A Nuphar lutea plant active ingredient, 6,6'-dihydroxythiobinupharidine, ameliorates kidney damage and inflammation in a mouse model of chronic kidney disease.

Chronic Kidney Disease (CKD) associated complications are associated with increased inflammation through the innate immune response, which can be modulated with anti-inflammatory agents. An active ingredient derived from the Nuphar lutea aquatic plant, 6,6'-dihydroxythiobinupharidine (DTBN) has anti-inflammatory properties, mainly through the inhibition of NF-κB. We tested the effects of DTBN on mice with CKD. After preliminary safety and dosing experiments, we exposed 8 weeks old male C57BL/6J mice to adenine diet to induce CKD. Control and CKD animals were treated with IP injections of DTBN (25 µg QOD) or saline and sacrificed after 8 weeks. Serum urea and creatinine were significantly decreased in CKD-DTBN Vs CKD mice. Kidney histology showed a decrease in F4/80 positive macrophage infiltration, damaged renal area, as well as decreased kidney TGF-ß in CKD-DTBN Vs CKD mice. Kidney inflammation indices (IL-1ß, IL-6 and P-STAT3) were significantly decreased in CKD-DTBN as compared to CKD mice. DTBN treatment showed no apparent damage to tissues in control mice, besides a decrease in weight gain and mild hypoalbuminemia without proteinuria. Thus, DTBN significantly improved renal failure and inflammation indices in CKD mice. Therefore, this and similar substances may be considered as an additional treatment in CKD patients.

In Vitro and In Vivo Therapeutic Potential of 6,6'-Dihydroxythiobinupharidine (DTBN) from Nuphar lutea on Cells and K18-hACE2 Mice Infected with SARS-CoV-2.

We have previously published research on the anti-viral properties of an alkaloid mixture extracted from Nuphar lutea, the major components of the partially purified mixture found by NMR analysis. These are mostly dimeric sesquiterpene thioalkaloids called thiobinupharidines and thiobinuphlutidines against the negative strand RNA measles virus (MV). We have previously reported that this extract inhibits the MV as well as its ability to downregulate several MV proteins in persistently MV-infected cells, especially the P (phospho)-protein. Based on our observation that the Nuphar extract is effective in vitro against the MV, and the immediate need that the coronavirus disease 2019 (COVID-19) pandemic created, we tested here the ability of 6,6'-dihydroxythiobinupharidine DTBN, an active small molecule, isolated from the Nuphar lutea extract, on COVID-19. As shown here, DTBN effectively inhibits SARS-CoV-2 production in Vero E6 cells at non-cytotoxic concentrations. The short-term daily administration of DTBN to infected mice delayed the occurrence of severe clinical outcomes, lowered virus levels in the lungs and improved survival with minimal changes in lung histology. The viral load on lungs was significantly reduced in the treated mice. DTBN is a pleiotropic small molecule with multiple targets. Its anti-inflammatory properties affect a variety of pathogens including SARS-CoV-2 as shown here. Its activity appears to target both pathogen specific (as suggested by docking analysis) as well as cellular proteins, such as NF-κB, PKCs, cathepsins and topoisomerase 2, that we have previously identified in our work. Thus, this combined double action of virus inhibition and anti-inflammatory activity may enhance the overall effectivity of DTBN. The promising results from this proof-of-concept in vitro and in vivo preclinical study should encourage future studies to optimize the use of DTBN and/or its molecular derivatives against this and other related viruses.

A practical method for real-time detection of pedicle wall breaching during funneling.

BACKGROUND: A reliable, real-time method for the detection of pedicle wall breaching during funnelling in spine deformity surgery could be accessible to any surgeon assisted with neuromonitoring. METHODS: Fifty-six consecutive patients (1066 pedicles), who were submitted to spinal deformity surgery from December 2013 to July 2015 were included in the study group. A control group of 13 consecutive patients (226 pedicles) with spinal deformity surgery were operated on from January to December 2013 and were excluded from finder stimulation. In the study cohort, continuous stimulation during funnelling was delivered via a finder and subsequently a compound muscle action potential (CMAP) threshold was determined. Following funnelling, manual inspection of the pedicular internal walls was performed. The CMAP thresholds were compared with the results of palpation to determine the sensitivity and specificity of the technique for detecting pedicular breaching. To cover common ranges of damage, the medial and lateral breaches were compared and the concave-apical breaches compared to the non-apical or convex-apical breaches. In addition, a pedicle screw test was estimated for all patients. RESULTS: ROC analysis showed 9 mA cut-off to have a sensitivity of 88.0% and a specificity of 89.5% for predicting pedicular breaching, with an area under the curve of 0.92 (95% confidence interval 0.90-0.94; P < 0.001). Using 9 mA threshold as an alert criterion, funnelling at the concave-apical pedicles showed significantly more true and false positive alerts and fewer true negative alerts when compared with the non-apical and convex-apical pedicles (P < 0.001). Medial breaches had significantly lower stimulation thresholds than lateral breaches (P < 0.001). Thresholds of screw-testing were significantly higher for study than for control-patients (P = 0.002). CONCLUSIONS: Finder stimulation has a considerably higher sensitivity and specificity for prediction of pedicular breaching, most prominent for medial breaches. Screw-testing displayed significantly better results in patients undergoing the finder stimulation technique, as compared with the control group. The main advantages of our method are its high safety level and low cost, which may be critical in less affluent countries. LEVEL OF EVIDENCE: III.

Splenic Micronodular T-Cell/Histiocyte-Rich Large B-Cell Lymphoma: The Corticosteroid Pretreatment Hypothesis.

Splenic micronodular T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is derived from diffuse large B-cell lymphoma N.O.S., perhaps with some affinity with nodal THRLBCL. Of note, in contrast with the latter, the only lymph nodes involved in association with the splenic micronodular pattern of the disease are the splenic hilar lymph nodes. The possibility that corticosteroids, when prescribed prior to splenectomy, cause histopathological and functional modulations, apoptosis, necrosis, tissue shrinkage, which may obscure the diagnostic morphological features of this variant lymphoma and cause an underdiagnosis of this condition. The indications for glucocorticoid therapy are either related to the lymphoma itself, or else to other comorbidities, like asthma and autoimmune disorders. We propose that patients with the splenic subset of the disease are likely to have been prescribed corticosteroids prior to histopathologic examination of the involved spleen, causing disparate morphologies. However, a reviewer might accidentally dismiss the corticosteroid pretreatment which is thus overlooked. Apoptosis, induced by corticosteroids, is hypothesized as the major mechanism initiating the histopathological and functional changes in the splenic micronodular variant of the lymphoma.

Transformation of low-grade follicular lymphoma with partial marginal zone differentiation: Two cases.

Two cases of low-grade follicular lymphoma, with marginal zone differentiation and/or with high proliferation rate in one of them, are reported with transformation into high grade B-cell and B-lymphoblastic lymphomas. The contribution of these features to the transforming process, although previously described, is infrequent, and has not been deciphered to date.

Multiple Myeloma with Foamy Mott Cells.

Intracytoplasmic assorted vacuoles containing immunoglobulin collections are occasionally seen in multiple myeloma. When abundant, they impart a foamy appearance to the tumor cells, which is a potential source for diagnostic pitfalls. Herein, we report the case of a patient who presented with skeletal pain and CT confirmed lytic lesions. A bone marrow biopsy revealed multiple myeloma with unusual foamy Mott cells. The patient was subsequently treated with four cycles of cyclophosphamide, bortezomib, and dexamethasone induction therapy, followed by 3 cycles of lenalidomide with dexamethasone. A biopsy performed following initial biological and immunomodulatory drugs revealed different morphological and clonal characteristics. These features were modified again, five years later, and again, after two years of close monitoring. Hematopathologists should be aware of this morphologic variant of myeloma as well as for the capacity of clonal characteristics, such as light chain monotype, to fluctuate subsequent to treatment.

Indirect formaldehyde exposure and the appearance of respiratory symptoms.

This 70 year-old female patient, previously described as having undergone a toxicant-associated steatohepatitis during her childhood, now represents the core of a follow-up case report. After an apparent complete recovery at 13 years of age, she developed a paroxysmal dry cough, predominantly nocturnal, starting at age 24, during her first pregnancy. A seasonal recurrence was observed and bouts of cough have been resurgent at every subsequent winter. Several diagnoses, including asthma, gastro-esophageal reflux, and chronic pertussis have been suggested, as well as a sequel of her severe scoliosis, but the consequent treatments were of no avail. Moreover, repeated lung function tests have remained normal ever since. We presently propose a possible explanation for the puzzle.

Incidental Durotomy Following Transforaminal Lumbar Interbody Fusion Performed with the Modified Wiltse Approach.

PURPOSE: Incidental durotomy is an intraoperative complication that occurs in 3 to 27% of lumbar spine surgeries. It has been reported more commonly following revision spinal procedures. STUDY OBJECTIVES: To investigate the frequency of incidental durotomy while performing transforaminal lumbar interbody fusion (TLIF) using the modified Wiltse approach. A secondary goal was to compare the incidence of durotomy in patients undergoing primary spine surgery with those undergoing revision surgery. METHODS: A group of consecutive patients who had undergone (TLIF) in the last 10 years ending in 2015 were enrolled in the study. All patients underwent TLIF via the modified Wiltse approach that included a central midline skin incision, followed by a paravertebral blunt dissection of the paraspinal muscles to reach the transverse processes. The deep paravertebral dissection was done conservatively, one side at a time. Demographic and clinical data were collected when relevant to the comparison. RESULTS: The study cohort encompassed 257 patients: 200 primary cases and 57 revisions. The frequency of incidental durotomy was equal in both groups: 3.5% each (7/200 and 2/57). All durotomies were repaired primarily. No other immediate or late complications were observed during follow-up. CONCLUSION: The present study displays a limited incidence of durotomy in the primary interventions and to a lesser degree in the revisions, all of which had used a TLIF performed with the modified Wiltse approach. This procedure probably circumvented the need for further revisions.

Nuphar lutea Extracts Exhibit Anti-Viral Activity against the Measles Virus.

Different parts of Nuphar lutea L. (yellow water lily) have been used to treat several inflammatory and pathogen-related diseases. It has shown that Nuphar lutea extracts (NUP) are active against various pathogens including bacteria, fungi, and leishmanial parasites. In an effort to detect novel therapeutic agents against negative-stranded RNA (- RNA) viruses, we have tested the effect of a partially-purified alkaloid mixture of Nuphar lutea leaves on the measles virus (MV). The MV vaccine's Edmonston strain was used to acutely or persistently infect cells. The levels of several MV proteins were detected by a Western blot and immunocytochemistry. Viral RNAs were quantitated by qRT-PCR. Virus infectivity was monitored by infecting African green monkey kidney VERO cells' monolayers. We showed that NUP protected cells from acute infection. Decreases in the MV P-, N-, and V-proteins were observed in persistently infected cells and the amount of infective virus released was reduced as compared to untreated cells. By examining viral RNAs, we suggest that NUP acts at the post-transcriptional level. We conclude, as a proof of concept, that NUP has anti-viral therapeutic activity against the MV. Future studies will determine the mechanism of action and the effect of NUP on other related viruses.

Pleural Dural Fistula After Anterior Excision of Thoracic Disc Hernia: Suggested Repair Procedure.

A young woman displayed a dural tear during thoracic spine surgery. The corpectomy was by anterior approach, after thoracotomy. The dural defect was plastered by a fatty flap and a pleural layer. One month later, she exhibited a right pleural effusion. No consensual intervention is available for this complication. This dural fistula was sealed by a triple patch comprising a flap of intercostal muscles. The incidence of dural leaks following an anterior thoracic spinal surgery is infrequent but not rare. A long delay from the index surgery is unusual. Three years after the repair, the patient is free from complaints.

Classification of Solitary Plasmacytoma, Is it more Intricate than Presently Suggested? A Commentary.

A query regarding the definition and the classification of solitary plasmacytoma is apparently still pending. The clinical course, the response to treatment and the propensity to progress to plasma cell myeloma, are all a function of the classification which must be established on a firm basis. Solitary plasmacytoma should be recognized in the continuum of the plasma cell neoplasms. Moreover, whether the solitary plasmacytoma of bone and the extramedullary type of the tumor represent two distinct disease entities, exhibiting separate biological characteristics, has not been finally established. To appraise the similarities and differences between these two types of lesion, we have scrutinized recent investigations relating their classification. A commentary highlighting our conclusions follows.

Traumatic glioblastoma: commentary and suggested mechanism.

The role of head trauma in the development of glioblastoma is highly controversial and has been minimized since first put forward. This is not unexpected because skull injuries are overwhelmingly more common than glioblastoma. This paper presents a commentary based on the contributions of James Ewing, who established a major set of criteria for the recognition of an official relationship between trauma and cancer. Ewing's criteria were very stringent. The scholars who succeeded Ewing have facilitated the characterization of traumatic brain injuries since the introduction of computed tomography and magnetic resonance imaging. Discussions of the various criteria that have since developed are now being conducted, and those of an unnecessarily limiting nature are being highlighted. Three transcription factors associated with traumatic brain injury have been identified: p53, hypoxia-inducible factor-1α, and c-MYC. A role for these three transcription factors in the relationship between traumatic brain injury and glioblastoma is suggested; this role may support a cause-and-effect link with the subsequent development of glioblastoma.

Gender Differences in Spinal Injuries: Causes and Location of Injury.

BACKGROUND: Spinal injury is common in trauma suffered by both men and women. A lesser degree of involvement of females with spinal trauma, or at least, the different nature of such injuries, has been suggested. It has been proposed that behavioral and structural characteristics may explain the differential type and severity of spinal injuries in women. We carried out this study to find women-specific divergences in spinal traumatic lesions, including suspected mechanisms for their generation. METHODS: All patients with spinal injury, documented by the Trauma Registry at our Medical Center and using the AIS code 65XXXX.X for spinal fractures and dislocations, were evaluated. The women-associated analysis included data related to: type of spinal lesion, area affected, possible mechanisms, associated damage, surgical procedures, and complications. Male-related data were collected for comparison. RESULTS: Between 2006 and 2010, 546 patients with traumatic spine injuries were documented. Of those, 30.6% were women (F:M-168:378). Average age was 43.5 years (women: 49.6 years and men: 40.1 years). Regarding the mechanisms of injury, women with spinal injuries were susceptible to falls from a standing position or had attempted suicide. However, men with similar lesions had a tendency to be more involved in motorcycle accidents or falls from height. Women involved in motor vehicle crashes showed statistically more significant lumbar spine lesions, whereas men in the same situation developed mainly cervical spine damage to a significant level. CONCLUSIONS: The characteristics of spinal injury in women, as opposed to men, stand out as divergent. The mechanisms of trauma and the site of injury differ significantly. We suggest this variance may be due, in part, to skeletal and muscular structure dissimilarity in women and in part to the spinal kinematics attending each group.

Challenge of handling a Charcot spinal arthropathy with a novel hybrid fibular autograft and expandable cage.

A 26-year-old man, who was paraplegic for 6 years due to a motor vehicle accident, presented to the authors' clinic following his incapacity to withstand a sitting posture, the frequent sensation of "clicks" in his back, and a complaint of back pain while in his wheelchair. On imaging, his dorsal spine showed a complete arthrodesis of the primarily fused vertebrae. However, distal to this segment, a Charcot spinal arthropathy with subluxation of T12-L1 was evident. Repair of this complex, uncommon, late complication of his paraplegia by the frequently used fusion techniques was shown to be inappropriate. A novel and elaborate surgical procedure is presented by which a complete fusion of the affected spine was secured. A left retrodiaphragmatic approach was used. Complete corpectomy of both the T-12 and L-1 vertebrae to the preserved endplates was performed. Most of the patient's fibula was resected and shaped for engrafting. The segment of the fibula was introduced into a mesh cage, before its intramedullary implantation into the T-12 and L-1 vertebrae. This 2-step procedure combined the hybrid use of a fibular autograft and an expandable mesh cage, incorporated one into the other, in an innovative intramedullary position. This intervention allowed the patient to resume his former condition as an extremely physically active patient with paraplegia. Nine years later, an asymptomatic early-stage Charcot spine was found at L5-S1, but no treatment is planned at this point.

Composite Nasopharyngeal plasmacytoma with nodal paraimmunoblastic variant of small lymphocytic lymphoma: A case report.

A 78-year-old male who presented with severe shortness of breath and bilateral nasal congestion was shown to exhibit ta mass localized in the nasopharynx. The tumor was diagnosed as an extramedullary plasmacytoma. Peripheral blood eosinophilia had been persistently noted in the preceding 12 years. The plasmacytoma exhibited a predominance of κ-light chain monotypic Mott cells and was admixed with numerous eosinophils. No history of allergic rhinitis, asthma or aspirin sensitivity was elicited. An axillary lymph node was excised two weeks after the nasopharyngeal biopsy, and it exhibited a paraimmunoblastic transformation of small lymphocytic lymphoma. A review of the literature identified few occurrences of such simultaneous tumors in individual patients.

Toxicant-associated steatohepatitis: à propos a case of benzene exposure.

An attempted interpretation of recurrent episodes of hepatitis in a girl at ages 6 and 13 years, which were followed by an interval of 35 years of apparent good health, is reported. A subsequent transient incidence of a halothane hypersensitivity reaction at age 48 years led to the disclosure of negative hepatitis A, B and C antigenicity. A tentative diagnosis may be reached if we accept, at its face value, the statement that a toy that the child played with before each hepatitis episode carried a very high benzene content. The toy was a "pate-à-ballon" or "magic balloon," and it can carry a benzene content that is seven to nine times higher than the traditionally authorized concentration.

VDAC1 is a molecular target in glioblastoma, with its depletion leading to reprogrammed metabolism and reversed oncogenic properties.

BACKGROUND: Glioblastoma (GBM), an aggressive brain tumor with frequent relapses and a high mortality, still awaits an effective treatment. Like many cancers, GBM cells acquire oncogenic properties, including metabolic reprogramming, vital for growth. As such, tumor metabolism is an emerging avenue for cancer therapy. One relevant target is the voltage-dependent anion channel 1 (VDAC1), a mitochondrial protein controlling cell energy and metabolic homeostasis. METHODS: We used VDAC1-specific short interfering (si)RNA (si-VDAC1) to treat GBM cell lines and subcutaneous or intracranial-orthotopic GBM xenograft mouse models. Tumors were monitored using MRI, immunohistochemistry, immunoblotting, immunofluorescence, quantitative real-time PCR, transcription factor expression, and DNA microarray analyses. RESULTS: Silencing VDAC1 expression using si-VDAC1 in 9 glioblastoma-related cell lines, including patient-derived cells, led to marked decreases in VDAC1 levels and cell growth. Using si-VDAC1 in subcutaneous or intracranial-orthotopic GBM models inhibited tumor growth and reversed oncogenic properties, such as reprogrammed metabolism, stemness, angiogenesis, epithelial-mesenchymal transition, and invasiveness. In cells in culture, si-VDAC1 inhibits cancer neurosphere formation and, in tumors, targeted cancer stem cells, leading to their differentiation into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks. CONCLUSION: VDAC1 offers a target for GBM treatment, allowing for attacks on the interplay between metabolism and oncogenic signaling networks, leading to tumor cell differentiation into neuron- and astrocyte-like cells. Simultaneously attacking all of these processes, VDAC1 depletion overcame GBM heterogeneity and can replace several anticancer drugs that separately target angiogenesis, proliferation, or metabolism.

Angioimmunoblastic T-Cell Lymphoma: A Questionable Association with Follicular Dendritic Cell Sarcoma.

An elderly woman presented with generalized lymphadenopathy, several systemic symptoms, and splenomegaly. An inguinal lymph node excision revealed a compound picture. One aspect of the lymph node morphology, including cells with follicular T-helper cell phenotype, was most consistent with angioimmunoblastic T-cell lymphoma. The other component, revealing spindle cells forming whorls with immunostaining for CD21, CD23, and fascin, might be an integral part of this T-cell lymphoma. However, due to the often massive involvement of the nodal tissue by these follicular dendritic cells, these areas were questionably suggestive of involvement by follicular dendritic cell sarcoma. We raise herein the issue of the borderline area between advanced follicular dendritic cell expansion in angioimmunoblastic T-cell lymphoma and a massive follicular dendritic cell proliferation consistent with follicular dendritic cells sarcoma, in the absence of a genomic analysis.

Malignant Melanoma in Association With a Thymic Nevus in a Patient With a Giant Congenital Nevus.

Nevi and melanocytic proliferations are known to appear in multiple extracutaneous sites, including lymph nodes and meninges. We report a case of an anterior mediastinal mass in a patient with a giant congenital nevus and neurofibromatosis type I. Histologically, the tumor was found to be a malignant melanoma in the thymus arising in association with a nevus that involved most of the thymic tissue. There was no sign of cutaneous melanoma on skin examination. We suggest that the tumor originated from the benign nevus in the thymus, a rare extracutaneous location for nevi and malignant melanoma.

Lymphangiogenesis in Classical Hodgkin Lymphoma - Preliminary Study with Clinicopathological Correlations.

A role for lymphangiogenesis in metastatic breast and prostate cancers has been suggested recently. The relevance of lymphangiogenesis in cancer as a rule, and more specifically in classical Hodgkin lymphoma, is poorly understood in comparison with that of angiogenesis. In a preliminary (pilot) study we have investigated the role of lymphatic vessels growth in 19 cases of classical Hodgkin lymphoma stained with the D2-40 (podoplanin) antibody. In each case, three lymphatic vessels hot spots were scrutinized twice. Of the 57 hot spots thus identified, we chose 15 at random for photography, microvessel counting and image analysis. We determined the mean perimeter, surface area, major axis length and complexity factor for each hot spot and correlated them with clinical and biological features of classical Hodgkin lymphoma. No correlations were found with clinical features. No associations were noted with the standard immuno-markers of classical Hodgkin lymphoma. However, significant inverse correlations were shown with pRb, BAX and IκB-α expression. The mean lymphatic major axis length was inversely correlated with the complexity factor. Last, we carried out an additional clinicopathological correlation of the expression of pRb, BAX and IκB-α in a cohort of classical Hodgkin lymphoma patients previously published.