Bilateral sequential ischemic retinopathy and optic neuropathy in IgG1 heavy chain deposition disease.

PURPOSE: To report a case of progressive ischemic retinopathy and optic neuropathy in a patient with heavy chain deposition disease (HCDD), a rare form of monoclonal immunoglobulin deposition disease (MIDD). OBSERVATIONS: Our case describes a 74-year-old woman diagnosed with IgG1 lambda HCDD. After treatment with daratumumab and intravenous IVIG therapy, the patient developed worsening ischemic retinopathy and optic neuropathy, neovascular glaucoma, and bilateral sequential vitreous hemorrhages, necessitating surgical intervention. We present multimodal imaging from the onset of ischemic retinopathy to end-stage maculopathy illustrated by optical coherence tomography (OCT) angiography. Despite discontinuing treatment with daratumumab and providing maximal ocular interventions to control the complications of neovascular disease, the patient's condition progressed, resulting in profound vision loss. CONCLUSIONS AND IMPORTANCE: Our case illustrates the potential for HCDD to cause end-organ disease, including ischemic retinopathy and optic neuropathy, possibly worsened by the patient's underlying cardiovascular risk factor status and medications. Daratumumab, a humanized IgG1 kappa monoclonal antibody that binds to CD38 used to treat specific blood cancers, has been reported to cause disturbances in retinal blood flow, including retinal artery and vein occlusions. It remains to be determined whether careful patient selection or dose adjustments and timing of HCDD treatments could protect vision by reducing the risk of these rare yet severe ocular complications.

Patient predictors of pathogenic versus commensal Gram-positive bacilli organisms isolated from blood cultures.

Objective: Gram-positive bacilli represent a diverse species of bacteria that range from commensal flora to pathogens implicated in severe and life-threatening infection. Following the isolation of Gram-positive bacilli from blood cultures, the time to species identification may take upward of 24 hours, leaving clinicians to conjecture whether they may represent a contaminant (inadvertent inoculation of commensal flora) or pathogenic organism. In this study, we sought to identify patient variables that could help predict the isolation of contaminant versus pathogenic Gram-positive bacilli from blood cultures. Design: Retrospective cohort study. Settings: One quaternary academic medical center affiliated with the University of Toronto. Patients: Adult inpatients were admitted to hospital over a 5-year period (May 2014 to December 2019). Methods: A total of 260 unique Gram-positive bacilli blood culture results from adult inpatients were reviewed and analyzed in both a univariable and multivariable model. Results: Malignancy (aOR 2.78, 95% CI 1.33-5.91, p = 0.007), point increments in the Quick Sepsis Related Organ Failure Assessment score for sepsis (aOR 2.25, 95% CI 1.50-3.47, p < 0.001), peptic ulcer disease (aOR 5.63, 95% CI 1.43-21.0, p = 0.01), and the receipt of immunosuppression prior to a blood culture draw (aOR 3.80, 95% CI 1.86-8.01, p < 0.001) were associated with an increased likelihood of speciating pathogenic Gram-positive bacilli from blood cultures such as Clostridium species and Listeria monocytogenes. Conclusion: Such predictors can help supplement a clinician's assessment on determining when empirical therapy is indicated when faced with Gram-positive bacilli from blood cultures and may direct future stewardship interventions for responsible antimicrobial prescribing.

Externalized histones fuel pulmonary fibrosis via a platelet-macrophage circuit of TGFß1 and IL-27.

Externalized histones erupt from the nucleus as extracellular traps, are associated with several acute and chronic lung disorders, but their implications in the molecular pathogenesis of interstitial lung disease are incompletely defined. To investigate the role and molecular mechanisms of externalized histones within the immunologic networks of pulmonary fibrosis, we studied externalized histones in human and animal bronchoalveolar lavage (BAL) samples of lung fibrosis. Neutralizing anti-histone antibodies were administered in bleomycin-induced fibrosis of C57BL/6 J mice, and subsequent studies used conditional/constitutive knockout mouse strains for TGFß and IL-27 signaling along with isolated platelets and cultured macrophages. We found that externalized histones (citH3) were significantly (P < 0.01) increased in cell-free BAL fluids of patients with idiopathic pulmonary fibrosis (IPF; n = 29) as compared to healthy controls (n = 10). The pulmonary sources of externalized histones were Ly6G+CD11b+ neutrophils and nonhematopoietic cells after bleomycin in mice. Neutralizing monoclonal anti-histone H2A/H4 antibodies reduced the pulmonary collagen accumulation and hydroxyproline concentration. Histones activated platelets to release TGFß1, which signaled through the TGFbRI/TGFbRII receptor complex on LysM+ cells to antagonize macrophage-derived IL-27 production. TGFß1 evoked multiple downstream mechanisms in macrophages, including p38 MAPK, tristetraprolin, IL-10, and binding of SMAD3 to the IL-27 promotor regions. IL-27RA-deficient mice displayed more severe collagen depositions suggesting that intact IL-27 signaling limits fibrosis. In conclusion, externalized histones inactivate a safety switch of antifibrotic, macrophage-derived IL-27 by boosting platelet-derived TGFß1. Externalized histones are accessible to neutralizing antibodies for improving the severity of experimental pulmonary fibrosis.

Histopathological changes in gall bladder mucosa in relation to the number, and size of gallstones, and analysis of the findings in the context of age distribution of the patients: A perspective.

Backgrounds/Aims: To study histopathological changes in gall bladder mucosa in cholelithiasis patients, and analyse their relation to the number and size of gallstones. These findings were evaluated in the context of age distribution of the study population. Methods: One hundred cases of cholecystectomy were part of the study, which was conducted in collaboration with the pathology department. The time period of the study was January 2020 to June 2021. Results: Maximum cases had multiple stones (69.0%), while one third cases (31.0%) had solitary stones. While initial univariate analysis showed age (odds ratio [OR], 6.882; p = 0.043), gallstone number (OR, 9.1; p = 0.050), gallstone size (OR, 17.111; p = 0.013), and duration of symptom (OR, 34.125; p = 0.001) to be significant risk factors associated with gallbladder carcinoma, multivariate analysis found none of these variables to be significant. However, conditional multivariate analysis for the duration of symptom (p = 0.008; OR, 21.118) yielded significant p- value. With histopathological diagnoses, 5% of cases had gallbladder cancer. Conclusions: This study shed light on the rising incidence of cholelithiasis in the young population and the high rate of gallbladder carcinoma in Punjab, India. Although gall stone characteristics (size, number) and patient age appeared to be significant risk factors when their individual relation with gallbladder carcinoma was studied, multivariate analysis, could not prove that. Conditional multivariate analysis showed the duration of symptom to be the only significant risk factor associated with gallbladder carcinoma. Further research with larger sample size is needed to study the rising incidence of gallbladder carcinoma, and the risk factors associated with it.

A MEMS-enabled portable gas chromatography injection system for trace analysis.

Growing concerns about environmental conditions, public health, and disease diagnostics have led to the rapid development of portable sampling techniques to characterize trace-level volatile organic compounds (VOCs) from various sources. A MEMS-based micropreconcentrator (µPC) is one such approach that drastically reduces the size, weight, and power constraints offering greater sampling flexibility in many applications. However, the adoption of µPCs on a commercial scale is hindered by a lack of thermal desorption units (TDUs) that easily integrate µPCs with gas chromatography (GC) systems equipped with a flame ionization detector (FID) or a mass spectrometer (MS). Here, we report a highly versatile µPC-based, single-stage autosampler-injection unit for traditional, portable, and micro-GCs. The system uses µPCs packaged in 3D-printed swappable cartridges and is based on a highly modular interfacing architecture that allows easy-to-remove, gas-tight fluidic, and detachable electrical connections (FEMI). This study describes the FEMI architecture and demonstrates the FEMI-Autosampler (FEMI-AS) prototype (9.5 cm × 10 cm x 20 cm, ≈500 gms). The system was integrated with GC-FID, and the performance was investigated using synthetic gas samples and ambient air. The results were contrasted with the sorbent tube sampling technique using TD-GC-MS. FEMI-AS could generate sharp injection plugs (≈240 ms) and detect analytes with concentrations <15 ppb within 20 s and <100 ppt within 20 min of sampling time. With more than 30 detected trace-level compounds from ambient air, the demonstrated FEMI-AS, and the FEMI architecture significantly accelerate the adoption of µPCs on a broader scale.

High-Frequency Oscillations in Tumor-Related Epilepsy.

INTRODUCTION: To define the patient characteristics, tumor characteristics, and clinical course of patients with primary brain tumors with high-frequency oscillations (HFOs) recorded on electrocorticography. Furthermore, we evaluated whether the presence of HFOs portends a greater risk of postoperative tumor-related epilepsy and whether the resection of HFO-generating tissue reduces likelihood of postoperative tumor-related epilepsy. METHODS: This was a retrospective study of 35 patients undergoing awake craniotomy for tumor resection, all of whom underwent intraoperative electrocorticography. Electrocorticography data were reviewed to assess the presence of HFOs and determine their contact locations. The data were analyzed to determine whether HFO-generating tissue was included in the resection and relationship to postoperative seizure outcome. RESULTS: Seventeen patients (48.5%) were found to have HFOs. Very few patients (4 of 35, 11.4%) had sharp waves. Patients with and without HFOs did not significantly differ in demographics, presentation, tumor characteristics, or tumor molecular genetics. A history of seizures prior to resection was not associated with the presence of HFOs ( P = 0.62), although when patients had seizures during the same hospitalization as the resection, HFOs were more likely to be present ( P = 0.045). Extent of HFO resection was not associated with the likelihood of postoperative seizure freedom. CONCLUSIONS: Approximately half (48.5%) of patients undergoing resection for a primary brain tumor had HFOs. Although HFO resection was not shown to lead to improved seizure freedom, this study was limited by a small sample size, and further investigation into HFO resection and patient outcomes in this population is warranted.

Multimodal Pediatric Lymphoma Detection using PET and MRI.

Lymphoma is one of the most common types of cancer for children (ages 0 to 19). Due to the reduced radiation exposure, PET/MR systems that allow simultaneous PET and MR imaging have become the standard of care for diagnosing cancers and monitoring tumor response to therapy in the pediatric population. In this work, we developed a multimodal deep learning algorithm for automatic pediatric lymphoma detection using PET and MRI. Through innovative designs such as standardized uptake value (SUV) guided tumor candidate generation, location aware classification model learning and weighted multimodal feature fusion, our algorithm can be effectively trained with limited data and achieved superior tumor detection performance over the state-of-the-art in our experiments.

Bacterial polyphosphates induce CXCL4 and synergize with complement anaphylatoxin C5a in lung injury.

Polyphosphates are linear polymers of inorganic phosphates that exist in all living cells and serve pleiotropic functions. Bacteria produce long-chain polyphosphates, which can interfere with host defense to infection. In contrast, short-chain polyphosphates are released from platelet dense granules and bind to the chemokine CXCL4. Here, we report that long-chain polyphosphates induced the release of CXCL4 from mouse bone marrow-derived macrophages and peritoneal macrophages in a dose-/time-dependent fashion resulting from an induction of CXCL4 mRNA. This polyphosphate effect was lost after pre-incubation with recombinant exopolyphosphatase (PPX) Fc fusion protein, demonstrating the potency of long chains over monophosphates and ambient cations. In detail, polyphosphate chains >70 inorganic phosphate residues were required to reliably induce CXCL4. Polyphosphates acted independently of the purinergic P2Y1 receptor and the MyD88/TRIF adaptors of Toll-like receptors. On the other hand, polyphosphates augmented LPS/MyD88-induced CXCL4 release, which was explained by intracellular signaling convergence on PI3K/Akt. Polyphosphates induced Akt phosphorylation at threonine-308. Pharmacologic blockade of PI3K (wortmannin, LY294002) antagonized polyphosphate-induced CXCL4 release from macrophages. Intratracheal polyphosphate administration to C57BL/6J mice caused histologic signs of lung injury, disruption of the endothelial-epithelial barrier, influx of Ly6G+ polymorphonuclear neutrophils, depletion of CD11c+SiglecF+ alveolar macrophages, and release of CXCL4. Long-chain polyphosphates synergized with the complement anaphylatoxin, C5a, which was partly explained by upregulation of C5aR1 on myeloid cells. C5aR1-/- mice were protected from polyphosphate-induced lung injury. C5a generation occurred in the lungs and bronchoalveolar lavage fluid (BALF) of polyphosphate-treated C57BL/6J mice. In conclusion, we demonstrate that polyphosphates govern immunomodulation in macrophages and promote acute lung injury.

Relationship between gene expression profile class and tumor thickness regression after plaque brachytherapy for choroidal melanoma.

BACKGROUND AND OBJECTIVE: To examine the relationship between gene expression profile class and tumor thickness reduction as measured by ultrasonography in response to plaque brachytherapy using a single-center, retrospective cohort study. METHODS: A total of 15 patients with choroidal melanoma who underwent biopsy for gene expression profiling and were treated with plaque brachytherapy from a single institution from 12/8/14 through 12/19/19 were retrospectively reviewed for clinical characteristics and rate of tumor regression. Ultrasonographic B-scan tumor height was recorded just prior to plaque placement and following plaque removal in the patient's chart to assess percent reduction in tumor thickness from baseline. RESULTS: A total of 15 patients met inclusion criteria and were analyzed in this study. Minimum follow-up was 6 months after plaque removal. The percent regression in tumor thickness from baseline as measured by ultrasonography was greater for class 2 tumors than for class 1 tumors at 12-month follow up after treatment, and this difference was statistically significant (P = 0.012). There was no statistical significance in reduction at 3 months (P = 0.46) and 9 months (P = 0.10) after plaque brachytherapy. Although not statistically significant, class 2 tumors appeared to regress more rapidly than class 1 tumors in response to radiation. CONCLUSIONS: In this study, class 2 choroidal melanoma tumors show a more rapid anatomic response to treatment than class 1 tumors at 12 months post plaque brachytherapy.

The MAVS Immune Recognition Pathway in Viral Infection and Sepsis.

Significance: It is estimated that close to 50 million cases of sepsis result in over 11 million annual fatalities worldwide. The pathognomonic feature of sepsis is a dysregulated inflammatory response arising from viral, bacterial, or fungal infections. Immune recognition of pathogen-associated molecular patterns is a hallmark of the host immune defense to combat microbes and to prevent the progression to sepsis. Mitochondrial antiviral signaling protein (MAVS) is a ubiquitous adaptor protein located at the outer mitochondrial membrane, which is activated by the cytosolic pattern recognition receptors, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation associated gene 5 (MDA5), following binding of viral RNA agonists. Recent Advances: Substantial progress has been made in deciphering the activation of the MAVS pathway with its interacting proteins, downstream signaling events (interferon [IFN] regulatory factors, nuclear factor kappa B), and context-dependent type I/III IFN response. Critical Issues: In the evolutionary race between pathogens and the host, viruses have developed immune evasion strategies for cleavage, degradation, or blockade of proteins in the MAVS pathway. For example, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) M protein and ORF9b protein antagonize MAVS signaling and a protective type I IFN response. Future Directions: The role of MAVS as a sensor for nonviral pathogens, host cell injury, and metabolic perturbations awaits better characterization in the future. New technical advances in multidimensional single-cell analysis and single-molecule methods will accelerate the rate of new discoveries. The ultimate goal is to manipulate MAVS activities in the form of immune-modulatory therapies to combat infections and sepsis. Antioxid. Redox Signal. 35, 1376-1392.

Pro- and Antitumorigenic Capacity of Immunoproteasomes in Shaping the Tumor Microenvironment.

Apart from the constitutive proteasome, the immunoproteasome that comprises the three proteolytic subunits LMP2, MECL-1, and LMP7 is expressed in most immune cells. In this study, we describe opposing roles for immunoproteasomes in regulating the tumor microenvironment (TME). During chronic inflammation, immunoproteasomes modulated the expression of protumorigenic cytokines and chemokines and enhanced infiltration of innate immune cells, thus triggering the onset of colitis-associated carcinogenesis (CAC) in wild-type mice. Consequently, immunoproteasome-deficient animals (LMP2/MECL-1/LMP7-null mice) were almost completely resistant to CAC development. In patients with ulcerative colitis with high risk for CAC, immunoproteasome-induced protumorigenic mediators were upregulated. In melanoma tumors, the role of immunoproteasomes is relatively unknown. We found that high expression of immunoproteasomes in human melanoma was associated with better prognosis. Similarly, our data revealed that the immunoproteasome has antitumorigenic activity in a mouse model of melanoma. The antitumor immunity against melanoma was compromised in immunoproteasome-deficient mice because of the impaired activity of CD8+ CTLs, CD4+ Th1 cells, and antigen-presenting cells. These findings show that immunoproteasomes may exert opposing roles with either pro- or antitumoral properties in a context-dependent manner.

Prostate artery embolization has long term efficacy for treatment of severe lower urinary tract symptoms from giant prostatic hyperplasia.

BACKGROUND: Patients with severe lower urinary tract symptoms (LUTS) from giant prostatic hyperplasia (GPH): prostate volume greater than 200 mL that do not respond to medical therapy may not be eligible for surgical treatments due to morbidities, technical challenges, and patient preference. This retrospective investigation examined the long-term efficacy and safety of prostatic arterial embolization (PAE) as a treatment option for severe LUTS due to GPH in a large patient cohort. METHODS: Of 529 patients who underwent PAE between January 2016 and January 2020, 72 patients had severe LUTS from GPH and were retrospectively evaluated. PAE was performed with two embolic agents in sequence: 100-250 µm particles followed by 2 mm and 3 mm coils. Clinical assessment was performed with international prostate symptoms score (IPSS), quality of life (QoL), peak flow rate (Qmax), post-void residual volume (PVR), and prostate specific antigen (PSA) measurements before and 12 months and 24 months after PAE. Prostate volume (PV) was measured by multiparametric magnetic resonance (MR) imaging before and 12 months and 24 months after PAE. RESULTS: Patients with severe LUTS from GPH experienced significant clinical improvements in IPSS, QoL, Qmax, PVR, PSA, and PV at 12 months and 24 months after PAE. Mean IPSS decreased from 26.5 to 18.0 (P < 0.01) to 10.5 (P < 0.01). Mean QoL decreased from 6.0 to 4.0 (P < 0.01) to 2.0 (P < 0.01). Mean Qmax increased from 8.0 to 14 mL/s (P < 0.01) to 18 mL/s (P < 0.01). Mean PVR decreased from 198.0 to 152.0 mL (P < 0.01) to 90 mL (P < 0.01). Mean PV decreased from 303.0 mL to 258.0 mL (P < 0.01) to 209.0 mL (P < 0.01). Mean PSA decreased from 11.2 ng/mL to 9.5 ng/mL (P < 0.05) to 7.9 ng/mL (P < 0.05). No major complications occurred. CONCLUSIONS: PAE is a safe treatment with long term efficacy for severe LUTS from GPH. PAE may be a viable therapeutic option for patients with severe LUTS from GPH whom fail medical therapy and are not candidates for surgical treatments.

SARS-CoV-2 Infection of Pluripotent Stem Cell-Derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response.

A hallmark of severe COVID-19 pneumonia is SARS-CoV-2 infection of the facultative progenitors of lung alveoli, the alveolar epithelial type 2 cells (AT2s). However, inability to access these cells from patients, particularly at early stages of disease, limits an understanding of disease inception. Here, we present an in vitro human model that simulates the initial apical infection of alveolar epithelium with SARS-CoV-2 by using induced pluripotent stem cell-derived AT2s that have been adapted to air-liquid interface culture. We find a rapid transcriptomic change in infected cells, characterized by a shift to an inflammatory phenotype with upregulation of NF-κB signaling and loss of the mature alveolar program. Drug testing confirms the efficacy of remdesivir as well as TMPRSS2 protease inhibition, validating a putative mechanism used for viral entry in alveolar cells. Our model system reveals cell-intrinsic responses of a key lung target cell to SARS-CoV-2 infection and should facilitate drug development.

Bacterial polyphosphates interfere with the innate host defense to infection.

Polyphosphates are linear polymers and ubiquitous metabolites. Bacterial polyphosphates are long chains of hundreds of phosphate units. Here, we report that mouse survival of peritoneal Escherichia coli sepsis is compromised by long-chain polyphosphates, and improves with bacterial polyphosphatekinase deficiency or neutralization using recombinant exopolyphosphatase. Polyphosphate activities are chain-length dependent, impair pathogen clearance, antagonize phagocyte recruitment, diminish phagocytosis and decrease production of iNOS and cytokines. Macrophages bind and internalize polyphosphates, in which their effects are independent of P2Y1 and RAGE receptors. The M1 polarization driven by E. coli derived LPS is misdirected by polyphosphates in favor of an M2 resembling phenotype. Long-chain polyphosphates modulate the expression of more than 1800 LPS/TLR4-regulated genes in macrophages. This interference includes suppression of hundreds of type I interferon-regulated genes due to lower interferon production and responsiveness, blunted STAT1 phosphorylation and reduced MHCII expression. In conclusion, prokaryotic polyphosphates disturb multiple macrophage functions for evading host immunity.

Outcomes of civilian pediatric craniocerebral gunshot wounds: A systematic review.

BACKGROUND: Pediatric craniocerebral gunshot injuries (CGIs) occur both in the context of accidental and intentional trauma. The incidence and physiology of pediatric CGIs merit reexamination of prognostic factors and treatment priorities. This study characterizes the current understanding of mortality and prognostic factors in this patient population. METHODS: A systematic search was conducted. Selection criteria included all studies published since 2000, which described civilian isolated CGIs in pediatric patients. Data were analyzed qualitatively and quantitatively to identify factors prognostic for the primary outcome of mortality. Secondary outcomes included functional outcome status, requirement for surgery, and injury complications. Study quality was assessed with the Newcastle-Ottawa Scale. This study was registered with PROSPERO (CRD42019134231). RESULTS: Initial search revealed 349 unique studies. Forty underwent full text screening, and eight studies were included in the final synthesis. The overall mortality rate was 44.8%. Most CGIs occurred in older teenagers. Aggressive surgical treatment was recommended by one author, while remaining studies emphasized clinical judgment. Reported prognostic factors include initial Glasgow Coma Scale, pupil reactivity, involvement of multiple lobes or deep nuclei, and bihemispheric injuries. Reported complications from CGIs included seizure, meningitis, abscess, cerebrospinal fluid leak, bullet migration, focal neurological deficits, endocrine abnormalities, cognitive deficits, and neuropsychological deficits. The Glasgow Outcome Scale was the predominant measure of function and demonstrated a moderate recovery in 17.4% and a good recovery in 27.3% of patients. CONCLUSION: This systematic review analyzed the existing evidence for prognostic factors in the context of pediatric CGIs. Significant long-term clinical improvement is possible with interventions including urgent surgical therapy. Fixed bilateral pupils and low initial Glasgow Coma Scale correlate with mortality but do not predict all patient outcomes. Patients younger than 15 years are underreported and may have differences in outcome. The literature on pediatric CGIs is limited and requires further characterization. LEVEL OF EVIDENCE: Systematic Review, level IV.

Cancer Fighting SiRNA-RRM2 Loaded Nanorobots.

BACKGROUND: Silencing of several genes is critical for cancer therapy. These genes may be apoptotic gene, cell proliferation gene, DNA synthesis gene, etc. The two subunits of Ribonucleotide Reductase (RR), RRM1 and RRM2, are critical for DNA synthesis. Hence, targeting the blockage of DNA synthesis at tumor site can be a smart mode of cancer therapy. Specific targeting of blockage of RRM2 is done effectively by SiRNA. The drawbacks of siRNA delivery in the body include the poor uptake by all kinds of cells, questionable stability under physiological condition, non-target effect and ability to trigger the immune response. These obstacles may be overcome by target delivery of siRNA at the tumor site. This review presents a holistic overview regarding the role of RRM2 in controlling cancer progression. The nanoparticles are more effective due to specific characteristics like cell membrane penetration capacity, less toxicity, etc. RRM2 have been found to be elevated in different types of cancer and identified as the prognostic and predictive marker of the disease. Reductase RRM1 and RRM2 regulate the protein and gene expression of E2F, which is critical for protein expression and progression of cell cycle and cancer. The knockdown of RRM2 leads to apoptosis via Bcl2 in cancer. Both Bcl2 and E2F are critical in the progression of cancer, hence a gene that can affect both in regulating DNA replication is essential for cancer therapy. AIM: The aim of the review is to identify the related gene whose silencing may inhibit cancer progression. CONCLUSION: In this review, we illuminate the critical link between RRM-E2F, RRM-Bcl2, RRM-HDAC for the therapy of cancer. Altogether, this review presents an overview of all types of SiRNA targeted for cancer therapy with special emphasis on RRM2 for controlling the tumor progression.

The pituitary gland prevents shock-associated death by controlling multiple inflammatory mediators.

Bacterial infections cause a major burden of disease worldwide. Sepsis and septic shock are life-threatening complications of infections. The hypothalamic-pituitary-adrenal (HPA) axis initiates the release of endogenous glucocorticoids that modulate the host stress response and acute inflammation during septic shock. It is an ongoing controversial debate, if therapeutic manipulations of the HPA axis could benefit the clinical situation in the context of shock. Here, we have studied Long Evans rats with hypophysectomy followed by endotoxic shock. The shock-associated lethality was substantially higher in hypophysectomized rats as compared to control mice after cranial sham surgery (7-day survival rates: 27% vs. 89%). Fluorimetric bead-based assays were used to quantify the release of >20 cytokines and chemokines. The surgical removal of the pituitary gland resulted in greatly increased plasma concentrations of mediators such as IL-1α/IL-1ß (10-12-fold), TNFα (19-fold), IL-6 (111-fold), IL-10 (10-fold) as well as the Th1 cytokines, Interferon-γ (8-fold), IL-12 (4-fold) and IL-18 (9-fold) after intra-peritoneal lipopolysaccharide (LPS) injections. In contrast, MIP-1α and Leptin were negatively associated with hypophysectomy. The Th2 cytokines, IL-4 and IL-13, as well as G-CSF, VEGF, IP-10 and RANTES were not significantly affected. The gene expression of the IL-6/IL-12 family cytokine, IL-27p28 was profoundly increased after pituitary gland removal followed by endotoxic shock. A dose-dependent reduction of LPS/TLR4-induced IL-27p28 release by glucococorticoids was observed in cultured rodent macrophages (C57BL/6J) as well as in vivo. This study reveals that the neuroendocrine influences of the HPA axis on the shock-associated inflammatory response are more selective and complex than previously known. These findings will be helpful to predict some of the consequences of therapeutic manipulations of the HPA in the context of sepsis and septic shock.

Heroin Use Is Associated with AA-Type Kidney Amyloidosis in the Pacific Northwest.

BACKGROUND AND OBJECTIVES: AA-type kidney amyloidosis is classically associated with chronic autoimmune or inflammatory disorders. However, some urban centers have reported a high prevalence of injection drug use among patients with kidney AA amyloidosis. Previous reports lack control groups to quantify associations and most predate the opioid epidemic in the United States. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a case-control study of 38 patients with biopsy-confirmed kidney AA amyloidosis and 72 matched control individuals without this condition from two large hospital systems in Seattle, Washington. We ascertained the pattern and duration of heroin use by medical chart review and determined associations using logistic regression. RESULTS: Among case patients, 95% had a prior history of heroin use, 87% had skin abscesses, and 76% and 27% had evidence of muscling and skin popping, respectively. After adjustment for age, race, sex, site, and year of biopsy, any heroin use (past or current) was associated with an estimated 170-times higher risk of kidney AA amyloidosis compared with no heroin use (95% confidence interval, 28 to 1018 times higher; P<0.001). Chronic autoimmune disorders were uncommon among case patients in this study. The median time to ESKD among patients with AA amyloidosis was 2.4 years (interquartile range, 0.5-7.5 years). CONCLUSIONS: Injection heroin use is strongly associated with kidney AA amyloidosis in the Pacific Northwest. Unique aspects of heroin use, in particular geographic regions or frequent associated soft-tissue infections, may be an important cause of this progressive kidney disease.

Early BAFF receptor blockade mitigates murine Sjögren's syndrome: Concomitant targeting of CXCL13 and the BAFF receptor prevents salivary hypofunction.

Sjögren's syndrome (SS) is a debilitating autoimmune disease. Patients with SS may develop xerostomia. This process is progressive, and there are no therapeutics that target disease etiology. We hypothesized BAFF receptor (BAFFR) blockade would mitigate SS disease development, and neutralization of CXCL13 and BAFF signaling would be more efficacious than BAFFR blockade alone. We treated NOD/ShiLtJ SS mice with soluble BAFF receptor (BAFFR-Fc) or anti-CXCL13/BAFFR-Fc in combination, prior to the development of clinical disease. Our results show treatment with BAFFR-Fc reduced peripheral B cell numbers and decreased sialadenitis. In addition, this treatment reduced total serum immunoglobulin as well as IgG and IgM specific anti-nuclear autoantibodies. NOD/ShiLtJ mice treated with BAFFR-Fc and anti-CXCL13 antibody were protected from salivary deficits. Results from this study suggest blockade of CXCL13 and BAFFR together may be an effective therapeutic strategy in preventing salivary hypofunction and reducing autoantibody titers and sialadenitis in patients with SS.