Cerebral monitoring with transcranial Doppler ultrasonography improves neurologic outcome during repairs of acute type A aortic dissection

ObjectiveNeurologic complications after repair of acute type A aortic dissection remain significant. The use of power M-mode transcranial Doppler monitoring to verify cerebral blood flow during these repairs might decrease cerebral ischemia by correcting malperfusion. The purpose of this study was to analyze the use of power M-mode transcranial Doppler monitoring during repairs of acute type A dissection with regard to neurologic outcome.MethodsWe performed a prospective study of patients undergoing repairs of acute type A aortic dissection. Repairs included profound hypothermic circulatory arrest and retrograde cerebral perfusion. Patients in whom transcranial Doppler monitoring was used to monitor cerebral blood flow and modify operative technique during repair (study group) were compared with those without monitoring and modification (control group).ResultsBetween September 2001 and October 2003, we repaired 56 cases of acute type A dissection. Power M-mode transcranial Doppler monitoring was used in 50% (28/56) of cases. Power M-mode transcranial Doppler monitoring altered operative cannulation and guided retrograde cerebral perfusion flow in 28.5% (8/28) and 78.6% (22/28) of cases, respectively. Two patients presented with preoperative stroke, one in each group. One operative death occurred in each group. In-hospital mortality and the occurrence of new stroke were not significantly different between the 2 groups. Temporary neurologic dysfunction occurred less often in the study group (14.8% [4/27] vs 51.8% [14/27], P = .008).ConclusionsIdentification of cerebral malperfusion requires cerebral monitoring. By ensuring cerebral blood flow by using power M-mode transcranial Doppler monitoring and correcting cerebral malperfusion by modifying operative technique, neurologic outcome was improved during repairs of acute type A aortic dissection

Cancer Rehabilitation Indicators for Europe

Little is known of cancer rehabilitation needs in Europe. EUROCHIP-3 organised a group of experts to propose a list of population-based indicators used for describing cancer rehabilitation across Europe. The aim of this study is to present and discuss these indicators. A EUROCHIP-3 expert panel reached agreement on two types of indicators. (a) Cancer prevalence indicators. These were proposed as a means of characterising the burden of cancer rehabilitation needs by time from diagnosis and patient health status. These indicators can be estimated from cancer registry data or by collecting data on follow-up and treatments for samples of cases archived in cancer registries. (b) Indicators of rehabilitation success. These include: return to work, quality of life, and satisfaction of specific rehabilitation needs. Studies can be performed to estimate these indicators in individual countries, but to obtain comparable data across European countries it will be necessary to administer a questionnaire to randomly selected samples of patients from population-based cancer registry databases. However, three factors complicate questionnaire studies: patients may not be aware that they have cancer; incomplete participation in surveys could lead to bias; and national confidentiality laws in some cases prohibit cancer registries from approaching patients. Although these studies are expensive and difficult to perform, but as the number of cancer survivors increases, it is important to document their needs in order to provide information on cancer control

Modest genetic influence on bronchodilator response: a study in healthy twins.

AIM: To determine the reasons for large standard deviation of bronchodilator response (BDR) and establish whether there is a potential heritable component in healthy subjects. METHODS: 67 monozygotic and 42 dizygotic adult twin pairs were assessed for bronchodilator response (% change in FEV1 after inhaling 400 microg salbutamol). Univariate quantitative genetic modeling was performed. RESULTS: Multiple regression modeling showed a significant association between BDR and sex and baseline FEV1 (P<0.05), while no association was found with smoking habits, body mass index, or age. Within pair correlation in monozygotic twins was modest (0.332), but higher than in dizygotic twins (0.258). Age-, sex-, and baseline FEV1-adjusted genetic effect accounted for 14.9% (95% confidence interval, CI 0%-53.1%) of the variance of BDR, shared environmental effect for 18.4% (95% CI 0%-46.8%), and unshared environmental effect for 66.8% (95% CI 46.8%-88.7%). CONCLUSION: Our twin study showed that individual differences in BDR can be mostly explained by unshared environmental effects. In addition, it is the first study to show low, insignificant hereditary influences, independently from sex, age, and baseline FEV1

Final results of the Choroid Plexus Tumor study CPT-SIOP-2000

INTRODUCTION: Standards for chemotherapy against choroid plexus tumors (CPT) have not yet been established. METHODS: CPT-SIOP-2000 (NCT00500890) was an international registry for all CPT nesting a chemotherapy randomization for high-risk CPT with Carboplatin/Etoposide/Vincristine (CarbEV) versus Cyclophosphamide/Etoposide/Vincristine (CycEV). Patients older than three years were recommended to receive irradiation: focal fields for non-metastatic CPC, incompletely resected atypical choroid plexus papilloma (APP) or metastatic choroid plexus papilloma (CPP); craniospinal fields for metastatic CPC/APP and non-responsive CPC. High risk was defined as choroid plexus carcinoma (CPC), incompletely resected APP, and all metastatic CPT. From 2000 until 2010, 158 CPT patients from 23 countries were enrolled. RESULTS: For randomized CPC, the 5/10 year progression free survival (PFS) of patients on CarbEV (n = 20) were 62%/47%, respectively, compared to 27%/18%, on CycEV (n = 15), (intention-to-treat, HR 2.6, p = 0.032). Within the registry, histological grading was the most influential prognostic factor: for CPP (n = 55) the 5/10 year overall survival (OS) and the event free survival (EFS) probabilities were 100%/97% and 92%/92%, respectively; for APP (n = 49) 96%/96% and 76%/76%, respectively; and for CPC (n = 54) 65%/51% and 41%/39%, respectively. Without irradiation, 12 out of 33 patients with CPC younger than three years were alive for a median of 8.52 years. Extent of surgery and metastases were not independent prognosticators. CONCLUSIONS: Chemotherapy for Choroid Plexus Carcinoma is feasible and effective. CarbEV is superior to CycEV. A subset of CPC can be cured without irradiation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11060-021-03942-0

The Hypothermic Effect of Hydrogen Sulfide Is Mediated by the Transient Receptor Potential Ankyrin-1 Channel in Mice

This is the final version. Available from MDPI via the DOI in this record.Data is contained within the article and Supplementary Materials.Hydrogen sulfide (H2S) has been shown in previous studies to cause hypothermia and hypometabolism in mice, and its thermoregulatory effects were subsequently investigated. However, the molecular target through which H2S triggers its effects on deep body temperature has remained unknown. We investigated the thermoregulatory response to fast-(Na2S) and slow-releasing (GYY4137) H2S donors in C57BL/6 mice, and then tested whether their effects depend on the transient receptor potential ankyrin-1 (TRPA1) channel in Trpa1 knockout (Trpa1-/-) and wild-type (Trpa1+/+) mice. Intracerebroventricular administration of Na2S (0.5-1 mg/kg) caused hypothermia in C57BL/6 mice, which was mediated by cutaneous vasodilation and decreased thermogenesis. In contrast, intraperitoneal administration of Na2S (5 mg/kg) did not cause any thermoregulatory effect. Central administration of GYY4137 (3 mg/kg) also caused hypothermia and hypometabolism. The hypothermic response to both H2S donors was significantly (p < 0.001) attenuated in Trpa1-/- mice compared to their Trpa1+/+ littermates. Trpa1 mRNA transcripts could be detected with RNAscope in hypothalamic and other brain neurons within the autonomic thermoeffector pathways. In conclusion, slow- and fast-releasing H2S donors induce hypothermia through hypometabolism and cutaneous vasodilation in mice that is mediated by TRPA1 channels located in the brain, presumably in hypothalamic neurons within the autonomic thermoeffector pathways.National Research, Development and Innovation OfficeMedical School, University of PecsNew National Excellence Program of the Hungarian Ministry for Innovation and TechnologyNew National Excellence Program of the Hungarian Ministry for Innovation and TechnologyHigher Education Institutional Excellence Program of the Ministry of Human Capacities in HungaryEuropean UnionNational Research, Development and Innovation Fund of HungaryJanos Bolyai Scholarship of the Hungarian Academy of Science

Discovery of Inhibitors of Leishmania β-1,2-Mannosyltransferases Using a Click-Chemistry-Derived Guanosine Monophosphate Library

Leishmania spp. are a medically important group of protozoan parasites that synthesize a novel intracellular carbohydrate reserve polymer termed mannogen. Mannogen is a soluble homopolymer of β-1,2-linked mannose residues that accumulates in the major pathogenic stages in the sandfly vector and mammalian host. While several steps in mannogen biosynthesis have been defined, none of the enzymes have been isolated or characterized. We report the development of a simple assay for the GDP-mannose–dependent β-1,2-mannosyltransferases involved in mannogen synthesis. This assay utilizes octyl α-d-mannopyranoside to prime the formation of short mannogen oligomers up to 5 mannose residues. This assay was used to screen a focussed library of 44 GMP-triazole adducts for inhibitors. Several compounds provided effective inhibition of mannogen β-1,2-mannosyltransferases in a cell-free membrane preparation. This assay and inhibitor compounds will be useful for dissecting the role of different mannosyltransferases in regulating de novo biosynthesis and elongation reactions in mannogen metabolism

Deletion of transketolase triggers a stringent metabolic response in promastigotes and loss of virulence in amastigotes of Leishmania mexicana

Transketolase (TKT) is part of the non-oxidative branch of the pentose phosphate pathway (PPP). Here we describe the impact of removing this enzyme from the pathogenic protozoan Leishmania mexicana. Whereas the deletion had no obvious effect on cultured promastigote forms of the parasite, the Δtkt cells were not infective to mice. Δtkt promastigotes were more susceptible to oxidative stress and various leishmanicidal drugs than wild-type, and metabolomics analysis revealed profound changes to metabolism in these cells. In addition to changes consistent with those directly related to the role of TKT in the PPP, central carbon metabolism was substantially decreased, the cells consumed significantly less glucose, flux through glycolysis diminished, and production of the main end products of metabolism was decreased. Only minor changes in RNA abundance from genes encoding enzymes in central carbon metabolism, however, were detected although fructose-1,6-bisphosphate aldolase activity was decreased two-fold in the knock-out cell line. We also showed that the dual localisation of TKT between cytosol and glycosomes is determined by the C-terminus of the enzyme and by engineering different variants of the enzyme we could alter its sub-cellular localisation. However, no effect on the overall flux of glucose was noted irrespective of whether the enzyme was found uniquely in either compartment, or in both

LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition

LKB1/STK11 is a multitasking tumour suppressor kinase. Germline inactivating mutations of the gene are responsible for the Peutz-Jeghers hereditary cancer syndrome. It is also somatically inactivated in approximately 30% of non-small-cell lung cancer (NSCLC). Here, we report that LKB1/KRAS mutant NSCLC cell lines are sensitive to the MEK inhibitor CI-1040 shown by a dose-dependent reduction in proliferation rate, whereas LKB1 and KRAS mutations alone do not confer similar sensitivity. We show that this subset of NSCLC is also sensitised to the mTOR inhibitor rapamycin. Importantly, the data suggest that LKB1/KRAS mutant NSCLCs are a genetically and functionally distinct subset and further suggest that this subset of lung cancers might afford an opportunity for exploitation of anti-MAPK/mTOR-targeted therapies

E2F1 Regulates Cellular Growth by mTORC1 Signaling

During cell proliferation, growth must occur to maintain homeostatic cell size. Here we show that E2F1 is capable of inducing growth by regulating mTORC1 activity. The activation of cell growth and mTORC1 by E2F1 is dependent on both E2F1's ability to bind DNA and to regulate gene transcription, demonstrating that a gene induction expression program is required in this process. Unlike E2F1, E2F3 is unable to activate mTORC1, suggesting that growth activity could be restricted to individual E2F members. The effect of E2F1 on the activation of mTORC1 does not depend on Akt. Furthermore, over-expression of TSC2 does not interfere with the effect of E2F1, indicating that the E2F1-induced signal pathway can compensate for the inhibitory effect of TSC2 on Rheb. Immunolocalization studies demonstrate that E2F1 induces the translocation of mTORC1 to the late endosome vesicles, in a mechanism dependent of leucine. E2F1 and leucine, or insulin, together affect the activation of S6K stronger than alone suggesting that they are complementary in activating the signal pathway. From these studies, E2F1 emerges as a key protein that integrates cell division and growth, both of which are essential for cell proliferation