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Article ; Online: Pro-inflammatory interactions of streptolysin O toxin with human neutrophils

Joseph, D / Theron, A J / Feldman, C / Anderson, R / Tintinger, G R

2024 Volume 21, Issue 1, Page(s) 2345152

Abstract: The recent global resurgence of severe infections caused by the Group A streptococcus (GAS) pathogen, ...

Abstract	The recent global resurgence of severe infections caused by the Group A streptococcus (GAS) pathogen,
MeSH term(s)	Humans ; Streptolysins/metabolism ; Neutrophils/immunology ; Neutrophils/metabolism ; Neutrophils/drug effects ; Streptococcus pyogenes/immunology ; Bacterial Proteins/metabolism ; Reactive Oxygen Species/metabolism ; Calcium/metabolism ; Extracellular Traps/immunology ; Extracellular Traps/metabolism ; Pancreatic Elastase/metabolism ; Cells, Cultured ; Neutrophil Activation/drug effects ; Streptococcal Infections/immunology ; Cell Degranulation/drug effects ; Inflammation/immunology
Chemical Substances	Streptolysins ; streptolysin O ; Bacterial Proteins ; Reactive Oxygen Species ; Calcium (SY7Q814VUP) ; Pancreatic Elastase (EC 3.4.21.36)
Language	English
Publishing date	2024-04-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2205064-4
ISSN	1547-6901 ; 1547-691X
ISSN (online)	1547-6901
ISSN	1547-691X
DOI	10.1080/1547691X.2024.2345152
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Article ; Online: Adverse effects of biologic anti-inflammatory agents on the respiratory system: A review.

Joseph, D / Tintinger, G R / Ker, J A / Pannell, N

African journal of thoracic and critical care medicine

2021 Volume 27, Issue 2

Abstract: The therapy of autoimmune rheumatological conditions has undergone significant changes with the introduction of biologic antiinflammatory agents including cytokine antagonists and agents that interfere with the function of T and B cells or those that ... ...

Abstract	The therapy of autoimmune rheumatological conditions has undergone significant changes with the introduction of biologic antiinflammatory agents including cytokine antagonists and agents that interfere with the function of T and B cells or those that inhibit intracellular enzymes such as Janus kinase (JAK). Although useful to control inflammation, these agents may be associated with druginduced lung disease, which may be difficult to differentiate from pulmonary disorders caused by the underlying autoimmune diseases. This review aims to provide a description of lung disease, both infectious and non-infectious, that may be induced by the administration of biologic anti-inflammatory agents with emphasis on inhibitors of tumour necrosis factor, interleukin-1, interleukin-6 and JAK.
Language	English
Publishing date	2021-06-23
Publishing country	South Africa
Document type	Journal Article ; Review
ZDB-ID	2945902-3
ISSN	2617-0205 ; 2617-0191
ISSN (online)	2617-0205
ISSN	2617-0191
DOI	10.7196/AJTCCM.2021.v27i2.117
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Article ; Online: Ex vivo platelet morphology assessment of chronic myeloid leukemia patients before and after Imatinib treatment.

Repsold, Lisa / Pool, Roger / Karodia, Mohammed / Tintinger, Gregory / Joubert, Anna Margaretha

Microscopy research and technique

2022 Volume 85, Issue 6, Page(s) 2222–2233

Abstract: Chronic myeloid leukemia (CML) is a myeloproliferative disease and the first line treatment is through the administration of Imatinib, a first generation tyrosine kinase inhibitor. Thrombocytosis and bleeding irregularities are common in CML, however, ... ...

Abstract	Chronic myeloid leukemia (CML) is a myeloproliferative disease and the first line treatment is through the administration of Imatinib, a first generation tyrosine kinase inhibitor. Thrombocytosis and bleeding irregularities are common in CML, however, the morphological variations in CML patients' platelets are not well documented. In this study, ex vivo platelet morphology of control participants, as well as CML patients were assessed before and after Imatinib treatment. The topographical and structural morphology of platelets were determined via scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Qualitative data of SEM and TEM revealed that CML patient's platelets were prone to aggregation and coagulation at time of diagnosis; the samples that were not aggregated at time of diagnosis showed typical discoid shaped platelets, which was comparable to control participants' platelets. TEM results of CML patients' platelets at diagnosis showed that internal granular constituents including dense bodies were decreased in comparison to control participants. In all CML patients, platelets appeared activated after 6 months of treatment with Imatinib with membrane structure abnormalities and constituent variations. Research to date has primarily focused on the effects of CML on leukocyte populations, however, the results of the current study implicate the impact of CML pathogenesis on platelets, seemingly as a result of alterations in normal hematopoiesis. In addition, the impact of Imatinib treatment on platelet morphology was also established, indicating an increase in platelet activation. Recognizing and understanding the impact of CML disease progression on platelets is of importance to aid improved patient treatment. RESEARCH HIGHLIGHTS: In the study, results from SEM and TEM indicated that CML patient's platelets were prone to aggregation at time of diagnosis, and activation after Imatnib treatment. Platelet samples that did not aggregate had decreased internal granular constituents.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Blood Platelets ; Humans ; Imatinib Mesylate/pharmacology ; Imatinib Mesylate/therapeutic use ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology ; Protein Kinase Inhibitors/adverse effects
Chemical Substances	Antineoplastic Agents ; Protein Kinase Inhibitors ; Imatinib Mesylate (8A1O1M485B)
Language	English
Publishing date	2022-02-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	1099714-3
ISSN	1097-0029 ; 1059-910X
ISSN (online)	1097-0029
ISSN	1059-910X
DOI	10.1002/jemt.24079
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Article ; Online: Lymphopenia and IgG2 subclass deficiency in patients with severe COVID-19 pneumonia.

Taban, E M / Tintinger, G R / Joseph, D / Gaylard, P / Richards, G

African journal of thoracic and critical care medicine

2021 Volume 27, Issue 2

Abstract: Background: COVID-19 caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) manifests with a range of disease severities. A small proportion of COVID-19 patients are severely ill; however, a significant proportion of these ... ...

Abstract	Background: COVID-19 caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) manifests with a range of disease severities. A small proportion of COVID-19 patients are severely ill; however, a significant proportion of these patients are critically ill, and require admission and mechanical ventilation, which is associated with a high mortality. Objective: To identify factors that may predispose patients with COVID-19 to severe disease that requires mechanical ventilation (MV). Methods: We performed a retrospective audit of patients admitted with COVID-19 pneumonia to the intensive care unit (ICU) and medical wards to evaluate the potential associations between comorbid conditions, lymphopenia and IgG subclass deficiency with a need for MV. Results: A total of 51 patients were included in the study. Almost half of the patients (47%; n=24) were documented to have IgG2 deficiency, 43% (n=22) had lymphopenia and 37% (n=19) had combined lymphopenia and IgG2 subclass deficiency. Of the 24 patients who required MV, 75% had IgG2 subclass deficiency, 73% had lymphopenia and 50% had both. The relative risk for requiring MV was 2.64, 3.38 and 2.81 for lymphopenia, IgG2 subclass deficiency and both, respectively. Conclusion: These findings suggest that lymphopenia, low IgG2 concentrations or the combination of both may be used to identify patients with severe COVID-19 that are at increased risk for MV. This may facilitate earlier identification of patients at high risk, who may benefit from more intensive therapy.
Language	English
Publishing date	2021-03-30
Publishing country	South Africa
Document type	Journal Article
ZDB-ID	2945902-3
ISSN	2617-0205 ; 2617-0191
ISSN (online)	2617-0205
ISSN	2617-0191
DOI	10.7196/AJTCCM.2021.v27i2.134
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Article ; Online: Pulmonary nodules associated with JAK inhibitor therapy in rheumatoid arthritis: A case report.

Pannell, N / Joseph, D / Ally, M M T M / Bida, N M / Tintinger, G R

African journal of thoracic and critical care medicine

2021 Volume 27, Issue 3

Abstract: Patients with rheumatoid arthritis (RA) may receive Janus kinase (JAK) inhibitors to achieve optimal control of their disease. We report a case of a patient who received a selective JAK1 inhibitor and subsequently developed multiple pulmonary nodules ... ...

Abstract	Patients with rheumatoid arthritis (RA) may receive Janus kinase (JAK) inhibitors to achieve optimal control of their disease. We report a case of a patient who received a selective JAK1 inhibitor and subsequently developed multiple pulmonary nodules with cavitation. Biopsies confirmed the presence of cryptococcosis and the patient responded well to anti-fungal therapy.
Language	English
Publishing date	2021-10-04
Publishing country	South Africa
Document type	Case Reports
ZDB-ID	2945902-3
ISSN	2617-0205 ; 2617-0191
ISSN (online)	2617-0205
ISSN	2617-0191
DOI	10.7196/AJTCCM.2021.v27i3.116
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Article: The COVID-19 Treatment Landscape: A South African Perspective on a Race Against Time.

Hendricks, Candice Laverne / Herd, Candice / Nel, Marcel / Tintinger, Gregory / Pepper, Michael Sean

Frontiers in medicine

2021 Volume 8, Page(s) 604087

Abstract: The pandemic caused by SARS-CoV-2 has infected more than 94 million people worldwide (as of 17 January 2020). Severe disease is believed to be secondary to the cytokine release syndrome (CRS or "cytokine storm") which causes local tissue damage as well ... ...

Abstract	The pandemic caused by SARS-CoV-2 has infected more than 94 million people worldwide (as of 17 January 2020). Severe disease is believed to be secondary to the cytokine release syndrome (CRS or "cytokine storm") which causes local tissue damage as well as multi-organ dysfunction and thrombotic complications. Due to the high mortality rates in patients receiving invasive ventilation, practice has changed from "early-intubation" for acute respiratory distress syndrome (ARDS) to a trial of non-invasive ventilation (NIV) or high flow nasal cannula (HFNC) oxygen. Reports indicating the benefit of NIV and HFNC have been encouraging and have led to more than 20,000 such devices being manufactured and ready for roll-out in South Africa (SA) as of July 2020. The need to identify drugs with clear clinical benefits has led to an array of clinical trials, most of which are repurposing drugs for COVID-19. The treatment landscape reflects the need to target both the virus and its effects such as the CRS and thrombotic complications. Conflicting results have the potential to confuse the implementation of coordinated treatment strategies and guidelines. The purpose of this review is to address pertinent areas in the current literature on the available medical treatment options for COVID-19. Remdesivir, tocilizumab, and dexamethasone are some of the treatment options that have shown the most promise, but further randomized trials are required to particularly address timing and dosages to confidently create standardized protocols. For the SA population, two healthcare sectors exist. In the private sector, patients with medical insurance may have greater access to a wider range of treatment options than those in the public sector. The latter serves >80% of the population, and resource constraints require the identification of drugs with the most cost-effective use for the greatest number of affected patients.
Language	English
Publishing date	2021-02-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2775999-4
ISSN	2296-858X
ISSN	2296-858X
DOI	10.3389/fmed.2021.604087
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Article ; Online: Apoptotic profiling of chronic myeloid leukaemia patients' platelets ex vivo before and after treatment with Imatinib.

Repsold, Lisa / Pool, Roger / Karodia, Mohammed / Tintinger, Gregory / Becker, Piet / Joubert, Anna Margaretha

Cell biochemistry and function

2021 Volume 39, Issue 4, Page(s) 562–570

Abstract: Chronic myeloid leukaemia (CML) is a malignancy of the haematopoietic stem cells. The first line of treatment for CML, especially in developing countries, remains the first-generation tyrosine kinase inhibitor, Imatinib. Patients with CML are frequently ... ...

Abstract	Chronic myeloid leukaemia (CML) is a malignancy of the haematopoietic stem cells. The first line of treatment for CML, especially in developing countries, remains the first-generation tyrosine kinase inhibitor, Imatinib. Patients with CML are frequently diagnosed with platelet abnormalities. However, the specific mechanism of platelet abnormalities in CML remains unclear and poorly understood. The aim of this study was therefore to determine the apoptotic profiles of CML patients ex vivo on platelets before and after treatment with Imatinib. Blood samples of healthy volunteers and CML patients at diagnosis and after 6 months treatment with Imatinib were collected. Platelet counts, viability and activation were determined. Results showed that CML patients' platelet counts were elevated upon diagnosis and these levels statistically significantly decreased after 6 months of treatment. Platelet activation was significantly increased after 6 months of treatment compared to levels at diagnosis (P-value < .05). Similarly, platelet apoptosis was also increased after 6 months of treatment. Abnormalities in platelet functioning found in this study may partly be due to clonal proliferation of haematopoietic cells in CML patients, specifically of megakaryocyte precursors as well as the inhibition of platelet tyrosine kinase's and the inhibition of platelet-derived growth factor.
MeSH term(s)	Adolescent ; Adult ; Antineoplastic Agents/blood ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Female ; Humans ; Imatinib Mesylate/blood ; Imatinib Mesylate/pharmacology ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy ; Male ; Middle Aged ; Platelet Activation/drug effects ; Platelet-Derived Growth Factor/antagonists & inhibitors ; Platelet-Derived Growth Factor/metabolism ; Protein Kinase Inhibitors/blood ; Protein Kinase Inhibitors/pharmacology ; Protein-Tyrosine Kinases/antagonists & inhibitors ; Protein-Tyrosine Kinases/metabolism ; Young Adult
Chemical Substances	Antineoplastic Agents ; Platelet-Derived Growth Factor ; Protein Kinase Inhibitors ; Imatinib Mesylate (8A1O1M485B) ; Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2021-02-10
Publishing country	England
Document type	Journal Article
ZDB-ID	283643-9
ISSN	1099-0844 ; 0263-6484
ISSN (online)	1099-0844
ISSN	0263-6484
DOI	10.1002/cbf.3625
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Article: ADP-Mediated Upregulation of Expression of CD62P on Human Platelets Is Critically Dependent on Co-Activation of P2Y1 and P2Y12 Receptors.

Anderson, Ronald / Theron, Annette J / Steel, Helen C / Nel, Jan G / Tintinger, Gregory R

Pharmaceuticals (Basel, Switzerland)

2020 Volume 13, Issue 12

Abstract: This study probed the differential utilization of P2Y1 and P2Y12 receptors in mobilizing CD62P (P-selectin) from intracellular granules following activation of human platelets with adenosine 5'-diphosphate (ADP, 100 µmol· ... ...

Abstract	This study probed the differential utilization of P2Y1 and P2Y12 receptors in mobilizing CD62P (P-selectin) from intracellular granules following activation of human platelets with adenosine 5'-diphosphate (ADP, 100 µmol·L
Language	English
Publishing date	2020-11-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph13120420
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Article: Pulmonary Toxicities Associated With the Use of Immune Checkpoint Inhibitors: An Update From the Immuno-Oncology Subgroup of the Neutropenia, Infection & Myelosuppression Study Group of the Multinational Association for Supportive Care in Cancer.

Rapoport, Bernardo L / Shannon, Vickie R / Cooksley, Tim / Johnson, Douglas B / Anderson, Lindsay / Blidner, Ada G / Tintinger, Gregory R / Anderson, Ronald

Frontiers in pharmacology

2021 Volume 12, Page(s) 743582

Abstract: The development of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, with agents such as nivolumab, pembrolizumab, and cemiplimab targeting programmed cell death protein-1 (PD-1) and durvalumab, avelumab, and atezolizumab targeting ...

Abstract	The development of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, with agents such as nivolumab, pembrolizumab, and cemiplimab targeting programmed cell death protein-1 (PD-1) and durvalumab, avelumab, and atezolizumab targeting PD-ligand 1 (PD-L1). Ipilimumab targets cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). These inhibitors have shown remarkable efficacy in melanoma, lung cancer, urothelial cancer, and a variety of solid tumors, either as single agents or in combination with other anticancer modalities. Additional indications are continuing to evolve. Checkpoint inhibitors are associated with less toxicity when compared to chemotherapy. These agents enhance the antitumor immune response and produce side- effects known as immune-related adverse events (irAEs). Although the incidence of immune checkpoint inhibitor pneumonitis (ICI-Pneumonitis) is relatively low, this complication is likely to cause the delay or cessation of immunotherapy and, in severe cases, may be associated with treatment-related mortality. The primary mechanism of ICI-Pneumonitis remains unclear, but it is believed to be associated with the immune dysregulation caused by ICIs. The development of irAEs may be related to increased T cell activity against cross-antigens expressed in tumor and normal tissues. Treatment with ICIs is associated with an increased number of activated alveolar T cells and reduced activity of the anti-inflammatory Treg phenotype, leading to dysregulation of T cell activity. This review discusses the pathogenesis of alveolar pneumonitis and the incidence, diagnosis, and clinical management of pulmonary toxicity, as well as the pulmonary complications of ICIs, either as monotherapy or in combination with other anticancer modalities, such as thoracic radiotherapy.
Language	English
Publishing date	2021-10-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2021.743582
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Article ; Online: Submission for Special Issue: The Role of Platelet Activation in the Pathophysiology of HIV, Tuberculosis, and Pneumococcal Disease. Bedaquiline Suppresses ADP-Mediated Activation of Human Platelets

Tintinger, Gregory R / Theron, Annette J / Steel, Helen C / Cholo, Moloko C / Nel, Jan G / Feldman, Charles / Anderson, Ronald

Frontiers in immunology

2021 Volume 11, Page(s) 621148

Abstract: Although bedaquiline has advanced the treatment of multidrug-resistant tuberculosis (TB), concerns remain about the cardiotoxic potential of this agent, albeit by unexplored mechanisms. Accordingly, we have investigated augmentation of the reactivity of ... ...

Abstract	Although bedaquiline has advanced the treatment of multidrug-resistant tuberculosis (TB), concerns remain about the cardiotoxic potential of this agent, albeit by unexplored mechanisms. Accordingly, we have investigated augmentation of the reactivity of human platelets
MeSH term(s)	15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/pharmacology ; Adenosine Diphosphate/pharmacology ; Adult ; Antitubercular Agents/adverse effects ; Antitubercular Agents/pharmacology ; Calcium Signaling ; Diarylquinolines/adverse effects ; Diarylquinolines/pharmacology ; Dose-Response Relationship, Drug ; Estrenes/pharmacology ; Female ; HIV Infections/blood ; HIV Infections/physiopathology ; Humans ; Long QT Syndrome/chemically induced ; Male ; Middle Aged ; P-Selectin/biosynthesis ; P-Selectin/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors/pharmacology ; Phosphorylation/drug effects ; Platelet Activation/drug effects ; Platelet Aggregation/drug effects ; Platelet-Rich Plasma ; Pneumococcal Infections/blood ; Pneumococcal Infections/physiopathology ; Protein Processing, Post-Translational/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Pyrrolidinones/pharmacology ; Thrombin/pharmacology ; Tuberculosis/blood ; Tuberculosis/physiopathology ; Wortmannin/pharmacology ; Young Adult
Chemical Substances	Antitubercular Agents ; Diarylquinolines ; Estrenes ; P-Selectin ; Phosphoinositide-3 Kinase Inhibitors ; Pyrrolidinones ; SELP protein, human ; 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (112648-68-7) ; Adenosine Diphosphate (61D2G4IYVH) ; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid (76898-47-0) ; bedaquiline (78846I289Y) ; AKT1 protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Thrombin (EC 3.4.21.5) ; Wortmannin (XVA4O219QW)
Language	English
Publishing date	2021-02-26
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.621148
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