Legg-Calvé-Perthes Disease: Diagnosis, Decision Making, and Outcome.

ABSTRACT: Legg-Calvé-Perthes disease (LCPD), or idiopathic avascular necrosis of the proximal capital femoral epiphysis in children, has a variable presentation and can result in significant femoral head deformity that can lead to long-term functional deficits. Plain radiographic imaging is crucial in diagnosing LCPD and guiding treatment. Although the etiology of LCPD remains unknown, the evolution of the disease has been well characterized to include the phases of ischemia, revascularization, and reossification. The mechanical weakening during these phases of healing place the femoral head at high risk of deformity. Treatment of LCPD, therefore, focuses on minimizing deformity through operative and nonoperative strategies to reduce the risk of premature osteoarthritis. Advanced imaging using perfusion MRI may refine surgical decision making in the future, and biological treatments to improve femoral head healing are on the horizon.

Morphology-guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasion.

Pancreatic ductal adenocarcinoma (PDAC) frequently presents with metastasis, but the molecular programs in human PDAC cells that drive invasion are not well understood. Using an experimental pipeline enabling PDAC organoid isolation and collection based on invasive phenotype, we assessed the transcriptomic programs associated with invasion in our organoid model. We identified differentially expressed genes in invasive organoids compared with matched noninvasive organoids from the same patients, and we confirmed that the encoded proteins were enhanced in organoid invasive protrusions. We identified 3 distinct transcriptomic groups in invasive organoids, 2 of which correlated directly with the morphological invasion patterns and were characterized by distinct upregulated pathways. Leveraging publicly available single-cell RNA-sequencing data, we mapped our transcriptomic groups onto human PDAC tissue samples, highlighting differences in the tumor microenvironment between transcriptomic groups and suggesting that non-neoplastic cells in the tumor microenvironment can modulate tumor cell invasion. To further address this possibility, we performed computational ligand-receptor analysis and validated the impact of multiple ligands (TGF-ß1, IL-6, CXCL12, MMP9) on invasion and gene expression in an independent cohort of fresh human PDAC organoids. Our results identify molecular programs driving morphologically defined invasion patterns and highlight the tumor microenvironment as a potential modulator of these programs.

Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by extensive local invasion and systemic spread. In this study, we employed a three-dimensional organoid model of human pancreatic cancer to characterize the molecular alterations critical for invasion. Time-lapse microscopy was used to observe invasion in organoids from 25 surgically resected human PDAC samples in collagen I. Subsequent lentiviral modification and small-molecule inhibitors were used to investigate the molecular programs underlying invasion in PDAC organoids. When cultured in collagen I, PDAC organoids exhibited two distinct, morphologically defined invasive phenotypes, mesenchymal and collective. Each individual PDAC gave rise to organoids with a predominant phenotype, and PDAC that generated organoids with predominantly mesenchymal invasion showed a worse prognosis. Collective invasion predominated in organoids from cancers with somatic mutations in the driver gene SMAD4 (or its signaling partner TGFBR2). Reexpression of SMAD4 abrogated the collective invasion phenotype in SMAD4-mutant PDAC organoids, indicating that SMAD4 loss is required for collective invasion in PDAC organoids. Surprisingly, invasion in passaged SMAD4-mutant PDAC organoids required exogenous TGFß, suggesting that invasion in SMAD4-mutant organoids is mediated through noncanonical TGFß signaling. The Rho-like GTPases RAC1 and CDC42 acted as potential mediators of TGFß-stimulated invasion in SMAD4-mutant PDAC organoids, as inhibition of these GTPases suppressed collective invasion in our model. These data suggest that PDAC utilizes different invasion programs depending on SMAD4 status, with collective invasion uniquely present in PDAC with SMAD4 loss. SIGNIFICANCE: Organoid models of PDAC highlight the importance of SMAD4 loss in invasion, demonstrating that invasion programs in SMAD4-mutant and SMAD4 wild-type tumors are different in both morphology and molecular mechanism.

Human hippocampal CA3 damage disrupts both recent and remote episodic memories.

Neocortical-hippocampal interactions support new episodic (event) memories, but there is conflicting evidence about the dependence of remote episodic memories on the hippocampus. In line with systems consolidation and computational theories of episodic memory, evidence from model organisms suggests that the cornu ammonis 3 (CA3) hippocampal subfield supports recent, but not remote, episodic retrieval. In this study, we demonstrated that recent and remote memories were susceptible to a loss of episodic detail in human participants with focal bilateral damage to CA3. Graph theoretic analyses of 7.0-Tesla resting-state fMRI data revealed that CA3 damage disrupted functional integration across the medial temporal lobe (MTL) subsystem of the default network. The loss of functional integration in MTL subsystem regions was predictive of autobiographical episodic retrieval performance. We conclude that human CA3 is necessary for the retrieval of episodic memories long after their initial acquisition and functional integration of the default network is important for autobiographical episodic memory performance.

Validation of a Newly Developed Food Frequency Questionnaire to Assess Dietary Intakes of Magnesium.

Magnesium (Mg) intake is an important indication of an individual's Mg status, but no validated food frequency questionnaire (FFQ) to assess intake currently exists. The purpose of this study was to develop and investigate the validity of a semi-quantitative Mg food frequency questionnaire (MgFFQ) against a 14-day food diary to assess average daily Mg intakes. In this cross-sectional study, 135 adults aged 18 to 75 completed the 33-item MgFFQ and a 14-day food diary to assess their Mg intakes. Coefficients of variance, Pearson's correlation coefficients, and/or Spearman's rank correlation coefficient tests were used to determine the relationship between the MgFFQ and the average Mg intake from the 14-day food diary among all participants, men, women, age groups, and body mass index (BMI) groups. The correlation between the MgFFQ and the 14-day food diary was significant (p < 0.05) for all participants (r = 0.798), men (r = 0.855), women (r = 0.759), normal weight (r = 0.762), overweight (r = 0.858), and obese (r = 0.675) weight statuses, and in all age groups. The calcium to magnesium intake (Ca:Mg) ratio in all participants was higher than optimal, 3.39 (2.11). Our results suggest that the MgFFQ is a valid method to capture Mg intake over an extended period of time, therefore acting as a valuable tool to quickly determine Mg intake.

Blocking tactile input to one finger using anaesthetic enhances touch perception and learning in other fingers.

Brain plasticity is a key mechanism for learning and recovery. A striking example of plasticity in the adult brain occurs following input loss, for example, following amputation, whereby the deprived zone is "invaded" by new representations. Although it has long been assumed that such reorganization leads to functional benefits for the invading representation, the behavioral evidence is controversial. Here, we investigate whether a temporary period of somatosensory input loss to one finger, induced by anesthetic block, is sufficient to cause improvements in touch perception ("direct" effects of deafferentation). Further, we determine whether this deprivation can improve touch perception by enhancing sensory learning processes, for example, by training ("interactive" effects). Importantly, we explore whether direct and interactive effects of deprivation are dissociable by directly comparing their effects on touch perception. Using psychophysical thresholds, we found brief deprivation alone caused improvements in tactile perception of a finger adjacent to the blocked finger but not to non-neighboring fingers. Two additional groups underwent minimal tactile training to one finger either during anesthetic block of the neighboring finger or a sham block with saline. Deprivation significantly enhanced the effects of tactile perceptual training, causing greater learning transfer compared with sham block. That is, following deafferentation and training, learning gains were seen in fingers normally outside the boundaries of topographic transfer of tactile perceptual learning. Our results demonstrate that sensory deprivation can improve perceptual abilities, both directly and interactively, when combined with sensory learning. This dissociation provides novel opportunities for future clinical interventions to improve sensation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Focal CA3 hippocampal subfield atrophy following LGI1 VGKC-complex antibody limbic encephalitis.

Magnetic resonance imaging has linked chronic voltage-gated potassium channel (VGKC) complex antibody-mediated limbic encephalitis with generalized hippocampal atrophy. However, autoantibodies bind to specific rodent hippocampal subfields. Here, human hippocampal subfield (subiculum, cornu ammonis 1-3, and dentate gyrus) targets of immunomodulation-treated LGI1 VGKC-complex antibody-mediated limbic encephalitis were investigated using in vivo ultra-high resolution (0.39 × 0.39 × 1.0 mm3) 7.0 T magnetic resonance imaging [n = 18 patients, 17 patients (94%) positive for LGI1 antibody and one patient negative for LGI1/CASPR2 but positive for VGKC-complex antibodies, mean age: 64.0 ± 2.55 years, median 4 years post-limbic encephalitis onset; n = 18 controls]. First, hippocampal subfield quantitative morphometry indicated significant volume loss confined to bilateral CA3 [F(1,34) = 16.87, P < 0.0001], despite hyperintense signal evident in 5 of 18 patients on presentation. Second, early and later intervention (<3 versus >3 months from symptom onset) were associated with CA3 atrophy. Third, whole-brain voxel-by-voxel morphometry revealed no significant grey matter loss. Fourth, CA3 subfield atrophy was associated with severe episodic but not semantic amnesia for postmorbid autobiographical events that was predicted by variability in CA3 volume. The results raise important questions about the links with histopathology, the impact of the observed focal atrophy on other CA3-mediated reconstructive and episodic mechanisms, and the role of potential antibody-mediated pathogenicity as part of the pathophysiology cascade in humans.

Generalisation of new sequence knowledge depends on response modality.

New visuomotor skills can guide behaviour in novel situations. Prior studies indicate that learning a visuospatial sequence via responses based on manual key presses leads to effector- and response-independent knowledge. Little is known, however, about the extent to which new sequence knowledge can generalise, and, thereby guide behaviour, outside of the manual response modality. Here, we examined whether learning a visuospatial sequence either via manual (key presses, without eye movements), oculomotor (obligatory eye movements), or perceptual (covert reorienting of visuospatial attention) responses supported generalisation to direct and indirect tests administered either in the same (baseline conditions) or a novel response modality (transfer conditions) with respect to initial study. Direct tests measured the use of conscious knowledge about the studied sequence, whereas the indirect tests did not ostensibly draw on the study phase and measured response priming. Oculomotor learning supported the use of conscious knowledge on the manual direct tests, whereas manual learning supported generalisation to the oculomotor direct tests but did not support the conscious use of knowledge. Sequence knowledge acquired via perceptual responses did not generalise onto any of the manual tests. Manual, oculomotor, and perceptual sequence learning all supported generalisation in the baseline conditions. Notably, the manual baseline condition and the manual to oculomotor transfer condition differed in the magnitude of general skill acquired during the study phase; however, general skill did not predict performance on the post-study tests. The results demonstrated that generalisation was only affected by the responses used to initially code the visuospatial sequence when new knowledge was applied to a novel response modality. We interpret these results in terms of response-effect distinctiveness, the availability of integrated effector- and motor-plan based information, and discuss their implications for neurocognitive accounts of sequence learning.

The under-compensatory roll aVOR does not affect dynamic visual acuity.

Rotations of the head evoke compensatory reflexive eye rotations in the orbit to stabilize images onto the fovea. In normal humans, the angular vestibulo-ocular reflex (aVOR) gain (eye/head velocity) changes depending on the head rotation plane. For pitch and yaw head rotations, the gain is near unity, but during roll head rotations, the aVOR gain is ∼ 0.7. The purpose of this study was to determine whether this physiological discrepancy affects dynamic visual acuity (DVA)--a functional measure of the aVOR that requires subjects to identify letters of varying acuities during head rotation. We used the scleral search coil technique to measure eye and head velocity during passive DVA testing in yaw, roll, and pitch head impulses in healthy controls and patients with unilateral vestibular hypofunction (UVH). For control subjects, the mean aVOR gain during roll impulses was significantly lower than the mean aVOR gain during yaw and pitch impulses; however, there was no difference in DVA between yaw, roll, or pitch. For subjects with UVH, only aVOR gain during head rotations toward the affected side (yaw) were asymmetric (ipsilesional, 0.32 ± 0.17, vs. contralesional, 0.95 ± 0.05), with no asymmetry during roll or pitch. Similarly, there was a large asymmetry for DVA only during yaw head rotations, with no asymmetry in roll or pitch. Interestingly, DVA during roll toward the affected ear was better than DVA during yaw toward the affected ear--even though the ipsilesional roll aVOR gain was 60 % lower. During roll, the axis of eye rotation remains nearly perpendicular to the fovea, resulting in minimal displacement between the fovea and fixation target image projected onto the back of the eye. For subjects with UVH, the DVA score during passive horizontal impulses is a better indicator of poor gaze stability than during passive roll or pitch.

Affect Expression and Self-Regulation Capacities of Infants Exposed in utero to Psychotropics.

This study explored the affect expression and self-regulation capacities of 8-month-old infants exposed in utero to psychotropic medications. This was a continuation of our previous study conducted on the same cohort when the infants were 3 months old. Psychotropics implicated included selective serotonin reuptake inhibitors (SSRIs), and a benzodiazepine derivative anxiolytic (clonazepam). The three comparison groups were: control (n = 23; infants not exposed to psychotropics in utero), SSRI-alone (n = 22; infants exposed to SSRIs only and having mothers who had a primary diagnosis of depressive disorder without having comorbid anxiety disorder), and SSRI+ group (n = 15; infants gestationally exposed to SSRIs and clonazepam and having mothers that had both clinical depression and anxiety disorder). Using the Parent-Child Early Relational Assessment Scale, infants were assessed in a dyadic context during free play and a structured task. There were significant differences in psychotropic exposed and non-exposed dyads regarding infant negative affect management. There were significant associations between the SSRI+ group of mothers and infant negative affect. This group of mothers also showed significant associations with infants' averting and avoiding behaviors in both play situations. The SSRI-alone group was similar to the control group and showed variable associations with infant's positive, negative, and sober moods unlike the SSRI+ group. There were no differences in infants' capacity for self-regulation in psychotropic exposed and non-exposed groups. Increased awareness of these vulnerable subgroups (SSRI-alone and SSRI+) is needed, in order to safeguard these dyads through better support systems and improved management.