Health-Related Quality of Life of Patients with Marfan Syndrome-Polish Study.

Background: Despite extensive knowledge about the quality of life of people suffering from rare diseases, data on patients with Marfan syndrome (MFS) are scarce and inconsistent. Hence, the problem of assessing the quality of life (QOL) and its relationship with the assessment of which ailments are the most burdensome for these patients is still open. Aim: Comparison of the quality of life of patients with MFS and determination as to which of the reported complaints in patients with MFS are related to the QOL of patients. Methods: The study included 35 patients with MFS and 35 healthy controls, matched for gender and age. In the study, the questionnaire of quality of life assessment SF-36 was used to assess the level of health-related quality of life, as well as an interview of the most severe symptoms reported by patients with MFS. Results: The level of the physical dimension of the QOL (p < 0.001) and limiting of roles due to physical health (p = 0.002), as well as the level of general index of the QOL (p < 0.001), were statistically significantly lower in MFS patients when compared to controls. People from both studied groups do not vary in the scope of pain, vitality, social functioning, limiting the roles due to emotional problems, and state of mind but also in the mental dimension of the health-related quality of life (HRQL). Additionally, there has been a correlation between HRQL and the subjective assessment of the effects of orthopedic, ophthalmic, and cardiological problems in life, as well as lower exercise tolerance in the evaluation of people with MFS and QOL in most areas. Conclusions: Patients with MFS present a reduced QOL in the areas of physical functioning, limiting roles due to physical health, general feeling of general health, the physical dimension of the HRQL, and the general index of the QOL; in these areas, they require careful evaluation, as well as medical and psychosocial assistance.

How to Distinguish Marfan Syndrome from Marfanoid Habitus in a Physical Examination-Comparison of External Features in Patients with Marfan Syndrome and Marfanoid Habitus.

Marfan Syndrome (MFS) is a systemic disorder caused by mutations in fibrillin-1. The most common cause of mortality in MFS is dissection and rupture of the aorta. Due to a highly variable and age-dependent clinical spectrum, the diagnosis of MFS still remains sophisticated. The aim of the study was to determine if there exist phenotypic features that can play the role of "red flags" in cases of MFS suspicion. The study population included 306 patients (199 children and 107 adults) who were referred to the Department of Pediatric Cardiology due to suspicion of MFS. All patients underwent complete clinical evaluation in order to confirm the diagnosis of MFS according to the modified Ghent criteria. MFS was diagnosed in 109 patients and marfanoid habitus in 168 patients. The study excluded 29 patients with other hereditary thoracic aneurysm syndromes. Comparative analysis between patients with Marfan syndrome and marfanoid habitus was performed. Symptoms with high prevalence and high positive likelihood ratio were identified (pectus carinatum, reduced elbow extension, hindfoot deformity, gothic palate, downslanting palpebral fissures, lens subluxation, myopia ≥ 3 dioptres remarkably high stature). The differentiation between patients with MFS and marfanoid body habitus is not possible by only assessing external body features; however, "red flags" could be helpful in the screening phase.

Families of people with Marfan syndrome. The relationship between the functioning of the family system and the life quality of the affected persons. / Rodzina osoby z zespolem Marfana. Zwiazki funkcjonowania systemu rodzinnego z jakoscia zycia osoby chorej.

OBJECTIVES: The purpose of the study was to analyze the functioning of afamily as perceived by a person with Marfan syndrome and to look for relationships between the characteristics of the system and the overall quality of life of the ill. METHODS: Participants included 33 individuals with Marfan syndrome and 33 individuals without chronic illness. We used the Family Evaluation Scale - the Polish adaptation of the FACES-IVby D.H. Olson and the Satisfaction with Life Scale (SWLS) by Diener, Emmons, Larson and Griffin. RESULTS: People with Marfan syndrome perceive their families as significantly less coherent and significantly more disengaged than people without chronic illness. This family system of people with Marfan syndrome can be characterized by low scores on the "Cohesion" and "Flexibility" and high scores on the other four scales showing the level of imbalance of the family as a system, which makes this family profile similar to an ?unbalanced' system. Life satisfaction of people with Marfan syndrome correlated positively with "Cohesion", "Flexibility" and "Family Satisfaction" as features of family system perceived by them. CONCLUSIONS: The obtained results confirm the importance of supporting families of people with Marfan syndrome and specialist help aimed at dealing with emotional burden related to the health of the patient.

New Screening Tool for Aortic Root Dilation in Children with Marfan Syndrome and Marfan-Like Disorders.

One of the roles of a pediatric cardiologist who suspects or diagnoses a genetically determined connective tissue disease (e.g., Marfan, Ehlers-Danlos, and Loeys-Dietz syndromes) is to assess whether the aortic root is dilated. The aortic root diameter is affected by the patient's age, sex, and body surface area. Therefore, the aortic root diameter needs to be determined and expressed as a z-score. Calculation of the z-score is time-consuming and problematic if used infrequently. This study aimed to introduce a simple screening method for identifying aortic root dilation in children. The study population consisted of 190 children who were diagnosed with Marfan syndrome or Marfan-like disorders. The aortic root ratio (ARr) was formulated. The value of the ARr was compared in each patient with the results in z-scores, which were obtained using on-line calculators based on the most widespread nomograms. The optimal cut-off value of the ARr was ≥ 18.7. At this cut-off point, the sensitivity of the ARr ranged from 88.3% to 100% and the specificity ranged from 94% to 97.8%. All of the patients in whom the ARr failed to identify aortic root dilation were also divergently classified by different nomograms. At the ARr cut-off point of ≥ 18.0, a sensitivity of 100% was achieved for all nomograms with minimal reduction in specificity. The ARr allows for rapid and precise screening for aortic root dilation in children. Unlike classic analysis, the ARr does not require nomograms or on-line calculations.

Fluoroaryl analogs of sulforaphane - A group of compounds of anticancer and antimicrobial activity.

A series of new sulforaphane analogs bearing various (poly)fluoroaryl substituents bonded to the sulfinyl sulfur atom in place of the original methyl group and having different number of methylene groups in the central alkyl chain were synthesized and fully characterized. The new compounds were tested in vitro for their anticancer, antibacterial, antifungal and antiviral properties. Some of them demonstrated a much higher anticancer activity against selected lines of cancer: skin (MALME-3M), colon (HT-29) and breast (MCF7 and MDA-MB-231) cells than that exhibited by native sulforaphane (SFN). Related lines of untransformed (normal) cells, taken from the same organs as the cancer ones, i.e. MALME3, CRL-1790 and MCF10, respectively, were checked, which allowed for the determination of the selectivity indexes (SI). In certain cases, the latter exceeded 3.2. Concerning the antibacterial activity, gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) were susceptible to some newly synthesized SFN analogs, while the selected probiotic strains were from 10 to 100 fold more resistant to them, which gives a possibility of protection of symbiont strains during a potential therapy with such compounds. The antifungal activity of the new compounds possessing the fluorophenyl substituent was found to be higher than the activity of the parent SFN. In turn, most of the new compounds showed generally no anti-HIV activity. The influence of the particular structural differences in the new molecules, analogs of SFN, on their biological activity is discussed.

In the triple-negative breast cancer MDA-MB-231 cell line, sulforaphane enhances the intracellular accumulation and anticancer action of doxorubicin encapsulated in liposomes.

A new combination of sulforaphane (a natural compound obtained from Brassicaceae vegetables) and the cytostatic drug doxorubicin was entrapped in nanometer-sized liposomes. In vitro experiments were performed to investigate the cytotoxicity of these structures on the human breast cancer cell line MDA-MB-231. Confocal microscopy studies revealed enhanced cellular endocytotic internalization, followed by the release of the examined combination from the lysosomes. The in vitro interaction analysis using the Chou-Talalay approach showed high synergistic activity of the examined combination. This synergistic activity enables a considerable reduction in cytostatic dosage and an increase in cancer treatment efficiency.

Sulforaphane-conjugated selenium nanoparticles: towards a synergistic anticancer effect.

Sulforaphane-modified selenium nanoparticles can be prepared in a simple aqueous-phase redox reaction through reduction of selenite with ascorbic acid. The sulforaphane molecules present in the reaction mixture adsorb on the nanoparticle surface, forming an adlayer. The resulting conjugate was examined with several physicochemical techniques, including microscopy, spectroscopy, x-ray diffraction, dynamic light scattering and zeta potential measurements. As shown in in vivo investigations on rats, the nanomaterial administered intraperitoneally is eliminated mainly in urine (and, to a lesser extent, in feces); however, it is also retained in the body. The modified nanoparticles mainly accumulate in the liver, but the basic parameters of blood and urine remain within normal limits. The sulforaphane-conjugated nanoparticles reveal considerable anticancer action, as demonstrated on several cancer cell cultures in vitro. This finding is due to the synergistic effect of elemental selenium and sulforaphane molecules assembled in one nanostructure (conjugate). On the other hand, the cytotoxic action on normal cells is relatively low. The high antitumor activity and selectivity of the conjugate with respect to diseased and healthy cells is extremely promising from the point of view of cancer treatment.

In Vitro Evaluation of Sulforaphane and a Natural Analog as Potent Inducers of 5-Fluorouracil Anticancer Activity.

Isothiocyanates (R-NCS) are sulphur-containing phytochemicals. The main source are plants of the Brassicaceae family. The best known plant-derived isothiocyanate is sulforaphane that has exhibited anticancer activity in both in vivo and in vitro studies. Recent attempts to expand their use in cancer therapy involve combining them with standard chemotherapeutics in order to increase their therapeutic efficacy. The aim of this paper is to determine the impact of sulforaphane and its natural analog alyssin on the anticancer activity of the well-known anticancer drug 5-fluorouracil. The type of drug-drug interactions was determined in prostate and colon cancer cell lines. Confocal microscopy, western blot and flow cytometry methods were employed to determine the mechanism of cytotoxic and cytostatic action of the combinations. The study revealed that additive or synergistic interactions were observed between 5-fluorouracil and both isothiocyanates, which enhanced the anticancer activity of 5-fluorouracil, particularly in colon cancer cell lines. An increased cytostatic effect was observed in case of alyssin while for sulforaphane the synergistic interaction with 5-fluorouracil involved an intensification of apoptotic cell death.

Oncotoxic Properties of Serotonin Transporter Inhibitors and 5-HT1A Receptor Ligands.

The cytotoxic activity of several serotonin transporter (SERT) inhibitors and subtype of serotonin receptor 1A (5-HT1A receptor) ligands have been examined in androgen-insensitive human PC-3 prostate and neuroblastoma SH-SY5Y cancer cells. Almost all of the studied compounds (except 5-HT1A receptor agonist (2R)-(+)-8-Hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT)) exhibited absolute cytotoxic activity against the examined cancer cells. The compound 4-Fluoro-N-[2-[4-(7-methoxy-1-naphthalenyl)-1-piperazinyl]ethyl]benzamide hydrochloride (S14506) that showed highest activity against neuroblastoma tumors was the 5-HT1A receptor agonist (although not alike other 5-HT1A receptor agonists). On the other hand, the compound 6-nitro-2-(4-undecylpiperazin-1-yl)quinoline hydrochloride (AZ07) that had the highest activity against PC-3 prostate cancer cells was a compound exhibiting antagonistic activity against the 5-HT1A receptor. Thus, compounds of oncotoxic properties S14506 and AZ07 should be evaluated further for their potential use in the prevention and treatment of cancer. Most of the 15 compounds tested exhibited either agonistic or antagonistic activity for both the cyclic adenosine monophosphate (cAMP) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathways in human embryonic kidney 293 (HEK293) cells that overexpress the 5HT1AR gene. However, compounds paroxetine, N-Ac-paroxetine and 2-[4-(cyclobutylmethyl)piperazin-1-yl]-6-nitroquinoline hydrochloride (AB22) simultaneously exhibited antagonistic activity on the cAMP pathway and agonistic activity on the ERK1/2 pathway. Fluoxetine relative to compound AZ07 had almost three times lower cytotoxic activity against PC-3 prostate cancer cells. However, the proapoptotic activity of fluoxetine compared to compound AZ07 is almost two times higher which would suggest that the cytotoxic activity of both compounds may be dependent on different cell death mechanisms. Compound S14506 was found to be an antagonist of the serine-threonine protein kinase B (Akt) pathway. Prosurvival Akt activity may be reversed by Akt antagonists. Therefore, the antagonistic activity of S14506 on the Akt pathway may evoke caspase-3 expression and cytotoxicity. It appears that one should not expect a straightforward relationship between the activation of particular serotonergic pathways by selective serotonin reuptake inhibitors (SSRIs) and 5-HT1A receptor ligands and their cytotoxic or cytoprotective activity. Additionally, nuclear transcription factor κB (NF-κB), which may be involved in 5-HT-dependent biochemical pathways by coordinating different subunits in the formation of a dimer, may regulate the transcription of different transduction pathways. Therefore, it can be suggested that the mechanism of the cytotoxic activity of certain compounds (serotonergic against nonserotonergic) may depend on the compound and cancer type being examined. Docking studies showed that S14506, buspirone and spiperone bind in similar ways in the 5-HT1A receptor model and interacted with similar 5-HT1A receptor residues. S14506 and spiperone were found to be located closer to both phenylalanines in TM6 than buspirone, thus exhibiting more antagonist binding modes.

Autophagic cell death and premature senescence: New mechanism of 5-fluorouracil and sulforaphane synergistic anticancer effect in MDA-MB-231 triple negative breast cancer cell line.

In view of the need for new, more effective therapies for the triple negative breast cancer treatment, the aim of the study was to evaluate the anticancer activity and mechanism of action of the sulforaphane and 5-fluorouracil combination in the triple negative breast cancer cell line MDA-MB-231. Changes in the number of live cells after alone and sequential treatment were determined by the MTT test. The Chou and Talaly method was used to identify the type of interaction. Confocal microscopy, flow cytometry, western blot and spectrophotometry were used to examine apoptosis, autophagy and premature senescence. The western blot method was applied to measure the level of enzymes that are crucial for the 5-fluorouracil activity. Sulforaphane and 5-fluorouracil have been shown to interact synergistically in the breast cancerMDA-MB-231 cell line, resulting in a significant reduction of the number of live cells compared to alone treatments. Sulforaphane has decreased the level of thymidylate synthetase, which was also observed in the case of the sequential sulforaphane and 5-fluorouracil treatment. Studies of the interaction mechanism have revealed that sulforaphane and 5-fluorouracil act synergistically in the MDA-MB-231 cells by inducing autophagic cell death and premature senescence.

Organofluorine Isoselenocyanate Analogues of Sulforaphane: Synthesis and Anticancer Activity.

A series of previously unknown sulforaphane analogues with organofluorine substituents bonded to the sulfinyl sulfur atom, an isoselenocyanate moiety in place of the isothiocyanate group, the central sulfur atom in various oxidation states, and different numbers of methylene groups in the central alkyl chain were synthesized and fully characterized. All new compounds were tested for their biological properties in vitro and demonstrated much higher anticancer activity against two breast cancer cell lines than that shown by native sulforaphane; at the same time, the compounds were less toxic for normal cells. The influence of the particular structural changes in the molecules on the cytotoxicity is discussed.

Sulforaphane Regulates NFE2L2/Nrf2-Dependent Xenobiotic Metabolism Phase II and Phase III Enzymes Differently in Human Colorectal Cancer and Untransformed Epithelial Colon Cells.

Sulforaphane (SFN), a naturally occurring chemopreventive and anticancer agent, is a nuclear factor, erythroid 2-like 2 (NFE2L2/Nrf2) inducer. Nrf2 plays a critical role in coordinating the cell defense system by initiating the transcription of cytoprotective genes, including detoxification enzymes such as NAD(P)H quinone dehydrogenase 1 (NQO1) and transport proteins such as ATP-binding cassette, subfamily C (CFTR/MRP). Recently, the essential role of Nrf2 in tumor development and progression and in the development of multidrug resistance in cancer cells has been highlighted. The aim of this study was to compare the effect of SFN on the Nrf2 system and the Nrf2-target enzymes NQO1 and MRP in human untransformed epithelial colon CRL-1790 cells and in HT-29 and Caco-2 colorectal cancer cells to elucidate the role of SFN in cancer prevention and treatment. We have demonstrated that SFN has excellent cytoprotective properties in CRL-1790 cells, as it induced Nrf2-dependent expression of MRP1 and NQO1. SFN induced Nrf2 target enzyme activity in HT-29 and Caco-2 cancer cells but regulated the Nrf2/ARE signaling pathway differently in cancer and untransformed cells.