Cardiovascular manifestations secondary to COVID-19: A narrative review.

The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly, becoming a major threat to global health. In addition to having required the adaptation of healthcare workers for almost 2 years, it has been much talked about, both in the media and among the scientific community. Beyond lung damage and respiratory symptoms, the involvement of the cardiovascular system largely explains COVID-19 morbimortality. In this review, we emphasize that cardiovascular involvement is common and is associated with a worse prognosis, and that earlier detection by physicians should lead to better management. First, direct cardiac involvement will be discussed, in the form of COVID-19 myocarditis, then secondary cardiac involvement, such as myocardial injury, myocardial infarction and arrhythmias, will be considered. Finally, worsening of previous cardiovascular disease as a result of COVID-19 will be examined, as well as long-term COVID-19 effects and cardiovascular complications of COVID-19 vaccines.

[Sudden cardiac death and anomalous connections of the coronary arteries: What is known and what is unknown?] / Mort subite cardiaque et anomalies de connexion des artères coronaires : connaissances et questions.

Some anomalous connections of the coronary arteries may be associated with a risk of sudden cardiac death. In opposite with others cardiac diseases at risk of sudden cardiac death, the relationship between these congenital abnormalities and the risk of sudden cardiac death are not well understood. A correction of the anomaly is generally indicated after an aborted sudden cardiac death. Primary prevention strategy after the discovery of an anomaly at risk is debated. Even if the absolute risk of sudden death is very low, a pre-participation screening in young athletes may be discussed due to a non-rare incidence.

[Sudden cardiac death: A better understanting for a better prevention]. / Mort subite de l'adulte : une meilleure compréhension pour une meilleure prévention.

Sudden cardiac death is defined as a natural and unexpected death, in a previous apparently healthy individual. It represents a major public health issue, with up to 50% of the cardiovascular mortality. Using data from the Paris Sudden Death Expertise Centre registry, this article summarises the main cardiovascular abnormalities associated with sudden cardiac death, the different preventives approaches, and provides a systematic diagnostic approach.

Absence of G(s)alpha gene mutations in childhood thyroid tumors after Chernobyl in contrast to sporadic adult thyroid neoplasia.

Heterotrimeric G proteins participate in the signal transduction cascade. Adult thyroid tumors have been shown to harbor specific point mutations in codons 201 and 227 of the G(s)alpha subunit of the adenylate cyclase stimulator. This protein affects the GDP/GTP turnover and finally results in an enhanced activation of G(s) and thus adenylate cyclase. We attempted to find out if G(s)alpha gene mutations were present in thyroid tumors of children from Belarus after the Chernobyl nuclear accident. Paraffin sections of 20 thyroid tumors were used for PCR amplification by oligonucleotide intron primers flanking exons 8 and 9, encompassing codon 201 and 227, respectively. By direct sequencing of the 274-bp amplification product, we did not detect any mutations of the G(s)alpha gene in codon 201 or 227. In contrast to thyroid neoplasia of adults, G(s)alpha gene mutations do not play a role in the development of childhood thyroid tumors after the Chernobyl reactor accident.

[Cardiac arrhythmias: Diagnosis and management]. / Troubles du rythme cardiaque : diagnostic et prise en charge.

Cardiac arrhythmias, with, on top of the list, atrial fibrillation, are frequent conditions and any physician might have to get involved at any stage of patient care (from diagnosis to treatment), without always having the opportunity to immediately refer to the cardiologist. The aim of this review is to present a summary of pathophysiology, clinical and electrocardiographic presentations, as well as diagnostic and therapeutic strategies for the main cardiac arrhythmias. Supra-ventricular tachycardias (atrial fibrillation and flutter, atrioventricular reciprocating tachycardias) and ventricular tachycardias will be consecutively presented and discussed.

S100-Beta, melanoma-inhibiting activity, and lactate dehydrogenase discriminate progressive from nonprogressive American Joint Committee on Cancer stage IV melanoma.

PURPOSE: Monitoring advanced malignant melanoma, serum levels of S100-beta (S100beta) and melanoma-inhibiting activity (MIA) were assessed for the ability to discriminate progressive from nonprogressive disease. S100beta and MIA were supposed to be superior to conventional variables, such as lactate dehydrogenase (LDH) level. PATIENTS AND METHODS: Seventy-one patients with stage IV malignant melanoma according to the criteria of the American Joint Committee on Cancer (AJCC) were included in the study. Results of restaging examinations were used as an independent reference standard for diagnosing progressive disease, and S100beta, MIA, LDH level, and erythrocyte sedimentation rate (ESR) were determined in venous blood just before restaging. Sensitivities and specificities of the parameters were calculated by logistic regression analysis. Discrimination ability was assessed by Somers' D(xy) rank correlation and the area under the receiver-operating characteristic curve (ROC-AUC). RESULTS: All tested serum parameters were significantly elevated in patients with progressive disease. The highest sensitivities according to the established thresholds were found for S100beta and MIA (91% and 88%, respectively). LDH had the highest specificity (92%). ESR was dropped from the analysis because of low specificity. In calculating Somers' D(xy) and ROC-AUC values, S100beta, MIA, and LDH showed high discrimination ability. By multiple logistic regression, LDH was identified to be the only statistically significant marker for progressive disease. S100beta and MIA did not provide additional significant information because of their high correlation with LDH with respect to clinical outcome. CONCLUSION: Elevated serum levels of S100beta, MIA, and LDH indicate current disease progression in AJCC stage IV melanoma. LDH was the most relevant overall parameter.

Proliferative heterogeneity of human renal cell carcinomas and prevalence of ras gene point mutations.

The variable prevalence and a possible stage-dependent increase of ras gene point mutations in human tumors might correspond to clonal growth advantages of ras-activated cells. Tumor areas with activated ras genes might thus differ in proliferative activity from those lacking ras gene activation. This hypothesis is studied in a series of human renal cell carcinomas that had been used previously for an analysis of proliferative compartments after post-operative vascular [3H]/[14C]thymidine perfusion [Rabes et al. (1979) Cancer 44: 799-813]. The growth fraction of different subcompartments of these tumors was studied by immunohistochemistry with mib1 antibody, recognizing a fixation- and embedding-resistant epitope of Ki-67 protein. Thirty subpopulations of 14 human renal cell carcinomas that exhibited a broad spectrum of proliferative activity were chosen for an analysis of the prevalence of K-ras point mutations in exon 1 by a mutation-enriching primer-mediated restriction-fragment-length-polymorphism analysis and/or direct sequencing of polymerase-chain-reaction-amplified material. The combined autoradiographic and immunohistochemical analysis confirmed the intra- and intertumoral proliferative heterogeneity. Compared to [3H]/[14C]thymidine labeling indices, mib1 labeling indices are higher. The ratio of mib1 to [3H]/[14C]thymidine labeling indices varies from 1.9 to 4.1 for the individual tumor subcompartments. However, neither in K-ras codons 12/13 nor in adjacent codons did we detect any mutations in the various tumor compartments. The results suggest that neither mode of proliferation nor type of differentiation is related to K-ras exon 1 point mutations in human renal cell carcinomas.

Prognosis of metastatic melanoma: no correlation of tyrosinase mRNA in bone marrow and survival time.

Recent publications suggest that tyrosinase mRNA in blood as well as in bone marrow is detectable only in a subgroup of patients with metastatic melanoma. This would imply that tyrosinase mRNA is of limited value as a tumor marker. We addressed the question of whether patients with metastatic melanoma and RT-PCR-detectable tyrosinase mRNA in blood or bone marrow have a different prognosis than tyrosinase mRNA-negative patients. Twenty melanoma patients with widespread clinical metastases were enrolled; the survival time after first diagnosis of visceral metastases was correlated to tyrosinase mRNA presence in blood and bone marrow samples. The time of survival of eight patients with metastatic melanoma and detectable tyrosinase mRNA in either blood or bone marrow was not different from the prognosis of 12 patients without detectable tyrosinase mRNA in either blood or bone marrow. Detection of tyrosinase mRNA in blood or bone marrow samples of melanoma patients with advanced disease seems to have no substantial relevance for survival time and outcome of disease. In this constellation, detection of tyrosinase mRNA by RT-PCR is not a valid tumor marker. Nevertheless, tyrosinase positivity in bone marrow in earlier tumor stages might indicate increased risk for the development of distant metastases. This should be addressed in further studies.

Absence of mutations in the pleckstrin homology (PH) domain of protein kinase B (PKB/Akt) in malignant melanoma.

During recent years it has become evident that protein kinase B (PKB)/Akt plays an important role in oncogenic transformation. The gene for PKB/Akt has been found to be overexpressed in certain human tumours and a viral fusion protein gains transforming capacity. Recruitment to the plasma membrane is mandatory for the physiological activation of PKB/Akt; this shift from cytoplasm to the membrane is achieved by the N-terminal pleckstrin homology (PH) domain. We attempted to find out whether mutations of this domain were present in human malignant melanoma. RNA from 18 primary melanoma lesions of different sizes and histological subtypes and two melanoma metastases from 20 Caucasian patients were used for reverse transcription and subsequent polymerase chain reaction (PCR) amplification of the PH domain of PKB/Akt alpha. Cycle sequencing of the purified PCR products showed that mutations of the PH domain of PKB/Akt were absent in all 20 melanoma specimens. In virtual Northern hybridizations PKB/Akt showed a low expression in both melanomas and acquired melanocytic naevi; however, no overexpression of PKB/Akt was detected. Thus in human melanoma PH domain mutations of PKB/Akt do not play a major role in melanoma carcinogenesis.

Are responses to therapy of metastasized malignant melanoma reflected by decreasing serum values of S100beta or melanoma inhibitory activity (MIA)?

In metastatic melanoma S100beta as well as melanoma inhibitory activity (MIA) are elevated in the serum in the majority of patients. Elevation has been found to correlate with shorter survival, and changes in these parameters in the serum during therapy were recently reported to predict therapeutic outcome in advanced disease. However, the value of these markers with respect to other possible markers by multivariate analysis has not yet been proven for individual patients. In this prospective study, S100beta and MIA were measured in the serum of 67 consecutive patients before and following treatment. Analysing both the sensitivity and the specificity of the serum parameters by the areas under the receiver operating characteristics (ROC) curves, decreases in S100beta and MIA during therapy were associated with response to therapy, while increases indicated progressive disease. Unexpectedly, the individual diagnostic value of changes in tumour markers during therapy was not superior to one-point measurements at restaging. Moreover, S100beta and MIA were not superior to the conventional parameters lactate dehydrogenase and C-reactive protein (CRP) on multiple logistic regression analysis. Applying classification and regression trees (CARTs), one-point measurements of CRP was shown to be the most relevant overall parameter.

What's new in ras genes? Physiological role of ras genes in signal transduction and significance of ras gene activation in tumorigenesis.

Ras gene mutations have been found with variable prevalence in different tumor types. While during the past decade a lot of information has been accumulated on the frequency of ras oncogene activation in tumors, the last two years brought considerable progress in elucidating molecular mechanisms of signal transduction for which cellular ras proteins are key elements. They transmit signals from upstream tyrosine kinases to downstream serine/threonine kinases ultimately leading to changes of gene expression cytoskeletal architecture, cell-to-cell interactions and metabolism. These signalling pathways are of interest for the physiological regulation of proliferation and differentiation in normal, as well as in cancer tissue. Mutational activation of cellular ras genes to transforming oncogenes is thought to promote cell growth even in the absence of extracellular stimuli, and may thereby contribute to the initiation and/or progression of tumors.

Massive lethal cerebral bleeding in a patient with melanoma without intracranial metastasis.

The case history is reported of a patient with melanoma and advanced metastases, who died from massive cerebral bleeding. The lethal event was not caused by intracerebral metastasis but by thrombocytopenia. Depression of the bone marrow resulted from tumour infiltration of the skeleton, chemotherapy and vertebral irradiation. An increase of intracranial pressure triggered the cerebral bleeding, caused by haematemesis from a gastric metastasis directly preceding sudden somnolence.

Interleukin-6 and its surrogate C-reactive protein are useful serum markers for monitoring metastasized malignant melanoma.

Malignant melanoma cells are known to secrete interleukin-6, and elevated interleukin-6 serum levels were reported to correlate with shorter median survival rates. We, therefore, investigated serum values of interleukin-6 and its surrogate C-reactive protein for the ability to discriminate progressive from non-progressive metastatic melanoma disease. Just prior to re-staging examinations, interleukin-6, C-reactive protein and the conventional parameter lactate dehydrogenase were determined in 74 patients with stage IV malignant melanoma according to the criteria of the American Joint Committee on Cancer. We found all tested serum parameters to be significantly elevated in progressive disease. Calculating sensitivities and specificities by logistic regression analysis, the highest sensitivities, according to the established thresholds, were found for interleukin-6 and C-reactive protein with 86% and 76%, respectively. Lactate dehydrogenase had the highest specificity with 94%. Calculating Somers' D rank correlation and the area under the "Receiver Operating Characteristic" curve, all three parameters showed high ability to driscriminate progressive from non-progressive disease. By multiple logistic regression, lactate dehydrogenase was identified to be the most statistically significant marker for progressive disease. We conclude that, comparable to lactate dehydrogenase, interleukin-6 and its surrogate C-reactive protein are useful serum markers for monitoring metastatic malignant melanoma.

[Consumption coagulopathies following peritoneojugular bypass. Prevention by a heparin-antithrombin III combination]. / Les coagulopathies de consommation après dérivations péritonéo-jugulaires. Prévention par l'association héparine-antithrombine III.

Consumption coagulopathy (CIVD) is a frequent complication of peritoneojugular bypass operation. Preventive treatment applied involves low-dose heparin (1.5 mg/kg/d) to maintain an antithrombin III concentration of at least 65%. Results are evaluated in 6 patients treated by 7 bypass operations. A biologic CIVD developed in 2 cases (29%) but no clinical coagulopathy was observed. This incidence is less than that usually reported, a literature review indicating a biologic coagulopathy in 65% of cases, with clinical evidence in 12.5%. Furthermore, patients with spontaneously elevated AT III levels did not develop CIVD while, in contrast, sufficiently high concentrations of AT III could not be maintained in the 2 patients with coagulopathy. These findings suggest the interest of prevention of a CIVD by the use of this procedure.

[Piglet castration--pain sensation and pain elimination]. / Ferkelkastration--Schmerzempfindung und Schmerzausschaltung.

Electroencephalographic (EEG) recordings performed in piglets during Trapanal anaesthesia showed distinct changes in bioelectrical brain activity in some piglets when castration was carried out. Only an additional extradural anaesthesia seemed to interrupt the transmission of peripheral pain stimuli to the central nervous system. Based on the protocol used EEG did not reveal a marked response to noxious stimulation. Castration of piglets up to two weeks of age were performed during general anaesthesia with Trapanal or Disoprivan or local anaesthesia with Hostacain or without any anaesthesia. The different modes of anaesthesia have had no effects to postoperative wound healing and weight gain between groups as well as between males and females within single groups. With regard to insufficient analgesia and/or partially extreme secondary effects the application of investigated anaesthetic methods on the occasion of castration of piglets is not justifiable at present. Castration in piglets up to an age of two month without anaesthesia is allowed by the animal protection law. However, due to improved wound healing and decreased response to surgical stimulus we suggest to perform castration during the first 10 days after delivery.

Mutations of the PH domain of protein kinase B (PKB/AKT) are absent in human epidermal skin tumors.

BACKGROUND: While for most human solid tumors genetic alterations of few distinct genetic regions have been found, studies on basal cell carcinomas (BCC) have shown the prevalence of several abnormalities including alterations of the three ras genes, GAP (GTPase activating protein), p53, PTCH (the human homologue of Drosophila patched) and SMOH (the human homologue of Drosophila smoothened). On the other hand, during the last decade, a new oncogene, protein kinase B (PKB/AKT), has been characterized and found to be overexpressed in certain human tumors. In vivo activation of PKB/AKT necessitates its recruitment to the cell membrane mediated by the N-terminal pleckstrin homology (PH) domain. OBJECTIVE: We investigated whether mutations of this mandatory domain are present in a subset of human epidermal skin tumors. METHODS: RNA of 19 human skin tumors including 13 BCC, 4 squamous cell carcinomas (SCC; including 1 keratoacanthoma) and 2 neurofibromas of different size and tumor stage were used for reverse transcription and subsequent PCR amplification of the PH domain of PKB/AKT. RESULTS: Cycle sequencing of the purified PCR products did not reveal any mutation of the PH domain of PKB/AKT. CONCLUSION: In human BCC and SCC, mutations of the PH domain of PKT/AKT do not play a major role during the carcinogenesis of these tumors.

Ras gene mutation-independent tumours in the intestine of the rat by a single dose of N-methyl-N-nitrosourea.

Aiming at a sequential analysis of the role of ras gene point mutations during intestinal carcinogenesis, we established an experimental rat tumour model using N-methyl-N-nitrosourea (MNU) as an initiating agent as this carcinogen has been found to induce rat mammary carcinomas with a high prevalence of ras gene mutations. MNU treatment of a total of 249 rats (25 or 50 mg/kg i.p.) in various combinations with partial hepatectomy, hydroxyurea infusion and/or phenobarbital exposure resulted in a high incidence of intestinal adenomas and carcinomas of different histological types, besides liver, soft tissue and auditory sebaceous gland tumours. With PCR-amplified DNA the prevalence of mutations of codon 12 and 61 of H-, K- and N-ras was determined in dot blots by hybridization with 32P-labelled allele-specific oligonucleotides. Ras gene point mutations were not observed in any of the 41 intestinal rat tumours randomly selected from various experimental groups. Considering the high prevalence of ras mutations in MNU-induced mammary carcinomas of the rat the observed complete lack of ras mutations in intestinal tumours induced in the rat by the same carcinogen suggests that organ-specific intraspecies differences in the mechanism of malignant transformation exist even for a heterolytically decomposing, direct acting carcinogen like MNU.

[Disseminated melanoma cells in blood and bone marrow. Significance and detection by potential tumor markers]. / Disseminierte Melanomzellen in Blut und Knochenmark. Bedeutung und Nachweis durch potenzielle Tumormarker.

As the majority of primary malignant melanomas can be cured by surgical excision, the prognosis of melanomas is dependent on whether tumor cells have disseminated orare capable of doing so at the time of surgery. A prospective and valid detection of this minimal residual disease is not currently possible. The most important known so-called markers of melanoma disease, tyrosinase, S100 and MIA, all are more likely to be present in patients with more advanced disease. A valid prognostic effect has only been shown for S100 in patients with already identified metastatic disease. Further prospective studies are required to determine the potential gain of information by routine determination of these markers in melanoma patients.

No correlation of tyrosinase mRNA in bone marrow with prognosis of metastatic melanoma.

BACKGROUND: Recent publications suggest that tyrosinase mRNA in blood as well as in bone marrow is detectable only in a subgroup of patients with metastatic melanoma. OBJECTIVE: We addressed the question, whether patients with metastatic melanoma and with RT-PCR-detectable tyrosinase mRNA in blood or bone marrow have a different prognosis compared to tyrosinase mRNA-negative patients. METHODS: 20 melanoma patients with widespread clinical metastases were enrolled and the survival time after first diagnosis of visceral metastases was correlated to tyrosinase mRNA presence in blood and bone marrow samples. RESULTS: The time of survival of 8 patients with metastatic melanoma and detectable tyrosinase mRNA in either blood or bone marrow was not different from the prognosis of 12 patients without detectable tyrosinase mRNA in either blood or bone marrow. CONCLUSION: Although based on a limited number of patients our results suggest that detection of tyrosinase mRNA in blood or bone marrow samples of melanoma patients with advanced disease seems to have no substantial relevance for survival time and outcome of disease. For this purpose, detection of tyrosinase mRNA by RT-PCR is not a valid tumor marker. Nevertheless, tyrosinase positivity in bone marrow in earlier tumor stages might indicate increased risk for the development of distant metastases. This should be addressed in further studies.