Periventricular heterotopia (PH) is a disorder characterized by neuronal nodules, ectopically positioned along the lateral ventricles of the cerebral cortex. Mutations in either of two human genes, Filamin A (FLNA) or ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2), cause PH (Fox et al. in 'Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia'. Neuron, 21, 1315-1325, 1998; Sheen et al. in 'Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex'. Nat. Genet., 36, 69-76, 2004). Recent studies have shown that mutations in mitogen-activated protein kinase kinase kinase-4 (Mekk4), an indirect interactor with FlnA, also lead to periventricular nodule formation in mice (Sarkisian et al. in 'MEKK4 signaling regulates filamin expression and neuronal migration'. Neuron, 52, 789-801, 2006). Here we show that neurons in post-mortem human PH brains migrated appropriately into the cortex, that periventricular nodules were primarily composed of later-born neurons, and that the neuroependyma was disrupted in all PH cases. As studied in the mouse, loss of FlnA or Big2 function in neural precursors impaired neuronal migration from the germinal zone, disrupted cell adhesion and compromised neuroepithelial integrity. Finally, the hydrocephalus with hop gait (hyh) mouse, which harbors a mutation in Napa [encoding N-ethylmaleimide-sensitive factor attachment protein alpha (alpha-SNAP)], also develops a progressive denudation of the neuroepithelium, leading to periventricular nodule formation. Previous studies have shown that Arfgef2 and Napa direct vesicle trafficking and fusion, whereas FlnA associates dynamically with the Golgi membranes during budding and trafficking of transport vesicles. Our current findings suggest that PH formation arises from a final common pathway involving disruption of vesicle trafficking, leading to impaired cell adhesion and loss of neuroependymal integrity.

Error rates on death certificates in Vermont are high and extend to ICD-10 coding, thereby affecting national mortality statistics. Surveillance and certifier education must expand beyond local and state efforts. Simplifying and standardizing underlying literal text for cause of death may improve accuracy, decrease coding errors, and improve national mortality statistics.

Each year in the United States, ∼3500 infants die of sleep-related infant deaths, including sudden infant death syndrome (SIDS) (International Classification of Diseases, 10th Revision [ICD-10] R95), ill-defined deaths (ICD-10 R99), and accidental suffocation and strangulation in bed (ICD-10 W75). After a substantial decline in sleep-related deaths in the 1990s, the overall death rate attributable to sleep-related infant deaths has remained stagnant since 2000, and disparities persist. The triple risk model proposes that SIDS occurs when an infant with intrinsic vulnerability (often manifested by impaired arousal, cardiorespiratory, and/or autonomic responses) undergoes an exogenous trigger event (eg, exposure to an unsafe sleeping environment) during a critical developmental period. The American Academy of Pediatrics recommends a safe sleep environment to reduce the risk of all sleep-related deaths. This includes supine positioning; use of a firm, noninclined sleep surface; room sharing without bed sharing; and avoidance of soft bedding and overheating. Additional recommendations for SIDS risk reduction include human milk feeding; avoidance of exposure to nicotine, alcohol, marijuana, opioids, and illicit drugs; routine immunization; and use of a pacifier. New recommendations are presented regarding noninclined sleep surfaces, short-term emergency sleep locations, use of cardboard boxes as a sleep location, bed sharing, substance use, home cardiorespiratory monitors, and tummy time. Additional information to assist parents, physicians, and nonphysician clinicians in assessing the risk of specific bed-sharing situations is also included. The recommendations and strength of evidence for each recommendation are included in this policy statement. The rationale for these recommendations is discussed in detail in the accompanying technical report.

Benign nerve sheath tumors include neurofibromas, schwannomas, and perineuriomas. In recent years, nerve sheath tumors showing discrete areas of more than one histologic type have been described. We have recently recognized tumors showing hybrid features of schwannoma and soft tissue perineurioma. To characterize the clinicopathologic and immunohistochemical features of these lesions, 42 cases received between 1994 and 2008 were retrieved from authors' consult and surgical pathology files. Clinical details and follow-up were obtained from referring pathologists. Hematoxylin and eosin-stained sections were reexamined, and immunohistochemistry was performed. On 10 cases, double labeling with epithelial membrane antigen (EMA) and S100 protein was performed. Twenty-two patients were female and 20 were male (mean age, 38 y; range: 2 to 85; 71% second to fifth decades). Most patients presented with a solitary painless nodule. The tumors arose in a wide distribution: 19 lower limb, 12 upper limb, 6 head and neck, 4 trunk, and 1 colon. None of the patients showed signs of neurofibromatosis. Tumor size ranged from 0.7 to 17.5 cm (mean, 3 cm). Most tumors involved superficial subcutis (11 also dermis); only 3 were intramuscular. Histologically, the tumors were usually well circumscribed but unencapsulated, and composed of spindle cells with plump, tapering nuclei, and palely eosinophilic cytoplasm with indistinct cell borders, arranged in a storiform, whorled, and/or lamellar architecture. Only 1 tumor showed infiltrative margins. One tumor showed a plexiform growth pattern. Antoni A and B zonation and hyaline vessels were absent. Six tumors showed focally myxoid stroma and 11 contained scattered cells with degenerative nuclear atypia. Mitoses ranged from 0 to 4 per 30 high power fields; 32 tumors had no mitoses. All tumors showed staining for S100 protein and EMA; 98% were positive for CD34, 84% for GFAP, and 80% for claudin-1. Fourteen tumors contained rare neurofilament protein-positive axons. Double staining for EMA and S100 protein revealed parallel layers of alternating S100 and EMA-positive cells with no coexpression of antigens by the same cells. Most tumors were composed of approximately 60% to 70% of Schwann cells and 30% to 40% of perineurial cells. After a mean follow-up of 24 months (range, 6 to 60 mo), 1 tumor recurred locally, after incomplete excision. Benign nerve sheath tumors showing predominantly schwannian cytomorphology and perineurioma-like architecture are composed of an admixture of both cell types. These tumors usually arise in the dermis and subcutis and occur over a wide age range and anatomic distribution. Degenerative nuclear atypia (akin to that seen in ancient schwannoma and atypical neurofibroma) is relatively common. Hybrid schwannoma/perineuriomas have no evident association with neurofibromatosis and rarely recur. The pathogenetic basis of the dual pattern of differentiation in these lesions remains poorly understood at this time.