An Immune-Deficient Prkdc Knockout Rat Model of Perinatal Hypoxic-Ischemic Brain Injury for Future Xenograft Studies

Perinatal hypoxia ischemia (HI) is a significant cause of brain damage leading to motor and cognitive impairments. There are no treatments that can repair the damage and improve outcomes, though preclinical research using neural precursor cell (NPC) transplantation as a therapy has shown promise. To promote clinical translation, it is essential that human-derived NPCs also be tested in animal models. To reduce the risk of xenograft rejection, we characterized a model of HI injury in immune-deficient Prkdc knockout rats. Knockout HI rats displayed sensorimotor deficits on the cylinder and pasta-handling tests, and reductions in size of and cellular loss in the hippocampus, cortex, and corpus callosum. Ventriculomegaly and grey matter gliosis were also prominent. Interestingly, knockout rats displayed overall more severe injuries than wildtype littermates. This model characterization will allow for future studies of human-derived NPCs in the rodent brain, paving the way for the clinical translation of this therapy.M.Sc

Physician Executive Leadership (PEL): Expanding Medical School Leadership and Management Education

Today’s doctors are expected to fulfill many roles, and yet, traditional medical education does not include the following: Interdisciplinary teamwork Leadership skills Management and business techniques Financial knowledge Quality improvement Information technology Systems based approaches Physician Executive Leadership (PEL) was founded in 2013 at Jefferson’s Sidney Kimmel Medical School to directly address gaps in medical education The PEL curriculum is both student run and student led, informed by student demand and feedback Students can complete the curriculum at the standard level of commitment or be more engaged to earn Distinction The PEL curriculum is centered around six pillars: Applied Leadership Care Quality & Experience Health Finance Health Policy Entrepreneurship & Innovation Law & Ethics Programming includes: Guest lectures (large and small groups) Student run journal, The Diagnostic PEL Plus, a s tructured capstone program focused on management/leadership, with Jefferson lecturers outside SKMC and industry lecturers Funded summer internship of up to $1,500; self directed student projects focused on innovatio

Rapidly progressive ACTH-dependent Cushing’s disease masquerading as ectopic ACTH-producing Cushing’s syndrome: illustrative case

BACKGROUND Cushing’s disease (CD) remains a challenging condition to diagnose and treat. This case study highlights the challenges of diagnosing CDwhen faced with discrepant clinical, biochemical, and radiologicalfindings. OBSERVATIONS A 62-year-old man presented with rapid evolution of symptoms, including depression, fatigue, and extreme muscle atrophy, whichresulted in the patient being a wheelchair user over the course of a few months. His rapid clinical course in conjunction with hypercortisolemia in thesetting of a pituitary macroadenoma involving the cavernous sinus, two large pulmonary nodules, and urine-free cortisol levels in the thousandssuggested an aggressive ectopic adrenocorticotropic hormone (ACTH) source. After extensive testing ruled out CD from an ectopic source andbecause of the patient’s abrupt clinical deterioration, the authors concluded that the source was likely an aggressive pituitary adenoma. Therefore, theauthors performed an endonasal transsphenoidal approach for resection of the pituitary adenoma involving the cavernous sinus, and the patient wasscheduled for radiosurgery to control tumor progression. LESSONS Although extremely high levels of cortisol and ACTH are associated with ectopic Cushing’s syndrome, they may also indicate anaggressive form of CD. Suspicion should be maintained for hypercortisolemia from a pituitary source even when faced with discrepant information thatmay suggest an ectopic source

The extent of intrauterine growth restriction determines the severity of cerebral injury and neurobehavioural deficits in rodents

<div><p>Background</p><p>Cerebral Palsy (CP) is the most common physical pediatric neurodevelopmental disorder and spastic diplegic injury is its most frequent subtype. CP results in substantial neuromotor and cognitive impairments that have significant socioeconomic impact. Despite this, its underlying pathophysiological mechanisms and etiology remain incompletely understood. Furthermore, there is a need for clinically relevant injury models, which a) reflect the heterogeneity of the condition and b) can be used to evaluate new translational therapies. To address these key knowledge gaps, we characterized a chronic placental insufficiency (PI) model, using bilateral uterine artery ligation (BUAL) of dams. This injury model results in intrauterine growth restriction (IUGR) in pups, and animals recapitulate the human phenotype both in terms of neurobehavioural and anatomical deficits.</p><p>Methods</p><p>Effects of BUAL were studied using luxol fast blue (LFB)/hematoxylin & eosin (H&E) staining, immunohistochemistry, quantitative Magnetic Resonance Imaging (MRI), and Catwalk neurobehavioural tests.</p><p>Results</p><p>Neuroanatomical analysis revealed regional ventricular enlargement and corpus callosum thinning in IUGR animals, which was correlated with the extent of growth restriction. Olig2 staining revealed reductions in oligodendrocyte density in white and grey matter structures, including the corpus callosum, optic chiasm, and nucleus accumbens. The caudate nucleus, along with other brain structures such as the optic chiasm, internal capsule, septofimbrial and lateral septal nuclei, exhibited reduced size in animals with IUGR. The size of the pretectal nucleus was reduced only in moderately injured animals. MAG/NF200 staining demonstrated reduced myelination and axonal counts in the corpus callosum of IUGR animals. NeuN staining revealed changes in neuronal density in the hippocampus and in the thickness of hippocampal CA2 and CA3 regions. Diffusion weighted imaging (DWI) revealed regional white and grey matter changes at 3 weeks of age. Furthermore, neurobehavioural testing demonstrated neuromotor impairments in animals with IUGR in paw intensities, swing speed, relative print positions, and phase dispersions.</p><p>Conclusions</p><p>We have characterized a rodent model of IUGR and have demonstrated that the neuroanatomical and neurobehavioural deficits mirror the severity of the IUGR injury. This model has the potential to be applied to examine the pathobiology of and potential therapeutic strategies for IUGR-related brain injury. Thus, this work has potential translational relevance for the study of CP.</p></div

Hippocampal structure is differentially affected according to the severity of IUGR.

<p>NeuN+ staining in the hippocampus (A-C) revealed severity-specific deficits in CA2 (D-E), CA3 (F-G) and the dentate gyrus (H). Quantification of hippocampal area revealed a significantly reduced size only in moderate IUGR animals when compared to sham animals (I). Scale Bar = 1000 μm;*p<0.05; **p<0.01; ***p<0.001.</p

Reduced area and number of tracts in the caudate nucleus.

<p>The caudate nucleus was affected by IUGR, as depicted in representative LFB/H&E stains (A-C). This structure showed reduced size in IUGR animals, regardless of severity (D). IUGR animals displayed decreased numbers of axonal tracts within the caudate nucleus (E), though mean axonal size was unaffected (F). Scale Bar = 1000 μm;*p<0.05; **p<0.01; ***p<0.001.</p

Motor gait deficits are present in IUGR rats.

<p>Animals with IUGR showed clear and consistent gait deficits at 3 weeks, some of which persisted into young adulthood. Paw intensity (0–255) for fore- and hindpaws was significantly increased in moderate IUGR animals (p<0.0001 for both) (A). Swing speed (m/s) for fore- and hindpaws did not show overall significance between IUGR and sham animals. There were, however, significant differences at early timepoints between moderate IUGR and sham animals (B). Relative print positions (mm) for right and left pairs of paws showed overall significant differences in the left paws of both mild and moderate IUGR animals when compared to sham animals (p = 0.0089 and p = 0.0019, respectively). There was a similar trend toward significance in the right paws of both mild and moderate IUGR groups (p = 0.0503 and p = 0.0603, respectively) (C). Phase dispersions (AU) of both fore and hind girdle paw pairs were significantly decreased in moderate IUGR animals when compared to sham animals (p = 0.0114 and p = 0.0002, respectively) (D). *p<0.05, **p<0.01, ***p<0.001.</p

IUGR is accompanied by a loss of white matter in the corpus callosum.

<p>Olig2+ OL counts in the corpus callosum revealed a decrease in OLs in mild IUGR (B), and moderate IUGR (C) animals, but not in sham controls (A). This decrease was significantly different in both IUGR groups when compared to sham controls; moderate IUGR animals also displayed significantly reduced counts when compared to mild IUGR animals (D). Both mild and moderate IUGR animals had decreased myelination (as assessed through MAG+ staining) when compared to sham controls (F-H). The number of NF200+ axons was also reduced in both mild and moderate IUGR groups when compared to sham controls (I-K). Merged images of MAG+/NF200+ staining are also shown (L-N). There were fewer axons in IUGR animals regardless of the severity of injury (O). A significantly greater proportion of the remaining axons were unmyelinated (MAG-/NF200+) in only moderate IUGR animals, while mild IUGR animals exhibited a phenotype similar to sham controls (P). When we investigated the results in (P) as a percentage of total axons in the CC, only moderately injured animals had a significantly higher proportion of unmyelinated axons when compared to other groups (Q). Scale Bar = 100 μm;*p<0.05; **p<0.01; ***p<0.001.</p

Structural abnormalities in sub-cortical structures of IUGR animals.

<p>Animals with IUGR displayed differences in sub-cortical structures when compared to Sham animals. Internal capsule size was reduced in both mild and moderate IUGR groups (A). The number of Olig2+ cells in the internal capsule remained unchanged (B). The optic chiasm showed similar results as the internal capsule (C), in addition to fewer OLs in the mildly injured group (D). There was no significant difference in the size of the nucleus accumbens between IUGR and sham animals (E). There were, however, fewer Olig2+ OLs in the nucleus accumbens of both mild and moderate IUGR animals when compared to sham animals (F). The septofimbrial and lateral septal nuclei were decreased in size in IUGR animals relative to sham controls (G). The pretectal nucleus was also significantly decreased in size in moderate IUGR animals only when compared to sham animals (H). *p<0.05; **p<0.01; ***p<0.001.</p