Coexistence of Diffuse Large B-Cell Lymphoma With Chronic Tubulointerstitial Nephritis: A Case Review and Pathophysiology.

There is an association between lymphomas and kidney disease with renal abnormalities found both in patients with direct infiltration by lymphoma as well as in patients without gross or microscopic evidence of renal involvement. Multiple mechanisms to explain the link between lymphomas and renal disease have been proposed, ranging from direct renal metastasis by the lymphoma to chemokine signaling pathways. In addition, there is a correlation between certain genetic mutations and an increased risk of lymphoma metastasizing to other organs. We present a case of a 41-year-old male who passed away due to end-stage kidney disease and was found on autopsy to have chronic tubulointerstitial nephritis and diffuse large B-cell lymphoma (DLBCL) without direct renal involvement by the lymphoma. The patient had been previously healthy with no significant prior medical history, NSAID, or other contributory medication use of note with the only presenting symptom being renal failure. Only upon autopsy was DLBCL discovered throughout the abdomen with no direct lymphoma involvement evident in the kidneys. To the author's knowledge, this is one of the few reported cases of DLBCL in English literature without renal infiltration in which the presenting symptom and cause of death was renal dysfunction. Several mechanisms have been theorized for how lymphomas can lead to kidney damage without direct metastasizes; however, more research still needs to be done to better understand the underlying etiology. Given the rarity and the lack of direct infiltration of lymphoma into the kidneys in this patient, we hope reporting this case will allow further advancements in this field of study as well as more comprehensive management.

Granulomatous lung disease: clinical aspects.

INTRODUCTION: Granulomatous lung diseases (GLD) are heterogeneous group of diseases that can be broadly categorized as infectious or noninfectious. This distinction is extremely important, as the misdiagnosis of a GLD can have serious consequences. In this manuscript, we describe the clinical manifestations, histopathology, and diagnostic approach to GLD. We propose an algorithm to distinguish infectious from noninfectious GLD. AREAS COVERED: We have searched PubMed and Medline database from 1950 to December 2019, using multiple keywords as described below. Major GLDs covered include those caused by mycobacteria and fungi, sarcoidosis, hypersensitivity pneumonitis, and vasculidities. EXPERT OPINION: The cause of infectious GLD is usually identified through microbiological culture and molecular techniques. Most noninfectious GLD are diagnosed by clinical and laboratory criteria, often with exclusion of infectious pathogens. Further understanding of the immunopathogenesis of the granulomatous response may allow improved diagnosis and treatment of GLD.

MiR-34a modulates ionizing radiation-induced senescence in lung cancer cells.

MicroRNAs (miRNAs) are a new class of gene expression regulators that have been implicated in tumorigenesis and modulation of the responses to cancer treatment including that of human non-small cell lung cancer (NSCLC). However, the role of miR-34a in ionizing radiation (IR)-induced senescence in NSCLC cells remains poorly understood. Here we report that IR-induced premature senescence correlates with upregulation of miR-34a expression in NSCLC cells. Ectopic overexpression of miR-34a by transfection with synthetic miR-34a mimics markedly enhances IR-induced senescence, whereas inhibition of miR-34a by transfection with a synthetic miR-34a inhibitor attenuates IR-induced senescence. Clonogenic assays reveal that treatment with miR-34a mimics augments IR-induced cell killing in human NSCLC cells. Mechanistically, we found that the senescence-promoting effect of miR-34a is associated with a dramatic down-regulation of c-Myc (Myc) expression, suggesting that miR-34a may promote IR-induced senescence via targeting Myc. In agreement with this suggestion, knockdown of Myc expression by RNAi recapitulates the senescence-promoting effect of miR-34a and enhances IR-induced cell killing in NSCLC cells. Collectively, these results demonstrate a previously unrecognized role for miR-34a in modulating IR-induced senescence in human NSCLC cells and suggest that pharmacological intervention of miR-34a expression may represent a new therapeutic strategy for improving the efficacy of lung cancer radiotherapy.

Atypical accessory intraparietal sutures mimicking complex fractures in a neonate.

Partial or complete division of the parietal bones resulting in anomalous cranial sutures is a rare entity and may raise concern for fracture and potential abuse when identified on radiological examination in young children. We present a case of a 4-week-old male found to have anomalous intraparietal sutures originally interpreted as fractures during a comprehensive evaluation for nonaccidental trauma. Our goal is to raise awareness of a complex branching pattern of accessory intraparietal sutures, which has not been previously described. Additionally, we will review the characteristics that aid in the radiologic differentiation of accessory cranial sutures and fractures.

Astrocyte pathology in Alexander disease causes a marked inflammatory environment.

Astrocytes and microglia are commonly involved in a wide variety of CNS pathologies. However, they are typically involved in a secondary response in which many cell types are affected simultaneously and therefore it is difficult to know their contributions to the pathology. Here, we show that pathological astrocytes in a mouse model of Alexander disease (AxD; GFAP (Tg);Gfap (+/R236H)) cause a pronounced immune response. We have studied the inflammatory response in the hippocampus and spinal cord of these mice and have found marked microglial activation, which follows that of astrocytes in a spatial pathological progression, as shown by increased levels of Iba1 and microglial cell (Iba1+) density. RNA sequencing and subsequent gene ontology (GO) analysis revealed that a majority of the most upregulated genes in GFAP (Tg);Gfap (+/R236H) mice are directly associated with immune function and that cytokine and chemokine GO attributes represent nearly a third of the total immune attributes. Cytokine and chemokine analysis showed CXCL10 and CCL2 to be the most and earliest increased molecules, showing concentrations as high as EAE or stroke models. CXCL10 was localized exclusively to astrocytes while CCL2 was also present in microglia. Despite the high levels of CXCL10 and CCL2, T cell infiltration was mild and no B cells were found. Thus, mutations in GFAP are sufficient to trigger a profound inflammatory response. The cellular stress caused by the accumulation of GFAP likely leads to the production of inflammatory molecules and microglial activation. Examination of human AxD CNS tissues also revealed microglial activation and T cell infiltrates. Therefore, the inflammatory environment may play an important role in producing the neuronal dysfunction and seizures of AxD.

Cryopreservation of viable human lung tissue for versatile post-thaw analyses and culture.

Clinical trials are currently used to test therapeutic efficacies for lung cancer, infections and diseases. Animal models are also used as surrogates for human disease. Both approaches are expensive and time-consuming. The utility of human biospecimens as models is limited by specialized tissue processing methods that preserve subclasses of analytes (e.g. RNA, protein, morphology) at the expense of others. We present a rapid and reproducible method for the cryopreservation of viable lung tissue from patients undergoing lobectomy or transplant. This method involves the pseudo-diaphragmatic expansion of pieces of fresh lung tissue with cryoprotectant formulation (pseudo-diaphragmatic expansion-cryoprotectant perfusion or PDX-CP) followed by controlled-rate freezing in cryovials. Expansion-perfusion rates, volumes and cryoprotectant formulation were optimized to maintain tissue architecture, decrease crystal formation and increase long-term cell viability. Rates of expansion of 4 cc/min or less and volumes ranging from 0.8-1.2 × tissue volume were well-tolerated by lung tissue obtained from patients with chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis, showing minimal differences compared to standard histopathology. Morphology was greatly improved by the PDX-CP procedure compared to simple fixation. Fresh versus post-thawed lung tissue showed minimal differences in histology, RNA integrity numbers and post-translational modified protein integrity (2-dimensional differential gel electrophoresis). It was possible to derive numerous cell types, including alveolar epithelial cells, fibroblasts and stem cells, from the tissue for at least three months after cryopreservation. This new method should provide a uniform, cost-effective approach to the banking of biospecimens, with versatility to be amenable to any post-acquisition process applicable to fresh tissue samples.

Bleomycin delivery by osmotic minipump: similarity to human scleroderma interstitial lung disease.

The interstitial lung diseases (ILD) include a large number of chronic, progressive, irreversible respiratory disorders involving pulmonary fibrosis, the most common of which are idiopathic pulmonary fibrosis and scleroderma lung disease (SSc ILD). Because bleomycin causes lung fibrosis when used in cancer chemotherapy, it is used to model human ILD in rodents. In most studies, bleomycin has been delivered directly into the lung by intratracheal or intraoral administration. Here we have compared the effects in mice of bleomycin delivered directly into the lungs (direct model) or systemically using osmotic minipumps (pump model) to determine which more closely resembles human ILD. The pump model is more similar to human SSc ILD in that: 1) lung injury/fibrosis is limited to the subpleural portion of the lung in the pump model and in SSc ILD, whereas the entire lung is affected in the direct model; 2) conversely, there is massive inflammation throughout the lung in the direct model, whereas inflammation is limited in the pump model and in SSc ILD; 3) hypertrophic type II alveolar epithelial cells are present at high levels in SSc ILD and in the pump model but not in the direct model; and 4) lung fibrosis is accompanied by dermal fibrosis. The pump model is also move convenient and humane than the direct model because there is less weight loss and mortality.

Activation of p53 with Nutlin-3a radiosensitizes lung cancer cells via enhancing radiation-induced premature senescence.

Radiotherapy is routinely used for the treatment of lung cancer. However, the mechanisms underlying ionizing radiation (IR)-induced senescence and its role in lung cancer treatment are poorly understood. Here, we show that IR suppresses the proliferation of human non-small cell lung cancer (NSCLC) cells via an apoptosis-independent mechanism. Further investigations reveal that the anticancer effect of irradiation correlates well with IR-induced premature senescence, as evidenced by increased senescence-associated ß-glactosidase (SA-ß-gal) staining, decreased BrdU incorporation and elevated expression of p16(INK4a) (p16) in irradiated NSCLC cells. Mechanistic studies indicate that the induction of senescence is associated with activation of the p53-p21 pathway, and that inhibition of p53 transcriptional activity by PFT-α attenuates IR-induced tumor cell killing and senescence. Gain-of-function assays demonstrate that restoration of p53 expression sensitizes H1299 cells to irradiation, whereas knockdown of p53 expression by siRNA inhibits IR-induced senescence in H460 cells. Furthermore, treatment with Nutlin-3a, a small molecule inhibitor of MDM2, enhances IR-induced tumor cell killing and senescence by stabilizing the activation of the p53-p21 signaling pathway. Taken together, these findings demonstrate for the first time that pharmacological activation of p53 by Nutlin-3a can sensitize lung cancer cells to radiation therapy via promoting IR-induced premature senescence.

Lack of nitric oxide synthases increases lipoprotein immune complex deposition in the aorta and elevates plasma sphingolipid levels in lupus.

Systemic lupus erythematosus (SLE) patients display impaired endothelial nitric oxide synthase (eNOS) function required for normal vasodilatation. SLE patients express increased compensatory activity of inducible nitric oxide synthase (iNOS) generating excess nitric oxide that may result in inflammation. We examined the effects of genetic deletion of NOS2 and NOS3, encoding iNOS and eNOS respectively, on accelerated vascular disease in MRL/lpr lupus mouse model. NOS2 and NOS3 knockout (KO) MRL/lpr mice had higher plasma levels of triglycerides (23% and 35%, respectively), ceramide (45% and 21%, respectively), and sphingosine 1-phosphate (S1P) (21%) compared to counterpart MRL/lpr controls. Plasma levels of the anti-inflammatory cytokine interleukin 10 (IL-10) in NOS2 and NOS3 KO MRL/lpr mice were lower (53% and 80%, respectively) than counterpart controls. Nodule-like lesions in the adventitia were detected in aortas from both NOS2 and NOS3 KO MRL/lpr mice. Immunohistochemical evaluation of the lesions revealed activated endothelial cells and lipid-laden macrophages (foam cells), elevated sphingosine kinase 1 expression, and oxidized low-density lipoprotein immune complexes (oxLDL-IC). The findings suggest that advanced vascular disease in NOS2 and NOS3 KO MRL/lpr mice maybe mediated by increased plasma triglycerides, ceramide and S1P; decreased plasma IL-10; and accumulation of oxLDL-IC in the vessel wall. The results expose possible new targets to mitigate lupus-associated complications.

Rapid development of sarcoid tenosynovitis.

We report a case of acute tenosynovitis from sarcoidosis and review previously reported cases of this entity. A woman with known pulmonary sarcoidosis rapidly developed painless nodules in the tendon sheaths of the dorsum of both hands and wrists. Sarcoid tenosynovitis is almost exclusively found in the upper extremity. The flexor and extensor tendons are equally affected. The condition may respond to medical therapy including corticosteroids and other immunomodulating medications. Surgical debulking and tendon sheathectomy have also been curative. The disease has also been reported to spontaneously resolve. Our patient dramatically improved while on methotrexate.

Anti-mitogenic effects of ß-agonists and PGE2 on airway smooth muscle are PKA dependent.

Inhaled ß-agonists are effective airway smooth muscle (ASM)-relaxing agents that help reverse bronchoconstriction in asthma, but their ability to affect the aberrant ASM growth that also occurs with asthma is poorly understood. ß-Agonists exhibit PKA-dependent antimitogenic effects in several cell types. However, recent studies suggest that Epac, and not PKA, mediates the antimitogenic effect of cAMP in both ASM and fibroblasts. This study aims to clarify the role of PKA in mediating the effect of G(s)-coupled receptors on human ASM growth. Pretreatment of ASM cultures with ß-agonists albuterol, isoproterenol, or salmeterol (100 nM to 10 µM) caused a significant (∼ 25-30%) inhibition of EGF-stimulated ASM thymidine incorporation and cell proliferation, whereas a much greater inhibition was observed from pretreatment with PGE(2) (75-80%). However, all agents were ineffective in cells expressing GFP chimeras of either PKI (a PKA inhibitor) or a mutant PKA regulatory subunit relative to the control cells expressing GFP. The antimitogenic efficacy of PGE(2) in inhibiting control cultures was associated with greater ability to stimulate sustained PKA activation and greater inhibition of late-phase promitogenic p42/p44 and PI3K activities. These findings suggest that therapeutic approaches enabling superior PKA activation in ASM will be most efficacious in deterring ASM growth.

Pulmonary involvement in Sjögren syndrome.

Sjögren syndrome is a slowly progressing autoimmune disease. Pulmonary manifestations are frequent in primary Sjögren syndrome but often not clinically significant; the most common are xerotrachea, interstitial lung diseases, and small airway obstruction. Pulmonary manifestations in Sjögren syndrome have a slow progression and favorable prognosis, with the exception of primary pulmonary lymphoma and pulmonary hypertension.

PKC-dependent regulation of the receptor locus dominates functional consequences of cysteinyl leukotriene type 1 receptor activation.

Leukotrienes are important lipid mediators of asthma that contribute to airway inflammation and bronchoconstriction. Critical mechanisms for physiological regulation of the main G protein-coupled receptor (GPCR) mediating the leukotriene responses in asthma, cysteinyl leukotriene type 1 receptor (CysLT1R), have not been delineated. Although desensitization of GPCRs is a well-established phenomenon, studies demonstrating its physiological relevance are lacking. Here, we demonstrate that relief of PKC-mediated desensitization of endogenous CysLT1Rs augments multiple LTD4-stimulated cellular functions, with associated increases in intracellular signaling events. In analyses of airway smooth muscle contraction ex vivo, PKC inhibition augmented LTD4-stimulated contraction, and increased phosphoinositide hydrolysis and calcium flux in both murine and human airway smooth muscle cells. Similarly, for human monocytes, PKC inhibition augmented LTD4-stimulated calcium flux and cell migration assessed in transwell chamber experiments and also augmented LTD4-induced production of monocyte chemotactic protein assessed by ELISA. In contrast, PKC inhibition had no effect or slightly attenuated these cell functions and signaling events promoted by other receptor agonists, suggesting that despite antithetical effects on downstream events, desensitization of the CysLT1R is the principal mechanism by which PKC regulates the functional consequences of CysLT1R activation.

Hemophagocytic lymphohistiocytosis complicating influenza A infection.

During the influenza A (H3N2) season of 2003-2004, several influenza-related complications and deaths were reported in children. Hemophagocytic lymphohistiocytosis complicating influenza A infection is very rare. We report a 3-year-old girl who presented with severe pneumonia and hemophagocytic lymphohistiocytosis associated with influenza A infection. Clinicians should be aware of hemophagocytic syndrome as a serious complication of influenza A infection.

Postmortem tissue distribution of atomoxetine following fatal and nonfatal doses--three case reports.

Atomoxetine (Strattera, Lilly) is a selective norepinephrine reuptake inhibitor (SNRI) prescribed for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. It is the first nonstimulant drug-therapy option for ADHD. Three case reports are presented in which atomoxetine was detected in two individuals who died from causes unrelated to the drug and a third from the intentional ingestion of atomoxetine and other drugs. In addition, a brief description of the pharmacokinetics and side effects of atomoxetine are given. Postmortem fluid and tissue concentrations of atomoxetine were as follows: aortic blood, <0.1-8.3 mg/L; femoral blood, 0.33-5.4 mg/L; vitreous humor, 0.1-0.96 mg/L; bile, 1.0-33 g/L; urine, <0.1 mg/L; liver, <0.44-29 mg/kg; and gastric contents, 0.0097-16.8 mg total. Autopsy findings in the two cases in which death was not attributed to drug toxicity included arrhythmogenic right ventricular dysplasia and hypertrophic cardiomyopathy. The analytical method utilized was a modified basic drug, liquid-liquid procedure followed by gas chromatography/mass spectrometry and nitrogen phosphorous detection. Atomoxetine can be considered nontoxic at whole blood and liver concentrations below 1.3 mg/L and 5 mg/kg, respectively.

Mediastinal aspergilloma: a rare manifestation of a common infection with CT and pathologic correlation.

Extra-pulmonary thoracic aspergilloma is an unusual pathologic manifestation of this organism. We present a case manifesting as a mediastinal mass on chest CT causing some diagnostic difficulty and requiring surgical resection.