Do Bayley-III Composite Scores at 18-22 Months Corrected Age Predict Full-Scale IQ at 6-7 Years in Children Born Extremely Preterm?

OBJECTIVE: To determine the ability of the Bayley-III cognitive and language composite scores at 18-22 months corrected age to predict WISC-IV Full Scale IQ (FSIQ) at 6-7 years in infants born extremely preterm. STUDY DESIGN: Children in this study were part of the Neuroimaging and Neurodevelopmental Outcome cohort, a secondary study to the SUPPORT trial and born 240/7-276/7 weeks gestational age. Bayley-III cognitive and language scores and WISC-IV FSIQ were compared with pairwise Pearson correlation coefficients and adjusted for medical and socioeconomic variables using linear mixed effect regression models. RESULTS: Bayley-III cognitive (r = 0.33) and language scores (r = 0.44) were mildly correlated with WISC-IV FSIQ score. Of the children with Bayley-III cognitive scores of <70, 67% also had FSIQ of <70. There was less consistency for children with Bayley-III scores in the 85-100 range; 43% had an FSIQ of <85 and 10% an FSIQ of <70. Among those with Bayley-III language scores >100, approximately 1 in 5 had an FSIQ of <85. A cut point of 92 for the cognitive composite score resulted in sensitivity (0.60), specificity (0.64). A cut point of 88 for the language composite score produced sensitivity (0.61), specificity (0.70). CONCLUSIONS: Findings indicate the Bayley-III cognitive and language scores correlate with later IQ, but may fail to predict delay or misclassify children who are not delayed at school age. The Bayley-III can be a useful tool to help identify children born extremely preterm who have below average cognitive scores and may be at the greatest risk for ongoing cognitive difficulties. TRIAL REGISTRATION: Extended Follow-up at School Age for the SUPPORT Neuroimaging and Neurodevelopmental Outcomes (NEURO) Cohort: NCT00233324.

Ex vivo evaluation of a novel suture loop method for equine intestinal biopsies.

OBJECTIVE: To compare a novel suture loop method for intestinal biopsies (SLB) with a two-layer, hand-sutured biopsy (HSB) technique in equine small and large intestines. STUDY DESIGN: Experimental, randomized, ex vivo study. ANIMALS: Eight healthy adult horses. METHODS: The duodenum, aboral jejunum, and ventral and dorsal large colon were harvested after euthanasia and divided into three sections each. The sections were randomized to SLB, HSB, or control (C, no biopsy) groups. Tissue samples were excised after placement of a suture loop formed by a 4S Roeder knot and oversewn with a Cushing pattern using barbed suture (SLB), or a simple continuous pattern oversewn with a Cushing pattern (HSB). Intraluminal diameter was assessed with contrast radiographs; bursting pressure and wall tension were determined using a solid-state sensor after instillation of fluid. Tissue samples were evaluated by a board-certified pathologist. RESULTS: Tissue samples were full thickness with similar depth and quality (p > .3). Changes in intraluminal diameter did not differ between methods (p > .16). The bursting pressures were higher for controls than biopsied sections (p < .009) but were not different between biopsy methods (p = .998). Bursting wall tension was higher for controls (p < .02) and was similar for both biopsy methods (p = .852). CONCLUSION: The SLB was equivalent to HSB in strength and effect on intraluminal diameter. The HSB samples were larger and more likely to contain mucosa/villi for histologic diagnosis. CLINICAL SIGNIFICANCE: The SLB method can be adapted for laparoscopic surgery to obtain both small and large intestinal biopsies. Further investigation is needed before clinical use.

Robust coagulation activation and coagulopathy in mice with experimental acetaminophen-induced liver failure.

BACKGROUND: Patients with acetaminophen (APAP)-induced acute liver failure (ALF) display both hyper- and hypocoagulable changes not necessarily recapitulated by standard hepatotoxic doses of APAP used in mice (eg, 300 mg/kg). OBJECTIVES: We sought to examine coagulation activation in vivo and plasma coagulation potential ex vivo in experimental settings of APAP-induced hepatotoxicity and repair (300-450 mg/kg) and APAP-induced ALF (600 mg/kg) in mice. RESULTS: APAP-induced ALF was associated with increased plasma thrombin-antithrombin complexes, decreased plasma prothrombin, and a dramatic reduction in plasma fibrinogen compared with lower APAP doses. Hepatic fibrin(ogen) deposits increased independent of APAP dose, whereas plasma fibrin(ogen) degradation products markedly increased in mice with experimental ALF. Early pharmacologic anticoagulation (+2 hours after 600 mg/kg APAP) limited coagulation activation and reduced hepatic necrosis. The marked coagulation activation evident in mice with APAP-induced ALF was associated with a coagulopathy detectable ex vivo in plasma. Specifically, prolongation of the prothrombin time and inhibition of tissue factor-initiated clot formation were evident even after restoration of physiological fibrinogen concentrations. Plasma endogenous thrombin potential was similarly reduced at all APAP doses. Interestingly, in the presence of ample fibrinogen, ∼10 times more thrombin was required to clot plasma from mice with APAP-induced ALF compared with plasma from mice with simple hepatotoxicity. CONCLUSION: The results indicate that robust pathologic coagulation cascade activation in vivo and suppressed coagulation ex vivo are evident in mice with APAP-induced ALF. This unique experimental setting may fill an unmet need as a model to uncover mechanistic aspects of the complex coagulopathy of ALF.

Baat Gene Knockout Alters Post-Natal Development, the Gut Microbiome, and Reveals Unusual Bile Acids in Mice.

Bile acids (BAs) are steroid detergents in bile that contribute to fat absorption, cell signaling, and microbiome interactions. The final step in their synthesis is amino acid conjugation with either glycine or taurine in the liver by the enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT). Here, we describe the microbial, chemical, and physiological consequences of Baat gene knockout. Baat-/- mice were underweight after weaning but quickly exhibited catch-up growth. At three weeks of age, KO animals had increased phospholipid excretion and decreased subcutaneous fat pad mass, liver mass, glycogen staining in hepatocytes, and hepatic vitamin A stores, but these were less marked in adulthood. Additionally, KO mice had an altered microbiome in early life. Their BA pool was highly enriched in cholic acid but not completely devoid of conjugated BAs. KO animals had 27-fold lower taurine-conjugated BAs than wild type in their liver but similar concentrations of glycine-conjugated BAs and higher microbially conjugated BAs. Furthermore, the BA pool in Baat-/- was enriched in a variety of unusual BAs that were putatively sourced from cysteamine conjugation with subsequent oxidation and methylation of the sulfur group mimicking taurine. Antibiotic treatment of KO mice indicated the microbiome was not the likely source of the unusual conjugations, instead, the unique BAs in KO animals were likely derived from the peroxisomal acyltransferases Acnat1 and Acnat2, which are duplications of Baat in the mouse genome that are inactivated in humans. This study demonstrates that BA conjugation is important for early life development of mice.

Pathology in Practice.

In collaboration with the American College of Veterinary Pathologists.

Pathology in Practice.

In collaboration with the American College of Veterinary Pathologists.

Comparative Genomics of Atypical Enteropathogenic Escherichia coli from Kittens and Children Identifies Bacterial Factors Associated with Virulence in Kittens.

Typical enteropathogenic Escherichia coli (tEPEC) is a leading cause of diarrhea and associated death in children worldwide. Atypical EPEC (aEPEC) lacks the plasmid encoding bundle-forming pili and is considered less virulent, but the molecular mechanism of virulence is poorly understood. We recently identified kittens as a host for aEPEC where intestinal epithelial colonization was associated with diarrheal disease and death. The purposes of this study were to (i) determine the genomic similarity between kitten aEPEC and human aEPEC isolates and (ii) identify genotypic or phenotypic traits associated with virulence in kitten aEPEC. We observed no differences between kitten and human aEPEC in core genome content or gene cluster sequence identities, and no distinguishing genomic content was observed between aEPEC isolates from kittens with nonclinical colonization (NC) versus those with lethal infection (LI). Variation in adherence patterns and ability to aggregate actin in cultured cells mirrored descriptions of human aEPEC. The aEPEC isolated from kittens with LI were significantly more motile than isolates from kittens with NC. Kittens may serve as a reservoir for aEPEC that is indistinguishable from human aEPEC isolates and may provide a needed comparative animal model for the study of aEPEC pathogenesis. Motility seems to be an important factor in pathogenesis of LI associated with aEPEC in kittens.

Effects of acellular equine amniotic allografts on the healing of experimentally induced full-thickness distal limb wounds in horses.

OBJECTIVE: To characterize the growth factors contained in equine amniotic membrane allograft (eAM; StemWrap scaffold and StemWrap+ injection) and to evaluate the effect of eAM on equine distal limb wound healing. STUDY DESIGN: Prospective experimental controlled study. SAMPLE POPULATION: Eight adult horses. METHODS: Transforming growth factor (TGF)-ß1, vascular endothelial growth factor (VEGF), epidermal growth factor, platelet-derived growth factor-BB, and prostaglandin E2 (PGE2 ) concentrations in StemWrap+ were assessed with enzyme-linked immunosorbent assay. Two full-thickness 6.25-cm2 skin wounds were created on each metacarpus. On one forelimb, one wound was treated with eAM, and the other was left untreated (eAM control). On the contralateral limb, one wound was treated with a silicone dressing, and the other served as negative control. Three-dimensional images were obtained to determine wound circumference and surface area analyses at each bandage change until healed. Excessive granulation tissue was debrided once weekly for 4 weeks. Biopsy samples were taken to evaluate quality of wound healing via histologic and immunohistochemistry assays. RESULTS: StemWrap+ contained moderate concentrations of TGF-ß1 (494.10 pg/mL), VEGF (212.52 pg/mL), and PGE2 (1811.61 pg/mL). Treatment of wounds with eAM did not affect time to healing or histologic quality of the healing compared with other groups but was associated with increased granulation tissue production early in the study, particularly on day 7. CONCLUSION: Application of eAM resulted in increased granulation tissue production while maintaining appropriate healing of experimental wounds. CLINICAL SIGNIFICANCE: Use of eAM is likely most beneficial for substantial wounds in which expedient production of large amounts of granulation tissue is desirable.

Influence of the intestinal microbiota on disease susceptibility in kittens with experimentally-induced carriage of atypical enteropathogenic Escherichia coli.

Typical enteropathogenic E. coli (tEPEC) carries the highest hazard of death in children with diarrhea and atypical EPEC (aEPEC) was recently identified as significantly associated with diarrheal mortality in kittens. In both children and kittens there is a significant association between aEPEC burden and diarrheal disease, however the infection can be found in individuals with and without diarrhea. It remains unclear to what extent, under what conditions, or by what mechanisms aEPEC serves as a primary pathogen in individuals with diarrhea. It seems likely that a combination of host and bacterial factors enable aEPEC to cause disease in some individuals and not in others. The purpose of this study was to determine the impact of aEPEC on intestinal function and diarrhea in kittens following experimentally-induced carriage and the influence of a disrupted intestinal microbiota on disease susceptibility. Results of this study identify aEPEC as a potential pathogen in kittens. In the absence of disruption to the intestinal microbiota, kittens are resistant to clinical signs of aEPEC carriage but demonstrate significant occult changes in intestinal absorption and permeability. Antibiotic-induced disruption of the intestinal microbiota prior to infection increases subsequent intestinal water loss as determined by % fecal wet weight. Enrichment of the intestinal microbiota with a commensal member of the feline mucosa-associated microbiota, Enterococcus hirae, ameliorated the effects of aEPEC experimental infection on intestinal function and water loss. These observations begin to unravel the mechanisms by which aEPEC infection may be able to exploit susceptible hosts.

Preterm Neuroimaging and School-Age Cognitive Outcomes.

BACKGROUND AND OBJECTIVES: Children born extremely preterm are at risk for cognitive difficulties and disability. The relative prognostic value of neonatal brain MRI and cranial ultrasound (CUS) for school-age outcomes remains unclear. Our objectives were to relate near-term conventional brain MRI and early and late CUS to cognitive impairment and disability at 6 to 7 years among children born extremely preterm and assess prognostic value. METHODS: A prospective study of adverse early and late CUS and near-term conventional MRI findings to predict outcomes at 6 to 7 years including a full-scale IQ (FSIQ) <70 and disability (FSIQ <70, moderate-to-severe cerebral palsy, or severe vision or hearing impairment) in a subgroup of Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial enrollees. Stepwise logistic regression evaluated associations of neuroimaging with outcomes, adjusting for perinatal-neonatal factors. RESULTS: A total of 386 children had follow-up. In unadjusted analyses, severity of white matter abnormality and cerebellar lesions on MRI and adverse CUS findings were associated with outcomes. In full regression models, both adverse late CUS findings (odds ratio [OR] 27.9; 95% confidence interval [CI] 6.0-129) and significant cerebellar lesions on MRI (OR 2.71; 95% CI 1.1-6.7) remained associated with disability, but only adverse late CUS findings (OR 20.1; 95% CI 3.6-111) were associated with FSIQ <70. Predictive accuracy of stepwise models was not substantially improved with the addition of neuroimaging. CONCLUSIONS: Severe but rare adverse late CUS findings were most strongly associated with cognitive impairment and disability at school age, and significant cerebellar lesions on MRI were associated with disability. Near-term conventional MRI did not substantively enhance prediction of severe early school-age outcomes.

Association of Atypical Enteropathogenic Escherichia coli with Diarrhea and Related Mortality in Kittens.

Diarrhea is responsible for the death of approximately 900,000 children per year worldwide. In children, typical enteropathogenic Escherichia coli (EPEC) is a common cause of diarrhea and is associated with a higher hazard of death. Typical EPEC infection is rare in animals and poorly reproduced in experimental animal models. In contrast, atypical EPEC (aEPEC) infection is common in both children and animals, but its role in diarrhea is uncertain. Mortality in kittens is often attributed to diarrhea, and we previously identified enteroadherent EPEC in the intestines of deceased kittens. The purpose of this study was to determine the prevalence and type of EPEC in kittens and whether infection was associated with diarrhea, diarrhea-related mortality, gastrointestinal pathology, or other risk factors. Kittens with and without diarrhea were obtained from two shelter facilities and determined to shed atypical EPEC at a culture-based prevalence of 18%. In contrast, quantitative PCR detected the presence of the gene for intimin (eae) in feces from 42% of kittens. aEPEC was isolated from kittens with and without diarrhea. However, kittens with diarrhea harbored significantly larger quantities of aEPEC than kittens without diarrhea. Kittens with aEPEC had a significantly greater severity of small intestinal and colonic lesions and were significantly more likely to have required subcutaneous fluid administration. These findings identify aEPEC to be prevalent in kittens and a significant primary or contributing cause of intestinal inflammation, diarrhea, dehydration, and associated mortality in kittens.

Cerebral oligodendroglioma mimicking intraventricular neoplasia in three dogs.

Oligodendroglioma is one of the most common primary central nervous system neoplasms of dogs. It is often diagnosed in older, brachycephalic breeds, and although its typical clinical features and neuroanatomic location have been well described, less common presentations may hinder its diagnosis. We describe 3 cases of canine cerebral oligodendroglioma that clinically and grossly present as intraventricular tumors. Histologic findings in all cases were typical of oligodendroglioma. Neoplastic cells were uniformly immunoreactive for Olig2 and negative for neuron-specific enolase, neurofilament, and glial fibrillary acidic protein. In addition to the immunopositivity for Olig2, a cluster of morphologically distinct neoplastic cells in one of the cases was immunoreactive for synaptophysin, and the case was diagnosed as an oligodendroglioma with neurocytic differentiation. Based on these findings, oligodendroglioma should be included as a differential diagnosis for intraventricular neoplasia in dogs. Furthermore, oligodendroglioma with ventricular involvement should be differentiated from central neurocytoma by immunohistochemistry.

Retrobulbar adenocarcinoma in an Amazon parrot (Amazona autumnalis).

Retrobulbar neoplasms are not common in mammals and are even more infrequently seen in nonmammalian species. The current report describes a retrobulbar mass creating exophthalmia and neurologic signs in a red-lored Amazon parrot (Amazona autumnalis). A 27-year-old female parrot presented for a 3-day history of anorexia and a 2-week history of periocular soft tissue swelling and exophthalmia of the right eye. Physical examination revealed 9% dehydration and right eye exophthalmia with inability to retropulse the globe. A fine-needle aspirate was performed, and cytologic evaluation revealed necrotic debris with scattered clusters of epithelial cells, moderate numbers of macrophages, and few heterophils. Given the possibility of neoplasia and paucity of treatment options, the owners elected euthanasia and submitted the body for necropsy. A large, fluctuant, friable, red, retrobulbar mass with multiple areas of hemorrhage, on cut surface, was noted at necropsy. Histologically, the mass was composed of neoplastic, cuboidal to columnar epithelial cells, forming rosette-like glandular structures, admixed with abundant necrotic debris. The neoplastic cells were strongly positive for cytokeratin (AE1/AE3) by immunohistochemistry. Based on histopathology and immunohistochemistry, the mass was diagnosed as an adenocarcinoma.

Screening for autism spectrum disorders in extremely preterm infants.

BACKGROUND: Extremely preterm (EP) infants screen positive for autism spectrum disorders (ASD) at high rates. However, it is not clear whether this is because of high rates of ASD in EPs or to high rates of false-positive screens for ASD in children with a high rate of underlying neurodevelopmental impairments. Combining a parent questionnaire designed to distinguish developmental delay from ASD with direct observation of infant behavior may more accurately screen for ASD in EPs. OBJECTIVES: To determine rates of positive screen for ASD at 18 to 22 months(m) in EPs using 3 screens; to determine factors associated with a positive screen. METHODS: Five hundred fifty-four infants born <27 weeks were screened at 18 to 22 m using the Pervasive Developmental Disorders Screening test, second edition Stage 2, and the response to name and response to joint attention items from the Autism Diagnostic Observation Schedule. Infants with severe cerebral palsy, deafness, and blindness were excluded. Associations between positive screen and neonatal/ infant characteristics were determined. RESULTS: Of 554 infants, 113 (20%) had ≥ 1 positive screen. 10% had a positive Pervasive Developmental Disorders Screening test, second edition, 6% response to name, 9% response to joint attention; in only 1 % all 3 screens were positive. Positive screen was associated with male gender, more hospital days, white race, lower maternal education, abnormal behavioral scores, and cognitive/ language delay. CONCLUSIONS: The use of 3 screens for ASD in EPs results in higher screen positive rates than use of 1 screen alone. Diagnostic confirmation is needed before true rates of ASD in EPs are known.