Kynurenines increase MRS metabolites in basal ganglia and decrease resting-state connectivity in frontostriatal reward circuitry in depression.

Inflammation is associated with the development of anhedonia in major depression (MD), but the pathway by which inflammatory molecules gain access to the brain and lead to anhedonia is not clear. Molecules of the kynurenine pathway (KP), which is activated by inflammation, readily influx into the brain and generate end products that alter brain chemistry, disrupt circuit functioning, and result in the expression of inflammatory behaviors such as anhedonia. We examined the impact of plasma and CSF KP metabolites on brain chemistry and neural function using multimodal neuroimaging in 49 depressed subjects. We measured markers of glial dysfunction and distress including glutamate (Glu) and myo-inositol in the left basal ganglia using magnetic resonance spectroscopy (MRS); metrics of local activity coherence (regional homogeneity, ReHo) and functional connectivity from resting-state functional MRI measures; and anhedonia from the Inventory for Depressive Symptoms-Self Report Version (IDS-SR). Plasma kynurenine/tryptophan (KYN/TRP) ratio and cerebrospinal fluid (CSF) 3-hydroxykynurenine (3HK) were associated with increases in left basal ganglia myo-inositol. Plasma kynurenic acid (KYNA) and KYNA/QA were associated with decreases and quinolinic acid (QA) with increases in left basal ganglia Glu. Plasma and CSF KP were associated with decreases in ReHo in the basal ganglia and dorsomedial prefrontal regions (DMPFC) and impaired functional connectivity between these two regions. DMPFC-basal ganglia mediated the effect of plasma and CSF KP on anhedonia. These findings highlight the pathological impact of KP system dysregulation in mediating inflammatory behaviors such as anhedonia.

Lumbar Spondylolisthesis Progression: What is the Effect of Lumbar Medial Branch Nerve Radiofrequency Ablation on Lumbar Spondylolisthesis Progression? A Single-Center, Observational Study.

BACKGROUND: Radiofrequency ablation (RFA) is a denervation therapy commonly performed for pain of facet etiology. Degenerative spondylolisthesis, a malalignment of the spinal vertebrae, may be a co-existing condition contributing to pain; yet the effect of RFA on advancing listhesis is unknown. To the extent that denervating RFA may weaken paraspinal muscles that provide stability to the spine, the therapy can potentially contribute to progressive spinal instability. METHODS: Single-center, prospective, observational pilot study in an interventional pain practice to test the hypothesis that RFA of painful facets in the setting of spondylolisthesis may contribute to advancement of further degenerative spondylolisthesis. Fifteen participants with pre-existing degenerative Grade I or Grade II spondylolisthesis and coexisting axial lumbar pain underwent lumbar RFA encompassing spondylolisthesis level and followed with post-RFA imaging at 12 months and beyond to measure percent change in spondylolisthesis. RESULTS: The primary outcome was the percent advancement of spondylolisthesis per year measured on post-RFA lateral lumbar spine imaging compared with non-intervention inferred baseline advancement of 2% per very limited observational studies. Among the 15 participants enrolled, 14 completed the study (median age 66; 64.3% women; median BMI 33.5; mean follow-up time 23.9 months). The mean advancement of spondylolisthesis per year after RFA was 1.30% (95% CI -0.14 to 2.78%), with 9/14 below 1.25%. CONCLUSION: Among patients with lumbar pain originating from facets in the setting of degenerative spondylolisthesis who underwent lumbar RFA, the observed advancement of spondylolisthesis is clinically similar to the estimated maximum baseline of 2% per year change. The study findings did not find a destabilizing effect of lumbar RFA in advancing spondylolisthesis in this patient population.

Associations among peripheral and central kynurenine pathway metabolites and inflammation in depression.

Kynurenine pathway (KP) metabolites are believed to be a link between inflammation and depression through effects on brain glutamate receptors. However, neither the relationship between plasma and cerebrospinal fluid (CSF) KP metabolites nor their association with inflammatory mediators is well-established in depression. Moreover, the clinical profile associated with combined activation of plasma inflammatory and kynurenine pathways is unknown. Accordingly, plasma and CSF-KP metabolites and inflammatory markers along with depressive symptoms and antidepressant treatment response were measured in 72 unmedicated depressed patients. Following bivariate analyses, component factors representing immune and kynurenine variables in the plasma and CSF were extracted and were used to examine directionality of associations in a path model. In addition, patients were clustered using individual markers that most accounted for the association between plasma immune and KP systems. Path analysis revealed a directional association extending from plasma inflammatory markers to plasma kynurenines, to CSF kynurenines. Among immune markers, plasma tumor necrosis factor (TNF) was robustly associated with plasma kynurenine (KYN) and KYN/tryptophan (TRP), which was in turn significantly associated with CSF KYN, kynurenic acid, and quinolinic acid. Clustering of patients based on plasma TNF and KYN/TRP yielded subgroups of high (N = 17) and low (N = 55) TNF-KYN/TRP groups. High TNF-KYN/TRP subjects exhibited greater depression severity, anhedonia, and treatment nonresponse. In conclusion, plasma-KP metabolites may mediate an inflammation-associated depressive symptom profile via CNS KP metabolites that can serve as a target for intervention at the level of inflammation, peripheral KYN metabolism, KYN transport to the brain, or effects of KP metabolites on glutamate receptors.

What does plasma CRP tell us about peripheral and central inflammation in depression?

Peripheral blood C-reactive protein (CRP) is a biomarker used clinically to measure systemic inflammation and is reproducibly increased in a subset of patients with major depressive disorder (MDD). Furthermore, increased peripheral blood CRP in MDD has been associated with altered reward circuitry and increased brain glutamate in relation with symptoms of anhedonia. Nevertheless, the relationship between peripheral CRP and other peripheral and central markers of inflammation in depressed patients has not been established. Plasma (n = 89) and CSF (n = 73) was collected from medically stable, currently unmedicated adult outpatients with MDD. Associations among plasma and CSF CRP and plasma and CSF inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF] and IL-1beta) and their soluble receptors/antagonists were examined. Relationships between plasma and CSF inflammatory markers and depressive symptoms including anhedonia and reduced motivation (RM) were also explored. Plasma CRP was correlated with multiple plasma inflammatory markers (all p < 0.05), and a strong correlation was found between plasma and CSF CRP (r = 0.855, p < 0.001). CSF CRP in turn correlated with CSF cytokine receptors/antagonists (all p < 0.05). Principal component analyses revealed clusters of CSF inflammatory markers that were associated with high plasma CRP (>3 mg/L) and correlated with depressive symptom severity. These findings were driven by CSF TNF, which correlated with RM (r = 0.236, p = 0.045), and CSF IL-6 soluble receptor, which correlated with anhedonia (r = 0.301, p = 0.010) in the sample as a whole and particularly females. CRP appears to be a peripheral biomarker that reflects peripheral and central inflammation and seems well-suited for guiding immunotherapies targeting TNF and IL-6 in patients with MDD.

Thoracic Sympathectomy for Refractory Chest Pain: A Case Report.

Pericarditis is a source of chest pain that can be chronic and debilitating. We describe a patient diagnosed with pericarditis with chest pain refractory to medical management. This pain was significantly relieved by a left stellate ganglion block, and a subsequent thoracic chain sympathectomy resulted in 3 months of gradually diminishing relief. Possible reasons for this result may include incomplete transection, a significant contribution of pain signaling from the phrenic and/or vagus nerve, or nerve regeneration. Literature describing these interventional techniques for pericardial pain is sparse, and more research is needed to determine their efficacy in refractory pericardial pain.

Vertebral augmentation for compression fractures caused by malignant disease.

Vertebral compression fractures are common in malignant disease and frequently cause severe back pain. However, management of that pain with conventional medical, radiotherapy, or surgical modalities is often inadequate. Vertebral augmentation techniques, such as vertebroplasty and kyphoplasty, are minimally invasive techniques in which methylmethacrylate bone cement is percutaneously injected into compressed vertebral bodies. Vertebral augmentation often improves mechanical stability of compressed vertebrae, provides pain relief, and may prevent progression of vertebral collapse. Kyphoplasty may provide increased chance for vertebral body height restoration, but the clinical importance of slight change in vertebral body height is unclear. Vertebral augmentation can be used in conjunction with other treatment modalities, and associated pain relief may improve patient tolerance of needed antitumor therapies, such as radiation therapy. Vertebral augmentation is generally very well tolerated, and complications associated with bone cement extravasation beyond the vertebral body have rarely been reported. Because it often provides good to excellent relief of otherwise intractable pain and is generally well tolerated, vertebral augmentation is becoming a first-line agent for management of painful vertebral compression fractures, especially in the setting of malignant disease.

E-cadherin is regulated by the transcriptional repressor SLUG during Ras-mediated transformation of intestinal epithelial cells.

BACKGROUND: Loss of the cell membrane protein E-cadherin is a critical event during Ras-mediated transformation of intestinal epithelial cells. The purpose of our study is to determine if activation of the transcriptional repressor SLUG is an important component of the mechanism of Ras-induced loss of E-cadherin. METHODS: Rat intestinal epithelial (RIE) cells were engineered to express mutated human Ha-Ras(Val12) complementary DNA (H-Ras cells). Cell morphology was examined by light microscopy. RNA and protein expression were measured by semiquantitative polymerase chain reaction and Western blot analyses, respectively. Short interfering RNA with 2 different oligos was used to knock down the expression of SLUG. RESULTS: Oncogenic ras induces upregulation of the transcriptional repressor SLUG and subsequent downregulation of the junctional protein E-cadherin. Gene silencing of SLUG by short interfering RNA allows E-cadherin to be reexpressed. E-cadherin protein reexpression allows partial rescue of the transformed phenotype. CONCLUSION: These data suggest a mechanism whereby Ras signaling causes an upregulation of transcriptional repressors and subsequent downregulation of E-cadherin as a malignant phenotype is propagated.