Deep Vein Thrombosis as the Presenting Sign in an Adolescent With New-Onset Type 2 Diabetes.

Prothrombin G20210A mutation occurs in only 2% to 3% of the population, but usually does not become apparent unless the individual exhibits another risk factor for clotting. A risk factor such as hyperglycemia in the setting of diabetes mellitus may accelerate this clotting process, even at a very young age. In this case report, we discuss a 15-year-old boy presenting with left calf swelling and pain, found to have extensive deep vein thrombosis in the setting of hyperglycemia and a newly discovered prothrombin G20210A mutation. Venous thromboembolism in the setting of type 2 diabetes mellitus has not been described in children.

The Use of Autologous Blood Patch in Ullrich Muscular Dystrophy and Recurrent Pneumothorax.

We present the case of a 19-year-old female with Ullrich congenital muscular dystrophy (UCMD1, a collagen VI defect) who developed a right-sided pneumothorax after choking on a piece of meat. She received two chest tubes (pigtails) that resolved the pneumothorax. She was discharged in stable condition, and a chest radiograph two weeks later showed total resolution of the pneumothorax. Two months after this episode, the patient presented with another small, right-sided pneumothorax that shortly progressed to extension throughout the right side of the chest. These pneumothoraces were treated with three different pigtails, but this intervention was ineffective. Providers chose to utilize an autologous blood patch, which is an injection of the patient's own blood instilled in the pleural cavity through a chest drain. The blood forms a clot and subsequently seals the lung tissues through inflammation. This technique was chosen because the patient had advanced neuromuscular weakness with chronic respiratory failure. Also, our patient was not a candidate for chemical or surgical pleurodesis due to the nature of the persistent pneumothorax and the underlying lung fibrosis and collagen defect. Subsequent reaccumulation of the pneumothorax led to a second blood patch procedure, which proved effective. The patient recovered and was discharged in stable condition with no further episodes of pneumothorax over the subsequent 14 months from the initial episode.

Updating Normal Organ Weights Using a Large Current Sample Database.

CONTEXT.­: Organ weights are an essential part of autopsy analysis. Deviations from normal organ weights provide important clues to disease processes. The assessment of normal organ weights depends on reliable reference tables, but most widely available reference tables are based on data that are either decades old or derived from relatively small sample sizes. OBJECTIVE.­: To provide an updated reference table of organ weights based on contemporary sources and a large sample size. DESIGN.­: Organ weights from 4197 carefully screened autopsies performed on adults at the Palm Beach County Medical Examiner's Office in West Palm Beach, Florida, and the Mayo Clinic Hospital in Rochester, Minnesota. RESULTS.­: Height and body weight data in this study reflect the well-recognized increases in both variables, but most particularly in body weight, seen during the last decades. The study data show a strong positive association between organ weight and body weight for the heart, liver, and spleen. There is a similar but weaker association between body weight and the weight of the lungs and kidneys. Brain weight is independent of body weight but shows a strong negative association with age. Even when controlling for body weight, men's organs are heavier, except for the weight of the liver, which is comparable in men and women. These associations are in agreement with the findings of previous studies. The current study suggests that, for some of the commonly weighed organs, there has been an increase in median organ weight when compared with existing references. CONCLUSIONS.­: The tables presented here provide an updated reference that should prove useful to autopsy pathologists in the forensic and hospital settings.

Rate and risk factors for post-adenotonsillectomy complications in children under 24 months and 24 to 36 months old.

PURPOSE: The primary purpose of this study was to assess the overall rate of postoperative complications after adenotonsillectomy in children under 24 months old relative to children 24-36 months old. Our secondary goal focused on quantifying specific preoperative risk factors that predispose children to postoperative complications. METHODS: We retrospectively reviewed 248 patients who underwent adenotonsillectomy at our ENT office from 2006 to 2011. We stratified these patients into two groups: under 2 years old; and 2-3 years old. We identified 42 preoperative risk factors and 22 postoperative complications for each age group and conducted tests of statistical significance. RESULTS: We found that children under 24 months old had a statistically significant higher postoperative complication rate of 38% compared to 22.3% in children 2-3 years old (p = 0.0320, chi-squared test). For specific complications, younger children had a higher rate of respiratory distress within 24 h (p = 0.0355), endotracheal re-intubation (p = 0.0281), and retractions (p = 0.0281). The only identified risk factors aside from age demonstrating statistical significance were nasal steroid sprays used preoperatively in children under 24 months (p = 0.005) and concurrent tympanostomy tube placement in children 24-36 months (p = 0.026). CONCLUSION: Our data demonstrates that children under 2 years of age have an overall increased rate of postoperative complications after adenotonsillectomy when compared to children between 2 and 3 years old, with a significantly higher rates of early respiratory distress, endotracheal re-intubation, and retractions. This study is one of the largest that compares postoperative complication rates and risk factors after adenotonsillectomy in this age group.

Overexpression of Desmoglein 2 in a Mouse Model of Gorlin Syndrome Enhances Spontaneous Basal Cell Carcinoma Formation through STAT3-Mediated Gli1 Expression.

Activation of the hedgehog pathway is causative of virtually all sporadic and Gorlin syndrome-related basal cell carcinomas (BCCs), with loss of function of Ptc1 being the most common genomic lesion. Sporadic BCCs also overexpress Dsg2, a desmosomal cadherin normally found in the basal layer. Using a mouse model of Gorlin syndrome (Ptc1+/lacZ mice), we found that overexpressing Dsg2 in the basal layer (K14-Dsg2/Ptc1+/lacZ mice) or the superficial epidermis (Inv-Dsg2/Ptc1+/lacZ mice) resulted in increased spontaneous BCC formation at 3 and 6 months, respectively. The tumors did not show loss of heterozygosity of Ptc1, despite high levels of Gli1 and phosphorylated Stat3. A panel of sporadic human BCCs showed increased staining of both Dsg2 and phosphorylated Stat3 in all nine samples. Overexpression of Dsg2 in ASZ001 cells, a Ptc1-/- BCC cell line, induced Stat3 phosphorylation and further increased Gli1 levels, in both an autocrine and paracrine manner. Three different Stat3 inhibitors reduced viability and Gli1 expression in ASZ001 cells but not in HaCaT cells. Conversely, stimulation of Stat3 in ASZ001 cells with IL-6 increased Gli1 expression. Our results indicate that Dsg2 enhances canonical hedgehog signaling downstream of Ptc1 to promote BCC development through the activation of phosphorylated Stat3 and regulation of Gli1 expression.

Enhancement of Cutaneous Wound Healing by Dsg2 Augmentation of uPAR Secretion.

In addition to playing a role in adhesion, desmoglein 2 (Dsg2) is an important regulator of growth and survival signaling pathways, cell proliferation, migration and invasion, and oncogenesis. Although low-level Dsg2 expression is observed in basal keratinocytes and is downregulated in nonhealing venous ulcers, overexpression has been observed in both melanomas and nonmelanoma malignancies. Here, we show that transgenic mice overexpressing Dsg2 in basal keratinocytes primed the activation of mitogenic pathways, but did not induce dramatic epidermal changes or susceptibility to chemical-induced tumor development. Interestingly, acceleration of full-thickness wound closure and increased wound-adjacent keratinocyte proliferation was observed in these mice. As epidermal cytokines and their receptors play critical roles in wound healing, Dsg2-induced secretome alterations were assessed with an antibody profiler array and revealed increased release and proteolytic processing of the urokinase-type plasminogen activator receptor. Dsg2 induced urokinase-type plasminogen activator receptor expression in the skin of transgenic compared with wild-type mice. Wounding further enhanced urokinase-type plasminogen activator receptor in both epidermis and dermis with a concomitant increase in the prohealing laminin-332, a major component of the basement membrane zone, in transgenic mice. This study demonstrates that Dsg2 induces epidermal activation of various signaling cascades and accelerates cutaneous wound healing, in part, through urokinase-type plasminogen activator receptor-related signaling cascades.

Susceptibility MRI captures nigral pathology in patients with parkinsonian syndromes.

BACKGROUND: Parkinsonisms are neurodegenerative disorders characterized pathologically by α-synuclein-positive (e.g., PD, diffuse Lewy body disease, and MSA) and/or tau-positive (e.g., PSP, cortical basal degeneration) pathology. Using R2* and quantitative susceptibility mapping, susceptibility changes have been reported in the midbrain of living parkinsonian patients, although the exact underlying pathology of these alterations is unknown. OBJECTIVE: The current study investigated the pathological correlates of these susceptibility MRI measures. METHODS: In vivo MRIs (T1- and T2-weighted, and T2*) and pathology were obtained from 14 subjects enrolled in an NINDS PD Biomarker Program (PDBP). We assessed R2* and quantitative susceptibility mapping values in the SN, semiquantitative α-synuclein, tau, and iron values, as well as neuronal and glial counts. Data were analyzed using age-adjusted Spearman correlations. RESULTS: R2* was associated significantly with nigral α-synuclein (r = 0.746; P = 0.003). Quantitative susceptibility mapping correlated significantly with Perls' (r = 0.758; P = 0.003), but not with other pathological measurements. Neither measurement correlated with tau or glial cell counts (r ≤ 0.11; P ≥ 0.129). CONCLUSIONS: Susceptibility MRI measurements capture nigral pathologies associated with parkinsonian syndromes. Whereas quantitative susceptibility mapping is more sensitive to iron, R2* may reflect pathological aspects of the disorders beyond iron such as α-synuclein. They may be invaluable tools in diagnosing differential parkinsonian syndromes, and tracking in living patients the dynamic changes associated with the pathological progression of these disorders. © 2018 International Parkinson and Movement Disorder Society.

c-Src/Cav1-dependent activation of the EGFR by Dsg2.

The desmosomal cadherin, desmoglein 2 (Dsg2), is deregulated in a variety of human cancers including those of the skin. When ectopically expressed in the epidermis of transgenic mice, Dsg2 activates multiple mitogenic signaling pathways and increases susceptibility to tumorigenesis. However, the molecular mechanism responsible for Dsg2-mediated cellular signaling is poorly understood. Here we show overexpression as well as co-localization of Dsg2 and EGFR in cutaneous SCCs in vivo. Using HaCaT keratinocytes, knockdown of Dsg2 decreases EGFR expression and abrogates the activation of EGFR, c-Src and Stat3, but not Erk1/2 or Akt, in response to EGF ligand stimulation. To determine whether Dsg2 mediates signaling through lipid microdomains, sucrose density fractionation illustrated that Dsg2 is recruited to and displaces Cav1, EGFR and c-Src from light density lipid raft fractions. STED imaging confirmed that the presence of Dsg2 disperses Cav1 from the cell-cell borders. Perturbation of lipid rafts with the cholesterol-chelating agent MßCD also shifts Cav1, c-Src and EGFR out of the rafts and activates signaling pathways. Functionally, overexpression of Dsg2 in human SCC A431 cells enhances EGFR activation and increases cell proliferation and migration through a c-Src and EGFR dependent manner. In summary, our data suggest that Dsg2 stimulates cell growth and migration by positively regulating EGFR level and signaling through a c-Src and Cav1-dependent mechanism using lipid rafts as signal modulatory platforms.

Deep clinical and neuropathological phenotyping of Pick disease.

OBJECTIVE: To characterize sequential patterns of regional neuropathology and clinical symptoms in a well-characterized cohort of 21 patients with autopsy-confirmed Pick disease. METHODS: Detailed neuropathological examination using 70µm and traditional 6µm sections was performed using thioflavin-S staining and immunohistochemistry for phosphorylated tau, 3R and 4R tau isoforms, ubiquitin, and C-terminally truncated tau. Patterns of regional tau deposition were correlated with clinical data. In a subset of cases (n = 5), converging evidence was obtained using antemortem neuroimaging measures of gray and white matter integrity. RESULTS: Four sequential patterns of pathological tau deposition were identified starting in frontotemporal limbic/paralimbic and neocortical regions (phase I). Sequential involvement was seen in subcortical structures, including basal ganglia, locus coeruleus, and raphe nuclei (phase II), followed by primary motor cortex and precerebellar nuclei (phase III) and finally visual cortex in the most severe (phase IV) cases. Behavioral variant frontotemporal dementia was the predominant clinical phenotype (18 of 21), but all patients eventually developed a social comportment disorder. Pathological tau phases reflected the evolution of clinical symptoms and degeneration on serial antemortem neuroimaging, directly correlated with disease duration and inversely correlated with brain weight at autopsy. The majority of neuronal and glial tau inclusions were 3R tau-positive and 4R tau-negative in sporadic cases. There was a relative abundance of mature tau pathology markers in frontotemporal limbic/paralimbic regions compared to neocortical regions. INTERPRETATION: Pick disease tau neuropathology may originate in limbic/paralimbic cortices. The patterns of tau pathology observed here provide novel insights into the natural history and biology of tau-mediated neurodegeneration.

Semi-Automated Digital Image Analysis of Pick's Disease and TDP-43 Proteinopathy.

Digital image analysis of histology sections provides reliable, high-throughput methods for neuropathological studies but data is scant in frontotemporal lobar degeneration (FTLD), which has an added challenge of study due to morphologically diverse pathologies. Here, we describe a novel method of semi-automated digital image analysis in FTLD subtypes including: Pick's disease (PiD, n=11) with tau-positive intracellular inclusions and neuropil threads, and TDP-43 pathology type C (FTLD-TDPC, n=10), defined by TDP-43-positive aggregates predominantly in large dystrophic neurites. To do this, we examined three FTLD-associated cortical regions: mid-frontal gyrus (MFG), superior temporal gyrus (STG) and anterior cingulate gyrus (ACG) by immunohistochemistry. We used a color deconvolution process to isolate signal from the chromogen and applied both object detection and intensity thresholding algorithms to quantify pathological burden. We found object-detection algorithms had good agreement with gold-standard manual quantification of tau- and TDP-43-positive inclusions. Our sampling method was reliable across three separate investigators and we obtained similar results in a pilot analysis using open-source software. Regional comparisons using these algorithms finds differences in regional anatomic disease burden between PiD and FTLD-TDP not detected using traditional ordinal scale data, suggesting digital image analysis is a powerful tool for clinicopathological studies in morphologically diverse FTLD syndromes.