Highly efficient maternal-fetal Zika virus transmission in pregnant rhesus macaques.

Infection with Zika virus (ZIKV) is associated with human congenital fetal anomalies. To model fetal outcomes in nonhuman primates, we administered Asian-lineage ZIKV subcutaneously to four pregnant rhesus macaques. While non-pregnant animals in a previous study contemporary with the current report clear viremia within 10-12 days, maternal viremia was prolonged in 3 of 4 pregnancies. Fetal head growth velocity in the last month of gestation determined by ultrasound assessment of head circumference was decreased in comparison with biparietal diameter and femur length within each fetus, both within normal range. ZIKV RNA was detected in tissues from all four fetuses at term cesarean section. In all pregnancies, neutrophilic infiltration was present at the maternal-fetal interface (decidua, placenta, fetal membranes), in various fetal tissues, and in fetal retina, choroid, and optic nerve (first trimester infection only). Consistent vertical transmission in this primate model may provide a platform to assess risk factors and test therapeutic interventions for interruption of fetal infection. The results may also suggest that maternal-fetal ZIKV transmission in human pregnancy may be more frequent than currently appreciated.

Wrist-Sensor Pulse Oximeter Enables Prolonged Patient Monitoring in Chronic Lung Diseases.

Pulse oximetry is an important diagnostic tool in monitoring and treating both in-patients and ambulatory patients. Modern pulse oximeters exploit different body sites (eg fingertip, forehead or earlobe). All those are bulky and uncomfortable, resulting in low patient compliance. Therefore, we evaluated the accuracy and precision of a wrist-sensor pulse oximeter (Oxitone-1000, Oxitone Medical) vs. the traditional fingertip device. Fifteen healthy volunteers and 23 patients were recruited. The patient group included chronic obstructive pulmonary disease (COPD) (N = 8), asthma (N = 6), sarcoidosis (N = 5) and others. Basic demographic data, skin tone type, smoking status and medical history were recorded. Blood oxygen level (SpO2) and pulse-rate values were determined by a non-invasive pulse oximeter (Reference, a conventional FDA-cleared fingertip pulse oximeter) and by Oxitone-1000. All tests were performed in singleton and in a blinded fashion. The measurements were done in sitting and standing positions, as well as after a 6-min walk test. The mean age was 60.4 ± 9.83 years, 55% were male. No significant differences were observed between the wrist-sensor and the traditional fingertip pulse oximeters in all tested parameters. Mean SpO2 was 96.45% vs. 97.18% and the mean pulse was 74.64 vs. 74.6 bpm (Oxitone-1000 vs. Reference, respectively, p < 0.0001). Precision rate was 2.28472% and the accuracy was met (Arms -Root mean-square-error < 3%). The Oxitone-1000 is both accurate and precise for SpO2 and pulse measurements during daily activities of pulmonary patients, and is not inferior to standard devices for spot checking or short period examinations. Its wrist-sensor design is comfortable and provides the advantage of extended use.

Three-dimensional Ultrasound Elasticity Imaging on an Automated Breast Volume Scanning System.

Ultrasound elasticity imaging has demonstrated utility in breast imaging, but it is typically performed with handheld transducers and two-dimensional imaging. Two-dimensional (2D) elastography images tissue stiffness of only a plane and hence suffers from errors due to out-of-plane motion, whereas three-dimensional (3D) data acquisition and motion tracking can be used to track out-of-plane motion that is lost in 2D elastography systems. A commercially available automated breast volume scanning system that acquires 3D ultrasound data with precisely controlled elevational movement of the 1D array ultrasound transducer was employed in this study. A hybrid guided 3D motion-tracking algorithm was developed that first estimated the displacements in one plane using a modified quality-guided search method, and then performed an elevational guided-search for displacement estimation in adjacent planes. To assess the performance of the method, 3D radiofrequency echo data were acquired with this system from a phantom and from an in vivo human breast. For both experiments, the axial displacement fields were smooth and high cross-correlation coefficients were obtained in most of the tracking region. The motion-tracking performance of the new method was compared with a correlation-based exhaustive-search method. For all motion-tracking volume pairs, the average motion-compensated cross-correlation values obtained by the guided-search motion-tracking method were equivalent to those by the exhaustive-search method, and the computation time was about a factor of 10 lesser. Therefore, the proposed 3D ultrasound elasticity imaging method was a more efficient approach to produce a high quality of 3D ultrasound strain image.

Can Sonography Distinguish a Supraorbital Notch From a Foramen?

Diagnostic tools for evaluating the supraorbital rim in preparation for nerve decompression surgery in patients with chronic headaches are currently limited. We evaluated the use of sonography to diagnose the presence of a supraorbital notch or foramen in 11 cadaver orbits. Sonographic findings were assessed by dissecting cadaver orbits to determine whether a notch or foramen was present. Sonography correctly diagnosed the presence of a supraorbital notch in 7 of 7 cases and correctly diagnosed a supraorbital foramen in 4 of 4 cases. We found that sonography had 100% sensitivity in diagnosing a supraorbital notch and foramen. This tool may therefore be helpful in characterizing the supraorbital rim preoperatively and may influence the decision to use a transpalpebral or endoscopic approach for supraorbital nerve decompression as well as the decision to use local or general anesthesia.

Heparin Effects on Serum Gonadotropins.

INTRODUCTION: Studies using lipid infusions to raise fatty acid levels require heparin to release lipoprotein lipase (LPL), thus calling into question the appropriate control infusion for this type of study: saline alone or saline plus heparin. We aimed to evaluate whether the addition of heparin alone, in doses needed to release LPL, would alter circulating free fatty acids (FFAs) and/or affect gonadotropins. MATERIALS AND METHODS: This was a secondary analysis using combined data from eumenorrheic normal-weight women subjected to "control" conditions in 1 of 2 separate studies. In 1 study, participants received saline alone (group 1) as a control, and in the other study participants received saline alone and/or saline plus heparin (groups 2-3) as a control. Both studies performed early follicular phase, frequent blood sampling. FSH and LH were compared across groups and in conditions with and without heparin. Linear mixed models were used to analyze the data. RESULTS: LH did not differ across any of the 3 groups. Estimated means (SE) for FSH differed between groups but this difference was marginal (P = .05) after adjusting for anti-Mullerian hormone and unrelated to heparin infusion (group 1: 4.47 IU/L [SE 1.19], group 2: 8.01 IU/L [SE 1.14], group 3: 7.94 IU/L [SE 1.13]). CONCLUSIONS: Heparin does not exert major effects on gonadotropins when infused in quantities sufficient to release LPL. However, because it can release other vascular membrane-bound proteins, heparin should be considered part of the control infusions in lipid infusion studies where increased FFA levels are the goal.

Human immune globulin treatment controls Zika viremia in pregnant rhesus macaques.

There are currently no approved drugs to treat Zika virus (ZIKV) infection during pregnancy. Hyperimmune globulin products such as VARIZIG and WinRho are FDA-approved to treat conditions during pregnancy such as Varicella Zoster virus infection and Rh-incompatibility. We administered ZIKV-specific human immune globulin as a treatment in pregnant rhesus macaques one day after subcutaneous ZIKV infection. All animals controlled ZIKV viremia following the treatment and generated robust levels of anti-Zika virus antibodies in their blood. No adverse fetal or infant outcomes were identified in the treated animals, yet the placebo control treated animals also did not have signs related to congenital Zika syndrome (CZS). Human immune globulin may be a viable prophylaxis and treatment option for ZIKV infection during pregnancy, however, more studies are required to fully assess the impact of this treatment to prevent CZS.

Quantitative definition of neurobehavior, vision, hearing and brain volumes in macaques congenitally exposed to Zika virus.

Congenital Zika virus (ZIKV) exposure results in a spectrum of disease ranging from severe birth defects to delayed onset neurodevelopmental deficits. ZIKV-related neuropathogenesis, predictors of birth defects, and neurodevelopmental deficits are not well defined in people. Here we assess the methodological and statistical feasibility of a congenital ZIKV exposure macaque model for identifying infant neurobehavior and brain abnormalities that may underlie neurodevelopmental deficits. We inoculated five pregnant macaques with ZIKV and mock-inoculated one macaque in the first trimester. Following birth, growth, ocular structure/function, brain structure, hearing, histopathology, and neurobehavior were quantitatively assessed during the first week of life. We identified the typical pregnancy outcomes of congenital ZIKV infection, with fetal demise and placental abnormalities. We estimated sample sizes needed to define differences between groups and demonstrated that future studies quantifying brain region volumes, retinal structure, hearing, and visual pathway function require a sample size of 14 animals per group (14 ZIKV, 14 control) to detect statistically significant differences in at least half of the infant exam parameters. Establishing the parameters for future studies of neurodevelopmental outcomes following congenital ZIKV exposure in macaques is essential for robust and rigorous experimental design.

Ocular and uteroplacental pathology in a macaque pregnancy with congenital Zika virus infection.

Congenital Zika virus (ZIKV) infection impacts fetal development and pregnancy outcomes. We infected a pregnant rhesus macaque with a Puerto Rican ZIKV isolate in the first trimester. The pregnancy was complicated by preterm premature rupture of membranes (PPROM), intraamniotic bacterial infection and fetal demise 49 days post infection (gestational day 95). Significant pathology at the maternal-fetal interface included acute chorioamnionitis, placental infarcts, and leukocytoclastic vasculitis of the myometrial radial arteries. ZIKV RNA was disseminated throughout fetal tissues and maternal immune system tissues at necropsy, as assessed by quantitative RT-PCR for viral RNA. Replicating ZIKV was identified in fetal tissues, maternal uterus, and maternal spleen by fluorescent in situ hybridization for viral replication intermediates. Fetal ocular pathology included a choroidal coloboma, suspected anterior segment dysgenesis, and a dysplastic retina. This is the first report of ocular pathology and prolonged viral replication in both maternal and fetal tissues following congenital ZIKV infection in a rhesus macaque. PPROM followed by fetal demise and severe pathology of the visual system have not been described in macaque congenital ZIKV infection previously. While this case of ZIKV infection during pregnancy was complicated by bacterial infection with PPROM, the role of ZIKV on this outcome cannot be precisely defined, and further nonhuman primate studies will determine if increased risk for PPROM or other adverse pregnancy outcomes are associated with congenital ZIKV infection.

Four-dimensional flow magnetic resonance imaging and ultrasound assessment of cerebrospinal venous flow in multiple sclerosis patients and controls.

A possibly causal relationship between multiple sclerosis and chronic cerebrospinal venous insufficiency has recently been hypothesized. Studies investigating chronic cerebrospinal venous insufficiency have reported conflicting results and few have employed multiple diagnostic imaging modalities across a large patient and control population. In this study, three complementary imaging modalities were used to investigate the chronic cerebrospinal venous insufficiency hypothesis in patients with multiple sclerosis and two age- and sex-matched control groups: healthy volunteers and patients with other neurological diseases. Strictly blinded Doppler ultrasound according to the original chronic cerebrospinal venous insufficiency hypothesis; four-dimensional flow magnetic resonance imaging of venous flow in the head, neck, and chest; and contrast-enhanced magnetic resonance venography for neck and chest venous luminography were acquired. An internal jugular vein stenosis evaluation was also performed across modalities. Percentage of subjects meeting ultrasound-based chronic cerebrospinal venous insufficiency criteria was small and similar between groups. In group-wise and pairwise testing, no four-dimensional flow magnetic resonance imaging variables were statistically significantly different, for any measurement location. In contrast-enhanced magnetic resonance venography of the internal jugular and azygos veins, no statistically significant differences were observed in stenosis scores between groups. These results represent compelling evidence against the chronic cerebrospinal venous insufficiency hypothesis in multiple sclerosis.

Hepatotoxicity of combined treatment with cisplatin and gentamicin in the guinea pig.

The damaging effects on the liver tissue of treatment with cisplatin followed by the aminoglycoside antibiotic gentamicin were studied in guinea pigs. The ultrastructural findings revealed foci of damage in the liver parenchyma, including its vascular component. Injurious effects to cytoplasmatic organelles such as mitochondria and endoplasmic reticulum as well as to nuclei were observed. In addition, abundance of lysosomes, autophagic vacuoles, and amorphous-granular bile in the lumina of bile canaliculi was found. Focal sinusoidal lining damage and capillarization of sinusoids were also present. In vascular lumina, some erythrocytes showed a deformed shape ("ropalocytosis"). Taken together, these findings indicate that the combined treatment with cisplatin followed by gentamicin is toxic to components of liver tissue. Since toxic changes have been shown in vessels of the inner ear and in renal-glomerular capillaries, the present observations of hepatotoxicity indicate the potential vascular damage to various tissues. The injurious effects of the cisplatin-aminoglycoside combination should be considered during its use in clinical conditions.

Nephrotoxicity of combined treatment with cisplatin and gentamicin in the guinea pig: glomerular injury findings.

The drugs cisplatin and gentamicin are given consecutively to various cancer patients suffering from infections. Little information exists about the ultrastructural alterations of kidney glomeruli caused by treatment with these drugs. Renal glomeruli of guinea pigs treated with cisplatin alone and in combination with gentamicin were studied by transmission electron microscopy. The findings revealed foci of damage induced by cisplatin and especially by cisplatin/gentamicin in all glomerular components: glomerular capillaries, including their endothelial cells; basement membrane, epithelial podocytes, mesangial cells, and parietal cells of Bowman's capsule. The damage was expressed by endothelial cytoplasmic extrusions into the vascular lumen, thickening and lamination of capillary basement membrane, focal foot process fusion of podocytes, vacuolization in cytoplasm of endothelial cells of epithelial podocytes and of parietal cells, and the presence of lipid bodies and myeloid bodies in all glomerular cell types. Additionally, injurious effects to cytoplasmic organelles such as mitochondria, nuclei, and endoplasmic reticulum were observed. The results indicate that cisplatin alone and in combination with gentamicin is toxic to renal glomerular tissue. Since these drugs were previously found toxic for strial capillaries in the inner ear and since the main glomerular component is the glomerular capillaries, potential vascular damage and vascular complications in different body systems have to be taken into consideration when these drugs are needed in clinical use.