa para eltratamiento de algunos tipos de anormalidades en el funcionamiento ovárico en las yeguas.parto. Este caso sugiere la posibilidad de combinar terapia hormonal con medicina alternativa para eltratamiento de algunos tipos de anormalidades en el funcionamiento ovárico en las yeguas.

Ovulation failure is one of the most frequent causes of infertility in mares. In the present case wereport a six-year-old Colombian Paso Fino maiden Mare that was attended for breeding purposes with aprevious history of ovulation failure. At ultrasound (US) examination of the reproductive tract and ovariesthe left ovary measured 15 x 13 cm and a pathologic 13 x 11 cm diameter anecoic structure was diagnosed.The right ovary was found of normal size, and the uterus was found flacid. An anti homotoxic theraphywith Ovarium compositum®, Damiana injeel®, Cerebrum compositum®, and Phosphor hommacord® for1½ months and FK (neural) therapy (twice/15 days) were then established, the ovary size was reduced,and softening of the follicular wall and a slight uterine response were observed. After 1½ month, the leftovary had 13 x 11 cm diameter and showed a 9 x 8 cm follicle, whereas the right ovary was multifollicular.Serum progesterone, estradiol and testosterone levels were those characteristics of an anestrous mare.The mare was treated with hCG (3.000 UI, i.v./3 days) and 4 days later a corpus luteum was diagnosedby US in the left ovary and serum progesterone levels raised to 14.91 ng/dl. At day 7 after hCG treatmentthe mare was given PGF2α (9 μg/kg/for two days) intramuscular, estrous was evident 5 days later, andartificial insemination (AI) with fertile semen was practiced resulting in a viable pregnancy as evaluatedby ultrasound at day 20; however, this pregnancy was lost at 40 days after AI. The mare returned to estrus20 days later, she was then inseminated and the resulting pregnancy was confirmed at day 20th resultingin a successful gestation and foaling of a full term viable foal. This report suggests hormonal therapy andalternative medicine could be successfully combined for treatment of specific ovarian pathologies in mares.

O fracasso ovulatório é uma das principais causas de infertilidade em éguas cíclicas. Neste caso, sedescreveu o acompanhamento de uma égua nulípara da paso fino colombiano, de seis anos idade queconsultou para serem sujeitos a reprodução. No exame ultra-som que ele encontrou o ovário esquerdo,15 x 13 cm, com uma estrutura patológica de 13 x 11 cm, o ovários direito sem estruturas e útero mau. Aégua sofreu tratamento com drogas Ovarium compositum®, Damiana injeel®, Cerebrum compositum®, ePhosphor hommacord® durante 1½ mês, FK terapêutica (terapia neural, duas em 15 dias), o que diminuiuo tamanho do folículo e do ovário, induzida amolecimento da parede uterina e leve resposta folicular.Um mês e meio depois, o ovário esquerdo tinha 13 x 11 cm e um folículo 9 x 8 cm, e do ovário direito foimultifolicular. As concentrações de progesterona, estradiol e testosterona foram características do anestro.A égua foi tratada com eCG (3.000 UI IV/3 dias), quatro dias após a progesterona ascendeu a 14.91 ng/dl, efoi visto por ultra-som corpo lúteo no ovário esquerdo. Em sete dias, a égua foi tratada com PGF2α (9 μg/kg/2 dias) i.m., introduzido estro após cinco dias, foi inseminada e teve uma gestação que perdeu a 40 dias;introduziu um novo estro em 20 dias, foi inseminação, a gravidez foi confirmada em 20 dias e atualmentemantém um 9 meses de gestação. Este caso sugere a utilidade da terapia hormonal combinando commedicina alternativa para o tratamento de certos tipos de anomalias no funcionamento do ovário em éguas.

Evaluation of a series of naphthamides as potent, orally active vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.

We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared and found to yield nanomolar inhibitors of VEGFR-2 (KDR) with an improved selectivity profile against a panel of tyrosine and serine/threonine kinases. The inhibitory activity of this series was retained at the cellular level. Naphthamides 3, 20, and 22 exhibited good pharmacokinetics following oral dosing and showed potent inhibition of VEGF-induced angiogenesis in the rat corneal model. Once-daily oral administration of 22 for 14 days led to 85% inhibition of established HT29 colon cancer and Calu-6 lung cancer xenografts at doses of 10 and 20 mg/kg, respectively.

Naphthamides as novel and potent vascular endothelial growth factor receptor tyrosine kinase inhibitors: design, synthesis, and evaluation.

A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure-activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure-activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.