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"Reynolds, Richard A."
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Early Hippocampal Synaptic Loss Precedes Neuronal Loss and Associates with Early Behavioural Deficits in Three Distinct Strains of Prion Disease
Prion diseases are fatal neurodegenerative diseases of the CNS that are associated with the accumulation of misfolded cellular prion protein. There are several different strains of prion disease defined by different patterns of tissue vacuolation in the brain and disease time course, but features of neurodegeneration in these strains have not been extensively studied. Our previous studies using the prion strains ME7, 79A and 22L showed that infected mice developed behavioural deficits in the same sequence and temporal pattern despite divergent end-stage neuropathology. Here the objective was to address the hypothesis that synaptic loss would occur early in the disease in all three strains, would precede neuronal death and would be associated with the early behavioural deficits. C57BL/6 mice inoculated with ME7, 79A, or 22L-infected brain homogenates were behaviourally assessed on species typical behaviours previously shown to change during progression and euthanised when all three strains showed statistically significant impairment on these tasks. A decrease in labelling with the presynaptic marker synaptophysin was observed in the stratum radiatum of the hippocampus in all three strains, when compared to control animals. Negligible cell death was seen by TUNEL at this time point. Astrocyte and microglial activation and protease resistant prion protein (PrP(Sc)) deposition were assessed in multiple brain regions and showed some strain specificity but also strongly overlapping patterns. This study shows that despite distinct pathology, multiple strains lead to early synaptic degeneration in the hippocampus, associated with similar behavioural deficits and supports the idea that the initiation of synaptic loss is a primary target of the misfolded prion agent.
Journal Article
Fashioned by Sargent
Fashioned by Sargent explores the complicated relationship of painting and dress through reproductions of portraits and other works by Sargent, alongside costumes of the period - including garments actually worn by his sitters. Essays illuminate topics such as portraits and performance, gender expression, the New Woman, and the pull of history and the excitement of new ideas.
Book
Brain Region Specific Pre-Synaptic and Post-Synaptic Degeneration Are Early Components of Neuropathology in Prion Disease
Synaptic abnormalities, one of the key features of prion disease pathogenesis, gives rise to functional deficits and contributes to the devastating clinical outcome. The synaptic compartment is the first to succumb in several neurodegenerative diseases linked with protein misfolding but the mechanisms underpinning this are poorly defined. In our current study we document that a focal intrahippocampal injection of the mouse-adapted 22L scrapie strain produces a complex, region-specific pathology in the brain. Our findings reveal that early synaptic changes in the stratum radiatum of the hippocampus, identical to those observed with the ME7 strain, occur when 22L strain is introduced into the hippocampus. The pathology was defined by degenerating Type I pre-synaptic elements progressively enveloped by the post-synaptic density of the dendritic spine. In contrast, the pathology in the cerebellum suggested that dendritic disintegration rather than pre-synaptic abnormalities dominate the early degenerative changes associated with the Purkinje cells. Indeed, both of the major synaptic inputs into the cerebellum, which arise from the parallel and climbing fibers, remained intact even at late stage disease. Immunolabeling with pathway selective antibodies reinforced these findings. These observations demonstrate that neuronal vulnerability to pathological protein misfolding is strongly dependent on the structure and function of the target neurons.
Journal Article
An evaluation of supracondylar humerus fractures: Is there a correlation between postponing treatment and the need for open surgical intervention?
Abstract
Purpose
The goal of this study was to evaluate the treatment and recovery of patients treated for Gartland type III supracondylar humerus fractures in order to determine if postponing treatment leads to a higher rate of open surgical treatment or complications.
Methods
A retrospective study was conducted examining the medical records of children with Gartland type III supracondylar humerus fractures at our institution for a two-year period. The patients included in the study were treated with closed reduction and percutaneous pinning (CRPP) or open reduction and internal fixation (ORIF).
Results
After exclusions, 134 patients were included in the study, with an average age of 5.6 years. The patients were grouped according to whether their treatment was postponed (39.6 %) or immediate (60.4 %). The majority of all patients were treated using CRPP: 46 (86.8 %) of the postponed patients and 75 (92.6 %) of the immediate patients. Very few postsurgical complications occurred in the patients; there was only one (1.6 %) case of iatrogenic nerve injury in a postponed patient as well as four (3.8 %) cases of loss of carrying angle: one (2.3 %) in postponed patients and three (4.8 %) in immediate patients.
Conclusions
Postponing treatment of type III supracondylar humerus fractures in children did not lead to an increase in open surgical treatment; nor did it lead to an increase in complications.
Journal Article
Intramedullary nails for pediatric diaphyseal femur fractures in older, heavier children: Early results
Abstract
Purpose
A common treatment for pediatric femur fractures is intramedullary nail (IMN) insertion. Elastic stable intramedullary nails (ESINs) are often used for these procedures in heavier patients, but the potential for complications and malunion is greater. We describe here a rigid IMN specifically designed for adolescents, the adolescent lateral entry femoral nail (ALFN). The purpose of this study was to compare the recovery and complications for patients treated with ESINs to those treated with the ALFN.
Methods
Our study design was a retrospective cohort study. We performed a review of medical records of 22 children ages 10–17 requiring surgical fixation of a femur fracture for a 2½-year period. Patients selected for the study had traumatic diaphyseal femur fractures and were treated with ESINs without end-caps or ALFNs. Our analyses evaluated injury, surgical, and outcome information for all patients.
Results
Twenty-two patients were eligible for inclusion and were divided into two groups according to their treatment: the ESIN group with 7 patients and the ALFN group with 15 patients. We then performed a comparison of complications and recovery for these patients. The mean time to full weight-bearing was significantly less for the ALFN group (4.1 weeks; SD, 2.2), than the ESIN group (9.4 weeks; SD 3.9). There was no statistical difference in the incidence of major or minor complications.
Conclusions
Older, heavier pediatric patients treated for femur fracture with ALFNs had a shorter recovery time than similar patients treated with ESINs. However, the outcomes for both groups were satisfactory.
Journal Article
The Delay in Diagnosis of Slipped Capital Femoral Epiphysis: A Review of 102 Patients
Objectives
The aim of this study were (1) to evaluate the incidence of apparent missed diagnosis of slipped capital femoral epiphysis (SCFE) by the primary care system and (2) to identify possible factors leading to a delay in diagnosis of this disorder.
Setting and Design
A retrospective review of emergency department records, outside medical charts, and preoperative and postoperative radiographs of children treated surgically for SCFE at the Children's Hospital of Los Angeles (CHLA) from 1989 to 1997 was done to assess the delay in diagnosis for SCFE. The primary care system included outside emergency department visits, urgent care clinic visits, and private office visits.
Results
Of 102 patients (69 men, 33 women; mean age at surgery, 11.9 years), 68% were above the 95th percentile mean weight for age. Pain in the hip and/or groin was documented in 60%. The mean duration of symptoms experienced before being seen at CHLA was 140 days (hours to 1.5 years) and the mean delay after the first primary care visit till being seen at CHLA was 76 days (hours to 1 year). Fifty-two percent of primary care visits for hip, groin, knee, or thigh pain in obese children did not lead to either a diagnosis of SCFE or a referral for orthopedic evaluation.
Conclusions
This study documents a 2 1/2-month delay and a 52% incidence of apparent missed diagnosis for SCFE by the primary care system. There seems to be a need for increased orthopedic education for primary care providers.
Journal Article
Early Hippocampal Synaptic Loss Precedes Neuronal Loss and Associates with Early Behavioural Deficits in Three Distinct Strains of Prion Disease. e68062
Prion diseases are fatal neurodegenerative diseases of the CNS that are associated with the accumulation of misfolded cellular prion protein. There are several different strains of prion disease defined by different patterns of tissue vacuolation in the brain and disease time course, but features of neurodegeneration in these strains have not been extensively studied. Our previous studies using the prion strains ME7, 79A and 22L showed that infected mice developed behavioural deficits in the same sequence and temporal pattern despite divergent end-stage neuropathology. Here the objective was to address the hypothesis that synaptic loss would occur early in the disease in all three strains, would precede neuronal death and would be associated with the early behavioural deficits. C57BL/6 mice inoculated with ME7, 79A, or 22L-infected brain homogenates were behaviourally assessed on species typical behaviours previously shown to change during progression and euthanised when all three strains showed statistically significant impairment on these tasks. A decrease in labelling with the presynaptic marker synaptophysin was observed in the stratum radiatum of the hippocampus in all three strains, when compared to control animals. Negligible cell death was seen by TUNEL at this time point. Astrocyte and microglial activation and protease resistant prion protein (PrPSc) deposition were assessed in multiple brain regions and showed some strain specificity but also strongly overlapping patterns. This study shows that despite distinct pathology, multiple strains lead to early synaptic degeneration in the hippocampus, associated with similar behavioural deficits and supports the idea that the initiation of synaptic loss is a primary target of the misfolded prion agent.
Journal Article
The carpal stretch test
To compare the sensitivity of traditional motion studies, bone scintigraphy and radiocarpal arthrography to a \"carpal stretch test,\" for evaluation of dynamic dissociative carpal instability.
Experimental study comparing the results of the tests to the findings of arthroscopy, the \"gold standard.\"
A university hospital-based upper extremity practice.
Six patients with chronic wrist pain, arthroscopically confirmed proximal row ligamentous disruption and radiographs not suggestive of proximal row instability.
The carpal stretch test: both affected and unaffected wrists were subjected to the same testing, wherein the wrist was suspended from finger traps for 10 minutes by a 4.5-kg weight. Standardized posteroanterior radiographs were taken of the suspended wrists.
Disruption of Gilula's arcs I and II, and sensitivity of the carpal stretch test compared with other investigations.
Step deformities ranging from 2.5 to 6 mm (average 3.7 mm) were recorded in the affected wrists and 0 to 4 mm (average 1.5 mm) in the \"unaffected\" wrists. The test was more sensitive than traditional radiography, arthrography and scintigraphy in defining both presence and site of proximal carpal row ligamentous tears and was almost as sensitive as arthroscopy.
In patients with chronic wrist pain and dynamic dissociative wrist instability, the carpal stretch test may prove to be a valuable screening tool for detecting ligamentous tears of the proximal carpal row.
Journal Article
