Body temperature around induced estrus in dairy cows

The overall objective of this study was to study the influence of induced estrus on body temperature, comparing 5 distinct intervals around induced estrus and to determine the diurnal pattern from 4 ± 1 d before to 4 ± 1 d after induced estrus. Sixteen estrous cycles of 9 postpartum dairy cows were synchronized with 2 injections of PGF(2α), 10 d apart. After the second PGF(2α) injection on d 10, temperature loggers were inserted into the vaginal cavity for a 12 ± 1-d period. Two days later, a third dose of PGF(2α) was injected to induce estrus. After confirmation of a corpus luteum, loggers were removed on d 5 ± 1. Observation of estrus, rectal palpation, and ultrasound scanning to determine ovulation were carried out every 4 ± 1h, beginning at 12h after the third PGF(2α) injection. Blood samples from the vena coccygea mediana were collected twice daily from d 11 to 12 and every 4 ± 1h after the third PGF(2α) injection until ovulation. Vaginal temperature was recorded every 5 min and averaged to hourly means for the following 5 periods: 1) 48 h preceding the third PGF(2α) injection, 2) from the third PGF(2α) injection to first signs of estrus, 3) estrus to ovulation, 4) a 4-h interval in which ovulation occurred, and 5) a 96-h post-ovulation period. High body temperatures (39.0 ± 0.5 °C) and low progesterone (P4) concentrations (<0.5 ng/mL) were observed during estrus, whereas low body temperatures were observed from PGF(2α) injection to estrus (38.6 ± 0.3 °C) and around ovulation (38.5 ± 0.2 °C), respectively. An association between body temperature and serum P4 concentrations did not exist. However, P4 concentrations on d 11 and 12 were high (5.0 ± 1.5 ng/mL) and decreased (0.9 ± 0.2 ng/mL) after ovulation. Diurnal temperature rhythms were similar before and after estrus. Vaginal temperature before estrus (d 11 and 12) was slightly (0.1 °C) higher compared with the post-ovulation period

Gene therapy for carcinoma of the breast: Genetic ablation strategies

The gene therapy strategy of mutation compensation is designed to rectify the molecular lesions that are etiologic for neoplastic transformation. For dominant oncogenes, such approaches involve the functional knockout of the dysregulated cellular control pathways provoked by the overexpressed oncoprotein. On this basis, molecular interventions may be targeted to the transcriptional level of expression, via antisense or ribozymes, or post-transcriptionally, via intracellular single chain antibodies (intrabodies). For carcinoma of the breast, these approaches have been applied in the context of the disease linked oncogenes erbB-2 and cyclin D(1), as well as the estrogen receptor. Neoplastic revision accomplished in modal systems has rationalized human trials on this basis

<i>GRIN2A</i>-related disorders:genotype and functional consequence predict phenotype

Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10-6) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a+/- cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and misATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of misTMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders

Tumour brain: pre‐treatment cognitive and affective disorders caused by peripheral cancers

People that develop extracranial cancers often display co-morbid neurological disorders, such as anxiety, depression and cognitive impairment, even before commencement of chemotherapy. This suggests bidirectional crosstalk between non-CNS tumours and the brain, which can regulate peripheral tumour growth. However, the reciprocal neurological effects of tumour progression on brain homeostasis are not well understood. Here, we review brain regions involved in regulating peripheral tumour development and how they, in turn, are adversely affected by advancing tumour burden. Tumour-induced activation of the immune system, blood–brain barrier breakdown and chronic neuroinflammation can lead to circadian rhythm dysfunction, sleep disturbances, aberrant glucocorticoid production, decreased hippocampal neurogenesis and dysregulation of neural network activity, resulting in depression and memory impairments. Given that cancer-related cognitive impairment diminishes patient quality of life, reduces adherence to chemotherapy and worsens cancer prognosis, it is essential that more research is focused at understanding how peripheral tumours affect brain homeostasis

Plasma potassium-lowering effect of oral glucose, sodium bicarbonate, and the combination thereof in healthy neonatal dairy calves

Hyperkalemia is a common complication in neonatal diarrheic dairy calves and is corrected by administration of glucose or sodium bicarbonate. Although the hypokalemic effect of glucose is well established in other species, controversial results are reported for sodium bicarbonate. Our objective was to study the effect and mechanism of action of glucose and sodium bicarbonate on the potassium homeostasis of healthy neonatal dairy calves. Nine healthy neonatal Holstein-Friesian calves underwent 3 oral treatments with 2L of NaHCO(3) (150 mmol/L), glucose (300 mmol/L), and glucose+NaHCO(3) solution (300 mmol/L+150 mmol/L) in randomized order. Blood was obtained before treatment (T(0)) and at 30-min intervals thereafter. Changes between each time point and T(0) were determined for all parameters. Urine was collected volumetrically to determine total renal potassium excretion over an 8-h posttreatment period. Plasma volume changes were extrapolated from changes in plasma protein concentration. Treatment and time effects were tested with repeated-measures ANOVA. Multivariate stepwise regression analysis using dummy variable coding was conducted to identify associations between changes in plasma potassium concentration ([K]) and changes in plasma glucose concentration ([glucose]), blood base excess, and plasma volume. Oral glucose and sodium bicarbonate treatments decreased [K] by 25 and 19%, respectively, whereas the combination of both compounds caused an intermediate [K] decline (22%). For the glucose treatment, the decline in [K] was only associated with changes in plasma [glucose] (partial R(2)=0.19). In NaHCO(3)-treated calves, [K] decline was associated with change of extracellular volume (partial R(2)=0.31) and blood base excess (partial R(2)=0.19). When glucose and NaHCO(3) were combined, [K] decline was associated with changes in plasma volume (partial R(2)=0.30), BE (R(2)=0.22), and [glucose] (partial R(2)=0.03). Our results indicate that glucose lowers plasma [K] mainly through an insulin- dependent intracellular translocation of K, whereas NaHCO(3) causes hypokalemia through hemodilution followed by intracellular translocation of K caused by the strong ion effect. The combination of glucose and NaHCO(3) at the dosage used in this study does not have an additive hypokalemic effect. When combined, hemodilution and strong ion effect have the strongest effect on plasma [K], whereas the insulin-dependent effect of glucose appears to be blunted

Alkalinizing effect of NaHCO3 with and without glucose when administered orally to euhydrated neonatal dairy calves

The use of oral rehydration solutions (ORS) is well established as an effective treatment to correct water-, electrolyte-, and acid-base balance in diarrheic calves. The main ingredients of a commercial ORS are Na, glucose, and alkalinizing agents, such as NaHCO3. Particular importance is attributed to the combination of glucose and Na at a specific ratio to optimize intestinal sodium, and thereby water uptake, through the sodium-glucose co- transport. Enhancing intestinal Na absorption by combining glucose and Na in an ORS has the potential to improve the alkalinizing effect of an ORS according the strong ion theory. The objective of this study was to investigate the effect of glucose on the alkalinizing effect of NaHCO3 when administered orally. Nine healthy neonatal Holstein-Friesian calves underwent 3 oral treatments with 2-L solutions of NaHCO3 (150 mmol/L), glucose (300 mmol/L), and glucose + NaHCO3 (300 mmol/L + 150 mmol/L, respectively) in randomized order. Arterial and venous blood was obtained before treatment and in 30-min intervals thereafter for blood gas analysis and determination of plasma protein and electrolyte concentrations. Urine was collected volumetrically to determine urine volume, osmolality, pH, net acid excretion, and renal Na excretion after treatment. Plasma volume changes were extrapolated from plasma protein concentration changes. Treatment and time effects were tested with repeated measures ANOVA. Only subtle differences between oral administration of NaHCO3, with and without glucose, were observed for the change of the standard HCO3 concentration relative to baseline. No differences in plasma Na, plasma volume expansion, renal Na, net base excretion, urine volume, or pH could be identified between animals treated orally with NaHCO3 with and without glucose. Similarly, no differences in blood glucose concentration, plasma volume expansion, urine volume, or renal glucose excretion were observed in the 8 h after treatment when comparing oral glucose treatment with and without NaHCO3. Our results indicate that combination of NaHCO3 with glucose in a hypertonic ORS only had a minor effect on the alkalinizing effect of NaHCO3, which is unlikely to be of clinical relevance. The combination of NaHCO3 and glucose neither improved Na, glucose, nor water absorption in euhydrated neonatal dairy calves, questioning the relevance of a specific ratio between Na and glucose in ORS for calves

Evaluation of calving indicators measured by automated monitoring devices to predict the onset of calving in Holstein dairy cows

Dystocias are common in dairy cows and often adversely affect production, reproduction, animal welfare, labor, and economics within the dairy industry. An automated device that accurately predicts the onset of calving could potentially minimize the effect of dystocias by enabling producers to intervene early. Although many well-documented indicators can detect the imminence of calving, research is limited on their effectiveness to predict calving when measured by automated devices. The objective of this experiment was to determine if a decrease in vaginal temperature (VT), rumination (RT), and lying time (LT), or an increase in lying bouts (LB), as measured by 3 automated devices, could accurately predict the onset of calving within 24, 12, and 6 h. The combination of these 4 calving indicators was also evaluated. Forty-two multiparous Holstein cows housed in tie-stalls were fitted with a temperature logger inserted in the vaginal cavity 7 ± 2 d before their expected calving date; VT was recorded at 1-min intervals. An ear-attached sensor recorded rumination time every hour based on ear movement while an accelerometer fitted to the right hind leg recorded cow position at 1-min intervals. On average, VT were 0.3 ± 0.03°C lower, and RT and LT were 41 ± 17 and 52 ± 28 min lower, respectively, on the calving day compared with the previous 4 d. Cows had 2 ± 1 more LB on the calving day. Of the 4 indicators, a decrease in VT = 0.1°C was best able to predict calving within the next 24 h with a sensitivity of 74%, specificity of 74%, positive and negative predictive values of 51 and 89%, and area under the curve of 0.80. Combining the indicators enhanced the performance to predict calving within the next 24, 12, and 6 h with best overall results obtained by combining the 3 devices for prediction within the next 24 h (sensitivity: 77%, specificity: 77%, positive and negative predictive values: 56 and 90%, area under the curve: 0.82). These results indicate that a device that could simultaneously measure these 4 calving indicators could not precisely determine the onset of calving, but the information collected would assist dairy farmers in monitoring the onset of calving