Microencephaly in fetal piglets following in utero inoculation of Zika virus.

Zika virus (ZIKV) is a mosquito-borne flavivirus that became associated with microcephaly in newborns and Guillain-Barré syndrome in adults after its emergence in the Pacific and the Americas in 2015. Newly developed rodent and nonhuman primate models have already revealed important insights into ZIKV-induced neuropathology. Nonhuman primates are phylogenetically closely related to humans and are therefore preferred human surrogates in ZIKV research. However, the use of nonhuman primates, particularly during gestation, raises ethical issues. Considering that pigs also share many anatomical and physiological features with humans, this species may be an attractive alternative human surrogate for ZIKV research. Here, we inoculated 20 porcine fetuses in utero and assessed the effect of ZIKV on brain development 4 weeks later. All inoculated fetuses presented mild to severe neuropathology, characterized by a depletion of neurons in the cerebral cortex. In most cases, neuronal depletion was confined to specific cerebral lobes without affecting brain size, whereas in severe cases a more generalized depletion resulted in microencephaly. Although the virus was widespread in the sows' placenta at the time of necropsy only low levels of viral RNA were detected in fetal brain samples, thereby preventing the identification of primary target cells. Our findings suggest that pigs can be used to study ZIKV-induced neurodevelopmental defects as currently observed in human neonates, varying from stunted brain growth to localized cortical neuronal depletion in the absence of major macroscopic abnormalities.

Cardiovascular performance of adult breeding sows fails to obey allometric scaling laws.

In view of the remarkable decrease of the relative heart weight (HW) and the relative blood volume in growing pigs, we investigated whether HW, cardiac output (CO), and stroke volume (SV) of modern growing pigs are proportional to BW, as predicted by allometric scaling laws: HW (or CO or SV) = a·BW(b), in which a and b are constants, and constant b is a multiple of 0.25 (quarter-power scaling law). Specifically, we tested the hypothesis that both HW and CO scale with BW to the power of 0.75 (HW or CO = a·BW(0.75)) and SV scales with BW to the power of 1.00 (SV = a·BW(1.0)). For this purpose, 2 groups of pigs (group 1, consisting of 157 pigs of 50 ± 1 kg; group 2, consisting of 45 pigs of 268 ± 18 kg) were surgically instrumented with a flow probe or a thermodilution dilution catheter, under open-chest anesthetized conditions to measure CO and SV, after which HW was determined. The 95% confidence intervals of power-coefficient b for HW were 0.74 to 0.80, encompassing the predicted value of 0.75, suggesting that HW increased proportionally with BW, as predicted by the allometric scaling laws. In contrast, the 95% confidence intervals of power-coefficient b for CO and SV as measured with flow probes were 0.40 to 0.56 and 0.39 to 0.61, respectively, and values obtained with the thermodilution technique were 0.34 to 0.53 and 0.40 to 0.62, respectively. Thus, the 95% confidence limits failed to encompass the predicted values of b for CO and SV of 0.75 and 1.0, respectively. In conclusion, although adult breeding sows display normal heart growth, cardiac performance appears to be disproportionately low for BW. This raises concern regarding the health status of adult breeding sows.

Does cardiovascular performance of modern fattening pigs obey allometric scaling laws?

In view of the remarkable decrease of the relative heart weight and the relative blood volume in growing pigs, we investigated whether cardiac output (CO) and stroke volume (SV) of modern growing pigs are proportional to body mass (M), as predicted by allometric scaling laws: CO (or SV) = a.M(b), in which b is a multitude of 0.25 (quarter power scaling law). Specifically, we tested the hypothesis that CO scales with M to the power of 0.75 (CO = a.M(0.75)) and SV scales with M to the power of 1.00 (SV = a.M(1.0)) and investigated whether these relations persisted during increased cardiac stress. For this purpose, 2 groups of pigs (group 1 of 57 +/- 3 kg in Lelystad, and group 2 of 28 +/- 1 kg in Rotterdam) were chronically instrumented with a flow probe to measure CO and SV; instrumented pigs were studied at rest and during strenuous exercise (at approximately 85% of maximum heart rate). Analysis of both groups of pigs (analyzed separately or combined) under resting conditions demonstrated that the 95% confidence intervals of power-coefficient b for CO encompassed 0.75 and for SV encompassed 1.0. During exercise, similar results were obtained, except for SV in group 2, in which the 95% confidence limits remained below 1.0, which may have been due to the relatively small range of BW in group 2. These observations indicate that CO and SV of growing pigs with M less than 75 kg are still proportional to M, even during strenuous exercise, and that CO and SV scale with M according to the quarter power scaling laws. In conclusion, the concerns about disproportional growth and development of modern growing pigs with BW up to 75 kg were not confirmed by the present study.