Solitary Metastasis of Colon Adenocarcinoma Mimicking Colloid Cyst of the Third Ventricle.

Metastatic lesions to the choroid plexus, although far less common than colloid cysts, can present very similarly both symptomatically and radiographically. Choroid plexus metastases are most common in the lateral ventricles, however, when they occur in the third and fourth ventricles they may cause obstructive hydrocephalus typical of a colloid cyst lesion. Renal cell carcinoma is the most common primary cancer, but many rare primaries have been reported. When patients are presenting with symptoms typical of colloid cysts it is important to consider past oncological history and if past medical history is significant for cancer using MR spectroscopy may be valuable in distinguishing between cystic and metastatic lesions.

A Case of Previously Unsuspected Cardiac Sarcoidosis Diagnosed at Autopsy and 23-Year Review of One Institution's Sarcoidosis Deaths.

Sarcoidosis is a noncaseating granulomatous disease of unknown etiology. The incidence is 11 per 100 000 white individuals and 34 per 100 000 black individuals. Cardiac involvement is seen in 2% to 5% of patients with systemic sarcoidosis and is often clinically undetected. This may be due to relative rarity of cardiac involvement, variability in presentation, or that there are no good clinical criteria for the diagnosis of cardiac sarcoidosis. Patients may be totally asymptomatic or have heart block, myocardial infarctions, heart failure, or sudden cardiac death, which may be due to involvement of the conduction system by sarcoidosis. We present a case of a 54-year-old black male with hypertension and hyperlipidemia. Prior to his death, he was witnessed to suddenly stand up, grab his chest, and collapse. His clinical cause of death was hypertensive and atherosclerotic cardiovascular disease. A retrospective review of autopsy cases over the last 23 years (1995-2018) at our institution (n = 6900) was undertaken. This case illustrates a rare disease and highlights the importance of complete autopsy even in patients who might otherwise be signed out as an external exam or records review only.

ATRX protein loss and deregulation of PI3K/AKT pathway is frequent in pilocytic astrocytoma with anaplastic features.

INTRODUCTION: Pilocytic astrocytoma (PA) with anaplastic features (PAAF) is a rare entity associated with decreased survival. It is characterized by hypercellularity, atypia, brisk mitotic activity, variable necrosis, and association with a classic PA component or anaplastic transformation in a recurrent tumor with a previously-documented classic PA. MATERIALS AND METHODS: We present 5 PAAF cases with clinical, radiological, pathological, and molecular correlation. We interrogated ATRX, IDH, TP53, PTEN, EGFR, BRAF, 6q23, p16(Ink4a) by sequencing, FISH, and immunohistochemistry. RESULTS: Four tumors were located in the cerebellum, and 1 was supratentorial. All showed ATRX protein loss by immunohistochemistry, loss of heterozygosity for PTEN, and had no IDH/TP53/BRAF mutations, nor EGFR amplification. Two of 5 tumors showed BRAF duplication by pyrosequencing. All showed loss of PTEN nuclear expression in subsets of tumor cells, which was associated with variable cytoplasmic positivity for pS6. There was a relative correlation between loss of PTEN expression and pS6 cytoplasmic expression. p53 was expressed in ~ 50% of tumor cells in all tumors. P16 was variably lost in all cases. One tumor showed MYB/6q23 deletion. CONCLUSION: We confirm ATRX protein loss suggestive of ATRX alteration as well as dysregulation of the PI3K/AKT pathway and, less often, of the MAPK/ERK pathway in PAAF.
.

Plexiform Schwannoma of the Tongue in a Pediatric Patient with Neurofibromatosis Type 2: A Case Report and Review of Literature.

INTRODUCTION: Plexiform schwannoma is a rare variant of schwannoma that accounts for only 5% of all schwannomas. Herein, we present a rare case of plexiform schwannoma of the tongue in a pediatric patient with neurofibromatosis type 2 (NF2). CASE PRESENTATION: A 13-year-old female presented with a growing left-sided tongue mass. The patient has a past medical history of NF2. The tongue mass was excised and histopathological examination revealed a spindle cell tumor with multinodular growth pattern, with Verocay bodies' formation. Tumor cells were strongly positive for S-100 protein and negative for smooth muscle actin (SMA), and EMA highlighted perineural fibroblasts surrounding tumor nodules. These findings were diagnostic of plexiform schwannoma. CONCLUSION: Plexiform schwannoma of the tongue is an extremely rare tumor seen in patients with NF2. Clinical examination and histopathological evaluation are important for diagnosis of plexiform schwannoma.

Characterization of a murine model of non-lethal, symptomatic dengue virus infection.

The mosquito-borne disease dengue is caused by four serologically- and genetically-related viruses, termed DENV-1 to DENV-4. Historical setbacks due to lack of human-like mouse models of dengue were partially remedied with characterization of lethal DENV-2 infection in immunocompromised AG129 mice (deficient in IFN-α/ß/γ receptors). Recently, our group established lethal AG129 mouse infection models of DENV-1, DENV-3, and DENV-4 using human isolates. Here we compare a non-lethal, disseminated model of DENV-3 infection using strain D83-144 to that of the lethal outcome following infection by strain C0360/94. Both strains belong to DENV-3 genotype II and differ by only 13 amino acids. Intraperitoneal inoculation of AG129 mice with strain D83-144 led to clinical signs of dengue infection, such as cytokine induction, thrombocytopenia, and systemic infection. However, C0360/94 infection led to features of severe human dengue, including coagulopathy and lethal outcome, whereas D83-144 infection does not. This study is the first to investigate a low passage, non-mouse lethal strain in AG129 mice and demonstrates that D83-144 infection induces milder features of human dengue than those induced by lethal C0360/94 infection. The results suggest that the AG129 mouse model has applications to investigate factors associated with mild or severe disease.

A lethal model of disseminated dengue virus type 1 infection in AG129 mice.

The mosquito-borne disease dengue is caused by four serologically and genetically related flaviviruses termed DENV-1 to DENV-4. Dengue is a global public health concern, with both the geographical range and burden of disease increasing rapidly. Clinically, dengue ranges from a relatively mild self-limiting illness to a severe life-threatening and sometimes fatal disease. Infection with one DENV serotype produces life-long homotypic immunity, but incomplete and short-term heterotypic protection. The development of small-animal models that recapitulate the characteristics of the disseminated disease seen clinically has been difficult, slowing the development of vaccines and therapeutics. The AG129 mouse (deficient in interferon alpha/beta and gamma receptor signalling) has proven to be valuable for this purpose, with the development of models of disseminated DENV-2,-3 and -4 disease. Recently, a DENV-1 AG129 model was described, but it requires antibody-dependent enhancement (ADE) to produce lethality. Here we describe a new AG129 model utilizing a non-mouse-adapted DENV-1 strain, West Pacific 74, that does not require ADE to induce lethal disease. Following high-titre intraperitoneal challenge, animals experience a virus infection with dissemination to multiple visceral tissues, including the liver, spleen and intestine. The animals also become thrombocytopenic, but vascular leakage is less prominent than in AG129 models with other DENV serotypes. Taken together, our studies demonstrate that this model is an important addition to dengue research, particularly for understanding the pathological basis of the disease between DENV serotypes and allowing the full spectrum of activity to test comparisons for putative vaccines and antivirals.

A Case of Previously Unsuspected Huntington Disease Diagnosed at Autopsy.

Huntington disease (HD) is a neurodegenerative disorder with a worldwide prevalence of four to ten per 100 000. It is characterized by choreiform movements, behavioral/psychiatric disturbances, and eventual cognitive decline. Symptoms usually present between 30 and 50 years of age and the diagnosis is based on the combination of clinical symptoms, family history, and genetic testing. A variation of HD, juvenile Huntington disease (JHD), presents earlier, with more severe symptoms and with a worse prognosis. Symptoms are different in JHD, with personality changes and learning difficulties being the predominant presenting features. Seizures are common in JHD, and chorea is uncommon; movement disorders at presentation of JHD are predominantly nonchoreiform. The inheritance pattern for both HD and JHD is autosomal dominant and the disease is caused by an elongation of the CAG repeat in the huntingtin gene. There are many published case reports of Huntington disease that were confirmed at autopsy, but to our knowledge, there are no reports in the literature where the diagnosis of Huntington disease was first made at autopsy. We present a case of a 28-year-old African-American male who was in a state of neglect due to a lifetime of abuse, cognitive difficulties, and seizures, whose cause of death was pneumonia. The gross autopsy findings included bilateral caudate nucleus atrophy and lateral ventricular dilation. Microscopically, severe bilateral neuronal loss and gliosis of the caudate and putamen nuclei were seen. Genetic testing for the number of CAG repeats confirmed the diagnosis and was consistent with JHD.

Characterization of lethal dengue virus type 4 (DENV-4) TVP-376 infection in mice lacking both IFN-α/ß and IFN-γ receptors (AG129) and comparison with the DENV-2 AG129 mouse model.

Dengue is a mosquito-borne disease caused by four related but distinct dengue viruses, DENV-1 to DENV-4. Dengue is endemic in most tropical countries, and over a third of the world's population is at risk of being infected. Although the global burden is high, no vaccine or antiviral is licensed to combat this disease. An obstacle complicating dengue research is the lack of animal challenge models that mimic human disease. Advances in immunocompromised murine infection models resulted in development of lethal DENV-2, DENV-3 and DENV-4 models in AG129 mice, which are deficient in both the IFN-α/ß receptor (IFN-α/ßR) and the IFN-γ receptor (IFN-γR). These models mimic features of dengue disease in humans. Here, we characterized lethal infection of AG129 mice by DENV-4 strain TVP-376 and found that AG129 mice developed clinical signs of illness and high viral loads in multiple tissues and succumbed 5 days after infection. Moreover, the splenic and hepatic histopathology of TVP-376-infected mice demonstrated the presence of cell activation and destruction of tissue architecture. Furthermore, infected mice had heightened levels of circulating cytokines. Comparison of the virulence phenotypes of DENV-4 strain TVP-376 and DENV-2 strain D2S10 revealed that TVP-376-induced mortality occurred in the absence of both IFN-α/ßR and IFN-γR signalling, but not with intact signalling from the IFN-γR, whereas D2S10 required the absence of IFN-α/ßR signalling only, indicating that it is more virulent than TVP-376. In conclusion, TVP-376 is lethal in AG129 mice, and this model provides a useful platform to investigate vaccine candidates and antivirals against DENV-4.

A Dengue Virus Type 4 Model of Disseminated Lethal Infection in AG129 Mice.

Dengue is a mosquito-borne disease of global public health significance that is caused by four serologically and genetically related viruses (DENV-1 to DENV-4). Most human DENV infections are asymptomatic, but clinical cases can range in severity from a relatively mild self-limiting illness to a severe life-threatening disease. Infection with one serotype of DENV results in life-long homotypic immunity but only short term heterotypic protection. There are no licensed vaccines or antivirals for dengue due in part to difficulty in developing small animal models that mimic the systemic disease seen in humans. Consequently, an important advance was the description of models of DENV-2 infection in AG129 mice (deficient in interferon alpha/beta and gamma receptor signaling) that resemble human disease. However, the need for well characterized models of disease due to DENV-1, -3, and -4 still remains. Here we describe a new AG129 mouse model utilizing a non-mouse-adapted Thai human DENV-4 strain 703-4. Following intraperitoneal challenge, animals experience a rapidly progressive lethal infection without developing neurologic clinical signs of disease. High virus titers are seen in multiple visceral tissues including the liver, spleen and large intestine, and the infected animals develop vascular leakage and thrombocytopenia, hallmarks of human dengue. Taken together, our studies demonstrate that this model is an important addition to the field of dengue research particularly in understanding similarities and differences in the pathologic basis of the disease caused by different DENV serotypes and in determining comparative efficacy of putative vaccines and antivirals.

A lethal murine infection model for dengue virus 3 in AG129 mice deficient in type I and II interferon receptors leads to systemic disease.

UNLABELLED: The mosquito-borne disease dengue (DEN) is caused by four serologically and genetically related viruses, termed DENV-1 to DENV-4. Infection with one DENV usually leads to acute illness and results in lifelong homotypic immunity, but individuals remain susceptible to infection by the other three DENVs. The lack of a small-animal model that mimics systemic DEN disease without neurovirulence has been an obstacle, but DENV-2 models that resemble human disease have been recently developed in AG129 mice (deficient in interferon alpha/beta and interferon gamma receptor signaling). However, comparable DENV-1, -3, and -4 models have not been developed. We utilized a non-mouse-adapted DENV-3 Thai human isolate to develop a lethal infection model in AG129 mice. Intraperitoneal inoculation of six to eight-week-old animals with strain C0360/94 led to rapid, fatal disease. Lethal C0360/94 infection resulted in physical signs of illness, high viral loads in the spleen, liver, and large intestine, histological changes in the liver and spleen tissues, and increased serum cytokine levels. Importantly, the animals developed vascular leakage, thrombocytopenia, and leukopenia. Overall, we have developed a lethal DENV-3 murine infection model, with no evidence of neurotropic disease based on a non-mouse-adapted human isolate, which can be used to investigate DEN pathogenesis and to evaluate candidate vaccines and antivirals. This suggests that murine models utilizing non-mouse-adapted isolates can be obtained for all four DENVs. IMPORTANCE: Dengue (DEN) is a mosquito-borne disease caused by four DENV serotypes (DENV-1, -2, -3, and -4) that have no treatments or vaccines. Primary infection with one DENV usually leads to acute illness followed by lifelong homotypic immunity, but susceptibility to infection by the other three DENVs remains. Therefore, a vaccine needs to protect from all four DENVs simultaneously. To date a suitable animal model to mimic systemic human illness exists only for DENV-2 in immunocompromised mice using passaged viruses; however, models are still needed for the remaining serotypes. This study describes establishment of a lethal systemic DENV-3 infection model with a human isolate in immunocompromised mice and is the first report of lethal infection by a nonadapted clinical DENV isolate without evidence of neurological disease. Our DENV-3 model provides a relevant platform to test DEN vaccines and antivirals.

Evidence for autophagic gridlock in aging and neurodegeneration.

Autophagy is essential to neuronal homeostasis, and its impairment is implicated in the development of neurodegenerative pathology. However, the underlying mechanisms and consequences of this phenomenon remain a matter of conjecture. We show that misexpression of human tau in Drosophila induces accumulation of autophagic intermediates with a preponderance of large vacuoles, which we term giant autophagic bodies (GABs), which are reminiscent of dysfunctional autophagic entities. Lowering basal autophagy reduces GABs, whereas increasing autophagy decreases mature autolysosomes. Induction of autophagy is also associated with rescue of the tauopathy phenotype, suggesting that formation of GABs may be a compensatory mechanism rather than a trigger of neurodegeneration. Last, we show that the peculiar Biondi bodies observed in the choroid epithelium of both elderly and Alzheimer's disease human brains express immunoreactive markers similar to those of GABs. Collectively, these data indicate that autophagic gridlock contributes to the development of pathology in aging and neurodegeneration.

Should high-risk adolescents have Papanicolaou tests?

BACKGROUND: The current American College of Obstetricians and Gynecologists guidelines state that cervical cancer screening should begin at age 21 years, regardless of sexual or obstetric history. However, previous studies have demonstrated that there is a small but significant subset of high-risk adolescents with extensive sexual and obstetric history who harbor a significant squamous cervical lesion. The objective of the current study was to use histologic and demographic data from adolescents (aged <21 years) who received Papanicolaou (Pap) tests to determine whether they benefited from early cervical cancer screening. METHODS: Adolescent girls who had Pap tests between 2000 and 2010 were included in the study. Demographic data, including obstetric history, number of sexual partners, age of first coitus, age at first pregnancy, menarche, smoking history, and Chlamydia and syphilis infection, were analyzed for associations with levels of cervical dysplasia. RESULTS: Of 56,785 adolescent Pap tests, 277 (0.5%) were diagnosed as high-grade squamous HSIL, and 56 of those Pap tests (20%) were from patients who had grade 3 cervical intraepithelial neoplasia (CIN-3) on subsequent biopsy and/or excision. One patient had microinvasive cervical carcinoma identified on loop electrosurgical excision procedure at age 27 years after an HSIL Pap test. Increased parity was associated significantly with higher rates of CIN-3. CONCLUSIONS: The study findings indicated that current American College of Obstetricians and Gynecologists guidelines to begin Pap testing at age 21 years are appropriate for the majority of adolescents, because the rate of HSIL is very low, and the risk for invasive carcinoma is minimal. Although higher parity was associated with a significantly increased grade of CIN, the conclusions are questionable because of the significant amount of missing demographic data points. That being said, this study should lead to other similar studies to determine any association of higher grade CIN with adolescent sexual and obstetric history.

Production of IL-8, IL-17, IFN-gamma and IP-10 in human astrocytes correlates with alphavirus attenuation.

Venezuelan equine encephalitis virus (VEEV) is an important, naturally emerging zoonotic pathogen. Recent outbreaks in Venezuela and Colombia in 1995 indicate that VEEV still poses a serious public health threat. Astrocytes may be target cells in human and mouse infection and they play an important role in repair through gliosis. In this study, we report that virulent VEEV efficiently infects cultured normal human astrocytes, three different murine astrocyte cell lines and astrocytes in the mouse brain. The attenuation of virus replication positively correlates with the increased levels of production of IL-8, IL-17, IFN-gamma and IP-10. In addition, VEEV infection induces release of basic fibroblast growth factor and production of potent chemokines such as RANTES and MIP-1-beta from cultured human astrocytes. This growth factor and cytokine profile modeled by astrocytes in vitro may contribute to both neuroprotection and repair and may play a role in leukocyte recruitment in vivo.

Topical metal chelation therapy ameliorates oxidation-induced toxicity in diabetic cataract.

Oxidative stress plays a critical role in cataractogenesis, the leading cause of blindness worldwide. Since transition metals generate reactive oxygen species (ROS) formation, metal chelation therapy has been proposed for treatment of cataracts. However, the effectiveness of most chelators is limited by low tissue penetrability. This study is the first to demonstrate that the topically applied divalent metal chelator ethylenediamine tetraacetic acid (EDTA) combined with the carrier and permeability enhancer methyl sulfonyl methane (MSM) ameliorates both oxidation-induced lens opacification and the associated toxic accumulation of protein-4-hydroxynonenal (HNE) adducts. Both in vitro (rat lens culture) and in vivo (diabetic rats), EDTA-MSM (1) significantly reduced lens opacification by about 40-50%, (2) significantly diminished lens epithelial cell proliferation and fiber cell swelling in early stages of cataract formation in vivo, and (3) notably decreased the levels of protein-HNE adducts. These findings have important implications specifically for the treatment of cataract and generally for other diseases in which oxidative stress plays a key pathogenic role.

Infratentorial angioleiomyoma: a new location for a rare neoplastic entity.

Angioleiomyomas are benign neoplasms most often located in the subcutaneous tissue of middle-aged individuals and usually confined to the subcuticular and deep dermal layers of the lower extremities. An intracranial site for this tumor is exceedingly rare, with very few reports documenting locations in the neuraxis. To the authors' knowledge the present case represents the first reported instance of an infratentorial angioleiomyoma. The authors conducted a review of selected English-language papers published since 1960 describing well-documented cases of intracranial vascular leiomyomas, with detailed information on the clinical presentation, radiology, pathology, and particulars of surgical management in each case.

Intraventricular ganglioglioma.

Gangliogliomas are mixed tumors consisting of both glial elements and differentiated neurons. Although any part of the central nervous system can be affected, little is known about intraventricular gangliogliomas. A patient with a ganglioglioma is presented in the previously unreported location of the anterior third ventricle at the foramen of Monro, mimicking a colloid cyst. We review all other reported cases of intraventricular ganglioglioma (n=6) to characterize this entity. Intraventricular gangliogliomas typically affect younger patients with female predominance (male:female, 2:5; median age 25 years). Symptoms occur secondary to obstruction of physiological cerebrospinal fluid circulation. Complete surgical resection with re-establishment of cerebrospinal fluid drainage is the goal of treatment.

Alpha-beta T cells provide protection against lethal encephalitis in the murine model of VEEV infection.

We evaluated the safety and immunogenicity of a chimeric alphavirus vaccine candidate in mice with selective immunodeficiencies. This vaccine candidate was highly attenuated in mice with deficiencies in the B and T cell compartments, as well as in mice with deficient gamma-interferon responsiveness. However, the level of protection varied among the strains tested. Wild type mice were protected against lethal VEEV challenge. In contrast, alpha/beta (alphabeta) TCR-deficient mice developed lethal encephalitis following VEEV challenge, while mice deficient in gamma/delta (gammadelta) T cells were protected. Surprisingly, the vaccine potency was diminished by 50% in animals lacking interferon-gamma receptor alpha chain (R1)-chain and a minority of vaccinated immunoglobulin heavy chain-deficient (microMT) mice survived challenge, which suggests that neutralizing antibody may not be absolutely required for protection. Prolonged replication of encephalitic VEEV in the brain of pre-immunized mice is not lethal and adoptive transfer experiments indicate that CD3(+) T cells are required for protection.

Hyaluronidase increases the biodistribution of acid alpha-1,4 glucosidase in the muscle of Pompe disease mice: an approach to enhance the efficacy of enzyme replacement therapy.

Pompe disease (glycogen storage disease type II) is a glycogen storage disease caused by a deficiency of the lysosomal enzyme, acid maltase/acid alpha-1,4 glucosidase (GAA). Deficiency of the enzyme leads primarily to intra-lysosomal glycogen accumulation, primarily in cardiac and skeletal muscles, due to the inability of converting glycogen into glucose. Enzyme replacement therapy (ERT) has been applied to replace the deficient enzyme and to restore the lost function. However, enhancing the enzyme activity to the muscle following ERT is relatively insufficient. In order to enhance GAA activity into the muscle in Pompe disease, efficacy of hyaluronidase (hyase) was examined in the heart, quadriceps, diaphragm, kidney, and brain of mouse model of Pompe disease. Administration of hyase 3000 U/mouse (intravenous) i.v. or i.p. (intraperitoneal) and 10 min later recombinant human GAA (rhGAA) 20 mg/kg i.v. showed more GAA activity in hyase i.p. injected mice compared to those mice injected with hyase via i.v. Injection of low dose of hyase (3000 U/mouse) or high dose of hyase (10,000 U/mouse) i.p. and 20 min or 60 min later 20 mg/kg rhGAA i.v. increased GAA activity into the heart, diaphragm, kidney, and quadriceps compared to hyase untreated mice. These studies suggest that hyase enhances penetration of enzyme into the tissues including muscle during ERT and therefore hyase pretreatment may be important in treating Pompe disease.

Fetal origin of adverse pregnancy outcome: the water disinfectant by-product chloroacetonitrile induces oxidative stress and apoptosis in mouse fetal brain.

Epidemiological studies indicate a relationship between water disinfectant by-products (DBP) and adverse pregnancy outcomes (APO) including neural tube defects. These studies suggest that fetal brain may be vulnerable to DBP during early stages of development. Therefore, we examined several molecular markers commonly known to indicate chemical-induced neurotoxicity during fetal brain development following prenatal exposure to the DBP; chloroacetonitrile (CAN). Pregnant mice, at gestation day 6 (GD6), were treated with a daily oral dose of CAN (25 mg/kg). At GD12, two groups of animals were treated with an i.v. tracer dose of [2-14C]-CAN. These animals were sacrificed at 1 and 24 h after treatment and processed for quantitative in situ micro-whole-body autoradiography. The remaining groups of animals continued to receive CAN. At GD18, control and treated animals were weighed, anesthetized, and fetuses were obtained and their brains were removed for biochemical and immunohistochemical analyses. Whole-body autoradiography studies indicate a significant uptake and retention of [2-14C]-CAN/metabolites (M) in fetal brain (cerebral cortex, hippocampus, cerebellum) at 1 and 24 h. There was a 20% reduction in body weight and a 22% reduction in brain weight of fetuses exposed to CAN compared to controls. A significant increase in oxidative stress markers was observed in various fetal brain regions in animals exposed to CAN compared to controls. This was indicated by a 3- to 4-fold decrease in the ratio of the reduced to oxidized form of glutathione (GSH/GSSG), increased lipid peroxidation (1.3-fold), and increased 8-hydroxy-2-deoxyguanosine levels (1.4-fold). Cupric silver staining indicated a significant increase in the number of degenerating neurons in cortical regions in exposed animals. In animals exposed to CAN there was increase in nuclear DNA fragmentation (TUNEL staining) detected in the cerebral cortex and cerebellum (2-fold increase in apoptotic indices). Caspase-3 activity in cerebral cortex and cerebellum of treated animals were also increased (1.7- and 1.5-fold, respectively). In conclusion, this study indicates that CAN/M crossed the placenta and accumulated in fetal brain tissues where it caused oxidative stress and neuronal apoptosis. These events could predispose the fetus to altered brain development leading to APO as well as behavioral and learning and memory deficits.