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Background and Aims: A new definition of dominant stricture (NDS) has recently been defined for patients with primary sclerosing cholangitis (PSC). Prevalence and clinical features of this, compared to traditional dominant stricture (TDS), have not been reported., Methods: In this single-centre longitudinal prospective cohort study, all PSC patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) between October 2021 and 2022 were recruited. Symptoms of cholestasis, laboratory values (P-alkaline phosphatase, P-Bilirubin), Helsinki PSC-score, brush cytology findings and need for endoscopic therapy (i.e. dilation, stenting) were prospectively collected., Results: Overall, 228 patients with PSC underwent 248 ERCPs. NDS was detected in 43 (17%; 36 patients) and TDS without NDS (TDS group) was detected in 62 (25%; 58 patients) ERCPs, respectively; in the remaining 143 ERCPs, neither TDS nor NDS was seen (no dominant stricture [NoDS] group). PSC duration (median 8 years) and patient's age did not differ between the three groups; males presented more often with NDS. Patients with NDS were more often symptomatic, had higher cholestatic liver enzymes, advanced bile duct disease and markers of biliary inflammation (p < .001). Patients with NDS needed dilation (81%) and stenting (21%) more often than the TDS group (60% and 5%, respectively). Dysplasia in brush cytology was more common in TDS (5%) and NDS (9%) than in NoDS (3%) groups (p = .04), but did not differ between TDS and NDS groups., Conclusions: Dominant stricture according to the new definition developed in 17% of PSC patients in our cohort and identifies patients with more advanced disease, biliary inflammation and need of endo-therapy., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Neuronal loss, alterations in dendritic arbor, and decreased synaptic density, in infected brain tissue, are neuropathological signatures of HIV-1-associated dementia (HAD). Brain mononuclear phagocyte (MP) (macrophage and microglia) secretory products can effect neuronal compromise, although the underlying mechanism(s) remain incompletely defined. To these ends, we quantitatively assessed the effects of virus-infected and/or immune activated MP secretory products on multiple aspects of neuronal morphology. Rat cortical and hippocampal neurons were exposed to secretory products from HIV-1-infected and lipopolysaccharide (LPS)-activated human monocyte-derived macrophage (MDM). Our assays for alterations in neuronal dendritic arbor and cell loss included the quantification of neurofilament (NF), neuron-specific enolase (NSE), and MAP-2 by ELISA and cellular morphology. MDM conditioned media (MCM) enhanced neuronal survival. HIV-1 infection or activation by LPS had modest neurotoxic effects. In contrast, the combination of HIV-1 infection and activation of MDM produced significant neurotoxicity. Such MDM products altered dendritic arbor, decreased synaptic density, and increased LDH release. Comparable neurotrophic/toxic responses were observed when neurons were exposed to MCM collected from 12 separate human donors. Similar responses were observed with MCM from human fetal microglia, further supporting the role of HIV-1-infected and immune-activated brain MP in the overall neurotoxic responses. This work provides quantitative measures of neuronal damage by which virus infected and activated MP can elicit neuronal injury in HAD.

Secretory products from HIV-1-infected immune-competent mononuclear phagocytes (MP) damage neuronal dendritic arbor (Zheng et al., 2001). The mechanism behind neuronal injury and whether it is species and/or viral strain dependent is not fully understood. To these ends, we investigated whether HIV-1-infected and lipopolysaccharide (LPS)-activated MDM elicit neuronal injury in primary human neurons. Neuronal damage was compared to that seen in rat neurons. Utilizing a spectrum of HIV-1 strains to infect human monocyte-derived macrophages (MDM), productive viral replication proved necessary, but not sufficient, for neuronal injury. Neuronal demise was induced by virion-free HIV-1-infected and immune-activated MDM culture supernatants. Maximal alterations in glutamate mediated neuronal signaling, resulted from exposure to secretory products from HIV-1-infected and immune-activated MDM. Apoptosis was the predominant mechanism of cell death induced by HIV-1-infected and LPS-treated MDM. Importantly, neuronal injury and increases in calcium influx mediated by HIV-1-infected and immune-activated MDM culture supernatants was partially blocked by the N-methyl D-aspartate (NMDA) receptor antagonist, MK 801. These data support a primary role for immune-activation in MP neurotoxic activities. The upregulation of NMDA receptor sensitive soluble factors and neuronal apoptosis by HIV-1-infected and immune-activated MDM provide unique insights into links between soluble factors, produced as a consequence of MP immunity, and neuronal demise in HAD.

Approximately one-quarter of individuals with AIDS develop neuropathological symptoms that are attributable to infection of the brain with HIV. The cognitive manifestations have been termed HIV-associated dementia. The mechanisms underlying HIV-associated neuronal injury are incompletely understood, but various studies have confirmed the release of neurotoxins by macrophages/microglia infected with HIV-1 or stimulated by viral proteins, including the envelope glycoprotein gp120. In the present study, we investigated the possibility that l -cysteine, a neurotoxin acting at the N-methyl-d -aspartate subtype of glutamate receptor, could contribute to HIV-associated neuronal injury. Picomolar concentrations of gp120 were found to stimulate cysteine release from human monocyte-derived macrophages (hMDM) in amounts sufficient to injure cultured rat cerebrocortical neurons. TNF-alpha and IL-1beta, known to be increased in HIV-encephalitic brains, as well as a cellular product of cytokine stimulation, ceramide, were also shown to induce release of cysteine from hMDM in a dose-dependent manner. A TNF-alpha-neutralizing Ab and an IL-1betaR antagonist partially blocked gp120-induced cysteine release, suggesting that these cytokines may mediate the actions of gp120. Interestingly, hMDM infected with HIV-1 produced significantly less cysteine than uninfected cells following stimulation with TNF-alpha. Our findings imply that cysteine may play a role in the pathogenesis of neuronal injury in HIV-associated dementia due to its release from immune-activated macrophages but not virus-infected macrophages. Such uninfected cells comprise the vast majority of mononuclear phagocytes (macrophages and microglia) found in HIV-encephalitic brains.

It is generally accepted that viral and cellular products from immune competent mononuclear phagocytes (MP) (brain macrophages and microglia) underlie the neuropathogenesis of HIV-1-associated dementia (HAD). What remains unanswered, however, is the composition of and mechanisms for such MP-induced neurological dysfunctions. In attempts to address these issues culture fluids from HIV-1ADA-infected monocyte-derived macrophages (MDMs) (depleted or enriched with progeny virus) were placed onto the CA1 area of rat hippocampal brain slices (the site of mammalian learning and memory) and neuronal long-term potentiation (LTP) assayed. LTP was induced by high frequency stimulation (HFS). Lipopolysaccharide (LPS) served as a surrogate macrophage activator. Synaptic strength was assayed by the initial slope of evoked field excitatory postsynaptic potentials (EPSPs). Synaptic potentiation following HFS was observed in slices incubated with uninfected (control) MDM culture fluids. The magnitude of the LTP response was 150.2 +/- 21.10% compared to basal levels (n=6). Synaptic strength was enhanced in virus-infected (135.7+/-28.9%, n=8) and LPS-activated MDM (123.3+/-5.1%, n=7) but at lower levels than controls. The lowest levels of LTP were in brain slices incubated with virus-infected and LPS-activated MDM fluids at (109.5+/-9.9% n=12). Interestingly, bath application of progeny HIV-1 virions showed minimal LTP effects. Virus-infected, LPS-activated MDM fluids, with progenyvirus, reduced synaptic strength but were not statistically different than replicate culture fluids depleted of virus. In contrast, IL-1beta and quinolinic acid, significantly diminished synaptic strength. These results, taken together, suggest that soluble HIV-1-infected MDM secretory products, but not virus per se, significantly affect LTP. This electrophysiological system, which monitors neuronal function following cell exposure to HIV-1 infected materials could provide a novel testing ground for therapeutics designed to protect brain function in HAD.

Chemokine receptors pivotal for human immunodeficiency virus type 1 (HIV-1) infection in lymphocytes and macrophages (CCR3, CCR5, and CXCR4) are expressed on neural cells (microglia, astrocytes, and/or neurons). It is these cells which are damaged during progressive HIV-1 infection of the central nervous system. We theorize that viral coreceptors could effect neural cell damage during HIV-1-associated dementia (HAD) without simultaneously affecting viral replication. To these ends, we studied the ability of diverse viral strains to affect intracellular signaling and apoptosis of neurons, astrocytes, and monocyte-derived macrophages. Inhibition of cyclic AMP, activation of inositol 1,4,5-trisphosphate, and apoptosis were induced by diverse HIV-1 strains, principally in neurons. Virions from T-cell-tropic (T-tropic) strains (MN, IIIB, and Lai) produced the most significant alterations in signaling of neurons and astrocytes. The HIV-1 envelope glycoprotein, gp120, induced markedly less neural damage than purified virions. Macrophage-tropic (M-tropic) strains (ADA, JR-FL, Bal, MS-CSF, and DJV) produced the least neural damage, while 89.6, a dual-tropic HIV-1 strain, elicited intermediate neural cell damage. All T-tropic strain-mediated neuronal impairments were blocked by the CXCR4 antibody, 12G5. In contrast, the M-tropic strains were only partially blocked by 12G5. CXCR4-mediated neuronal apoptosis was confirmed in pure populations of rat cerebellar granule neurons and was blocked by HA1004, an inhibitor of calcium/calmodulin-dependent protein kinase II, protein kinase A, and protein kinase C. Taken together, these results suggest that progeny HIV-1 virions can influence neuronal signal transduction and apoptosis. This process occurs, in part, through CXCR4 and is independent of CD4 binding. T-tropic viruses that traffic in and out of the brain during progressive HIV-1 disease may play an important role in HAD neuropathogenesis.

The mechanism(s) by which HIV-1 affects neural injury in HIV-1-associated dementia (HAD) remains unknown. To ascertain the role that cellular and viral macrophage products play in HAD neurotoxicity, we explored one potential route for neuronal demise, CXCR4. CXCR4, expressed on lymphocytes and neurons, is both a part of neural development and a co-receptor for HIV-1. Its ligand, stromal cell-derived factor-1alpha (SDF-1alpha), affects neuronal viability. GTP binding protein (G-protein) linked signaling after neuronal exposure to SDF-1alpha, virus-infected monocyte-derived macrophage (MDM) secretory products, and virus was determined. In both human and rat neurons, CXCR4 was expressed at high levels. SDF-1alpha/beta was detected predominantly in astrocytes and at low levels in MDM. SDF-1beta/beta was expressed in HAD brain tissue and upregulated in astrocytes exposed to virus infected and/or immune activated MDM conditioned media (fluids). HIV-1-infected MDM secretions, virus and SDF-1beta induced a G inhibitory (Gi) protein-linked decrease in cyclic AMP (cAMP) and increase inositol 1,4, 5-trisphosphate (IP3) and intracellular calcium. Such effects were partially blocked by antibodies to CXCR4 or removal of virus from MDM fluids. Changes in G-protein-coupled signaling correlated, but were not directly linked, to increased neuronal synaptic transmission, Caspase 3 activation and apoptosis. These data, taken together, suggest that CXCR4-mediated signal transduction may be a potential mechanism for neuronal dysfunction during HAD.

The cognitive and motor impairments of HIV-1-associated dementia (HAD) often result from neuronal damage of drop-out. In the infected human host, virus-infected immune-competent mononuclear phagocytes (MPs) (brain macrophages and microglia) are the target cells for HIV-1 and the producers of bioactive molecules that mediate neural damage. Indeed, in laboratory experiments, activated HIV-1-infected macrophages placed into human or rodent brain tissues induce neuronal apoptosis. Nonetheless, the mechanisms for neuronal dysfunction in HAD have yet to be discerned. To these ends, we studied the effects of HIV-1-infected monocyte-derived macrophage (MDM) secretions, electrophysiologically, on neuronal synaptic transmission. Bath application of HIV-1-infected MDM culture fluids onto rat hippocampal brain slices resulted in inhibition of evoked field excitatory postsynaptic potentials (EPSPs). In contrast, fluids from uninfected MDMs showed mild effects on the EPSPs. HIV-1-associated inhibition of EPSPs was enhanced by LPS activation, both for HIV-1-infected and uninfected MDMs. Importantly, paired-pulse facilitation ratio tests showed that factors secreted by HIV-1-infected MDMs acted transiently on presynaptic terminals, providing insights into the site of action and mechanism of the MDM-induced neuronal dysfunction. These results, taken together, demonstrate that factors produced as a consequence of MDM infection and activation affect neuronal synaptic transmission.

A human immunodeficiency virus type 1 (HIV)-seropositive, antiretroviral-naive patient presented with significant cognitive dysfunction. Neuropsychologic, neuroradiologic, immunologic, and virologic studies confirmed HIV-associated dementia (HAD). After 12 weeks of highly active antiretroviral therapy (HAART) with ibuprofen, dramatic improvements were demonstrated in neurologic function and were sustained for > 1 year. HIV-1 RNA in cerebrospinal fluid (CSF) decreased from 10(5) to 10(4) copies/mL after 4 weeks. After 20 weeks of therapy, plasma viremia decreased from 10(6) copies/mL to undetectable (< 96 copies/mL). Assays of neurotoxins (tumor necrosis factor-alpha, quinolinic acid, and nitric oxide) in plasma and CSF were considerably elevated at presentation and significantly decreased after therapy. Baseline plasma and CSF demonstrated neurotoxic activities in vitro, which also reduced markedly. These data, taken together, support the notion that HAD is a reversible metabolic encephalopathy fueled by viral replication. HAART used with nonsteroidal antiinflammatory agents leads to the suppression of inflammatory neurotoxins and can markedly improve neurologic function in HAD.