Fetal akinesia deformation sequence with pontocerebellar hypoplasia, and migration and gyration defects.

Fetal akinesia deformation sequence (FADS), or Pena-Shokeir phenotype is a constellation of deformational changes resulting from decreased or absent fetal movement, and include arthrogryposis, and craniofacial and central nervous system anomalies. We report an autopsy case of a 36-6/7week female neonate with a normal female karyotype and chromosome microarray demonstrating findings consistent with FADS. We provide a detailed examination of the severe and complex central nervous system abnormalities, including marked pontocerebellar hypoplasia and cortical and cerebellar migration and gyration defects. This case represents a rare detailed examination of the central nervous system of a patient with FADS.

Fetal akinesia deformation sequence with pontocerebellar hypoplasia, and migration and gyration defects

Fetal akinesia deformation sequence (FADS), or Pena-Shokeir phenotype is a constellation of deformational changes resulting from decreased or absent fetal movement, and include arthrogryposis, and craniofacial and central nervous system anomalies. We report an autopsy case of a 36-6/7week female neonate with a normal female karyotype and chromosome microarray demonstrating findings consistent with FADS. We provide a detailed examination of the severe and complex central nervous system abnormalities, including marked pontocerebellar hypoplasia and cortical and cerebellar migration and gyration defects. This case represents a rare detailed examination of the central nervous system of a patient with FADS.

Endogenous Serratia marcescens panophthalmitis: A case series.

PURPOSE: - Two rare and unusual cases of endogenous panophthalmitis from Serratia marcescens are presented with mechanisms for infection explored. Observations - The first patient had history of intravenous drug use (IVDU) without any medical implants. The second patient, in addition to IVDU, had a history of end-stage renal disease with upper extremity arteriovenous fistula graft infection from Serratia marcescens confirmed by wound culture. One patient had a history of licking the needles prior to IV drug injection. Clinical exam in both cases revealed light perception vision, relative afferent pupillary defect, periorbital edema with limited extraocular motility, and hypopyon in the affected eyes. Cultures from the anterior chamber aspirate were positive for Serratia marcescens in the first case and demonstrated Gram-negative rods in the second. Attempted vitreous aspiration was unsuccessful at obtaining specimens. Computed tomography demonstrated orbital fat stranding without abscess, and histopathology showed intense neutrophilic infiltration in all layers of enucleated specimen in case one. CONCLUSIONS AND IMPORTANCE: Needle licking may be an underappreciated mechanism for endogenous endophthalmitis in intravenous drug users. This report includes the first case in the literature, to authors' knowledge, of non-nosocomial endogenous Serratia marcescens panophthalmitis with orbital cellulitis. The second case illustrates a rare consequence of the rise in arteriovenous fistula placement and dialysis across the United States, which may predispose to future cases of endogenous Serratia marcescens endophthalmitis. This series supports previous observations of Serratia marcescens endogenous endophthalmitis exhibiting a generally poor visual prognosis.

Neuroepithelial Cyst of the Optic Nerve in a Newborn.

Cystic lesions of the optic nerve are uncommon findings that have been associated with neoplasms, systemic disorders, or described as idiopathic. They have been described in a wide range of ages, with few congenital cysts having been described in infants. Surgical excision of these lesions may lead to significant morbidity as previously reported cases often involved transection of the optic nerve. The authors describe a unique case of a newborn with a rare neuroepithelial cyst of the intraorbital optic nerve that was successfully excised while sparing the optic nerve, ultimately resulting in the resolution of an afferent pupillary defect. This case demonstrates that careful surgical excision of a benign optic nerve cyst can be performed without significant morbidity to potentially preserve vision.

Hybrid Neurofibroma/Schwannoma of the Supraorbital Nerve: Clinicopathologic Correlation of a Rare Tumor.

Benign peripheral nerve sheath tumors such as schwannoma and neurofibroma have long been considered distinct entities. Recently, hybrid tumors demonstrating combined morphological features of neurofibroma and schwannoma have been described, primarily in dermal locations. Only 1 case of hybrid peripheral nerve sheath tumor of the orbit has been reported in the literature. Hybrid morphology is important to recognize because of its association with the neurofibromatoses, including schwannomatosis; however, the paucity of literature on orbital hybrid peripheral nerve sheath tumor poses a diagnostic challenge. This article describes a case of hybrid neruofibroma/schwannoma of the orbit arising from the supraorbital nerve with clinicopathologic correlation.

Response of silent corticotroph pituitary carcinoma to chemotherapy: case report.

Silent pituitary corticotroph carcinomas are rare, with only six previously described cases in the literature. We report a patient with a silent pituitary corticotroph adenoma treated with multiple trans-sphenoidal resections. Twelve years after her initial presentation, she returned with leptomeningeal metastases to the posterior fossa, foramen magnum, and numerous other subarachnoid locations involving the spine. Histopathology obtained from the metastatic foci was identical to previous trans-sphenoidal specimens - consistent with the diagnosis of corticotroph pituitary carcinoma. A carboplatin and etoposide chemotherapy regimen successfully arrested disease progression and produced regression of multiple radiographically documented leptomeningeal deposits. To the authors' knowledge, this is the first report of a patient with silent pituitary carcinoma treated successfully with chemotherapy.

Lethal neonatal meningoencephalitis caused by multi-drug resistant, highly virulent Escherichia coli.

Neonatal meningitis is a rare but devastating condition. Multi-drug resistant (MDR) bacteria represent a substantial global health risk. This study reports on an aggressive case of lethal neonatal meningitis due to a MDR Escherichia coli (serotype O75:H5:K1). Serotyping, MDR pattern and phylogenetic typing revealed that this strain is an emergent and highly virulent neonatal meningitis E. coli isolate. The isolate was resistant to both ampicillin and gentamicin; antibiotics currently used for empiric neonatal sepsis treatment. The strain was also positive for multiple virulence genes including K1 capsule, fimbrial adhesion fimH, siderophore receptors iroN, fyuA and iutA, secreted autotransporter toxin sat, membrane associated proteases ompA and ompT, type II polysaccharide synthesis genes (kpsMTII) and pathogenicity-associated island (PAI)-associated malX gene. The presence of highly-virulent MDR organisms isolated in neonates underscores the need to implement rapid drug resistance diagnostic methods and should prompt consideration of alternate empiric therapy in neonates with Gram negative meningitis.

Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology.

Low-grade neuroepithelial tumors (LGNTs) are diverse CNS tumors presenting in children and young adults, often with a history of epilepsy. While the genetic profiles of common LGNTs, such as the pilocytic astrocytoma and 'adult-type' diffuse gliomas, are largely established, those of uncommon LGNTs remain to be defined. In this study, we have used massively parallel sequencing and various targeted molecular genetic approaches to study alterations in 91 LGNTs, mostly from children but including young adult patients. These tumors comprise dysembryoplastic neuroepithelial tumors (DNETs; n = 22), diffuse oligodendroglial tumors (d-OTs; n = 20), diffuse astrocytomas (DAs; n = 17), angiocentric gliomas (n = 15), and gangliogliomas (n = 17). Most LGNTs (84 %) analyzed by whole-genome sequencing (WGS) were characterized by a single driver genetic alteration. Alterations of FGFR1 occurred frequently in LGNTs composed of oligodendrocyte-like cells, being present in 82 % of DNETs and 40 % of d-OTs. In contrast, a MYB-QKI fusion characterized almost all angiocentric gliomas (87 %), and MYB fusion genes were the most common genetic alteration in DAs (41 %). A BRAF:p.V600E mutation was present in 35 % of gangliogliomas and 18 % of DAs. Pathogenic alterations in FGFR1/2/3, BRAF, or MYB/MYBL1 occurred in 78 % of the series. Adult-type d-OTs with an IDH1/2 mutation occurred in four adolescents, the youngest aged 15 years at biopsy. Despite a detailed analysis, novel genetic alterations were limited to two fusion genes, EWSR1-PATZ1 and SLMAP-NTRK2, both in gangliogliomas. Alterations in BRAF, FGFR1, or MYB account for most pathogenic alterations in LGNTs, including pilocytic astrocytomas, and alignment of these genetic alterations and cytologic features across LGNTs has diagnostic implications. Additionally, therapeutic options based upon targeting the effects of these alterations are already in clinical trials.

VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy.

Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) have potential applications in the treatment of fragile X syndrome, levodopa-induced dyskinesia in Parkinson disease, Alzheimer disease, addiction, and anxiety; however, clinical and preclinical studies raise concerns that complete blockade of mGlu5 and inverse agonist activity of current mGlu5 NAMs contribute to adverse effects that limit the therapeutic use of these compounds. We report the discovery and characterization of a novel mGlu5 NAM, N,N-diethyl-5-((3-fluorophenyl)ethynyl)picolinamide (VU0477573) that binds to the same allosteric site as the prototypical mGlu5 NAM MPEP but displays weak negative cooperativity. Because of this weak cooperativity, VU0477573 acts as a "partial NAM" so that full occupancy of the MPEP site does not completely inhibit maximal effects of mGlu5 agonists on intracellular calcium mobilization, inositol phosphate (IP) accumulation, or inhibition of synaptic transmission at the hippocampal Schaffer collateral-CA1 synapse. Unlike previous mGlu5 NAMs, VU0477573 displays no inverse agonist activity assessed using measures of effects on basal [(3)H]inositol phosphate (IP) accumulation. VU0477573 acts as a full NAM when measuring effects on mGlu5-mediated extracellular signal-related kinases 1/2 phosphorylation, which may indicate functional bias. VU0477573 exhibits an excellent pharmacokinetic profile and good brain penetration in rodents and provides dose-dependent full mGlu5 occupancy in the central nervous system (CNS) with systemic administration. Interestingly, VU0477573 shows robust efficacy, comparable to the mGlu5 NAM MTEP, in models of anxiolytic activity at doses that provide full CNS occupancy of mGlu5 and demonstrate an excellent CNS occupancy-efficacy relationship. VU0477573 provides an exciting new tool to investigate the efficacy of partial NAMs in animal models.

Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects.

Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu5) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant- and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu5 NAMs in these assays corresponded with increasing in vivo mGlu5 occupancy, demonstrating an orderly occupancy-to-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu5 NAMs, but with a broader therapeutic index.

Papillary tumor of the pineal region with synchronous suprasellar focus and novel cytogenetic features.

Papillary tumor of the pineal region (PTPR) is an uncommon neoplasm with variable biologic behavior. Cytogenetic and molecular diagnostic studies are rare, yielding no definitive genetic signature. We report a case of PTPR with a multicentric presentation and unusual cytogenetic features. A 25-year-old man presented with headache, disconjugate gaze, and confusion. Mass lesions in the pineal and suprasellar regions, with identical imaging characteristics, were identified. The former extended partially into the fourth ventricle. It showed typical PTPR histology and losses of chromosomes 3, 7, 10, 14, 18, and Y with gains of chromosomes 3, 8, and 9. Seventeen months postsurgery, the patient is stable without disease progression after radiation therapy. Synchronous mass lesions at presentation and losses of chromosomes 3, 7, 14, 18, and Y are unusual features, adding to the available data and underscoring the biologic and genetic variability associated with these neoplasms.

Retinal metastasis from unknown primary: diagnosis, management, and clinicopathologic correlation.

A 75-year-old man was incidentally found to have a yellow-white retinal lesion with scattered hemorrhages. He was empirically treated elsewhere for viral retinitis without resolution and later transferred to the Vanderbilt Eye Institute, where retinal biopsy with silicone oil tamponade showed retinal metastasis. He had no prior history of cancer, and multiple systemic imaging evaluations failed to identify a primary site. Histopathology and immunohistochemistry of the biopsy were consistent with non-small-cell lung carcinoma. Due to the radiation-attenuating properties of silicone oil, the patient underwent silicone oil removal prior to receiving external beam radiotherapy (EBRT). The retinal metastasis responded completely to EBRT, and at final follow-up, 18 months after initial presentation, no primary tumor has been identified.

Design and synthesis of systemically active metabotropic glutamate subtype-2 and -3 (mGlu2/3) receptor positive allosteric modulators (PAMs): pharmacological characterization and assessment in a rat model of cocaine dependence.

As part of our ongoing small-molecule metabotropic glutamate (mGlu) receptor positive allosteric modulator (PAM) research, we performed structure-activity relationship (SAR) studies around a series of group II mGlu PAMs. Initial analogues exhibited weak activity as mGlu2 receptor PAMs and no activity at mGlu3. Compound optimization led to the identification of potent mGlu2/3 selective PAMs with no in vitro activity at mGlu1,4-8 or 45 other CNS receptors. In vitro pharmacological characterization of representative compound 44 indicated agonist-PAM activity toward mGlu2 and PAM activity at mGlu3. The most potent mGlu2/3 PAMs were characterized in assays predictive of ADME/T and pharmacokinetic (PK) properties, allowing the discovery of systemically active mGlu2/3 PAMs. On the basis of its overall profile, compound 74 was selected for behavioral studies and was shown to dose-dependently decrease cocaine self-administration in rats after intraperitoneal administration. These mGlu2/3 receptor PAMs have significant potential as small molecule tools for investigating group II mGlu pharmacology.

Development of allosteric modulators of GPCRs for treatment of CNS disorders.

The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as "bitopic" ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction.

Orally active metabotropic glutamate subtype 2 receptor positive allosteric modulators: structure-activity relationships and assessment in a rat model of nicotine dependence.

Compounds that modulate metabotropic glutamate subtype 2 (mGlu(2)) receptors have the potential to treat several disorders of the central nervous system (CNS) including drug dependence. Herein we describe the synthesis and structure-activity relationship (SAR) studies around a series of mGlu(2) receptor positive allosteric modulators (PAMs). The effects of N-substitution (R(1)) and substitutions on the aryl ring (R(2)) were identified as key areas for SAR exploration (Figure 3). Investigation of the effects of varying substituents in both the isoindolinone (2) and benzisothiazolone (3) series led to compounds with improved in vitro potency and/or efficacy. In addition, several analogues exhibited promising pharmacokinetic (PK) properties. Furthermore, compound 2 was shown to dose-dependently decrease nicotine self-administration in rats following oral administration. Our data, showing for the first time efficacy of an mGlu(2) receptor PAM in this in vivo model, suggest potential utility for the treatment of nicotine dependence in humans.

Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats.

The modification of 3'-((2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yloxy)methyl)biphenyl-4-carboxylic acid (BINA, 1) by incorporating heteroatoms into the structure and replacing the cyclopentyl moiety led to the development of new mGluR2 positive allosteric modulators (PAMs) with optimized potency and superior druglike properties. These analogues are more potent than 1 in vitro and are highly selective for mGluR2 vs other mGluR subtypes. They have significantly improved pharmacokinetic (PK) properties, with excellent oral bioavailability and brain penetration. The benzisothiazol-3-one derivative 14 decreased cocaine self-administration in rats, providing proof-of-concept for the use of mGluR2 PAMs for the treatment of cocaine dependence.

Intramedullary spinal immature teratoma: resolution of quadriplegia following resection in a 4-week-old infant.

Intramedullary spinal cord teratomas are rare entities in infants. Management of these lesions is primarily surgical, with outcome dependent on rapid surgical decompression and complete gross-total tumor resection. The lesions are typically of the mature type, with immature teratomas displaying unique pathological features. The authors report a case of an extensive intramedullary immature teratoma in an infant with resolution of quadriplegia following gross-total radical resection. At the 1-year follow-up, there was radiographic evidence of tumor, and surgical reexploration yielded portions of immature teratoma and extensive gliosis.