Retrosternal pain is an early indicator of oxygen toxicity

To determine the most sensitive early indicator of toxicity from exposure to O2, we measured respiratory clearance of 99mTc-diethylenetriamine pentaacetate (Tc-DTPA), pulmonary function, serum Factor VIII antigen, and plasma fibronectin values and monitored symptoms in six normal volunteers who breathed 21, 40, and 100% O2, administered in random order, for 17 h at least 1 wk apart. Twenty minutes after beginning O2, arterial PO2 differed among the three exposure groups. After exposure to the three concentrations of O2, there were no differences in Tc-DTPA clearance, vital capacity, FEV1/FVC, diffusing capacity, Factor VIII antigen, or fibronectin concentration. In contrast, all subjects complained of retrosternal pain during and after breathing 100% O2 (p less than 0.001). We conclude that with exposure to 100% O2, retrosternal pain, presumably from tracheal inflammation, occurs before detectable abnormalities of epithelial solute permeability (Tc-DTPA clearance), endothelial O2 injury (fibronectin concentration and Factor VIII), or pulmonary function. These findings indicate that symptoms are more sensitive than signs in detecting early O2 toxicity.     

Variation in the HTR1A and HTR2A genes and social adjustment in depressed patients

Background

Social adjustment is impaired in depressed patients. The difficulty to adjust to social circumstances has been hypothesized to be one of the causes of depression, as well as a consequence of the disorder. Genetic variation in the serotonin transporter gene has been previously associated with social adjustment levels in patients with mood disorders.

Methods

We investigated whether variations on the HTR1A (rs6295) and HTR2A (rs7997012) genes were associated with levels of social adjustment using the Social Adjustment Scale in two samples of depressed patients (total n=156).

Results

Patients carrying the GG genotype of the HTR2A-rs7997012 showed better social adjustment in areas of work and family unit bonding.

Limitations

These findings did not survive correction for multiple testing and should be interpreted with caution.

Conclusion

Our finding is in line with previous observations that have associated the G allele of the HTR2A-rs7997012 with higher rate of antidepressant response. The HTR2A-rs7997012 is worthy of further investigation in studies examining factors that are related to depression course and outcome.     

Chronic Neuron- and Age-Selective Down-Regulation of TNF Receptor Expression in Triple-Transgenic Alzheimer Disease Mice Leads to Significant Modulation of Amyloid- and Tau-Related Pathologies

Neuroinflammation, through production of proinflammatory molecules and activated glial cells, is implicated in Alzheimer''s disease (AD) pathogenesis. One such proinflammatory mediator is tumor necrosis factor α (TNF-α), a multifunctional cytokine produced in excess and associated with amyloid β–driven inflammation and cognitive decline. Long-term global inhibition of TNF receptor type I (TNF-RI) and TNF-RII signaling without cell or stage specificity in triple-transgenic AD mice exacerbates hallmark amyloid and neurofibrillary tangle pathology. These observations revealed that long-term pan anti–TNF-α inhibition accelerates disease, cautions against long-term use of anti–TNF-α therapeutics for AD, and urges more selective regulation of TNF signaling. We used adeno-associated virus vector–delivered siRNAs to selectively knock down neuronal TNF-R signaling. We demonstrate divergent roles for neuronal TNF-RI and TNF-RII where loss of opposing TNF-RII leads to TNF-RI–mediated exacerbation of amyloid β and Tau pathology in aged triple-transgenic AD mice. Dampening of TNF-RII or TNF-RI+RII leads to a stage-independent increase in Iba-1–positive microglial staining, implying that neuronal TNF-RII may act nonautonomously on the microglial cell population. These results reveal that TNF-R signaling is complex, and it is unlikely that all cells and both receptors will respond positively to broad anti–TNF-α treatments at various stages of disease. In aggregate, these data further support the development of cell-, stage-, and/or receptor-specific anti–TNF-α therapeutics for AD.CME Accreditation Statement: This activity (“ASIP 2013 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2013 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.Alzheimer''s disease (AD) pathophysiology is described by chronic and progressive neurodegeneration involving the genesis of extracellular amyloid β (Aβ) plaques, intraneuronal filamentous inclusions called neurofibrillary tangles (NFTs), synapse loss, inflammation, and neuronal cell death, ultimately leading to severe memory loss and cognitive impairment. Neuroinflammation is a highly enigmatic process contributing to disease pathogenesis in AD, where elevated levels of proinflammatory molecules have been associated with Aβ-induced inflammation, neurotoxicity, and cognitive decline.^1–4 In AD-afflicted brains, microglia intimately co-localize with Aβ plaques and serve as major sources of proinflammatory mediators, including cytokines and chemokines.⁵ The pleiotropic proinflammatory cytokine tumor necrosis factor α (TNF-α) is produced in excess concurrently with increased Aβ plaque deposition, an observation that suggests that TNF-α levels reflect the pathologic progression of AD.^6–8 Moreover, three TNF-α promoter polymorphisms have been associated with late-onset AD, and two of the three polymorphisms are linked to increased TNF-α production, further connecting this cytokine to the exacerbated chronic inflammatory disease status in AD.⁹ We and others have demonstrated that TNF-α expression is enhanced in AD mouse models where TNF-α is prepathologically up-regulated in 6-month-old triple-transgenic AD (3xTg-AD) mice,^10,11 which corresponds with an enhancement of F4/80-positive microglial cell numbers.¹² In addition, when neuron-specific TNF-α is chronically overexpressed in 3xTg-AD mice using adeno-associated virus (AAV) vectors, there is increased severity of inflammation, intracellular Aβ, and Tau pathology that leads to neuronal cell death portending that excessive and unopposed TNF-α signaling enhances AD-associated pathology and is detrimental to neuronal viability.¹³TNF-α signals through two cognate transmembrane receptors, TNF receptor type I (TNF-RI) and TNF-RII, which are differentially expressed and regulated. TNF-RI is expressed constitutively on most cell types, whereas TNF-RII expression is induced and is restricted to specific cell populations, including hematopoietic cells, microglia, neurons, and endothelial cells.^14,15 TNF-R engagement to its ligand mediates distinct cellular responses through the activation of several downstream signal transduction cascades involving the NFκB and JNK pathways. In the context of AD, several reports demonstrate differential roles and activation of TNF-RI and TNF-RII such that genetic deletion of TNF-RI, but not TNF-RII, results in reduced plaque deposition in the APP23 mouse model.¹⁶ Moreover, in human brain tissue, TNF-RI protein levels are increased, whereas TNF-RII levels are reduced in patients with AD relative to nondemented control brain.¹⁷ Taken together, these data imply an overall negative role for excessive TNF signaling on AD pathophysiology but, perhaps more importantly, illustrate the complexity of this signaling pathway.Despite a large body of literature indicating detrimental roles for TNF-α, neuroprotective effects have also been reported. Early experiments revealed that TNF-α is protective in cultured neurons during glucose deprivation–induced injury and excitotoxicity by preserving Ca²⁺ homeostasis.¹⁸ Barger et al¹⁹ further demonstrated in dissociated neuronal cultures that pretreatment with TNF-α and Aβ peptide spares cells from Aβ-induced neuronal death, iron toxicity, and intracellular Ca²⁺ accumulation via an NF-κB–dependent mechanism. Moreover, neurons are vulnerable to ischemic injury and oxidative stress in TNF-R null mice, indicating that TNF-α is protective.²⁰ Mice lacking TNF-R expression exhibited reduced manganese superoxide dismutase activity and lacked a robust microglial response to kainic acid.²⁰ Similarly, cultured neurons pretreated with TNF-α resulted in a significant increase in manganese superoxide dismutase activity and a reduction in superoxide accumulation.²¹ These data add to the complexity of the TNF signaling pathway and suggest that strategies to modulate TNF-α in the disease setting may require selective tuning and specificity to ensure that protective signaling outcomes are not compromised.Nonetheless, given the compelling data supporting the pathologic role of TNF-α in AD, the potential of using anti–TNF-α therapeutics has become a viable strategy for subverting the disease course. Preclinical data by McAlpine et al²² demonstrate that transiently inhibiting soluble TNF signaling in the 3xTg-AD mouse model using a dominant-negative inhibitor in conjunction with enhanced systemic inflammation prevents AD-associated amyloid pathology. Tobinick et al²³ reported in a short-term, prospective, open-label pilot study that semiweekly perispinal administration of etanercept, a receptor decoy biological agent antagonizing the actions of TNF-α, in 15 patients with mild to severe AD led to significant and rapid cognitive improvements compared with untreated control patients as assessed by three separate tests measuring cognitive function.Although previous studies provide evidence suggesting that TNF-α inhibition in the short-term may lead to improved pathologic and functional outcomes, they lack data addressing the long-term consequences of blocking TNF-α in a global manner, where cell, stage, and receptor specificity were not examined. To this end, we recently demonstrated that long-term global inhibition of TNF-R signaling in 3xTg-AD mice where TNF-RI and TNF-RII were ablated in all cell types results in a robust increase in hallmark amyloid and NFT pathology. Furthermore, in the absence of TNF signaling, microglia seem nonresponsive to the developing amyloid pathology, which correlates with an impairment of microglial-mediated Aβ₄₂ phagocytosis activity in vitro.²⁴ These data suggest that caution should be taken with the use of broad long-term anti-TNF inhibitors and that a more selective strategy should be investigated.To add to our understanding of TNF signaling biology and the consequences of selectively modulating this pathway, we investigated the cell- and stage-specific role of TNF-R signaling in AD by using recombinant AAV (rAAV) vector–delivered siRNA technology to selectively knock down neuronal TNF-R signaling at stages preceding progressive pathology or in the presence of extant disease using the 3xTg-AD mouse model. We demonstrate that neuronal TNF-RI and TNF-RII exert differential actions where intact TNF-RII signaling results in suppressed Aβ plaque deposition and paired helical filament (PHF) formation in the context of progressive and established disease pathogenesis. In addition, we report a substantial reduction in Iba-1–positive microglia when rAAV2-delivered siTNF-RII or siTNF-RI+RII viral vectors are administered at 2 and 12 months of age. Taken together, these data demonstrate that selectively suppressing neuronal TNF-RI and/or TNF-RII leads to distinct and significant changes in AD pathogenesis, which is most likely a consequence of the divergent signaling pathways associated with these receptors. The present findings support further development and rigorous study of highly selective strategies designed to inhibit specific TNF-α–mediated signals and potentially disrupt the onset and/or progression of this debilitating disease.     

External validation of OroGrams as a predictive model for overall and progression-free survival in Scottish patients with oropharyngeal squamous cell carcinoma: a retrospective cohort study

The aims of this study were to externally validate the OroGrams (oropharyngeal cancer survival calculator) nomogram in a Scottish cohort with high endemic smoking rates, and to compare survival rates with the original validation cohort. A retrospective cohort study in Greater Glasgow and Clyde ENT and OMFS departments was performed to investigate survival outcomes of patients with oropharyngeal squamous cell carcinoma (OPSCC) from January 2012 - December 2017. The main outcome measures were progression-free (PFS) and overall survival (OS), and Kaplan Meier curves. The predictive accuracy of OroGrams was investigated for survival probabilities at one, three, and five years. Smoking and HPV-negative cancer rates were significantly higher in Scottish patients than in the UK consortium cohort. A greater proportion of Scottish patients had advanced UICC8 stages. PFS in patients with HPV-negative cancer appeared better in the Scottish cohort than in the original cohort. Calculated mean standardised Brier scores for PFS and OS were below 0.2 at all three follow-up points, suggesting good overall prognostic accuracy, but there was wide variation between predictive accuracy in individual patients. OroGrams shows prognostic accuracy at one-year follow up in Scotland. The accuracy decreases with longer follow-up periods.