scholarly journals Inhibition of Clostridioides difficile Toxins TcdA and TcdB by Ambroxol

2022 ◽  
Vol 12 ◽  
Author(s):  
Sebastian Heber ◽  
Lara Barthold ◽  
Jan Baier ◽  
Panagiotis Papatheodorou ◽  
Giorgio Fois ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Morphological Changes ◽  
Therapeutic Option ◽  
Small Gtpases ◽  
Target Cells ◽  
Cytotoxic Activities ◽  
Intracellular Enzyme ◽  
Early Endosomes ◽  
Endosomal Acidification ◽  
Enzyme Subunits

Clostridioides (C.) difficile produces the exotoxins TcdA and TcdB, which are the predominant virulence factors causing C. difficile associated disease (CDAD). TcdA and TcdB bind to target cells and are internalized via receptor-mediated endocytosis. Translocation of the toxins’ enzyme subunits from early endosomes into the cytosol depends on acidification of endosomal vesicles, which is a prerequisite for the formation of transmembrane channels. The enzyme subunits of the toxins translocate into the cytosol via these channels where they are released after auto-proteolytic cleavage. Once in the cytosol, both toxins target small GTPases of the Rho/Ras-family and inactivate them by mono-glucosylation. This in turn interferes with actin-dependent processes and ultimately leads to the breakdown of the intestinal epithelial barrier and inflammation. So far, therapeutic approaches to treat CDAD are insufficient, since conventional antibiotic therapy does not target the bacterial protein toxins, which are the causative agents for the clinical symptoms. Thus, directly targeting the exotoxins represents a promising approach for the treatment of CDAD. Lately, it was shown that ambroxol (Ax) prevents acidification of intracellular organelles. Therefore, we investigated the effect of Ax on the cytotoxic activities of TcdA and TcdB. Ax significantly reduced toxin-induced morphological changes as well as the glucosylation of Rac1 upon intoxication with TcdA and TcdB. Most surprisingly, Ax, independent of its effects on endosomal acidification, decreased the toxins’ intracellular enzyme activity, which is mediated by a catalytic glucosyltransferase domain. Considering its undoubted safety profile, Ax might be taken into account as therapeutic option in the context of CDAD.

Off-Pump Supraarterial Decompression Myotomy for Myocardial Bridging

2005 ◽  
Vol 8 (1) ◽  
pp. 49 ◽  
Author(s):  
Mersa M. Baryalei ◽  
Theodorus Tirilomis ◽  
Wolfgang Buhre ◽  
Stephan Kazmaier ◽  
Friedrich A. Schoendube ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Exercise Testing ◽  
Clinical Symptoms ◽  
Therapeutic Option ◽  
Median Sternotomy ◽  
Myocardial Bridging ◽  
Off Pump ◽  
Hemodynamic Compromise ◽  
Artery Disease ◽  
The Right

Background: Myocardial bridging of the left anterior descending (LAD) artery may result in clinical symptoms. Surgery with cardiopulmonary bypass (CPB) is a therapeutic option with considerable risk. We hypothesized that off-pump supraarterial myotomy could be an effective treatment modality. Methods: Between October 1998 and May 2000, 13 patients were referred for surgery. All were symptomatic despite medical therapy. Anteroseptal ischemia had been proven by thallium scintigraphy in all 13 patients, exercise testing was positive in 11. All patients were operated on with an off-pump approach after median sternotomy. Results: Mean patient age was 61 8 years (range, 43-71 years). Coronary artery disease mandating additional bypasses was present in 3 patients. The bypasses were done off pump in 2 patients. Conversion to on-pump surgery was necessary in 3 of 13 patients (23%) because of hemodynamic compromise (1 patient), opening of the right ventricle (1 patient), and injury to the LAD (1 patient). Supraarterial myotomy was performed in all patients. One patient who underwent surgery with CPB developed postoperative anteroseptal myocardial infarction. Postoperative exercise testing was performed in all patients and did not reveal any persistent ischemia. Mortality was 0%. All patients were free from symptoms and had not undergone repeat interventions after an average of 51 7 months of follow-up. Conclusions: Off-pump supraarterial myotomy effectively relieves coronary obstruction but has a certain periprocedural risk as evidenced by 1 myocardial infarction, 1 right ventricular injury, and 1 LAD injury. Long-term freedom from symptoms and from reintervention favor further investigation of this surgical therapy.

scholarly journals Chondrosternal Arthritis in Infant: An Unusual Entity

2014 ◽  
Vol 2014 ◽  
pp. 1-4
Author(s):  
Athina Nikolarakou ◽  
Dana Dumitriu ◽  
Pierre-Louis Docquier
Keyword(s):  
Clinical Symptoms ◽  
Therapeutic Option ◽  
White Blood Cells ◽  
Laboratory Data ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
History Of ◽  
Local Tenderness ◽  
Wait And See

Primary arthritis of chondrosternal joint is very rare and occurs in infants less than 18 months of age. Presentation is most often subacute but may be acute. Child presents with a parasternal mass with history of fever and/or local signs of infection. Clinical symptoms vary from a painless noninflammatory to a painful mass with local tenderness and swelling, while fever may be absent. Laboratory data show low or marginally raised levels of white blood cells and C-reactive protein, reflecting, respectively, the subacute or acute character of the infection. It is a self-limiting affection due to the adequate immune response of the patient. Evolution is generally good without antibiotherapy with a progressive spontaneous healing. A wait-and-see approach with close follow-up in the first weeks is the best therapeutic option.

scholarly journals Evidence of Human Parvovirus B19 Infection in the Post-Mortem Brain Tissue of the Elderly

Viruses ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 582 ◽  
Author(s):  
Sandra Skuja ◽  
Anda Vilmane ◽  
Simons Svirskis ◽  
Valerija Groma ◽  
Modra Murovska
Keyword(s):  
White Matter ◽  
Frontal Lobe ◽  
Brain Tissue ◽  
Morphological Changes ◽  
Structural Characteristics ◽  
Parvovirus B19 ◽  
Elderly Subjects ◽  
Target Cells ◽  
Human Parvovirus B19 ◽  
Pathogenic Potential

After primary exposure, the human parvovirus B19 (B19V) genome may remain in the central nervous system (CNS), establishing a lifelong latency. The structural characteristics and functions of the infected cells are essential for the virus to complete its life cycle. Although B19V has been detected in the brain tissue by sequencing PCR products, little is known about its in vivo cell tropism and pathogenic potential in the CNS. To detect B19V and investigate the distribution of its target cells in the CNS, we studied brain autopsies of elderly subjects using molecular virology, and optical and electron microscopy methods. Our study detected B19V in brain tissue samples from both encephalopathy and control groups, suggesting virus persistence within the CNS throughout the host’s lifetime. It appears that within the CNS, the main target of B19V is oligodendrocytes. The greatest number of B19V-positive oligodendrocytes was found in the white matter of the frontal lobe. The number was significantly lower in the gray matter of the frontal lobe (p = 0.008) and the gray and white matter of the temporal lobes (p < 0.0001). The morphological changes observed in the encephalopathy group, propose a possible B19V involvement in the demyelination process.

scholarly journals HIV-1 uncoating occurs via a series of rapid biomechanical changes in the core related to individual stages of reverse transcription

2021 ◽  
Author(s):  
Sanela Rankovic ◽  
Akshay Deshpande ◽  
Shimon Harel ◽  
Christopher Aiken ◽  
Itay Rousso
Keyword(s):  
Reverse Transcription ◽  
Viral Genome ◽  
Morphological Changes ◽  
Viral Capsid ◽  
Target Cells ◽  
Viral Core ◽  
Successful Infection ◽  
Capsid Shell ◽  
Hiv 1

AbstractThe HIV core consists of the viral genome and associated proteins encased by a cone-shaped protein shell termed the capsid. Successful infection requires reverse transcription of the viral genome and disassembly of the capsid shell within a cell in a process known as uncoating. The integrity of the viral capsid is critical for reverse transcription, yet the viral capsid must be breached to release the nascent viral DNA prior to integration. We employed atomic force microscopy to study the stiffness changes in HIV-1 cores during reverse transcription in vitro in reactions containing the capsid-stabilizing host metabolite IP6. Cores exhibited a series of stiffness spikes, with up to three spikes typically occurring between 10-30, 40-80, and 120-160 minutes after initiation of reverse transcription. Addition of the reverse transcriptase (RT) inhibitor efavirenz eliminated the appearance of these spikes and the subsequent disassembly of the capsid, thus establishing that both result from reverse transcription. Using timed addition of efavirenz, and analysis of an RNAseH-defective RT mutant, we established that the first stiffness spike requires minus-strand strong stop DNA synthesis, with subsequent spikes requiring later stages of reverse transcription. Additional rapid AFM imaging experiments revealed repeated morphological changes in cores that were temporally correlated with the observed stiffness spikes. Our study reveals discrete mechanical changes in the viral core that are likely related to specific stages of reverse transcription. Our results suggest that reverse-transcription-induced changes in the capsid progressively remodel the viral core to prime it for temporally accurate uncoating in target cells.

scholarly journals Lectin Activity of the TcdA and TcdB Toxins ofClostridium difficile

2018 ◽  
Vol 87 (3) ◽  
Author(s):  
Lauren E. Hartley-Tassell ◽  
Milena M. Awad ◽  
Kate L. Seib ◽  
Maria Scarselli ◽  
Silvana Savino ◽  
...  
Keyword(s):  
Blood Group ◽  
Small Gtpases ◽  
Lewis Antigens ◽  
Target Cells ◽  
Ofclostridium Difficile ◽  
Content Type ◽  
Affinity Ligand ◽  
Wide Range ◽  
Hospital Acquired

ABSTRACTClostridium difficileis a major cause of hospital-acquired antibiotic-associated diarrhea.C. difficileproduces two cytotoxins, TcdA and TcdB; both toxins are multidomain proteins that lead to cytotoxicity through the modification and inactivation of small GTPases of the Rho/Rac family. Previous studies have indicated that host glycans are targets for TcdA and TcdB, with interactions thought to be with both α- and β-linked galactose. In the current study, screening of glycan arrays with different domains of TcdA and TcdB revealed that the binding regions of both toxins interact with a wider range of host glycoconjugates than just terminal α- and β-linked galactose, including blood groups, Lewis antigens,N-acetylglucosamine, mannose, and glycosaminoglycans. The interactions of TcdA and TcdB with ABO blood group and Lewis antigens were assessed by surface plasmon resonance (SPR). The blood group A antigen was the highest-affinity ligand for both toxins. Free glycans alone or in combination were unable to abolish Vero cell cytotoxicity by TcdB. SPR competition assays indicate that there is more than one glycan binding site on TcdB. Host glycoconjugates are common targets of bacterial toxins, but typically this binding is to a specific structure or related structures. The binding of TcdA and TcdB is to a wide range of host glycans providing a wide range of target cells and tissuesin vivo.

scholarly journals Preliminary evaluation of the endovascular treatment of intracranial aneurysms with detachable coils in vigil patients

2006 ◽  
Vol 64 (4) ◽  
pp. 899-904
Author(s):  
José Roberto Falco Fonseca ◽  
Nitamar Abdala ◽  
Dárcio Roberto Nalli ◽  
Marcos Hideki Idagawa ◽  
João de Deus da Costa Alves Jr ◽  
...  
Keyword(s):  
Endovascular Treatment ◽  
General Anaesthesia ◽  
Intracranial Aneurysms ◽  
Clinical Symptoms ◽  
Therapeutic Option ◽  
Mortality Rates ◽  
Psychological Characteristics ◽  
Preliminary Evaluation ◽  
Detachable Coils

Endovascular treatment of intracranial aneurysms with coil embolization became the most important therapeutic option with better morbidity and mortality rates and quality of life. Following immobility, patients are treated with general anaesthesia. OBJECTIVE: To test viability of endovascular treatment on wake patients. METHOD: Considering clinical symptoms, psychological characteristics and aneurysmal morphology, four patients with five intracranial aneurysms were selected. RESULTS: Four among five cases were completed with this technique. Patient 1 was partially treated after 75 minutes presenting vesical stress. Patient 2 presented subarachnoid hemorrhage after aneurysmal re-rupture, and the procedure was completed under general anaesthesia. The other three patients presented no intercurrences during the treatment. CONCLUSION: Endovascular treatment on wake patients with intracranial aneurysm can be an alternative to a selected group of patients.

Pulmonary aspergilloma: from classification to management

2019 ◽  
Vol 28 (1) ◽  
pp. 33-38 ◽  
Author(s):  
Hicham Harmouchi ◽  
Rabiou Sani ◽  
Ibrahim Issoufou ◽  
Marouane Lakranbi ◽  
Yassine Ouadnouni ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Respiratory Failure ◽  
Clinical Symptoms ◽  
Therapeutic Option ◽  
Severe Respiratory Failure ◽  
Poor General Condition ◽  
Thoracic Computed Tomography ◽  
Life Threatening ◽  
Pulmonary Aspergilloma ◽  
Pulmonary Cavity

Pulmonary aspergilloma is a form of aspergillosis characterized by the colonization of a preexisting pulmonary cavity, most often of tuberculosis origin. Clinical symptoms are predominately hemoptysis that can be life-threatening, and thoracic computed tomography can distinguish simple from complex pulmonary aspergilloma. The best therapeutic option remains surgery which allows surgical resection of the mycetoma and the underlying cavity. Nonsurgical treatment is performed in inoperable patients because of severe respiratory failure or a poor general condition.

Functional Improvement of Chimeric Antigen Receptor Through Intrinsic Interleukin-15Rα Signaling

2019 ◽  
Vol 19 (1) ◽  
pp. 40-53 ◽  
Author(s):  
Sushmita Nair ◽  
Jing-Bo Wang ◽  
Shih-Ting Tsao ◽  
Yuchen Liu ◽  
Wei Zhu ◽  
...  
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Target Cell ◽  
Intracellular Signaling ◽  
Lymphoblastic Leukemia ◽  
Antigen Receptor ◽  
Functional Improvement ◽  
Target Cells ◽  
Cytotoxic Activities ◽  
Immune Effector

<P>Introduction: Recent studies on CD19-specific chimeric antigen receptor (CAR)-modified T cells (CARTs) have demonstrated unprecedented successes in treating refractory and relapsed B cell malignancies. The key to the latest CART therapy advances can be attributed to the improved costimulatory signals in the CAR design. </P><P> Methods: Here, we established several novel CARs by incorporating T cell signaling domains of CD28 in conjunction with intracellular signaling motif of 4-1BB, CD27, OX40, ICOS, and IL-15Rα. These novel CARs were functionally assessed based on a simple target cell killing assay. </P><P> Results: The results showed that the CD28/IL-15R&#945; co-signaling (153z) CAR demonstrated the fastest T cell expansion potential and cytotoxic activities. IL-15 is a key cytokine that mediates immune effector activities. The 153z CARTs maintained prolonged killing activities after repetitive rounds of target cell engagement. Consistent with the enhanced target killing function, the 153z CARTs produced increased amount of effector cytokines including IFN-&#947;, TNF&#945; and IL-2 upon interaction with the target cells. </P><P> Conclusion: In a follow-up clinical study, an acute lymphoblastic leukemia (ALL) patient, who experienced multiple relapses of central nervous system leukemia (CNSL) and failed all conventional therapies, was enrolled to receive the CD19-specific 153z CART treatment. The patient achieved complete remission after the 153z CART cell infusion. The translational outcome supports further investigation into the safety and enhanced therapeutic efficacy of the IL-15Rα-modified CART cells in cancer patients.</P>

Analysis of therapeutic choices for slit ventricle syndrome after cyst-peritoneal shunting for temporal arachnoid cysts in children

2010 ◽  
Vol 6 (5) ◽  
pp. 474-480 ◽  
Author(s):  
Tie Fang ◽  
Jinshan Xu ◽  
Shejun Wang ◽  
Zhenyu Ma ◽  
Jian Xing
Keyword(s):  
Temporal Lobe ◽  
Clinical Symptoms ◽  
Morphological Changes ◽  
Arachnoid Cysts ◽  
Slit Ventricle Syndrome ◽  
Delayed Treatment ◽  
Radiological Data ◽  
Programmable Valve ◽  
Slit Ventricle ◽  
Radiological Studies

Object The goal in this study was to investigate early diagnostic evidence, optimal therapeutic strategies, and prophylactic methods for slit ventricle syndrome (SVS) in patients with temporal lobe arachnoid cysts who received cyst-peritoneal (CP) shunts. Methods Six cases of SVS in patients with temporal lobe arachnoid cysts who received CP shunts were treated by the senior authors in 2 institutions between January 2005 and January 2009. The radiological data, treatment process, and therapeutic results were reviewed retrospectively. Results There were 4 boys and 2 girls, whose mean age at presentation was 4 years and 1 month. The main clinical symptoms were severe headache, nausea, vomiting, and decreasing eyesight. Radiological studies showed normal or slightly smaller than normal ventricles, and arachnoid cysts that had shrunk dramatically. The most effective treatment for SVS was to replace the original shunts with devices that had a programmable valve, or if this was unsuccessful, to replace the original shunts with ventriculoperitoneal (VP) shunts. All symptoms in these patients disappeared, and the mean follow-up duration was 24 months. Conclusions The SVS presents more often in patients with hydrocephalus who undergo VP shunting. However, it is also a serious complication in patients with arachnoid cysts who receive a CP shunt. The SVS is not a single condition; rather, different pathophysiological conditions can underlie this complicated syndrome. Because there are no striking morphological changes on radiological studies of the SVS in the patients with CP shunts, it is not easy for this syndrome to be diagnosed in time and treated rationally. Misdiagnosis and delayed treatment usually occur. The use of programmable shunts or VP shunts to replace the original shunt is an optimal therapeutic choice. The use of low-pressure shunts to treat arachnoid cysts should be abandoned unless dictated by specific indications.

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