Neither lymphotoxin alpha nor lymphotoxin beta receptor expression is required for biogenesis of lymphoid aggregates or differentiation of natural killer cells in the pregnant mouse uterus

Gene ablation studies in mice indicate that lymphotoxin (LT)alpha, LTbeta and LTbetaR are essential for the genesis of lymph nodes (LN), normal structural development of peripheral lymphoid tissues and the differentiation of natural killer (NK) cells. LTbetaR binds to the heterotrimeric cytokines LTalpha1beta2 and LIGHT. LTs also regulate stromal cell expression of lymphocyte homing chemokines. Uterine decidualization in normal (+/+) mice is accompanied by the appearance and maturation of large numbers of uterine NK (uNK) cells that differentiate from precursors mobilized to the uterus from secondary lymphoid tissues. uNK cells accumulate in a transient, lymphocyte-rich region known as the metrial gland or, more recently, the mesometrial lymphoid aggregrate of pregnancy (MLAp). To determine if LTs contribute to development of the MLAp, and to the differentiation and/or localization of uNK cells, a histological study was undertaken of implantation sites from LTalpha null, LTbetaR null and gestation day-matched, normal mice. Implantation sites from the gene-ablated mice contained abundant numbers of uNK cells that localized appropriately. This indicates that the stromally derived molecules supporting NK cell differentiation in the uterus differ from those used in secondary lymphoid organs.     

β-Adrenergic receptor coupled-adenylate cyclase of human fat cell ghosts

Summary The effects of beta-adrenergic agonists such as isoproterenol, norepinephrine and epinephrine upon the adenylate cyclase activity of human fat cell ghosts were tested, each alone and in combination with the beta-blocking agent propranolol. Saturating concentrations of these agents showed a 2–6.5-fold increase of enzyme activity without addition of any artificial cofactors. Isoproterenol was more potent in stimulating the enzyme system than epinephrine and nor-epinephrine. Propranolol caused a dose-dependent rightward shift of the log-dose response curve of these beta-adrenergic agonists. The assay of human fat cell adenylate cyclase in vitro may provide a simple and convenient assay system for the screening of beta-adrenergic drugs of potential therapeutic importance.Herrn Prof. Dr. Dr. h.c. G. Schettler zum 60. Geburtstag gewidmet     

Cyst-like cerebral lesions in tuberous sclerosis

Known brain manifestations of tuberous sclerosis (TSC) are cortical sclerotic tubera, giant cell astrocytomas, subependymal calcified nodules in the lateral walls of the lateral ventricles, and white matter heterotopias. In addition, small cyst-like lesions in the white matter have been described. We report on three TSC patients with hitherto undescribed large cyst-like cerebral lesions in subcortical and white matter locations. We emphasize that cystoid brain degeneration is a rare but typical cerebral manifestation of TSC and suggest that, in patients with such lesions, TSC should be taken into consideration.     

Recombinant dissection of myosin heavy chain of Toxocara canis shows strong clustering of antigenic regions

Myosins from nematode parasites elicit strong humoral and cellular immune responses and have been investigated as vaccine candidates. In this study we cloned and sequenced a cDNA coding for myosin heavy chain from Toxocara canis, a nematode parasite of canids which may also infect humans and cause various unspecific symptoms. To determine the major antigenic regions the myosin heavy chain was systematically dissected into ten overlapping recombinant fusion polypeptides which were purified by metal chelate chromatography. Single fragments were then tested for their IgG reactivity in sera from toxocarosis patients and healthy probands. Two regions, one region at the mid to carboxy-terminal end of the head domain and one region in the rod domain, were identified as major antigens, which in combination were positive with 86% of the sera. The other domains were less reactive. This shows that the patients' IgG reactivity was not directed evenly against all parts of the molecule, but was rather clustered in few regions.     

Interinstitutional variations of sensitometric curves of radiographic dosimetric films

Depth and field size dependence of the sensitometric curves of radiographic films have been studied by various groups. Limited information is, however, available on the magnitude of the variations in sensitometric curves applied in clinical practice in different institutions. In this study we assessed in a systematic way the effect of the various parameters influencing the shape of the sensitometric curve: batch composition, irradiation conditions, film processing, and film scanning. Two types of film, Kodak X-Omat V and CEA TVS, were irradiated, processed, and analyzed in three different institutions. The interinstitutional variation of the sensitometric curves, expressed as the OD variation at 50 cGy, can be up to 32% and is mainly caused by differences in film processing and to a lesser degree to differences in batch composition, film scanning, and irradiation conditions. For the Kodak films, the average OD difference at 50 cGy between the three institutions is 17% as a result of differences in batch composition and 25% due to differences in processing conditions. For the CEA films these data are 6% and 24%, respectively. The long-term variation of the sensitometric curves of KODAK films in one institution was smaller than the differences in batch composition between the three institutions. The sensitometric curves of CEA films showed in one institution a large variation with time; the shape gradually varied from sigmoidal to quasilinear. By using relative OD values rather than absolute OD values, variations in sensitometric curves of KODAK films can be reduced to 2%. Consequently, one sensitometric curve is sufficient to derive relative dose values. If processing conditions are well controlled, it might therefore be advantageous to determine the absolute OD only at one or two dose values, in combination with a "universal" relative sensitometric curve.     

The Etruscan skulls of the Rostock anatomical collection — How do they compare with the skeletal findings of the first thousand years B.C.?

Seven Etruscan skulls were found in Corneto Tarquinia in the years 1881 and 1882 and were given as present to Rostock's anatomical collection in 1882. The origin of the Etruscans who were contemporary with the Celts is not yet clear; according to Herodotus they had emigrated from Lydia in Asia Minor to Italy. To fit the Etruscan skulls into an ethnological grid they were compared with skeletal remains of the first thousand years B.C. E. All skulls were found to be male; their age ranged from 20 to 60 years, with an average age of about thirty. A comparison of the median sagittal outlines of the Etruscan skulls and the contemporary Hallstatt-Celtic skulls from North Bavaria showed that the former were shorter and lower. Maximum skull length, minimum frontal breadth, ear bregma height, bizygomatical breadth and orbital breadth of the Etruscan skulls were statistically significantly less developed compared to Hallstatt-Celtics from North Bavaria. In comparison to other contemporary skeletal remains the Etruscan skulls had no similarities in common with Hallstatt-Celtic skulls from North Bavaria and Baden-Württemberg but rather with Hallstatt-Celtic skulls from Hallstatt in Austria. Compared to chronologically adjacent skeletal remains the Etruscan skulls did not show similarities with Early Bronze Age skulls from Moravia but with Latène-Celtic skulls from Manching in South Bavaria. Due to the similarities of the Etruscan skulls with some Celtic skulls from South Bavaria and Austria, it seems more likely that the Etruscans were original inhabitants of Etruria than immigrants.     

Mild phenotype in two unrelated patients with a partial deletion of 21q22.2-q22.3 defined by FISH and molecular studies

We describe two unrelated patients with cytogenetically visible deletions of 21q22.2-q22.3 and mild phenotypes. Both patients presented minor dysmorphic features including thin marfanoid build, facial asymmetry, downward-slanting palpebral fissures, depressed nasal bridge, small nose with bulbous tip, and mild mental retardation (MR). FISH and molecular studies indicated common deleted areas but different breakpoints. In patient 1, the breakpoint was fine mapped to a 5.2 kb interval between exon 5 and exon 8 of the ETS2 gene. The subtelomeric FISH probe was absent on one homologue 21 indicating a terminal deletion spanning approximately 7.9 Mb in size. In patient 2, the proximal breakpoint was determined to be 300-700 kb distal to ETS2, and the distal breakpoint 2.5-0.3 Mb from the 21q telomere, indicating an interstitial deletion sized approximately 4.7-7.3 Mb. The 21q- syndrome is rare and typically associated with a severe phenotype, but different outcomes depending on the size and location of the deleted area have been reported. Our data show that monosomy 21q of the area distal to the ETS2 gene, representing the terminal 7.9 Mb of 21q, may result in mild phenotypes comprising facial anomalies, thin marfanoid build, and mild MR, with or without signs of holoprosencephaly.     

Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus

The availability of highly active antiretroviral therapies (HAART) has not eliminated HIV-1 infection of the central nervous system (CNS) or the occurrence of HIV-associated neurological problems. Thus, the neurobiology of HIV-1 is still an important issue. Here, we review key features of HIV-1-cell interactions in the CNS and their contributions to persistence and pathogenicity of HIV-1 in the CNS. HIV-1 invades the brain very soon after systemic infection. Various mechanisms have been proposed for HIV-1 entry into the CNS. The most favored hypothesis is the migration of infected cells across the blood-brain barrier ("Trojan horse" hypothesis). Virus production in the CNS is not apparent before the onset of AIDS, indicating that HIV-1 replication in the CNS is successfully controlled in pre-AIDS. Brain macrophages and microglia cells are the chief producers of HIV-1 in brains of individuals with AIDS. HIV-1 enters these cells by the CD4 receptor and mainly the CCR5 coreceptor. Various in vivo and cell culture studies indicate that cells of neuroectodermal origin, particularly astrocytes, may also be infected by HIV-1. These cells restrict virus production and serve as reservoirs for HIV-1. A limited number of studies suggest restricted infection of oligodendrocytes and neurons, although infection of these cells is still controversial. Entry of HIV-1 into neuroectodermal cells is independent of the CD4 receptor, and a number of different cell-surface molecules have been implicated as alternate receptors of HIV-1. HIV-1-associated injury of the CNS is believed to be caused by numerous soluble factors released by glial cells as a consequence of HIV-1 infection. These include both viral and cellular factors. Some of these factors can directly induce neuronal injury and death by interacting with receptors on neuronal membranes (neurotoxic factors). Others can activate uninfected cells to produce inflammatory and neurotoxic factors and/or promote infiltration of monocytes and T-lymphocytes, thus amplifying the deleterious effects of HIV-1 infection. CNS responses to HIV-1 infection also include mechanisms that enhance neuronal survival and strengthen crucial neuronal support functions. Future challenges will be to develop strategies to prevent HIV-1 spread in the brain, bolster intrinsic defense mechanisms of the brain and to elucidate the impact of long-term persistence of HIV-1 on CNS functions in individuals without AIDS.     

Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses

Five TLRs are thought to play an important role in antiviral immunity, sensing viral products and inducing IFN-alpha/beta and -lambda. Surprisingly, patients with a defect of IRAK-4, a critical kinase downstream from TLRs, are resistant to common viruses. We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. In contrast, IFN-alpha/beta and -lambda were induced normally by TLR-3 and TLR-4 agonists. Moreover, IFN-beta and -lambda were normally induced by TLR-3 agonists and viruses in IRAK-4-deficient fibroblasts. We further show that IFN-alpha/beta and -lambda production in response to 9 of 11 viruses tested was normal or weakly affected in IRAK-4-deficient blood cells. Thus, IRAK-4-deficient patients may control viral infections by TLR-3- and TLR-4-dependent and/or TLR-independent production of IFNs. The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent and paradoxically redundant for protective immunity to most viruses in humans.