The association between daytime sleepiness and sleep-disordered breathing in NREM and REM sleep

BACKGROUND: Daytime sleepiness is common in patients with sleep-disordered breathing. Although respiratory events during sleep are associated with the occurrence of daytime sleepiness, the differential impact of these events during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep on daytime sleepiness has not been well characterized. STUDY OBJECTIVES: To determine the effect of respiratory events during REM sleep and NREM sleep on daytime sleepiness, as assessed by the multiple sleep latency test (MSLT). DESIGN: Cross-sectional study. SETTING: University-based sleep disorders laboratory. PARTICIPANTS: Patients referred for polysomnography and daytime MSLT (n=1,821). INTERVENTIONS: N/A MEASUREMENTS AND RESULTS: The study sample was initially divided into quartiles based on the level of the apnea-hypopnea index (AHI) during NREM sleep. Within the first NREM-AHI quartile (NREM-AHI < 8.3 events/hr), the association between REM-related respiratory events and daytime sleepiness was examined using the method of Kaplan-Meier analysis and Cox proportional hazards regression. After adjusting for age, gender, body mass index, and the duration of NREM and REM sleep, REM-AHI was not associated with daytime sleepiness (Relative Risk: 1.01; 95%CI: 0.94-1.10). Similarly, no significant association was observed between REM-AHI and the MSLT in patients within the second through fourth NREM-AHI quartiles. In contrast, increasing severity of disordered breathing during NREM sleep was associated with daytime sleepiness. For a 10-point increase in NREM-AHI, the adjusted relative risks for daytime sleepiness in the second through fourth NREM-AHI quartile were 1.21 (95%CI: 1.01-1.46), 1.20 (95%CI: 1.05-1.37), and 1.10 (95%CI: 1.04-1.16), respectively. CONCLUSION: Sleep-disordered breathing during NREM sleep, but not REM sleep, is associated with increased risk of daytime sleepiness.     

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Recurrent genetic aberrations in thymoma and thymic carcinoma

Apart from single reported aberrant karyotypes, genetic alterations in thymic epithelial neoplasms have not been investigated so far. In this study, 12 World Health Organization classification type A thymomas (medullary thymomas), 16 type B3 thymomas (well-differentiated thymic carcinomas), and nine type C thymomas, all of them primary thymic squamous cell carcinomas, were analyzed by comparative genomic hybridization and fluorescence in situ hybridization. With the exception of one single case, type A thymomas did not reveal chromosomal gains or losses in comparative genomic hybridization. In contrast, all type B3 thymomas showed chromosomal imbalances, with gain of 1q, loss of chromosome 6, and loss of 13q occurring in 11 (69%), six (38%), and five (31%) of 16 cases, respectively. In primary thymic squamous cell carcinoma, the most frequent chromosomal losses were observed for 16q (six of nine cases, 67%), 6 (4 of 9, 44%), and 3p and 17p (three of nine each, 33%), whereas recurrent gains of chromosomal material were gains of 1q (5 of 9, 56%), 17q, and 18 (three of nine each, 33%). This study shows that the distinct histological thymoma types A and B3 exhibit distinct genetic phenotypes, whereas type B3 thymoma and primary thymic squamous cell carcinoma partially share genetic aberrations. In addition to the possible tumorigenic role, the deletion in type B3 thymoma of chromosome 6, harboring the HLA locus, might play a role in the pathogenesis of paraneoplastic autoimmunity characteristic of thymoma.     

Localization of simian immunodeficiency virus in the central nervous system of rhesus monkeys.

Simian immunodeficiency virus (SIV), like the human immunodeficiency virus (HIV), is a lentivirus that is both immunosuppressive and neurovirulent. Rhesus macaques (Macaca mulatta) inoculated with SIV often develop a giant cell encephalitis similar to that seen in humans infected with HIV. The authors examined SIV expression by immunohistochemistry and RNA in situ hybridization in the cerebrum, cerebellum, choroid plexus, and spinal cord from five macaques with and two macaques without giant cell encephalitis. Selected portions of the central nervous system (CNS) also were examined by electron microscopy. Simian immunodeficiency virus was detected in the CNS of all seven monkeys whether or not they had giant cell encephalitis. Both SIV antigen and RNA were present in all levels of the CNS examined. Macrophage/giant cell lesions always contained viral RNA and antigen and were the only sites where viral particles were detected by electron microscopy. However, SIV antigen and RNA also were commonly associated with small vessels, the choroid plexus, and meninges; these were the only locations where virus was detected in animals without giant cell encephalitis. Immunophenotyping showed that the cellular infiltrates consisted primarily of monocyte/macrophages and occasional CD8-positive T cells. Macrophages and T cells also were present in the stroma of the choroid plexus and were intimately associated with vessels in the CNS of SIV-infected but not uninfected macaques. Simian immunodeficiency virus infection of the macaque CNS provides an excellent model for studying the pathogenesis, treatment, and prevention of HIV-1-encephalitis.     

Regulation of thrombin-induced mast cell degranulation by zinc and manganese

This study was undertaken to determine whether zinc, manganese and copper could regulate the thrombin-induced secretion of the granule-associated mediator, beta-hexosaminidase, from mast cells derived from mouse bone marrow. Exposure of thrombin to copper (2-100 microM) does not affect the enzyme-induced release of beta-hexosaminidase from the mast cells. Zinc at 50 microM reduced the degranulation of calcium ionophore A23187 activated cells by 75% and that of immunological challenge or thrombin by 30% each. Exposure of the thrombin to incremental concentrations of manganese (2-100 microM) prevents its degranulation activity in a dose-related fashion. 75% inhibition of the enzyme activity was achieved at 100 microM manganese. However, exposure of IgE sensitized or unsensitized cells to incremental concentrations of manganese (2-400 microM) prior to antigen or calcium ionophore A23187 stimulation, does not significantly affect the exocytosis of beta-hexosaminidase. The binding of purified human FITC-thrombin to E-mast cells was analyzed by fluorescence flow cytometry. All cells bound specifically the labelled thrombin. Pretreatment of the FITC-thrombin with 100 micron zinc or manganese had no effect on the binding of the labelled thrombin to the cells. It was assumed that manganese modulates either directly the thrombin activity or the substrate for the enzyme on the cell surface.     

Sarcoma of follicular dendritic cells in the dorsal mediastinum

Follicular dendritic cell sarcomas (FDCSs) are very rare and usually originate in lymph nodes. We report an exceedingly rare case with localization in the dorsal mediastinum and, for the first time, provide positron emission tomography (PET) data for this tumor. This report describes the case of a 76-year-old man with a clinically aggressive tumor in the dorsal mediastinum. Computed tomography scan revealed displacement of soft tissue and lymph nodes. PET showed that the tumor had a high proliferation rate. Investigation of the successfully removed tumor mass revealed reactivity of the tumor cells for follicular dendritic cell markers and desmosomes linking adjacent tumor cells at the ultrastructural level. Marked atypia, a high mitotic rate, and areas of coagulative necrosis were found. The tumor in our case revealed the typical features and thus was classified as FDCS. In contrast to previous reports in the literature, preoperative imaging, histology, and immunohistochemistry studies indicated at least an intermediate degree of malignancy. Nevertheless, the patient made a good postoperative recovery and remained apparently disease-free 2 years later.     

Charcot-Marie-Tooth neuropathy type 2 and P0 point mutations: two novel amino acid substitutions (Asp61Gly; Tyr119Cys) and a possible "hotspot" on Thr124Met

Mutations in the gene for the major protein component of peripheral nerve myelin, myelin protein zero (MPZ, P0), cause hereditary disorders of Schwann cell myelin such as Charcot-Marie-Tooth neuropathy type 1B (CMT1B), Dejerine-Sottas syndrome (DSS), and congenital hypomyelinating neuropathy (CHN). More recently, P0 mutations were identified in the axonal type of CMT neuropathy, CMT2, which is different from the demyelinating variants with respect to electroneurography and nerve pathology. We screened 49 patients with a clinical and histopathological diagnosis of CMT2 for mutations in the P0 gene. Three heterozygous single nucleotide changes were detected: two novel missense mutations, Asp61Gly and Tyr119Cys, and the known Thr124Met substitution, that has already been reported in several CMT patients from different European countries. Haplotype analysis for the P0 locus proved that our patients with the 124Met allele were not related to a cohort of patients with the same mutation, all of Belgian descent and all found to share a common ancestor. Our data suggest that P0 mutations account for a detectable proportion of CMT2 cases with virtually every patient harbouring a different mutation but recurrence of the Thr124Met amino acid substitution. The high frequency of this peculiar genotype in the European CMT population is presumably not only due to a founder effect but Thr124Met might constitute a mutation hotspot in the P0 gene as well.     

The myelin basic protein-specific T cell repertoire in (transgenic) Lewis rat/SCID mouse chimeras: preferential Vβ8.2 T cell receptor usage depends on an intact Lewis thymic microenvironment

In the Lewis rat, myelin basic protein (MBP)-specific, encephalitogenic T cells preferentially recognize sequence 68–88, and use the Vβ8.2 gene to encode their T cell receptors. To analyze the structural prerequisites for the development of the MBP-specific T cell repertoire, we reconstituted severe-combined immunodeficient (SCID) mice with fetal (embryonic day 15–16) Lewis rat lymphoid tissue, and then isolated MBP-specific T cell lines from the adult chimeras after immunization. Two types of chimera were constructed: SCID mice reconstituted with rat fetal liver cells only, allowing T cell maturation within a chimeric SCID thymus consisting of mouse thymic epithelium and rat interdigitating dendritic cells, and SCID mice reconstituted with rat fetal liver cells and rat fetal thymus grafts, allowing T cell maturation within the chimeric SCID and the intact Lewis rat thymic microenvironment. Without exception, the T cell lines isolated from MBP-immunized SCID chimeras were restricted by MHC class II of the Lewis rat (RT1.B¹), and none by I-A^d of the SCID mouse. Most of the T cell lines recognized the immunodominant MBP epitope 68–88. In striking contrast to intact Lewis rats, in SCID mice reconstituted by rat fetal liver only, MBP-specific T cell clones used a seemingly random repertoire of Vβ genes without a bias for Vβ8.2. In chimeras containing fetal Lewis liver plus fetal thymus grafted under the kidney capsule, however, dominant utilization of Vβ8.2 was restored. The migration of liver-derived stem cells through rat thymus grafts was documented by combining fetal tissues from wild-type and transgenic Lewis rats. The results confirm that the recognition of the immunodominant epitope 68–88 by MBP-specific encephalitogenic T cells is a genetically determined feature of the Lewis rat T cell repertoire. They further suggest that the formation of the repertoire requires T cell differentiation in a syngeneic thymic microenvironment.     

Parathyroid mitogenic activity in plasma from patients with familial multiple endocrine neoplasia type 1

Hyperplasia of the parathyroid glands is a central feature of familial multiple endocrine neoplasia type 1. We used cultured bovine parathyroid cells to test for mitogenic activity in plasma from patients with this disorder. Normal plasma stimulated [3H]thymidine incorporation, on the average, to the same extent as it was stimulated in a plasma-free control culture. This contrasted with the results of the tests with plasma from patients with familial multiple endocrine neoplasia type 1, in which parathyroid mitogenic activity increased 2400 percent over the control value (P less than 0.001). Plasma from these patients also stimulated the proliferation of bovine parathyroid cells in culture, whereas plasma from normal subjects inhibited it. Parathyroid mitogenic activity in plasma from the patients with familial multiple endocrine neoplasia type 1 was greater than that in plasma from patients with various other disorders, including sporadic primary hyperparathyroidism (with adenoma, hyperplasia, or cancer of the parathyroid), sporadic primary hypergastrinemia, sporadic pituitary tumor, familial hypocalciuric hypercalcemia, and multiple endocrine neoplasia type 2 (P less than 0.05). Parathyroid mitogenic activity in the plasma of patients with familial multiple endocrine neoplasia type 1 persisted for up to four years after total parathyroidectomy. The plasma also had far more mitogenic activity in cultures of parathyroid cells than did optimal concentrations of known growth factors or of any parathyroid secretagogue. This mitogenic activity had an apparent molecular weight of 50,000 to 55,000. We conclude that primary hyperparathyroidism in familial multiple endocrine neoplasia type 1 may have a humoral cause.