Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurons may be particularly sensitive to disruptions in transcription factor trafficking. Survival and injury signals must traverse dendrites or axons, in addition to soma, to affect nuclear transcriptional responses. Transcription factors exhibit continued nucleocytoplasmic shuttling; the predominant localization is regulated by binding to anchoring proteins that mask nuclear localization/export signals and/or target the factor for degradation. Two functional groups of karyopherins, importins and exportins, mediate RanGTPase-dependent transport through the nuclear pore. A growing number of recent studies, in Alzheimer, Parkinson, and Lewy body diseases, amyotrophic lateral sclerosis, and human immunodeficiency virus encephalitis, implicate aberrant cytoplasmic localization of transcription factors and their regulatory kinases in degenerating neurons. Potential mechanisms include impaired nuclear import, enhanced export, suppression of degradation, and sequestration in protein aggregates or organelles and may reflect unmasking of alternative cytoplasmic functions, both physiologic and pathologic. Some "nuclear" factors also function in mitochondria, and importins are also involved in axonal protein trafficking. Detrimental consequences of a decreased nuclear to cytoplasmic balance include suppression of neuroprotective transcription mediated by cAMP- and electrophile/antioxidant-response elements and gain of toxic cytoplasmic effects. Studying the pathophysiologic mechanisms regulating transcription factor localization should facilitate strategies to bypass deficits and restore adaptive neuroprotective transcriptional responses.
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PMID:Location, location, location: altered transcription factor trafficking in neurodegeneration. 1791 81

The primate lentiviral vector system based on human immunodeficiency virus type 1 (HIV-1) has been used for a wide range of gene therapy trials in animal models. Axonal transport in the retrograde direction, which is observed with some viral vectors, confers a considerable advantage to gene transfer into neuronal cell bodies that are localized in regions remote from the injection site of the vectors. However, retrograde axonal transport of the HIV-1-based lentiviral vector pseudotyped with vesicular stomatitis virus glycoprotein is reported to be inefficient. In the present study, we developed an efficient gene transfer system through retrograde transport in the brain with the HIV-1-based vector pseudotyped with rabies virus glycoprotein (RV-G). Injection of the RV-G-pseudotyped HIV-1 vector into the dorsal striatum of mice yielded an increase in gene transfer into neuronal populations in the cerebral cortex, thalamus, and ventral midbrain, each of which innervates the striatum. In addition, injection of the RV-G-pseudotyped vector into the monkey striatum (putamen) resulted in highly efficient transfer into neurons in the ventral midbrain (nigrostriatal dopamine neurons). Our results indicate that pseudotyping of the HIV-1 vector with RV-G enhances the efficiency of gene transfer through retrograde axonal transport in both mouse and monkey brains. This primate lentiviral vector system will provide a powerful approach to gene therapy for neurological and neurodegenerative diseases by means of enhanced retrograde transport.
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PMID:Efficient gene transfer via retrograde transport in rodent and primate brains using a human immunodeficiency virus type 1-based vector pseudotyped with rabies virus glycoprotein. 1794 73

Human immunodeficiency virus-associated distal-symmetric neuropathy (HIV-DSP) is the most common neurological complication of HIV infection. The pathophysiology of HIV-DSP is poorly understood and no treatment is available for this entity. The dorsal root ganglia (DRG) are the principal sites of neuronal damage and are associated with reactive mononuclear phagocytes as well as HIV-infected macrophages. To determine the role of HIV-infected macrophages in the pathogenesis of HIV-DSP, we developed a technique for culturing human DRG's. When the dissociated DRG neurons were exposed to supernatants from macrophages infected with CXCR4 or CCR5 tropic HIV-1 strains axonal retraction was observed without neuronal cell death but there was mitochondrial dysfunction in the neuronal cell body. Even though CXCR4 and CCR5 were expressed on the DRG neurons, the effects were independent of these receptors. Antioxidants rescued the neuronal cell body but not the axon from the toxic effects of the culture supernatants. Further, peripheral nerves of HIV-infected patients obtained at autopsy did not show evidence of increased oxidative stress. These observations suggest a differential effect on the axon and cell body. Different mechanisms of injury may be operative in these two structures.
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PMID:Differential effects of HIV infected macrophages on dorsal root ganglia neurons and axons. 1817 40

Human immunodeficiency virus encephalitis causes dementia in acquired immune deficiency syndrome patients. Using proteomic analysis of postmortem cerebrospinal fluid (CSF) and brain tissue from the simian immunodeficiency virus primate model, we demonstrate here a specific increase in YKL-40 that was tightly associated with lentiviral encephalitis. Longitudinal analysis of CSF from simian immunodeficiency virus-infected pigtailed macaques showed an increase in YKL-40 concentration 2 to 8 weeks before death from encephalitis. This increase in YKL-40 correlated with an increase in CSF viral load; it may therefore represent a biomarker for the development of encephalitis. Analysis of banked human CSF from human immunodeficiency virus-infected patients also demonstrated a correlation between YKL-40 concentration and CSF viral load. In vitro studies demonstrated increased YKL-40 expression and secretion by macrophages and microglia but not by neurons or astrocytes. We found that YKL40 displaced extracellular matrix-bound basic fibroblast growth factor (bFGF) as well as inhibited the mitogenic activity of both fibroblast growth factor receptor 1-expressing BaF3 cells and bFGF-induced axonal branching in hippocampal cultures. Taken together, these findings demonstrate that during lentiviral encephalitis, YKL-40 may interfere with the biological activity of bFGF and potentially of other heparin-binding growth factors and chemokines that can affect neuronal function or survival.
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PMID:YKL-40, a marker of simian immunodeficiency virus encephalitis, modulates the biological activity of basic fibroblast growth factor. 1858 23

We report here a case of progressive tumefactive inflammatory central nervous system (CNS) demyelinating disease in a human immunodeficiency virus (HIV)-seropositive patient treated with highly active antiretroviral therapy (HAART). Biopsy revealed diffuse macrophage and perivascular T-lymphocytic infiltrates with severe demyelination and relative axonal sparing. The disease progressed in a centrifugal fashion, to involve bihemispheric cerebral white matter, with subsequent central necrotic changes and atrophy. Treatment with HAART was discontinued, and inflammatory disease was treated with subcutaneous interferon (IFN)beta-1a. Massive brain edema was controlled with courses of intravenous corticosteroids. Following fulminant monophasic disease, the patient stabilized with no evidence of disease progression over long-term follow up. We propose that immune response reconstituted by HAART can unmask an autoimmune response in susceptible individuals, analogous to the enhanced immune response to the preexisting acquired immunodeficiency syndrome (AIDS) opportunistic infections. Therapeutic options are considered.
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PMID:Progressive tumefactive inflammatory central nervous system demyelinating disease in an acquired immunodeficiency syndrome patient treated with highly active antiretroviral therapy. 1902 Oct 74

Neurodegeneration and gliosis are prominent pathological features of subjects with human immunodeficiency virus (HIV) dementia complex (HAD). In these patients, neurodegeneration occurs in uninfected neurons. In addition, these patients develop sensory neuropathy despite the antiretroviral therapy. The HIV protein gp120, which mimics some of the pathological alterations seen in HAD, is retrogradely transported in rodent neurons. However, it is still unclear whether gp120 can also be transported anterogradely and whether axonal transport can occur in the peripheral nervous system (PNS). To determine whether gp120 is transported retrogradely and/or anterogradely, we injected gp120IIIB together with the retrograde tracer fluoro-ruby (FR) or the anterograde tracer 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyamine perchlorate (DiI) into the rat superior colliculi. We discovered that gp120 is retrogradely transported with FR along a direct pathway from the superior colliculus to the retina and anterogradely transported with DiI to several areas of the occipital cortex. To determine whether gp120 is also axonally transported in the peripheral nerves, gp120 and FR were injected into the sciatic nerve. No gp120 immunoreactivity was found in the sciatic nerve or dorsal root ganglia, suggesting that gp120 axonal transport does not occur in the PNS. Gp120 axonal transport may play a role in neuronal injury. Therefore, we examined apoptosis at various time points after gp120 injection. Activated caspase-3 was evident within neurons transporting gp120. These results indicate that axonal transport of gp120 might exacerbate the pathogenesis of HIV-1.
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PMID:Retrograde and anterograde transport of HIV protein gp120 in the nervous system. 1911 24

In recent years, human immunodeficiency virus (HIV)-infected patients under highly active anti-retroviral therapy (HAART) regimens have shown a markedly improved general clinical status; however, the prevalence of mild cognitive disorders has increased. We propose that increased longevity with HIV-mediated chronic inflammation combined with the secondary effects of HAART may increase the risk of early brain aging as shown by intraneuronal accumulation of abnormal protein aggregates like amyloid beta (Abeta), which might participate in worsening the neurodegenerative process and cognitive impairment in older patients with HIV. For this purpose, levels and distribution of Abeta immunoreactivity were analyzed in the frontal cortex of 43 patients with HIV (ages 38-60) and HIV- age-matched controls. Subcellular localization of the Abeta-immunoreactive material was analyzed by double labeling and confocal microscopy and by immunono-electron microscopy (EM). Compared to HIV- cases, in HIV+ cases, there was abundant intracellular Abeta immunostaining in pyramidal neurons and along axonal tracts. Cases with HIV encephalitis (HIVE) had higher levels of intraneuronal Abeta immunoreactivity compared to HIV+ cases with no HIVE. Moreover, levels of intracellular Abeta correlated with age in the group with HIVE. Double-labeling analysis showed that the Abeta-immunoreactive granules in the neurons co-localized with lysosomal markers such as cathepsin-D and LC3. Ultrastructural analysis by immuno-EM has confirmed that in these cases, intracellular Abeta was often found in structures displaying morphology similar to autophagosomes. These findings suggest that long-term survival with HIV might interfere with clearance of proteins such as Abeta and worsen neuronal damage and cognitive impairment in this population.
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PMID:Increased accumulation of intraneuronal amyloid beta in HIV-infected patients. 1928 97

To characterize the regenerative pattern of cutaneous nerves in simian immunodeficiency virus (SIV)-infected and uninfected macaques, excisional axotomies were performed in nonglabrous skin at 14-day intervals. Samples were examined after immunostaining for the pan-axonal marker PGP 9.5 and the Schwann cell marker p75 nerve growth factor receptor. Collateral sprouting of axons from adjacent uninjured superficial dermal nerve bundles was the initial response to axotomy. Both horizontal collateral sprouts and dense vertical regeneration of axons from the deeper dermis led to complete, rapid reinnervation of the epidermis at the axotomy site. In contrast to the slower, incomplete reinnervation previously noted in humans after this technique, in both SIV-infected and uninfected macaques epidermal reinnervation was rapid and completed by 56 days postaxotomy. p75 was densely expressed on the Schwann cells of uninjured nerve bundles along the excision line and on epidermal Schwann cell processes. In both SIV-infected and uninfected macaques, Schwann cell process density was highest at the earliest timepoints postaxotomy and then declined at a similar rate. However, SIV-infection delayed epidermal nerve fiber regeneration and remodeling of new sprouts at every timepoint postaxotomy, and SIV-infected animals consistently had lower mean epidermal Schwann cell densities, suggesting that Schwann cell guidance and support of epidermal nerve fiber regeneration may account for altered nerve regeneration. The relatively rapid regeneration time and the completeness of epidermal reinnervation in this macaque model provides a useful platform for assessing the efficacy of neurotrophic or regenerative drugs for sensory neuropathies including those caused by HIV, diabetes mellitus, medications, and toxins.
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PMID:Altered cutaneous nerve regeneration in a simian immunodeficiency virus / macaque intracutaneous axotomy model. 1929 76

Human immunodeficiency virus (HIV)-associated sensory neuropathy (HIV-SN) occurs in a large fraction of patients infected with HIV. Viral components, including the coat protein gp120, are thought to exert toxic actions on dorsal root ganglia (DRG) sensory neurons that can be further exacerbated by treatment of HIV infection with some antiretroviral agents. In a tissue culture model of HIV-SN, we found that gp120-induced axonal degeneration in DRG sensory neurons was prevented by treatment with the immunophilin ligand GPI-1046. Gp120 induced a rapid and large release of endoplasmic reticulum (ER) calcium in DRG neurons that was attenuated by treatment with GPI-1046. Further experiments suggested that GPI-1046 reduced the total ER calcium load by attenuating store-operated calcium (SOC) entry. Together, these results suggest that GPI-1046 protects DRG from gp120-induced axonal damage by decreasing the entry of calcium through SOC, thus reducing the total volume of ER calcium that is available to be released by gp120.
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PMID:GPI-1046 protects dorsal root ganglia from gp120-induced axonal injury by modulating store-operated calcium entry. 1933 37

In the orthopedic patient, the diagnosis of a compression neuropathy may be straightforward. However, various medical comorbidities can obscure this diagnosis. It is paramount for the practicing orthopedic surgeon to have an appreciation for the medical pathology of common axonal neuropathies to properly diagnose, treat, and refer a patient with altered sensation in the upper extremity. The prevalence of diabetes in the United States is 10%, and roughly 20% of diabetic patients have peripheral neuropathy. In addition to diabetes, 32% of heavy alcohol users present with polyneuropathy. With advancements in the treatment of human immunodeficiency virus/acquired immunodeficiency syndrome clinicians may see the long-term effects of the virus manifested as axonal neuropathies and extreme allodynia. In some regions of the world, Hansen's disease usurps diabetes as the most common cause of polyneuropathy. Based on patient demographics and social habits, Lyme disease, multiple sclerosis, and syphilis can all manifest as polyneuropathies. Understanding the common medical causes of neuropathy will aid the orthopedic surgeon in differentiating simple compression neuropathies from diseases mimicking or confounding them.
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PMID:Peripheral neuropathy of the upper extremity: medical comorbidity that confounds common orthopedic pathology. 1982 82


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