Intraoperative discovery of a radiographically occult subependymoma obstructing the obex in a patient with a Chiari malformation - A rare case.

Background: Chiari (type I) malformations are typically congenital. Occasionally, however, tonsillar herniation can arise secondary to cerebrospinal fluid leakage, posterior fossa or intraventricular mass lesions, or other etiologies. We present the first-ever case of an intramedullary subependymoma at the cervicomedullary junction associated with vertebral bone abnormalities and an acquired secondary Chiari malformation. Case Description: A 60-year-old woman presented with a 3-year history of occipital, tussive headaches. Preoperative imaging was negative for mass lesions but demonstrated a Chiari malformation. She was recommended posterior fossa decompression with tonsillar shrinkage. During surgery, an intramedullary mass was incidentally observed, obstructing the obex at the cervicomedullary junction. Histopathological analysis of the resected lesion revealed a diagnosis of subependymoma. Conclusion: Subependymomas can sometimes present a diagnostic challenge due to their subtle appearance in neuroimaging. Only rarely are such masses associated with an acquired Chiari malformation. No such case has previously been reported. We present a literature review on acquired Chiari malformations and discuss their management.

Cervicomedullary junction mature teratoma with pulmonary differentiation and diastematomyelia in an adult - A rare case.

Background: Intradural extramedullary teratomas in the cervical or cervicomedullary region are rare in adults. Case Description: We report a symptomatic, mature teratoma at the cervicomedullary junction in a 52-year-old Hispanic female who also has a type I diastematomyelia in the thoracolumbar spine. The patient underwent surgical resection of the lesion with the resolution of presenting symptoms. Histopathology of the lesion revealed a mature cystic teratoma with pulmonary differentiation. Conclusion: We discuss the case along with a review of pertinent literature and considerations with regard to the diagnosis, etiology, prognosis, and management of this unusual pathology.

Sensitivity of Hypocretin System to Chronic Alcohol Exposure: A Human and Animal Study.

Human heroin addicts and mice administered morphine for a 2 week period show a greatly increased number of hypothalamic hypocretin (Hcrt or orexin) producing neurons with a concomitant reduction in Hcrt cell size. Male rats addicted to cocaine similarly show an increased number of detectable Hcrt neurons. These findings led us to hypothesize that humans with alcohol use disorder (AUD) would show similar changes. We now report that humans with AUD have a decreased number and size of detectable Hcrt neurons. In addition, the intermingled melanin concentrating hormone (MCH) neurons are reduced in size. We saw no change in the size and number of tuberomammillary histamine neurons in AUD. Within the Hcrt/MCH neuronal field we found that microglia cell size was increased in AUD brains. In contrast, male rats with 2 week alcohol exposure, sufficient to elicit withdrawal symptoms, show no change in the number or size of Hcrt, MCH and histamine neurons, and no change in the size of microglia. The present study indicates major differences between the response of Hcrt neurons to opioids and that to alcohol in human subjects with a history of substance abuse.

Nemaline myopathy in newly diagnosed systemic lupus erythematosus and Sjögren's overlap syndrome complicated by macrophage activation syndrome.

BACKGROUND: Nemaline myopathies are congenital or acquired muscle disorders that typically present in childhood but can occasionally occur in adults with underlying malignant, infectious or autoimmune disorders. There is a great genetic heterogeneity as well as clinical variability among the disease. CASE PRESENTATION: Here, we present a case of nemaline myopathy in a young woman who was newly diagnosed with systemic lupus erythematosus (SLE) and Sjögren's overlap syndrome complicated by macrophage activation syndrome (MAS). She had no personal or family history of myopathy and was reporting progressive thigh weakness. A muscle biopsy revealed type 1 myofiber predominance with granular material in atrophic myocytes consistent with nemaline myopathy. Her symptoms markedly improved with immunotherapy for her SLE and MAS supporting the diagnosis of sporadic late-onset nemaline myopathy (SLONM) associated with her autoimmune disease. CONCLUSIONS: SLONM is a type of nemaline myopathy that presents in adults and can occasionally be associated with autoimmune disease. In these cases, treatment of the underlying disorder with immunosuppression appears to improve symptoms of myopathy.

Educational Case: Incidental Gallbladder Adenocarcinoma.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. 1.

Opiates increase the number of hypocretin-producing cells in human and mouse brain and reverse cataplexy in a mouse model of narcolepsy.

The changes in brain function that perpetuate opiate addiction are unclear. In our studies of human narcolepsy, a disease caused by loss of immunohistochemically detected hypocretin (orexin) neurons, we encountered a control brain (from an apparently neurologically normal individual) with 50% more hypocretin neurons than other control human brains that we had studied. We discovered that this individual was a heroin addict. Studying five postmortem brains from heroin addicts, we report that the brain tissue had, on average, 54% more immunohistochemically detected neurons producing hypocretin than did control brains from neurologically normal subjects. Similar increases in hypocretin-producing cells could be induced in wild-type mice by long-term (but not short-term) administration of morphine. The increased number of detected hypocretin neurons was not due to neurogenesis and outlasted morphine administration by several weeks. The number of neurons containing melanin-concentrating hormone, which are in the same hypothalamic region as hypocretin-producing cells, did not change in response to morphine administration. Morphine administration restored the population of detected hypocretin cells to normal numbers in transgenic mice in which these neurons had been partially depleted. Morphine administration also decreased cataplexy in mice made narcoleptic by the depletion of hypocretin neurons. These findings suggest that opiate agonists may have a role in the treatment of narcolepsy, a disorder caused by hypocretin neuron loss, and that increased numbers of hypocretin-producing cells may play a role in maintaining opiate addiction.

An unusual presentation of primary pulmonary extranodal marginal zone lymphoma of mucosal associated lymphoid tissue: An autopsy case report.

A 40 year old female with no documented medical history presented to the Emergency Department with several days of lethargy and altered mental status. She was found to be anemic, thrombocytopenic, and hypotensive. The patient was found to be in severe metabolic acidosis, became bradycardic, and quickly deteriorated. Clinicians suspected thrombotic thrombocytopenic purpura, and the diagnosis was supported by ADAMTS13 testing. The clinicians attempted to place a Quinton catheter for emergent plasmapheresis, but the patient expired before definitive treatment could be initiated. Autopsy was obtained and revealed a right middle lobe consolidation grossly consistent with lymphoid tissue or tumor.

Non-invasive gene targeting to the fetal brain after intravenous administration and transplacental transfer of plasmid DNA using PEGylated immunoliposomes.

Research was undertaken to establish transplacental delivery of active genes to fetal brain by a non-viral vector, antibody-specific targeted therapeutic procedure. PEGylated immunoliposomes (PILs) containing firefly luciferase DNA under the influence of the SV40 promoter injected intravenously into near-term pregnant mice produced luminometric evidence of CNS tissue luciferase activity at 48-h post-injection in all newborn pups. In utero delivery of this pGL3 DNA was shown after a single i.v. injection in maternal and neonatal brains, spleen and lesser amounts in lungs, with only negligible background levels in negative controls exposed to unencapsulated pDNA. In addition to studies of normal wild-type mice, we similarly injected pregnant Lafora Knockout (EPM2a null-mutant) and demonstrated luciferase activity days later in the maternal and newborn pup brains of both types. Delivery of PILs containing a second reporter gene (the pSV40 beta-galactosidase transgene) transplacentally by the same procedure was also successful. Histochemical and biochemical demonstration of beta-galactosidase was documented for all mutant and non-mutant neonates. Brain areas of highest Lafora body development (such as the hippocampus and pontine nuclei) showed intraneuronal beta-glucosidase activity. We conclude that receptor-mediated transport of PIL-borne gene therapeutics across both the placental barrier as well as the fetal BBB in utero is feasible.

Greatly increased numbers of histamine cells in human narcolepsy with cataplexy.

OBJECTIVE: To determine whether histamine cells are altered in human narcolepsy with cataplexy and in animal models of this disease. METHODS: Immunohistochemistry for histidine decarboxylase (HDC) and quantitative microscopy were used to detect histamine cells in human narcoleptics, hypocretin (Hcrt) receptor-2 mutant dogs, and 3 mouse narcolepsy models: Hcrt (orexin) knockouts, ataxin-3-orexin, and doxycycline-controlled-diphtheria-toxin-A-orexin. RESULTS: We found an average 64% increase in the number of histamine neurons in human narcolepsy with cataplexy, with no overlap between narcoleptics and controls. However, we did not see altered numbers of HDC cells in any of the animal models of narcolepsy. INTERPRETATION: Changes in histamine cell numbers are not required for the major symptoms of narcolepsy, because all animal models have these symptoms. The histamine cell changes we saw in humans did not occur in the 4 animal models of Hcrt dysfunction we examined. Therefore, the loss of Hcrt receptor-2, of the Hcrt peptide, or of Hcrt cells is not sufficient to produce these changes. We speculate that the increased histamine cell numbers we see in human narcolepsy may instead be related to the process causing the human disorder. Although research has focused on possible antigens within the Hcrt cells that might trigger their autoimmune destruction, the present findings suggest that the triggering events of human narcolepsy may involve a proliferation of histamine-containing cells. We discuss this and other explanations of the difference between human narcoleptics and animal models of narcolepsy, including therapeutic drug use and species differences.

Intraspinal primitive neuroectodermal tumor in a man with neurofibromatosis type 1: Case report and review of the literature.

BACKGROUND: The occurrence of primitive neuroectodermal tumors (PNET) in patients with neurofibromatosis type 1 (NF1) has only been reported in two other cases in English-Language literature. Owing to the rarity of intraspinal PNET and the extremely high gene mutation variability in NF1, there is currently no conclusive evidence to suggest that PNET is associated with NF1. Here, we report a case of intradural PNET in a patient with NF1. CASE DESCRIPTION: A 27-year-old male underwent a C1-C3 laminectomy for resection of an intramedullary mass. Histopathology and immunohistopathology analysis was performed. Microscopic examination and immunohistochemical staining indicated the mass was a primitive neuroectodermal tumor. Within 1 month after tumor resection, the patient developed leptomeningeal carcinomatosis. The patient was not a candidate for radiation therapy but underwent palliative systemic chemotherapy. He subsequently developed neutropenia and died 3 months after tumor resection. CONCLUSION: To our knowledge, this is the first reported intraspinal PNET associated with NF1. Genetic analysis of CNS PNETs suggests a possible correlation, but larger case series are needed to support this theory.

Effects of testosterone supplementation on skeletal muscle fiber hypertrophy and satellite cells in community-dwelling older men.

OBJECTIVE: In this study, we determined the effects of graded doses of testosterone on muscle fiber cross-sectional area (CSA) and satellite cell number and replication in older men. PARTICIPANTS: Healthy men, 60-75 yr old, received a long-acting GnRH agonist to suppress endogenous testosterone production and 25, 50, 125, 300, or 600 mg testosterone enanthate im weekly for 20 wk. METHODS: Immunohistochemistry, light and confocal microscopy, and electron microscopy were used to perform fiber typing and quantitate myonuclear and satellite cell number in vastus lateralis biopsies, obtained before and after 20 wk of treatment. RESULTS: Testosterone administration in older men was associated with dose-dependent increases in CSA of both types I and II fibers. Satellite cell number increased dose dependently at the three highest doses (3% at baseline vs. 6.2, 9.2, and 13.0% at 125, 300, and 600 mg doses, P < 0.05). Testosterone administration was associated with an increase in the number of proliferating cell nuclear antigen+ satellite cells (1.8% at baseline vs. 3.9, 7.5, and 13% at 125, 300, and 600 mg doses, P < 0.005). The expression of activated Notch, examined only in the 300-mg group (baseline, 2.3 vs. 9.0% after treatment, P < 0.005), increased in satellite cells after testosterone treatment. The expression of myogenin (baseline, 6.2 vs. 20.7% after treatment, P < 0.005), examined only in the 300-mg group, increased significantly in muscle fiber nuclei after testosterone treatment, but Numb expression did not change. CONCLUSIONS: Older men respond to graded doses of testosterone with a dose-dependent increase in muscle fiber CSA and satellite cell number. Testosterone-induced skeletal muscle hypertrophy in older men is associated with increased satellite cell replication and activation.

Concurrent cerebral american trypanosomiasis and toxoplasmosis in a patient with AIDS.

We report a case of concurrent cerebral infection with Trypanosoma cruzi and Toxoplasma gondii in a patient with acquired immunodeficiency syndrome (AIDS). A 22-year-old El Salvadoran man initially improved during receipt of antitoxoplasmosis therapy, but he had rapidly progressive hemiplegia. Magnetic resonance imaging showed an abnormal finding in the left internal capsule, and cytological analysis of cerebrospinal fluid revealed T. cruzi trypomastigotes. Despite prompt therapy with nifurtimox, the patient's mental status declined, and he died of nosocomial complications. Although infrequent, T. cruzi infection should be considered in the differential diagnosis of brain lesions in patients with AIDS from regions of endemicity.

Acute chagas' disease presenting with a suprasellar mass and panhypopituitarism.

Although intrinsic pituitary lesions are the most common cause of hypopituitarism, suprasellar masses can produce similar symptoms. The differential diagnosis of a suprasellar mass includes cystic lesions, tumors, granulomatous disease, and infection. The etiology is not always obvious, and despite extensive work-up, may remain elusive. A 28-year-old Mexican man presented with complaints of headache and weakness for two weeks duration. He became increasingly lethargic and an MRI revealed a two centimeter suprasellar mass. Testing of the hypothalamic-pituitary axis suggested panhypopituitarism. He was prescribed treatment with hydrocortisone, DDAVP, and levothyroxine. Open craniotomy and biopsy of the hypothalamus revealed marked inflammation with plasma cells, histiocytes, and small lymphocytes. Light microscopy revealed macrophage-contained leishmania-like organisms although results were not immediately available. Pathological data was consistent with acute infection by Trypanasoma cruzi. Despite supportive efforts, the patient expired two months after presentation. This case illustrates the difficulty of diagnosing and the potential rapid mortality of a suprasellar mass. Because of the wide consideration of etiologies, a tissue diagnosis is needed. However, as this case illustrates, a definitive tissue diagnosis is not always possible, even following biopsy during open craniotomy.

Coincident choroid plexus carcinoma and adrenocortical carcinoma with elevated p53 expression: a case report of an 18-month-old boy with no family history of cancer.

We describe a young patient with no known family history of cancer who presented at 18 months with 2 advanced primary tumors, choroid plexus carcinoma and adrenal cortical carcinoma. Immunohistochemical studies demonstrated high levels of nuclear p53 protein expression in both tumors, as well as in the adjacent normal-appearing adrenal cortical cell nuclei of the adrenal gland. The immunohistologic distribution of elevated p53 expression suggests that this individual has a de novo germline mutation affecting p53 gene expression.

New systems for delivery of drugs to the brain in neurological disease.

The restricted or regulated entry of most blood-borne substances into the brain has been recognised for more than a century. The blood-brain barrier (BBB)-shielding function provided by endothelial cells is important in the treatment of neurological diseases because this exclusion of foreign substances also restricts entry of many potentially therapeutic agents into the brain. The recent identification of several neuroactive proteins of potential therapeutic value has highlighted the crucial need for effective and safe transcapillary delivery methods to the brain. One promising method is delivery through brain capillaries by augmentation of pinocytotic vesicles delivery systems that use this cellular mechanism are in development. Recent investigations in animal models show that large molecules of neurotherapeutic potential can be conjugated to peptidomimetic ligands, which bind to selected peptide receptors, and are then internalised and transported in small vesicles across the cytoplasmic brain capillary barrier. These conjugates have been shown to remain functionally active and effective in animal models of neurological disease.