Altered behavior, brain structure, and neurometabolites in a rat model of autism-specific maternal autoantibody exposure.

Maternal immune dysregulation is a prenatal risk factor for autism spectrum disorder (ASD). Importantly, a clinically relevant connection exists between inflammation and metabolic stress that can result in aberrant cytokine signaling and autoimmunity. In this study we examined the potential for maternal autoantibodies (aAbs) to disrupt metabolic signaling and induce neuroanatomical changes in the brains of exposed offspring. To accomplish this, we developed a model of maternal aAb exposure in rats based on the clinical phenomenon of maternal autoantibody-related ASD (MAR-ASD). Following confirmation of aAb production in rat dams and antigen-specific immunoglobulin G (IgG) transfer to offspring, we assessed offspring behavior and brain structure longitudinally. MAR-ASD rat offspring displayed a reduction in pup ultrasonic vocalizations and a pronounced deficit in social play behavior when allowed to freely interact with a novel partner. Additionally, longitudinal in vivo structural magnetic resonance imaging (sMRI) at postnatal day 30 (PND30) and PND70, conducted in a separate cohort of animals, revealed sex-specific differences in total and regional brain volume. Treatment-specific effects by region appeared to converge on midbrain and cerebellar structures in MAR-ASD offspring. Simultaneously, in vivo 1H magnetic resonance spectroscopy (1H-MRS) data were collected to examine brain metabolite levels in the medial prefrontal cortex. Results showed that MAR-ASD offspring displayed decreased levels of choline-containing compounds and glutathione, accompanied by increased taurine compared to control animals. Overall, we found that rats exposed to MAR-ASD aAbs present with alterations in behavior, brain structure, and neurometabolites; reminiscent of findings observed in clinical ASD.

A pragmatic approach using magnetic resonance imaging to treat ischemic strokes of unknown onset time in a thrombolytic trial.

BACKGROUND AND PURPOSE: Toward the goal of designing a clinical trial using imaging parameters to treat stroke patients with unknown onset time, we investigated the timing of changes on MRI in patients with well-defined stroke onset. METHODS: Hypothesis-generating (n=85) and confirmatory (n=111) samples were scored by blinded readers for fluid-attenuated inversion recovery (FLAIR) hyperintensity in diffusion-positive regions. Reader-measured signal intensity ratio (SIR) of the lesion to contralateral tissue was compared with SIR measured by coregistration. RESULTS: Lesion conspicuity increased with time on FLAIR (P=0.006). Qualitative assessment of FLAIR-negative vs FLAIR hyperintensity (k=0.7091; 95% CI, 0.61-0.81) showed good interrater agreement. Subtle hyperintensity was less reliably categorized (k=0.59; 95% CI, 0.47-0.71). Reader-measured SIR <1.15 can identify patients within the treatable time window of 4.5 hours (positive predictive value=0.90). The SIR was greater for right hemisphere lesions (P=0.04) for a given reported time from stroke symptom onset. CONCLUSIONS: The SIR on FLAIR provides a quantitative tool to identify early ischemic strokes. In developing SIR thresholds, right hemisphere lesions may confound the accurate estimate of stroke onset time. Image coregistration for thrombolytic trial enrollment is not necessary. A SIR <1.15 on FLAIR yields a practical estimate of stroke onset within 4.5 hours.

Visual perfusion-diffusion mismatch is equivalent to quantitative mismatch.

BACKGROUND AND PURPOSE: The concept of stroke MRI mismatch based on qualitative evaluation of diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) has been applied in clinical practice for several years. The benefit of MRI in providing pathological evidence of ischemia before thrombolytic treatment has been demonstrated. The purpose of this study is to determine the reliability of the qualitative method and compare it with quantitative mismatch measurement in thrombolytic-treated patients. METHODS: Patients (n=70) were selected from the Lesion Evolution of Stroke and Ischemic On Neuroimaging (LESION) database if they: (1) were treated with intravenous recombinant tissue plasminogen activator; (2) had a pretreatment MRI with evaluable DWI and PWI; and (3) had acute ischemic lesion volume >10 mL on DWI as determined by core imaging laboratory measurements. Quantitative mismatch was defined as a difference of >50 mL between abnormal mean transit time and DWI volumes. Sample characteristics and postdischarge modified Rankin Scale for the positive mismatch patients were compared between the subgroups identified by qualitative versus quantitative methods. RESULTS: Patient characteristics and thrombolytic outcomes (sex, age, National Institutes of Health Stroke Scale, mismatch volume, and modified Rankin Scale) did not differ for mismatch patients identified by qualitative versus quantitative methods. Qualitative mismatch selection among neurologists had a high sensitivity (0.82), specificity (0.80), accuracy (0.81), and positive predictive value (0.88) compared with quantitative measurements. CONCLUSIONS: We observed that qualitative evaluation of mismatch identified the same thrombolytic-treated patients compared with retrospective quantitative mismatch measurements.

Acute Influenza Encephalitis/Encephalopathy Associated with Influenza A in an Incompetent Adult.

A 32-year-old male presented to the emergency department (ED) with a productive cough for 4 days and confusion for 2 days prior to presentation. He was febrile, tachycardic, and hypotensive. Initially, labs and influenza A/B PCR were performed. An elevated WBC of 17.3 and a lactate level of 3.1 were noted. He was given a bolus of normal saline and broad spectrum antibiotics, ceftriaxone and azithromycin. The patient was then subsequently found to be positive for influenza A via rapid antigen testing of the nares. On hospital day 2, the patient's mental status and respiratory distress worsened requiring intubation with mechanical ventilation. CT of the head without contrast revealed symmetric areas of hypoattenuation in the frontoparietal deep white matter. Lumbar puncture showed a slight elevation in WBCs and mild lymphocytic pleocytosis. Brain MRI without contrast revealed symmetric hyperintense T2 FLAIR signaling in the periventricular white matter and the splenium of the corpus callosum. He was found to have encephalitis secondary to influenza A and was started on a course of oseltamivir at higher doses of 150 mg BID for 2 weeks. On hospital day 10, after nine days of intubation, the patient received a tracheostomy due to failure to extubate and no improvement in mental status. He remained ventilator-dependent with little improvement in mental status; the patient was transferred to a long-term acute care hospital (LTACH) facility for further specialized care. He did not show any neurologic recovery or improvement in the three months after initial presentation of symptoms. In the fifth month after the initial symptoms, there was no recovery of preinsult neurologic function. The family had a palliative care meeting to discuss the plan and goals of care. It was decided by close family members that "compassionate extubation" would be done due to ongoing stress on the patient's body physically and neurologically. This case illustrates the importance of prompt identification and treatment of influenza in the prevention of rapidly progressive sequelae.

Variability in PolyIC induced immune response: Implications for preclinical maternal immune activation models.

Maternal infection during pregnancy may increase the risk of offspring neurodevelopmental disorders. The preclinical Polyinosinic-polycytidylic acid (PolyIC) model has become one of the most widely used approaches in maternal immune activation (MIA) research. However, variability in molecular weight may impact the immune activating potential of PolyIC. Nulliparous rats injected with high molecular weight PolyIC exhibit pronounced cytokine response and sickness behavior that was not observed in rats injected low molecular weight PolyIC. Although an essential next step is to extend these studies to pregnant animals, the preliminary results suggest that PolyIC molecular weight is an important experimental design consideration.

Behavioral Phenotyping of Juvenile Long-Evans and Sprague-Dawley Rats: Implications for Preclinical Models of Autism Spectrum Disorders.

The laboratory rat is emerging as an attractive preclinical animal model of autism spectrum disorder (ASD), allowing investigators to explore genetic, environmental and pharmacological manipulations in a species exhibiting complex, reciprocal social behavior. The present study was carried out to compare two commonly used strains of laboratory rats, Sprague-Dawley (SD) and Long-Evans (LE), between the ages of postnatal day (PND) 26-56 using high-throughput behavioral phenotyping tools commonly used in mouse models of ASD that we have adapted for use in rats. We detected few differences between young SD and LE strains on standard assays of exploration, sensorimotor gating, anxiety, repetitive behaviors, and learning. Both SD and LE strains also demonstrated sociability in the 3-chamber social approach test as indexed by spending more time in the social chamber with a constrained age/strain/sex matched novel partner than in an identical chamber without a partner. Pronounced differences between the two strains were, however, detected when the rats were allowed to freely interact with a novel partner in the social dyad paradigm. The SD rats in this particular testing paradigm engaged in play more frequently and for longer durations than the LE rats at both juvenile and young adult developmental time points. Results from this study that are particularly relevant for developing preclinical ASD models in rats are threefold: (i) commonly utilized strains exhibit unique patterns of social interactions, including strain-specific play behaviors, (ii) the testing environment may profoundly influence the expression of strain-specific social behavior and (iii) simple, automated measures of sociability may not capture the complexities of rat social interactions.

Fibrocartilage tissue engineering: the role of the stress environment on cell morphology and matrix expression.

Although much is known about the effects of uniaxial mechanical loading on fibrocartilage development, the stress fields to which fibrocartilaginous regions are subjected to during development are mutiaxial. That fibrocartilage develops at tendon-to-bone attachments and in compressive regions of tendons is well established. However, the three-dimensional (3D) nature of the stresses needed for the development of fibrocartilage is not known. Here, we developed and applied an in vitro system to determine whether fibrocartilage can develop under a state of periodic hydrostatic tension in which only a single principal component of stress is compressive. This question is vital to efforts to mechanically guide morphogenesis and matrix expression in engineered tissue replacements. Mesenchymal stromal cells in a 3D culture were exposed to compressive and tensile stresses as a result of an external tensile hydrostatic stress field. The stress field was characterized through mechanical modeling. Tensile cyclic stresses promoted spindle-shaped cells, upregulation of scleraxis and type one collagen, and cell alignment with the direction of tension. Cells experiencing a single compressive stress component exhibited rounded cell morphology and random cell orientation. No difference in mRNA expression of the genes Sox9 and aggrecan was observed when comparing tensile and compressive regions unless the medium was supplemented with the chondrogenic factor transforming growth factor beta3. In that case, Sox9 was upregulated under static loading conditions and aggrecan was upregulated under cyclic loading conditions. In conclusion, the fibrous component of fibrocartilage could be generated using only mechanical cues, but generation of the cartilaginous component of fibrocartilage required biologic factors in addition to mechanical cues. These studies support the hypothesis that the 3D stress environment influences cell activity and gene expression in fibrocartilage development.