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Biomedical subjects

R Gold

Publications and source records attributed to R Gold.

At least 37 records · Page 2Linked to original sources
PubMed2001

Vaccination, prevention, and treatment of experimental autoimmune neuritis (EAN) by an oligomerized T cell epitope.

Using a polypeptide oligomer harboring 16 repeats of the neuritogenic epitope (aa 58-73) of myelin P2 protein separated by spacers, enhancement of the immune response to the P2 protein, an important neuritogenic autoantigen in experimental autoimmune neuritis (EAN), was attempted. In contrast to a previous study with PLP-16-mer antigen-specific response of T cells was attenuated at all doses examined to a variable degree. Treatment of Lewis rats with the P2-16-mer up to 2 months before immunization with P2(53-78) (vaccination) or after immunization but before appearance of disease (prevention) had a strong tolerizing effect against the induction of EAN on immunization with P2(53-78). Moreover, rats injected with 200 microg of the P2-16-mer i.v. on day 11 after disease induction, at which time the initial signs of disease had appeared, were almost completely protected against progression of clinical disease, whereas animals treated with the same amount of monomeric control peptide developed severe disease (treatment). Similar results were obtained by i.v. treatment of adoptive-transfer EAN with the P2-16-mer. The lack of clinical signs of disease after 16-mer therapy could be correlated with a reduced proliferative response of P2(53-78)-specific lymph node cells. The frequency of apoptotic T cells in sciatic nerve or in lymph node cells, however, was not increased by the 16-mer treatment, suggesting that induction of anergy or other forms of peripheral tolerance may be responsible for the effect. Thus, the oligomerized P2 peptide antigen was highly effective in all three treatment modalities examined in this specific autoreactive T cell-mediated immune response.

Animals↗
PubMed2001

Oxides and apoptosis in inflammatory myopathies.

Reactive oxygen intermediates (ROI) and nitric oxide (NO(.)) are produced in abundance in the inflammatory muscle diseases of autoimmune origin polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). However, their role in the pathogenesis of these diseases is so far not clear. In contrast to demyelinating neuropathies, there is no convincing evidence for oxide-induced apoptosis either in myocytes or in lymphocytes and phagocytes in inflammatory myopathies. On the contrary, NO(.) released at low concentrations at target sites may even have cell-protective effects. A major mechanism of protection from apoptosis in both myocytes and inflammatory cells seems to be the upregulation of anti-apoptotic proteins like Bcl-2. Caution is warranted to apply antioxidative and anti-apoptotic agents to patients with inflammatory myopathies as long as the pathogenic role of oxides and apoptosis in the individual case is not resolved.

Animals↗
PubMed2001

Microglial phagocytosis of apoptotic inflammatory T cells leads to down-regulation of microglial immune activation.

Apoptotic cell death is an established mechanism to terminate an inflammatory response in rodent or human brains. Microglia, as the resident phagocyte, is a strong candidate for the clearance of apoptotic lymphocytes. Apoptosis was induced in cultured autologous thymocytes and in myelin basic protein (MBP)-specific, encephalitogenic T cells from Lewis rats by the addition of 0.1 microg/ml methylprednisolone. The amount of phagocytosis of apoptotic cells was assessed using an in vitro phagocytosis assay. Supernatants were collected to measure microglial cytokine secretion. The state of immune activation in microglia was investigated by a T cell proliferation assay and by flow cytometric analysis of microglial surface expression of immune molecules. Microglia ingested specifically apoptotic cells (apoptotic thymocytes as well as MBP-specific T cells) in contrast to nonapoptotic control cells (p < 0.0001). Subsequent secretion of the proinflammatory cytokines TNF-alpha and IL-12 was significantly decreased, while the secretion of IL-10 and TGF-beta was not affected. Furthermore, ingestion of apoptotic cells led to increased microglial MHC class II expression without concomitant increase in MHC class I, costimulatory molecules, and ICAM expression. The Ag-specific activation of MBP-specific T cells in cocultures with microglia that had ingested apoptotic cells was significantly less than that of identical T cells that interacted with nonphagocytosing microglia. Together with negative results obtained in a trans-well system, this is in support of a cell contact-mediated effect. Microglia might play an important role in the clearance of apoptotic cells. The uptake of apoptotic cells by microglia is tolerogenic and results in a reduced proinflammatory cytokine production and a reduced activation of encephalitogenic T cells. This might help to restrict an autoimmune inflammation and minimize damage in the inflamed brain.

Animals↗
PubMed2001

Blockade of signaling via the very late antigen (VLA-4) and its counterligand vascular cell adhesion molecule-1 (VCAM-1) causes increased T cell apoptosis in experimental autoimmune neuritis.

We characterized the early effects of anti-very late antigen (VLA-4) and its counterligand vascular cell adhesion molecule-1 (VCAM-1) antibody therapy on T cell infiltration and apoptosis in adoptive transfer experimental autoimmune neuritis of female Lewis rats. At the peak of disease, animals were treated with anti-VCAM-1 monoclonal antibody (mAb), anti-VLA-4 mAb, or the respective isotype mAb controls 18, 12, or 6 h before perfusion. Anti-VCAM-1 led to a rapid, significant increase of apoptotic T cells in the sciatic nerve with a maximum after 6 h, preceding the significant decrease of T cell infiltration seen after 18 h. This was accompanied by a significant reduction in mRNA levels for IFN-gamma and inducible nitric oxide synthase. The results for anti-VLA-4 treatment showed a similar trend. The early increase of T cell apoptosis following disruption of VLA-4/VCAM-1 interaction may reflect a novel signaling component of proapoptotic pathways.

Animals↗
PubMed2001

Leptin attenuates follicular apoptosis and accelerates the onset of puberty in immature rats.

Human and rat granulosa cells express receptors to leptin which synergies with glucocorticoid hormones in stimulation of ovarian steroidogenesis. To examine whether leptin affects follicular development and maturation, we injected recombinant ovine leptin (300 ng-10 microg/animal) daily to immature 21 day-old female rats. Non-treated rats reached puberty at 44.5+/-1.6 (n=9) days. In contrast, in leptin treated animals, puberty was reached at 34.5+/-1.6 (n=9) days. Ovarian sections revealed hypertrophy of granulosa cells in leptin treated animals. Moreover, the number of ovulations was 2-fold higher in the treated animals compared to controls (3-4 ovulations versus 7-8 on the first three estrous cycles, P<0.001). Leptin dramatically reduced incidence of follicular apoptosis measured by TUNEL, and was already evident after 7 days of leptin injection (12% of apoptosis in leptin treated group compared to 52% in controls, P<0.001). Maximal protection against apoptosis was achieved at 1-3 microg leptin/animal. The levels of FSH, LH, progesterone and the steroidogenic factors ADX and STAR were elevated earlier in development in the leptin treated animals compared to control animals which is in line with the achievement of early puberty in the leptin treated animals compared to non treated ones. To reveal whether modulation of death and survival genes is involved in leptin attenuation of follicular apoptosis, we examined the expression of the survival gene Bcl-2 and the death gene Bax in Western blots of ovarian homogenates. There was a pronounced elevation in Bcl-2 expression during 7-14 days of leptin injections up to 16.3-fold (P<0.001) compared to Bcl-2 expression in controls. Bax expression was elevated only 3.4 fold (P<0.001), leading to an increase in the Bcl-2/Bax ratio of 4.7 fold (P<0.001). Expression of the tumor suppressor gene p 53 and the oncogene Mdm2 did not change significantly. Our data suggests that leptin may be involved in accelerating follicular maturation by attenuating follicular atresia and increasing the ratio of Bcl-2/Bax.

Adrenodoxin↗
PubMed2001

Guillain-Barré syndrome serum and anti-Campylobacter antibody do not exacerbate experimental autoimmune neuritis.

To investigate whether antibodies are pathogenic in Guillain-Barré syndrome (GBS), we injected pre-treatment serum from 11 GBS patients intraperitoneally into rats in which the blood-nerve barrier had been opened by induction of mild adoptive transfer experimental autoimmune neuritis. There was no significant clinical, neurophysiological or pathological difference between rats receiving GBS serum compared with those receiving control serum, except that GBS serum caused minor excess weight loss. Murine monoclonal antibody to Campylobacter jejuni and gangliosides also did not exacerbate disease. This experiment failed to show antibody-mediated disease exacerbation and so does not support an antibody-mediated mechanism in GBS.

Animals↗
PubMed2001

Mechanism of action of glucocorticosteroid hormones: possible implications for therapy of neuroimmunological disorders.

Glucocorticosteroids are the most potent immunosuppressive and antiinflammatory drugs. Over the six decades that have passed since their discovery, a variety of genomic effector mechanisms of steroid hormones has been described which are mediated by the cytosolic steroid receptor. Recent evidence supports a direct effect of glucocorticosteroids on cellular membranes that occurs at higher hormone concentrations, termed nongenomic effects. These imply a qualitatively distinct mode of steroid action leading to cellular apoptosis. In this review, we discuss in vitro and in vivo data on nongenomic effects of glucocorticosteroids and their possible implications for the therapy of human neuroimmunological diseases.

Animals↗
PubMed2001

Interferon-beta treatment of experimental autoimmune encephalomyelitis leads to rapid nonapoptotic termination of T cell infiltration.

We investigated the possible mechanisms how interferon (IFN)-beta may control T cell infiltration in the CNS in experimental autoimmune encephalomyelitis (EAE). Adoptive transfer (AT) EAE was induced in groups of six female Lewis rats. Animals were treated with 3 x 10(5) units of recombinant rat IFN-beta s.c. once at 18 hr, or with 10 mg/kg methylprednisolone (MP) i.v. twice at 18 and 6 hr prior to dissection, or with a combination of both. T cell apoptosis was detected by immunohistochemistry on paraffin sections of spinal cord, using morphological criteria and TUNEL staining. Double labeling of immune cells was done for tumor necrosis factor (TNF)-alpha and metalloproteinase (MMP) 2. Disruption of the blood-brain barrier (BBB) was visualized by staining for albumin. In severe EAE, an increase of T cell apoptosis was seen after IFN-beta alone (all data presented as mean +/- SD: 24.5% +/- 2.2%, P < 0.05, vs. 19.4% +/- 3.1% in controls), and in combination with MP (29.4% +/- 7.3%, P < 0.05 vs. controls). Only the combination therapy decreased T cell infiltration (53.9 +/- 17.7 cells/mm(2), P < 0.05, vs. 99.5 +/- 35.2 cells/mm2 in controls). In moderate EAE, the rate of T cell apoptosis was slightly increased after IFN-beta (21.2% +/- 5.2% vs. 17.4% +/- 5.0% in controls), whereas MP alone (25.5% +/- 3.5%, P < 0.01 vs. controls) and the combination therapy (22.4% +/- 4.8%, P < 0.05 vs. controls) had a clear augmenting effect. IFN-beta tended to decrease T cell infiltration (46.1 +/- 12.7 cells/mm2) compared to controls (59.2 +/- 18.5 cells/mm2). The rate of TNF-alpha-expressing T cells was significantly decreased by IFN-beta and in combination with MP. Also, TNF-alpha expression in macrophages was significantly reduced by IFN-beta and by the combination therapy. The rate of MMP2-expressing macrophages was lower after IFN-beta but clearly decreased only in combination with MP. BBB disruption was ameliorated after IFN-beta but significantly only in combination with MP. Our study indicates that IFN-beta affects the immunopathological process in EAE in several ways, but apoptosis appears as a minor component. In view of treatment of MS relapses, the synergistic effects in this study corroborate the use of a combination therapy with high-dose MP and IFN-beta.

Animals↗
PubMed2001

Schwann cell apoptosis in experimental autoimmune neuritis of the Lewis rat and the functional role of tumor necrosis factor-alpha.

Schwann cell (SC) apoptosis may be a critical factor challenging nerve remyelination and regeneration in experimental autoimmune neuritis (EAN) in the Lewis rat. We therefore analyzed the fate of SC during high-dose antigen therapy of adoptive transfer-(AT-) EAN using rhP2 protein. P2 antigen therapy was associated with an increase of tumor necrosis factor (serum levels 1 h after intravenous (i.v.) injection and an augmentation of T-cell apoptosis. Antigen specific therapy had no clear effect on SC apoptosis. The effects on SC apoptosis were determined by morphological criteria or by in situ tailing (IST) followed by immunocytochemical analysis. Secondly, we neutralized TNF-alpha, released in abundance by antigen treatment but only in small concentrations during natural disease course. We found that the addition of a TNF-alpha neutralizing antiserum resulted in a significant decrease in the rate of SC apoptosis in vivo compared to animals treated with control antigen rhP0 or with rhP2 only.

Adoptive Transfer↗
PubMed2001

High-dose methylprednisolone therapy in multiple sclerosis induces apoptosis in peripheral blood leukocytes.

BACKGROUND: Apoptosis is supposed to contribute to the elimination of T cells from the inflamed central nervous system in the natural disease course of multiple sclerosis (MS). In the animal model experimental autoimmune encephalomyelitis, T-cell apoptosis can be induced by high-dose glucocorticoid (GC) administration. OBJECTIVE: To study the effects of intravenous high-dose GC therapy in MS on T-cell apoptosis ex vivo. PATIENTS: Sixty-six patients with MS (28 with relapsing-remitting MS, 22 with secondary chronic progressive MS, and 16 with primary chronic progressive MS) and 16 control patients receiving corticosteroids for other disorders were included in the study. METHODS: Blood samples were collected before and immediately after the first infusion of 500 to 1000 mg of methylprednisolone given during 2 hours in the early morning. Gradient-isolated peripheral blood leukocytes (PBLs) were cultured, unstimulated, with corticosteroids (positive control), the mitogen phytohemagglutinin, or anti-T-cell receptor monoclonal antibody. For investigation of apoptosis, PBLs were cultured overnight and analyzed by immunoflow cytometry using TUNEL (terminal transferase-mediated dUTP biotin nick end labeling) or annexin labeling in combination with CD4, CD8, CD22, CD56, or bcl-2 staining. Proliferation was measured by (3)H-thymidine incorporation. For cytokine determination, supernatants were collected after 48 hours of culture. RESULTS: After in vivo corticosteroid treatment, apoptosis of unstimulated PBLs was markedly and significantly augmented in all 3 MS subgroups. Fluorescence-activated cell sorter analysis showed that apoptosis affected predominantly CD4 T cells. Natural killer cells showed a relative increase after GC therapy without a change in the rate of apoptotic cells. Expression of bcl-2 in T-cell subpopulations was not significantly modified by high-dose GC therapy. Culture supernatants of T-cell receptor-stimulated PBLs after GC therapy contained lower concentrations of interleukin 2, interferon gamma, and tumor necrosis factor alpha than those from PBLs taken before pulse therapy. Similar changes in the rate of apoptosis and cytokine production were seen in controls. CONCLUSIONS: Corticosteroid pulse therapy is a strong inducer of leukocyte apoptosis. Induction of apoptosis might contribute to the down-regulation of T-cell activity and thereby terminate inflammation in the central nervous system.

Adult↗
PubMed2001

Phagocytosis of apoptotic inflammatory cells by microglia and modulation by different cytokines: mechanism for removal of apoptotic cells in the inflamed nervous system.

Apoptosis of autoaggressive T cells in the central nervous system (CNS) is an effective, nonphlogistic mechanism for the termination of autoimmune inflammation in experimental autoimmune encephalomyelitis (EAE). The clearance of apoptotic leukocytes by tissue-specific phagocytes is a critical event in the resolution of the inflammatory attack. To investigate the role of microglia in the removal of apoptotic cells and potential regulatory mechanisms of microglial phagocytosis, an in vitro phagocytosis assay was established, using Lewis rat microglia. Microglia exhibited a high capacity for the uptake of apoptotic autologous thymocytes, as well as apoptotic encephalitogenic myelin basic protein (MBP)-specific T cells, in contrast to nonapoptotic target cells. Pretreatment of microglia with interferon-gamma (IFN-gamma) raised the proportion of microglia capable of phagocytosing apoptotic cells to 75% above the untreated controls. The increased phagocytic activity was selective for apoptotic target cells and was not dependent on phosphatidylserine-mediated recognition mechanisms. In contrast, preincubation of microglia with interleukin-4 (IL-4) inhibited the uptake of apoptotic cells, whereas tumor-necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) did not alter phagocytosis. Phagocytic clearance of apoptotic inflammatory cells by microglia may be an important mechanism for the termination of autoimmune inflammation in the CNS. Augmentation of microglial phagocytosis by the Th-1-type cytokine IFN-gamma suggests a feedback mechanism for the accelerated clearance of the inflammatory infiltrate in the CNS.

Animals↗
PubMed2001

[Treatment of relapsing-remitting multiple sclerosis with recombinant interferon-beta preparations].

Three recombinant interferon-beta preparations, Betaferon (IFN beta-1b) and Avonex and Rebif (INF beta-1a) have been approved for the therapy of relapsing-remitting multiple sclerosis (MS). The results from pharmacokinetic and pharmacodynamic studies with different interferon-beta preparations reflect only in part the mechanisms of action of this substance, because standard assays primarily measure antiviral bioactivity. These studies are often overinterpreted in relation to the therapy of MS. In this article, we critically evaluate the results of pharmacologic studies with respect to the dose-dependent efficacy of different interferon-beta preparations.

Adjuvants, Immunologic↗
PubMed2001

[Glucocorticosteroid therapy in optic neuritis and multiple sclerosis. Evidence from clinical studies and practical recommendations].

High-dose intravenous glucocorticosteroids (GS) are the treatment of choice for acute relapses in patients with multiple sclerosis. We review the evidence from published trials on GS treatment in MS. Several controlled clinical trials have proven the efficacy of high-dose GS in accelerating the recovery from acute attacks. With serial MRI recordings, a reduction in the number of enhancing lesions has been observed after high-dose GS treatment. Definitive long-term effects of GS on disease evolution could not been demonstrated. There is now evidence that ultra-high doses of GS might be superior in comparison to standard pulse treatment regarding relapse rate and disease progression. In experimental autoimmune encephalomyelitis (EAE), an animal model for some features of MS, doses of up to 50 mg/kg methylprednisolone markedly augmented T cell apoptosis in situ, leading to a faster clearance of inflammatory infiltrates. Apoptosis in peripheral blood leukocytes could also be detected after i.v. GS treatment in MS patients. In a recent MRI study, ultra-high doses of GS were significantly more effective in reducing contrast-enhancing lesions and in maintaining blood-brain barrier integrity after a clinical relapse. Further clinical trials are necessary to study the long-term effects of ultra-high doses of GS on disease progression and disability.

Animals↗
PubMed2001

Glucocorticosteroids modulate antigen-induced T cell apoptosis in experimental autoimmune neuritis and cause T cell proliferation in situ.

Treatment of experimental autoimmune disorders of the nervous system with high doses of glucocorticosteroids (GC) or with administration of the specific antigen is effective and associated with marked T cell apoptosis in situ. Here we investigated in adoptive transfer-experimental autoimmune neuritis (AT-EAN) of the Lewis rat whether induction of T cell apoptosis resulting from T cell activation by antigen therapy can be further augmented by glucocorticosteroids (GC). AT-EAN was induced by intravenous injection of P2-specific T cell blasts. At the maximum of disease two pulses of the antigen recombinant human P2 (rhP2) were given within 12 h. Methylprednisolone was administered simultaneously or 2 h after the antigen and animals were killed 6 h after the second antigen injection. Using an in situ tailing technique followed by immunocytochemical analysis, the presence of DNA fragmentation in T lymphocytes was confirmed. The bromodeoxyuridine (BrdU) technique was employed to detect in situ proliferating cells. T cell apoptosis in sciatic nerve was enhanced after monotherapy with either antigen or GC compared to the control group receiving an irrelevant myelin protein, recombinant human P0. In combination therapy, a synergistic effect on T cell apoptosis in sciatic nerve was obtained when methylprednisolone was injected sequentially, 2 h after rhP2 protein. BrdU incorporation in the sciatic nerve as well as in the spleen, a major lymphoid organ, was significantly enhanced in animals treated with antigen followed by GC 2 h later as compared to rats receiving rhP2 only, speaking for T cell proliferation in situ associated with T cells undergoing apoptosis. Our findings underscore that different proapoptotic stimuli may act synergistically, depending on the timing of the second treatment. In this scenario even local T cell proliferation in the inflamed nervous system occurs. These results support the paradigm of antigen presentation in the nervous system.

Adrenal Cortex Hormones↗
PubMed2001

Role of urethrocystoscopy in the evaluation of refractory idiopathic detrusor instability.

OBJECTIVES: To assess the role of diagnostic urethrocystoscopy in the evaluation of women with idiopathic detrusor instability (DI) refractory to conventional pharmacologic management. METHODS: One hundred consecutive women (mean age 62.1 +/- 15.1 years) with idiopathic DI refractory to conventional pharmacologic management were prospectively enrolled. All patients underwent a meticulous evaluation, including a detailed history, urogynecologic questionnaire, micturition diary and pad test, urinalysis and culture, physical examination, and urodynamic studies. Refractory DI was defined as the lack of clinical improvement after at least 6 months of conventional drug therapy. These patients underwent additional evaluation with diagnostic urethrocystoscopy. RESULTS: All patients had a normal urinalysis and negative cytologic findings. Diagnostic urethrocystoscopy revealed isolated bladder tuberculosis in one and transitional cell carcinoma in another. Seven other patients had bladder diverticula (only one of which was also diagnosed by sonographic examination) and 22 had mild-to-moderate bladder trabeculations. CONCLUSIONS: The absence of other alarming signs (ie, recurrent urinary tract infection, hematuria, significant residual urinary volume, positive cytologic findings, or suspicious sonographic findings) cannot confirm the lack of significant lower urinary tract abnormalities among patients with refractory DI. Diagnostic urethrocystoscopy, a simple and safe office procedure, facilitates timely diagnosis and appropriate treatment for these patients.

Cystoscopy↗
PubMed2001

Ecological analysis of teen birth rates: association with community income and income inequality.

OBJECTIVES: To examine whether per capita income and income inequality are independently associated with teen birth rate in populous U.S. counties. METHODS: This study used 1990 U.S. Census data and National Center for Health Statistics birth data. Income inequality was measured with the 90:10 ratio, a ratio of percent of cumulative income held by the richest and poorest population deciles. Linear regression and analysis of variance were used to assess associations between county-level average income, income inequality, and teen birth rates among counties with population greater than 100,000. RESULTS: Among teens aged 15-17, income inequality and per capita income were independently associated with birth rate; the mean birth rate was 54 per 1,000 in counties with low income and high income inequality, and 19 per 1,000 in counties with high income and low inequality. Among older teens (aged 18-19) only per capita income was significantly associated with birth rate. CONCLUSIONS: Although teen childbearing is the result of individual behaviors, these findings suggest that community-level factors such as income and income inequality may contribute significantly to differences in teen birth rates.

Adolescent↗
PubMed2001

Cardiac metabolism and function in patients with multiple sclerosis: a combined 31P-MR-spectroscopy and MRI study.

OBJECTIVE: Involvement of the autonomic system in multiple sclerosis (MS) may concur with dysfunction of the cardiovascular system. The introduction of potentially cardiotoxic immunosuppressive drugs like Mitoxantrone into the treatment of MS warrants proper assessment of preexisting heart disease. However, systematic analyses of functional and metabolic derangements in MS are missing. Using quantitative 31P-MR-spectroscopy (MRS) and MR-imaging (MRI) metabolic and functional parameters were analyzed in patients with MS in comparison to healthy volunteers. SUBJECTS/METHODS: 14/15 patients with MS could be included in the study, as the MRS examination of one patient had to be excluded from analysis due to movement during the examination. Using chemical shift imaging (CSI) and AMARES, phosphocreatine (PCr) to adenosine triphosphate (ATP) ratios, characterizing myocardial high-energy phosphate metabolism, were determined. Additionally, absolute concentrations of PCr and ATP were calculated by SLOOP (Spatial Localization with Optimal Pointspread Function). Analysis of functional changes was performed by Cine-MRI. 14 healthy volunteers matched for age and gender served as control. RESULTS: A significant decrease of absolute PCr concentration was observed in patients with MS compared to matched volunteers (p < 0.05), whereas ATP concentrations showed no significant changes (p = 0.27). Metabolite ratios calculated by SLOOP or AMARES showed a tendency to be reduced in patients, however, did not reach significance (p = 0.08, SLOOP; p = 0.47, AMARES). Using volunteers' mean values +/- 2 x SD as cut off value revealed PCr changes in 5 of 14 patients, whereas only 2 also had pathologic PCr/ATP ratios. Functional analysis by MRI depicted depressed left ventricular ejection fraction in 4 patients. CONCLUSIONS: The reduction in cardiac high-energy phosphates in some patients with MS points to a subclinical involvement of the heart. This may be important for treatment with potentially cardiotoxic drugs. Longitudinal studies are need to understand the clinical relevance of our findings.

Adenosine Triphosphate↗