A study to examine the relationship between uterine pathology and depletion of oxytetracycline in plasma and milk after intrauterine infusion

Citation: Gorden, P. J., Ydstie, J., Kleinhenz, M. D., Wulf, L. W., Gehring, R., Wang, C., & Coetzee, J. F. (2016). A study to examine the relationship between uterine pathology and depletion of oxytetracycline in plasma and milk after intrauterine infusion. Journal of Animal Science, 94, 30-30. doi:10.2527/msasas2016-065Metritis is a frequent problem in postpartum dairy cows. Intrauterine therapy with oxytetracycline (OTC) is often used to improve therapeutic outcomes, although efficacy data supporting this therapy are ambiguous. Several manuscripts describe the depletion of OTC from milk following intrauterine therapy. However, none of these studies have correlated uterine severity scores with milk OTC concentrations using highly sensitive detection systems. Our objective was to do this to test the hypothesis that cows with more severe uterine severity would have higher OTC residues in milk following intrauterine therapy. Thirty-two cows received a single treatment of 4 g of OTC via intrauterine infusion. Blood and milk samples were collected before intrauterine therapy and throughout the trial period of 96 h after infusion. Uterine severity scores were assigned at initiation of therapy and every 24 h throughout the remainder of the trial. Plasma and milk samples were analyzed for OTC concentrations using liquid chromatography coupled with mass spectrometry. Following treatment, OTC rapidly diffused from the uterus to plasma and from plasma to milk. Maximum concentration in plasma and milk occurred within 24 h following intrauterine infusion and 18 of the cows still had detectable levels of OTC in milk 4 d after intrauterine infusion. Greater uterine severity score at the initiation of treatment showed a significant positively correlation with higher milk OTC concentration at the second milking following treatment (R2 = 0.46, P = 0.01) but there was no correlation between initial uterine severity score and OTC concentration at the conclusion of the study (R2 = ?0.06, P = 0.75). In the United States, intrauterine administration of OTC is considered to be an extra-label therapy. The use of uterine severity score can be used to predict OTC concentration in the first day following therapy but should not be used as a predictor of OTC concentrations 96 h after treatment. Dairy producers should consult with their veterinarian to develop strategies that will prevent the presence of violative residues of OTC in bulk tank milk following intrauterine therapy

A sampling method for quantifying the information content of IASI channels

There is a vast amount of information about the atmosphere available from instruments on board satellites. One example is the Infrared Atmospheric Sounding Interferometer (IASI) instrument, which measures radiances emitted from Earth’s atmosphere and surface in 8461 channels. It is difficult to transmit, store, and assimilate such a large amount of data. A practical solution to this has been to select a subset of a few hundred channels based on those that contain the most useful information. Different measures of information content for objective channel selection have been suggested for application to variational data assimilation. These include mutual information and the degrees of freedom for signal. To date, the calculation of these measures of information content has been based on the linear theory that is at the heart of operational variational data assimilation. However, the retrieval of information about the atmosphere from the satellite radiances can be highly nonlinear. Here, a sampling method for calculating the mutual information that is free from assumptions about the linearity of the relationship between the observed radiances and the state variables is examined. It is found that large linearization errors can indeed lead to large discrepancies in the value of mutual information. How this new estimate of information content can be used in channel selection is addressed, with particular attention given to the efficiency of the new method. It is anticipated that accounting for the nonlinearity in the channel selection will be beneficial when using nonlinear data assimilation methods currently in development

Understanding signaling cascades in melanoma

Understanding regulatory pathways involved in melanoma development and progression has advanced significantly in recent years. It is now appreciated that melanoma is the result of complex changes in multiple signaling pathways that affect growth control, metabolism, motility and the ability to escape cell death programs. Here we review the major signaling pathways currently known to be deregulated in melanoma with an implication to its development and progression. Among these pathways are Ras, B-Raf, MEK, PTEN, phosphatidylinositol-3 kinase (PI3Ks) and Akt which are constitutively activated in a significant number of melanoma tumors, in most cases due to genomic change. Other pathways discussed in this review include the [Janus kinase/signal transducer and activator of transcription (JAK/STAT), transforming growth factor-beta pathways which are also activated in melanoma, although the underlying mechanism is not yet clear. As a paradigm for remodeled signaling pathways, melanoma also offers a unique opportunity for targeted drug development.Fil: Lopez Bergami, Pablo Roberto. Sanford-burnham Medical Research Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Fitchmann, B. Sanford-burnham Medical Research Institute; Estados UnidosFil: Ronai, Ze´ev. Sanford-burnham Medical Research Institute; Estados Unido

Founder effect in the Horn of Africa for an insulin receptor mutation that may impair receptor recycling.

AIMS/HYPOTHESIS: Genetic insulin receptoropathies are a rare cause of severe insulin resistance. We identified the Ile119Met missense mutation in the insulin receptor INSR gene, previously reported in a Yemeni kindred, in four unrelated patients with Somali ancestry. We aimed to investigate a possible genetic founder effect, and to study the mechanism of loss of function of the mutant receptor. METHODS: Biochemical profiling and DNA haplotype analysis of affected patients were performed. Insulin receptor expression in lymphoblastoid cells from a homozygous p.Ile119Met INSR patient, and in cells heterologously expressing the mutant receptor, was examined. Insulin binding, insulin-stimulated receptor autophosphorylation, and cooperativity and pH dependency of insulin dissociation were also assessed. RESULTS: All patients had biochemical profiles pathognomonic of insulin receptoropathy, while haplotype analysis revealed the putative shared region around the INSR mutant to be no larger than 28 kb. An increased insulin proreceptor to β subunit ratio was seen in patient-derived cells. Steady state insulin binding and insulin-stimulated autophosphorylation of the mutant receptor was normal; however it exhibited decreased insulin dissociation rates with preserved cooperativity, a difference accentuated at low pH. CONCLUSIONS/INTERPRETATION: The p.Ile119Met INSR appears to have arisen around the Horn of Africa, and should be sought first in severely insulin resistant patients with ancestry from this region. Despite collectively compelling genetic, clinical and biochemical evidence for its pathogenicity, loss of function in conventional in vitro assays is subtle, suggesting mildly impaired receptor recycling only

Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis)

OBJECTIVE: To identify genetic causes of COACH syndrome BACKGROUND: COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD). METHODS: In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced. RESUlTS: 19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%). CONCLUSIONS: Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L