The role of DC-SIGN and DC-SIGNR in HIV and SIV attachment, infection, and transmission.
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Animals↗
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DC-SIGN and DC-SIGNR bind ebola glycoproteins and enhance infection of macrophages and endothelial cells.
Ebola virus exhibits a broad cellular tropism in vitro. In humans and animal models, virus is found in most tissues and organs during the latter stages of infection. In contrast, a more restricted cell and tissue tropism is exhibited early in infection where macrophages, liver, lymph node, and spleen are major initial targets. This indicates that cellular factors other than the broadly expressed virus receptor(s) modulate Ebola virus tropism. Here we demonstrate that the C-type lectins DC-SIGN and DC-SIGNR avidly bind Ebola glycoproteins and greatly enhance transduction of primary cells by Ebola virus pseudotypes and infection by replication-competent Ebola virus. DC-SIGN and DC-SIGNR are expressed in several early targets for Ebola virus infection, including dendritic cells, alveolar macrophages, and sinusoidal endothelial cells in the liver and lymph node. While DC-SIGN and DC-SIGNR do not directly mediate Ebola virus entry, their pattern of expression in vivo and their ability to efficiently capture virus and to enhance infection indicate that these attachment factors can play an important role in Ebola transmission, tissue tropism, and pathogenesis.
Cell Adhesion Molecules↗
Fusion mediated by the HIV-1 envelope protein.
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Gene Products, env↗
The assembly of the HIV-1 env glycoprotein into dimers and tetramers.
The envelope (env) glycoprotein of human immunodeficiency virus 1 (HIV-1), initially synthesized as a precursor molecule termed gp160, is cleaved into two noncovalently associated subunits prior to delivery to the plasma membrane. We have studied the oligomeric structure of this protein using chemical cross-linking, velocity gradient sedimentation, and SDS-resistance. We find that gp160 forms stable homodimers after synthesis. After cleavage to gp120/gp41 the molecule becomes less stable to detergent solubilization and centrifugation but remains dimeric. Interactions between the 129 amino terminal residues in the ectodomains of adjoining gp41 subunits are both sufficient and necessary for assembly. In addition, tetramers composed of two dimers were also formed. Larger structures were not observed. The tetrameric paramyxovirus F protein, which has structural and functional similarities to the HIV-1 env protein, also forms a dimer of dimers.
Gene Products, env↗
Kallikrein localization in rat brain by immunohistochemistry.
Using an antibody-peroxidase bridge technique with either polyclonal antibodies or a specific monoclonal antibody, immunoreactive kallikrein was localized in all three lobes of the pituitary, in ependymal cells lining the third ventricle, and in cell bodies of the following hypothalamic neuronal nuclei: supraoptic, arcuate, paraventricular and ventromedial.
Animals↗
HIV-1 coreceptors and their inhibitors.
Entry of human immunodeficiency virus (HIV) into target cells is mediated by the viral Envelope glycoprotein (Env) and its coordinated interaction with a receptor (CD4) and a coreceptor (usually the chemokine receptors CCR5 or CXCR4). This review describes the identification of chemokine receptors as coreceptors for HIV-1 Env-mediated fusion, the determinants of chemokine receptor usage, and the impact of nonfunctional chemokine receptor alleles on HIV-1 resistance and disease progression. Due to the important role of chemokine receptors in HIV-1 entry, inhibitors of these coreceptors are good candidates for blocking entry and development of antiretroviral therapies. We discuss the different CCR5- and CXCR4-based antiretroviral drugs that have been developed thus far, highlighting the most promising drug candidates. Resistance to these coreceptor inhibitors as well as the impact of these drugs on clinical monitoring and treatment are also discussed.
Antiviral Agents↗
HIV-1 entry and its inhibition.
Entry of HIV-1 virions into cells is a complex and dynamic process carried out by envelope (Env) glycoproteins on the surface of the virion that promote the thermodynamically unfavorable fusion of highly stable viral and target cell membranes. Insight gained from studies of the mechanism of viral entry allowed insight into the design of novel inhibitors of HIV-1 entry, several of which are now in clinical trials. This review highlights the mechanism by which viral and cellular proteins mediate entry of HIV-1 into permissive cells, with an emphasis on targeting this process in the design of novel therapies that target distinct steps of the entry process, including antagonizing receptor binding events and blocking conformational changes intimately involved in membrane fusion.
Anti-HIV Agents↗
Electrical stimulation of the central gray for pain relief in human: autopsy data.
Anatomopathological studies are reported of 5 brains in which electrical stimulation of the periventricular--periaqueductal gray was applied for the treatment of chronic pain. It was found that the recommended target was reached in 4 cases (only 1 case out of 5 was successful as far as a pain relief is concerned). PtIr electrodes caused little tissue reaction. The chronic stimulation had not provoked lesions observable by light-microscopy.
Brain↗
(+/-)-1-(2,5-Dimethoxy-4-ethylthiophenyl)-2-aminopropane (ALEPH-2), a novel putative anxiolytic agent lacking affinity for benzodiazepine sites and serotonin-1A receptors.
Serotonergic behavioral responses, effects on motor activity and core temperature, and binding properties of the novel putative anxiolytic amphetamine derivative (+/-)1-(2,5-dimethoxy-4-ethylthio-phenyl)-2-aminopropane (ALEPH-2), were examined in rodents in order to elucidate the mechanism underlying its anxiolytic-like effect. After peripheral administration in rats, ALEPH-2 induced some symptoms of the serotonergic syndrome, e.g. forepaw treading and flat body posture. Additionally, a decrease in motor activity was observed. No significant effects on the number of head shakes were observed after injection, although high inter-subject variability was noted. Higher doses of ALEPH-2, in the range exhibiting anxiolytic properties (4mg/kg), elicited significant hypothermia in mice. The affinity of the drug for 5-HT2A/2C receptors ([3H]ketanserin sites) was in the nanomolar range (Ki = 173 nM), whereas for 5-HT1A, benzodiazepine sites, and GABAA receptors, the affinity was micromolar of lower. Based on these results the mechanism of action and the anxiolytic-like properties of ALEPH-2 are discussed.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
R(-)-2,5-dimethoxy-4-77 bromoamphetamine [77Br-R(-)DOB]: a novel radioligand which labels a 5-HT binding site subtype.
R(-)-2,5-Dimethoxy-4-77Br-amphetamine [77Br-R(-)DOB], a radioligand of high specific activity (1500 +/- 200 Ci/mmol), was used to label membrane-associated recognition sites in rat brain. 77Br-R(-)DOB sites were of high affinity (KD = 0.19 nM) but low density (Bmax = 0.32 pmol/g tissue) in rat brain preparations. Competition experiments show that both 5-hydroxytryptamine (5-HT) and 5-HT2 antagonists display nanomolar potency for these sites. We conclude that 77Br-R(-)DOB labels 5-HT recognition sites in rat brain which do not fit into current classifications of 5-HT binding subtypes. This finding may be of aid in deciphering the mechanism of action of hallucinogens in man.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
Technetium-99m hexamethylpropylene amine oxime single photon emission tomography in febrile convulsions.
We report our initial experience with technetium-99m hexamethyl propylene amine oxime (99mTC-HMPAO) brain single photon emission tomography (SPET) in the investigation of 19 children presenting with febrile convulsions. Two patients with complex febrile convulsions showed focal SPET lesions contralateral to the neurological deficit. However, in 9 out of 17 patients with simple febrile convulsions, focally disturbed perfusion was shown. In 4 out of 6 patients with electroencephalogram (EEG) abnormalities on admittance, SPET revealed at least 2 focal lesions. The temporofrontal region was the one most commonly involved. The SPET findings presented here also suggest a temporal relationship with the febrile convulsions, with markedly fewer lesions if examined after 12 days. In our initial experience, perfusion SPET did not show any particular pattern helpful in the differential diagnosis of the child presenting with febrile convulsions. Physiopathologically, our findings may support the hypothesis that brain tissue is regionally more vulnerable to fever, in patients presenting with febrile convulsions.
Brain↗
Distribution of glycoconjugates in the optic vesicle and optic cup.
Lectin histochemical methods and immunohistochemical techniques have been utilized to investigate and partially characterize glycoconjugates in the developing eye. Peanut-lectin-binding sites associated with radial glial cells were found in the diencephalon. In the optic primordia, binding sites associated with radial glia were masked by terminal sialic acid, and only reacted with peanut lectin when pretreated with sialidase. This finding indicates that glycoconjugates associated with diencephalic radial glia contain terminal galactose-beta-(1----3)N-acetyl galactosamine, but glycoconjugates associated with radial glia in the optic primordia contain sialic acid----galactose-beta(1----3)N-acetyl galactosamine. The selective distribution of galactose, N-acetyl galactosamine and fucose associated with radial glial cells has also been demonstrated. We postulate that these distributions mediate the shaping of the developing eye.
Animals↗
Further evidence for myelinated as well as unmyelinated fibre damage in a rat model of neuropathic pain.
A mononeuropathy, produced by ligation of the sciatic nerve in rats, has recently been proposed as an animal model of experimental pain and pain-related disorders (hyperalgesia and allodynia). We investigated quantitatively the morphological changes in myelinated and unmyelinated fibres of the sciatic nerves 2 weeks after ligation in rats exhibiting allodynia to thermal stimulation. There was a marked reduction in the number of large myelinated fibres distal to the ligature (711 +/- 34 compared with 5315 +/- 230 in normal nerves). We also found a significant loss of small myelinated fibres (2429 +/- 109 compared with 3197 +/- 308 in normal nerves), the remaining fibres of this type showing pathological properties. Finally, ultrastructural evidence of damage to unmyelinated fibres was found. The typical pattern of large clusters of normal unmyelinated axons was no longer present within most regions of the nerve. There was a significant reduction in the size of the unmyelinated fibres (0.41 micron +/- 0.15 compared with 0.71 micron +/- 0.08 in normal nerves), together with a twofold increase in their number per cluster. Hypotheses about the mechanism of thermal allodynia in this pain model therefore must take into account the fact that all fibre classes show pathological changes.
Animals↗
The price of better diagnostic accuracy in suspected appendicitis in Jerusalem.
We studied changes in diagnostic accuracy and in perforation rates in cases of suspected appendicitis at two major Jerusalem hospitals. In females, a major improvement in accuracy was observed over the past decade which was not accompanied by higher perforation rates. In males, on the other hand, the reduction in the rate of negative appendectomies was accomplished at the expense of a large increase in perforations. At the end of the decade of observation, diagnostic accuracy in males was still far better than for females, but the perforation rate in males had become worse than the rate for females. We conclude from our work and that of others that at high baseline negative appendectomy rates much improvement is possible without causing higher perforation rates, whereas at relatively low negative appendectomy rates, further decreases will, perforce, cause more perforations, a poor trade-off in the opinion of most investigators.
Adolescent↗
A mesencephalic locked-in syndrome.
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Aged↗
Cerebral disseminated coagulation. An encephalitis-like syndrome in a boy with dissecting aortic aneurysm.
A boy was suspected of having meningoencephalitis probably of viral origin, although all microbiological, including virological, tests were negative. Postmortem examination revealed a dissecting aortic aneurysm and disseminated intravascular coagulation involving the central nervous system exclusively. The clinical evolution, the age of the patient, and the association of DAA with this cerebral disseminated coagulation is very unusual.
Adolescent↗
Wallenberg's syndrome caused by a craniopharyngioma "en plaque".
Wallenberg's syndrome is the clinical manifestation of the obliteration of arterial blood vessels supplying the dorsolateral part of the medulla oblongata, the posterior inferior cerebellar artery being involved in most cases. A patient is described in whom the typical features of Wallenberg's syndrome correlated with cystic necrosis in the perfusion area of the posterior inferior cerebellar artery. A craniopharyngioma spreading along the pons and involving the posterior inferior cerebellar artery, the basilar artery, and its branches was found to be responsible for the infarction of the dorsolateral medulla oblongata.
Calcinosis↗
Motor neuron rigidity. An electrophysiological, pharmacological and pathological study.
A 28-year-old male with generalized muscle stiffness and widespread muscle twitching is described. Continuous electrical activity was present at rest and could be abolished only by succinylcholine, curare, and block of the distal part of the peripheral nerve. Muscle biopsy revealed mild myopathic changes. In addition glycogen depletion was found in muscle fibres which were type IIb in one region of the biopsy and type I in another. With carbamazepine treatment marked improvement occurred both clinically and electromyographically. It is concluded that the abnormal electrical activity originated in the terminal branches of the peripheral motor nerve and that this activity was confined to muscle fibres belonging to single motor unit territories.
Adult↗