Prevention of Radial Artery Occlusion of 3 Hemostatic Methods in Transradial Intervention for Coronary Angiography.

OBJECTIVES: The main objective of this study was to compare the efficacy of 3 hemostatic methods for the prevention of early radial artery occlusion (RAO): standard patent hemostasis, patent hemostasis with ulnar compression or the ulnar artery transient compression facilitating radial artery patent hemostasis (ULTRA) method, and facilitated hemostasis with a hemostatic disc. BACKGROUND: There are no prospective randomized studies that compare early RAO rates with the 3 most used nonocclusive hemostatic methods. METHODS: This was a prospective, longitudinal, comparative, and randomized study. The final population analyzed was 1,469, and they were randomized into 3 groups: 491 patients in group 1 with standard patent hemostasis, 490 patients in group 2 with the ULTRA method, and 488 patients in group 3 with facilitated hemostasis with a hemostatic disc. RESULTS: The RAO rate at 24 hours of the total population analyzed was 4.6%. By hemostasis groups, it was 3.6% for patent hemostasis, 5.5% for the ULTRA method, and 4.7% for facilitated hemostasis with a hemostatic disc, with no statistical difference among the 3 groups (P = 0.387). At 30 days, the overall rate of RAO was 1.8%, and by groups, it was 1.4% for the patent hemostasis group, 1.8% for the ULTRA method group, and 2.2% for the facilitated hemostasis with a hemostatic disc group, respectively (P = 0.185). CONCLUSIONS: The rates of RAO at 24 hours evaluated by plethysmography oximetry and confirmed by ultrasound among 3 current radial hemostasis methods (ie, patent hemostasis, the ULTRA method, and facilitated hemostasis with a hemostatic disc) are not different.

Bioprosthetic valve failure. Comparative trial of two balloon-expandable transcatheter heart valve systems in intermediate-risk patients: a propensity score analysis.

BACKGROUND: The comparative mid and long-term durability, including the rates of bioprosthetic valve failure (BVF) of the Sapien XT® and Sapien 3® transcatheter heart valve (THV) in patients with intermediate surgical risk has not been reported. METHODS: Consecutive intermediate-risk patients with severe aortic stenosis from the Mexican registry of transcatheter aortic valve replacement (TAVR) with Sapien® THVs were included. The primary endpoint was to compare the BVF rate between THVs at 2 years of follow-up. Secondary endpoints were comparisons of the composite of global mortality, cardiovascular mortality, and neurological events at 30 d and 24 months of follow-up. RESULTS: During 2014-2019, 115 (60 Sapien XT® and 55 Sapien 3®) patients met the inclusion criteria in five medical centres. The mean age was 77.3 ± 8.4 years. The average Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) was 5.6 ± 2.9. There was no statistically significant difference between the groups in BVF rate. At 30 d, overall, cardiovascular and non-cardiovascular mortality was 4.3%, 2.6%, and 1.7%, respectively. Neurological events rate was 1.73%. The mean long-term follow-up was 25.3 ± 14.2 months with an overall mortality of 9.56% but lower for the Sapien 3® group (15% vs. 3.6%, p=.037). The only independent predictor of composite mortality and neurological events that occurred in the long term was using a Sapien XT® [OR 1.6, CI 95%, 1.0-24.9; p=.049]. CONCLUSIONS: The BVF rate at 25 months of follow-up was similar with the XT and S3 systems. During this follow-up period, the major composite events of death from any cause and neurological events were significantly lower with the S3 system.

Distal Radial Artery Approach to Prevent Radial Artery Occlusion Trial.

OBJECTIVES: The aim of this study was to compare the rate of proximal radial artery occlusion (RAO) with Doppler ultrasound between distal and conventional radial access 24 h and 30 days after a transradial coronary procedure. BACKGROUND: The use of distal radial access to prevent proximal RAO (PRAO) in the proximal segment at 24 h and 30 days after a procedure, compared with conventional radial access, is unknown. METHODS: This was a prospective, comparative, longitudinal, randomized study. A total of 282 patients were randomized to either proximal radial access (n = 142) or distal radial access (n = 140) to evaluate the superiority of the distal approach in the prevention of PRAO with Doppler ultrasound 24 h and 30 days after a transradial coronary procedure. RESULTS: In the per protocol analysis, the rates of PRAO at 24 h and 30 days were 8.4% and 5.6% in the proximal group and 0.7% and 0.7% in the distal group, respectively (24 h: odds ratio [OR]: 12.8; 95% confidence interval [CI]: 1.6 to 100.0; p = 0.002; 30 days: OR: 8.2; 95% CI: 1.0 to 67.2; p = 0.019). In an intention-to-treat analysis, the 24-h and 30-day rates of PRAO were 8.8% and 6.4% for proximal radial access and 1.2% and 0.6% in the distal radial access group (24 h: OR: 7.4; 95% CI: 1.6 to 34.3; p = 0.003; 30 days: OR: 10.6; 95% CI: 1.3 to 86.4; p = 0.007). CONCLUSIONS: Distal radial access prevents RAO in the proximal segment at 24 h and 30 days after the procedure compared with conventional radial access.

Interventional and surgical therapeutic strategies for pulmonary arterial hypertension: Beyond palliative treatments.

Despite significant advances in pharmacological treatments, pulmonary arterial hypertension remains an incurable disease with an unreasonably high morbidity and mortality. Although specific pharmacotherapies have shifted the survival curves of patients and improved exercise endurance as well as quality of life, it is also true that these pharmacological interventions are not always accessible (particularly in developing countries) and, perhaps most importantly, not all patients respond similarly to these drugs. Furthermore, many patients will continue to deteriorate and will eventually require an additional, non-pharmacological, intervention. In this review we analyze the role of atrial septostomy and Potts anastomosis in the management of patients with pulmonary arterial hypertension, we summarize the current worldwide clinical experience (case reports and case series), and discuss why these interventional/surgical strategies might have a therapeutic role beyond that of a "bridge" to transplantation.

Increased levels of chromosomal aberrations and DNA damage in a group of workers exposed to formaldehyde.

Formaldehyde (FA) is a commonly used chemical in anatomy and pathology laboratories as a tissue preservative and fixative. Because of its sensitising properties, irritating effects and cancer implication, FA accounts probably for the most important chemical-exposure hazard concerning this professional group. Evidence for genotoxic effects and carcinogenic properties in humans is insufficient and conflicting, particularly in regard to the ability of inhaled FA to induce toxicity on other cells besides first contact tissues, such as buccal and nasal cells. To evaluate the effects of exposure to FA in human peripheral blood lymphocytes, a group of 84 anatomy pathology laboratory workers exposed occupationally to FA and 87 control subjects were tested for chromosomal aberrations (CAs) and DNA damage (comet assay). The level of exposure to FA in the workplace air was evaluated. The association between genotoxicity biomarkers and polymorphic genes of xenobiotic-metabolising and DNA repair enzymes were also assessed. The estimated mean level of FA exposure was 0.38±0.03 ppm. All cytogenetic endpoints assessed by CAs test and comet assay % tail DNA (%TDNA) were significantly higher in FA-exposed workers compared with controls. Regarding the effect of susceptibility biomarkers, results suggest that polymorphisms in CYP2E1 and GSTP1 metabolic genes, as well as, XRCC1 and PARP1 polymorphic genes involved in DNA repair pathways are associated with higher genetic damage in FA-exposed subjects. Data obtained in this study show a potential health risk situation of anatomy pathology laboratory workers exposed to FA (0.38 ppm). Implementation of security and hygiene measures may be crucial to decrease risk. The obtained information may also provide new important data to be used by health care programs and by governmental agencies responsible for occupational health and safety.

The Brazilian founder mutation TP53 p.R337H is uncommon in Portuguese women diagnosed with breast cancer.

Since the first studies reporting the TP53 p.R337H mutation as founder mutation in Southern and Southeastern Brazil, there has been controversy on its origin. Preliminary analysis of a small subset of Brazilian mutation carriers revealed that the haplotype incided on a Caucasian background. The vast majority of carriers identified today reside in Brazil or, if identified in other countries, are Brazilian immigrants. To our knowledge, the only two exceptions of carriers without a recognizable link with Brazil are two European families, from Portugal and Germany. Haplotype analysis in the Portuguese family revealed the same haplotype identified in Brazilian individuals, but in the German family, a distinct haplotype was found. Knowing that a significant proportion of women with breast cancer (BC) in Southern Brazil are p.R337H carriers, we analyzed p.R337H in a Portuguese cohort of women diagnosed with this disease. Median age at diagnosis among the first 573 patients tested was 60 years and 100 (17.4%) patients had been diagnosed at or under the age of 45 years. Mutation screening failed to identify the mutation in the 573 patients tested. These results are in contrast with the mutation frequency observed in a study including 815 BC-affected women from Brazil, in which carrier frequencies of 12.1 and 5.1% in pre- and postmenopausal women were observed, respectively. These findings suggest that the Brazilian founder mutation p.R337H, the most frequent germline TP53 mutation reported to date, is not a common germline alteration in Portuguese women diagnosed with BC.

Mechanistic insights into the cytotoxicity and genotoxicity induced by glycidamide in human mammary cells.

Acrylamide (AA) is a well-known industrial chemical classified as a probable human carcinogen. Benign and malignant tumours at different sites, including the mammary gland, have been reported in rodents exposed to AA. This xenobiotic is also formed in many carbohydrate-rich foods prepared at high temperatures. For this reason, AA is an issue of concern in terms of human cancer risk. The epoxide glycidamide (GA) is thought to be the ultimate genotoxic AA metabolite. Despite extensive experimental and epidemiological data focused on AA-induced breast cancer, there is still lack of information on the deleterious effects induced by GA in mammary cells. The work reported here addresses the characterisation and modulation of cytotoxicity, generation of reactive oxygen species, formation of micronuclei (MN) and quantification of specific GA-DNA adducts in human MCF10A epithelial cells exposed to GA. The results show that GA significantly induces MN, impairs cell proliferation kinetics and decreases cell viability at high concentrations by mechanisms not involving oxidative stress. KU55933, an inhibitor of ataxia telangiectasia mutated kinase, enhanced the cytotoxicity of GA (P < 0.05), supporting a role of this enzyme in regulating the repair of GA-induced DNA lesions. Moreover, even at low GA levels, N7-GA-Gua adducts were generated in a linear dose-response manner in MCF10A cells. These results confirm that human mammary cells are susceptible to GA toxicity and reinforce the need for additional studies to clarify the potential correlation between dietary AA exposure and breast cancer risk in human populations.

Genotoxic effect of exposure to metal(loid)s. A molecular epidemiology survey of populations living and working in Panasqueira mine area, Portugal.

Previous studies investigating the exposure to metal(loid)s of populations living in the Panasqueira mine area of central Portugal found a higher internal dose of elements such as arsenic, chromium, lead, manganese, molybdenum and zinc in exposed individuals. The aims of the present study were to evaluate the extent of genotoxic damage caused by environmental and occupational exposure in individuals previously tested for metal(loid) levels in different biological matrices, and the possible modulating role of genetic polymorphisms involved in metabolism and DNA repair. T-cell receptor mutation assay, comet assay, micronucleus (MN) test and chromosomal aberrations (CA) were performed in a group of 122 subjects working in the Panasqueira mine or living in the same region. The modifying effect of polymorphisms in GSTA2, GSTM1, GSTP1, GSTT1, XRCC1, APEX1, MPG, MUTYH, OGG1, PARP1, PARP4, ERCC1, ERCC4, and ERCC5 genes was investigated. Significant increases in the frequency of all biomarkers investigated were found in exposed groups, however those environmentally exposed were generally higher. Significant influences of polymorphisms were observed for GSTM1 deletion and OGG1 rs1052133 on CA frequencies, APEX1 rs1130409 on DNA damage, ERCC1 rs3212986 on DNA damage and CA frequency, and ERCC4 rs1800067 on MN and CA frequencies. Our results show that the metal(loid) contamination in the Panasqueira mine area induced genotoxic damage both in individuals working in the mine or living in the area. The observed effects are closely associated to the internal exposure dose, and are more evident in susceptible genotypes. The urgent intervention of authorities is required to protect exposed populations.

The role of CCNH Val270Ala (rs2230641) and other nucleotide excision repair polymorphisms in individual susceptibility to well-differentiated thyroid cancer.

Well-differentiated thyroid cancer (DTC) is the most common form of thyroid cancer (TC); however, with the exception of radiation exposure, its etiology remains largely unknown. Several single nucleotide polymorphisms (SNPs) have previously been implicated in DTC risk. Nucleotide excision repair (NER) polymorphisms, despite having been associated with cancer risk at other locations, have received little attention in the context of thyroid carcinogenesis. In order to evaluate the role of NER pathway SNPs in DTC susceptibility, we performed a case-control study in 106 Caucasian Portuguese DTC patients and 212 matched controls. rs2230641 (CCNH), rs2972388 (CDK7), rs1805329 (RAD23B), rs3212986 (ERCC1), rs1800067 (ERCC4), rs17655, rs2227869 (ERCC5), rs4253211 and rs2228529 (ERCC6) were genotyped using TaqMan® methodology, while conventional PCR-RFLP was employed for rs2228000 and rs2228001 (XPC). When considering all DTC cases, only rs2230641 (CCNH) was associated with DTC risk; a consistent increase in overall DTC risk was observed for both the heterozygous genotype (OR=1.89, 95% CI=1.14-3.14) and the variant allele carriers (OR=1.79, 95% CI=1.09-2.93). Histological stratification analysis confirmed an identical effect on follicular TC (OR=2.72, 95% CI=1.19-6.22, for heterozygous; OR=2.44, 95% CI=1.07­5.55, for variant allele carriers). Considering papillary TC, the rs2228001 (XPC) variant genotype was associated with increased risk (OR=2.33, 95% CI=1.05-5.16), while a protective effect was observed for rs2227869 (ERCC5) (OR=0.26, 95% CI=0.08­0.90, for heterozygous; OR=0.25, 95% CI=0.07-0.86, for variant allele carriers). No further significant results were observed. Our results suggest that NER polymorphisms such as rs2230641 (CCNH) and, possibly, rs2227869 (ERCC5) and rs2228001 (XPC), may influence DTC susceptibility. However, larger studies are required to confirm these results.

Lack of relevance of HIF-1α polymorphisms in breast cancer in a Portuguese population.

We aimed to study the prevalence of Hypoxia inducible factor-1α (HIF-1α) P582S and A588T polymorphisms in a Portuguese breast cancer population and its effect on the transcriptional activity of HIF-1α in MCF7 breast adenocarcinoma cells. We performed a polymerase chain Reaction--restriction fragment length polymorphism (PCR-RFLP)-based genotyping of a Portuguese breast cancer population for two HIF-1α polymorphisms. Furthermore, by site-directed mutagenesis, we generated a variant form of HIF-1α and compared its transcriptional activity with the wild-type HIF-1α in MCF7 cells. There were no significant differences in genotypic frequencies for P582S and A588T between breast cancer patients and controls, nor between the transcriptional activity of the 582S mutant and the wild-type HIF-1α. In conclusion, there is no association between HIF-1α polymorphisms and incidence of breast cancer in the Portuguese examined population. Furthermore, the P582S mutation does not affect transcriptional activity of HIF-1α in breast cancer cells, contrary to previous findings in other cell lines, suggesting that the impact of this mutation is cell-type specific.

Endovascular treatment of type B dissection in patients with Marfan syndrome: mid-term outcomes and aortic remodeling.

OBJECTIVES: To evaluate the mid-term outcomes, and the aortic remodeling in Marfan syndrome (MFS) patients with type B dissection that were treated with endovascular repair. BACKGROUND: MFS is a relative contraindication to thoracic endovascular aortic repair (TEVAR). Mid-term aortic outcomes data in MFS after TEVAR are limited, and the occurrence of late events remains unclear. METHODS: Of 89 patients that underwent TEVAR between September 2002 and February 2011, 10 patients with mid-term follow-up fulfilled the Ghent criteria for MFS and complicated type B dissection. High risk for open surgery was documented in 90%. RESULTS: The mean age was 35.1 ± 9.4 years and all patients presented with acute aortic syndrome complicating a chronic type B dissection (DeBakey type IIIb). Five patients underwent a Bentall surgical procedure previous to endovascular repair, and in four patients initial TEVAR was followed by surgery of the ascending aorta. Treatment was limited to endovascular repair in only one patient. In-hospital mortality was 10%. At a mean follow-up of 59.6 ± 38.9 months, the cumulated mortality was of 20% and late mortality 11.1%. The rate of secondary endoleak was 44.4%, and late reintervention of 33.3%. Survival freedom from cardiovascular death at 8 years was 80.0%, and positive remodeling was documented in 37.5% of patients. CONCLUSIONS: Our results suggest that TEVAR is feasible, safe, and associated with a high reintervention rate and reduced rate of positive aortic remodeling in patients with Marfan syndrome. Survival at 8 years was comparable to contemporary series of open repair.

Induction of sister chromatid exchange by acrylamide and glycidamide in human lymphocytes: role of polymorphisms in detoxification and DNA-repair genes in the genotoxicity of glycidamide.

Acrylamide (AA) is a probable human carcinogen generated in carbohydrate-rich foodstuffs upon heating. Glycidamide (GA), formed via epoxidation, presumably mediated by cytochrome P450 2E1, is considered to be the active metabolite that plays a central role in the genotoxicity of AA. The aim of this work was to evaluate the cytogenetic damage induced by AA and GA in cultured human lymphocytes by use of the sister chromatid exchange (SCE) assay. Furthermore, this report addresses the role of individual genetic polymorphisms in key genes involved in detoxification and DNA-repair pathways (BER, NER, HRR and NHEJ) on the induction of SCE by GA. While AA induced the number of SCE/metaphase only slightly, especially for the highest concentration tested (2000µM), GA markedly induced SCEs in a concentration-dependent manner up to concentrations of 750µM, leading to an increase in SCEs of up to about 10-fold compared with controls. By combining DNA damage in GA-treated lymphocytes and data on polymorphisms, associations between the induction of SCEs with GSTP1 (Ile105Val) and GSTA2 (Glu210Ala) genotypes are suggested.

Polymorphisms in base excision repair genes and thyroid cancer risk.

Thyroid cancer (TC) is the most frequent endocrine malignancy, accounting however for only 1-2% of all human cancers, and the best-established risk factor for TC is radiation exposure, particularly during childhood. Since the BER pathway seems to play an important role in the repair of DNA damage induced by IR and other genotoxicants, we carried out a hospital-based case-control study in order to evaluate the potential modifying role of 6 BER polymorphisms on the individual susceptibility to non-familial TC in 109 TC patients receiving iodine-131, and 217 controls matched for age (± 2 years), gender and ethnicity. Our results do not reveal a significant involvement of XRCC1 Arg194Trp and Arg399Gln, OGG1 Ser326Cys, APEX1 Asp148Glu, MUTYH Gln335His and PARP1 Val762Ala polymorphisms on the individual susceptibility towards TC, mostly in agreement with the limited available evidence. By histological stratification analysis, we observed that the association between the presence of heterozygosity in the MUTYH Gln335His polymorphism and TC risk almost reached significance for the papillary subtype of TC. This was the first time that the putative association between this polymorphism and TC susceptibility was evaluated. However, since the sample size was modest, the possibility of a type I error should not be excluded and this result should, therefore, be interpreted with caution. More in depth studies involving larger populations should be pursued in order to further clarify the potential usefulness of the MUTYH Gln335His genotype as a predictive biomarker of susceptibility to TC and the role of the remaining BER polymorphisms on TC susceptibility.

DNA damage and susceptibility assessment in industrial workers exposed to styrene.

Styrene is a widely used chemical in the manufacture of synthetic rubber, resins, polyesters, and plastics. The highest levels of human exposure to styrene occur during the production of reinforced plastic products. The objective of this study was to examine occupational exposure to styrene in a multistage approach, in order to integrate the following endpoints: styrene in workplace air, mandelic and phenylglyoxylic acids (MA + PGA) in urine, sister chromatid exchanges (SCE), micronuclei (MN), DNA damage (comet assay), and genetic polymorphisms of metabolizing enzymes (CYP2E1, EPHX1, GSTM1, GSTT1, and GSTP1). Seventy-five workers from a fiberglass-reinforced plastics factory and 77 unexposed controls took part in the study. The mean air concentration of styrene in the breathing zone of workers (30.4 ppm) and the mean concentration of urinary metabolites (MA + PGA = 443 ± 44 mg/g creatinine) exceeded the threshold limit value (TLV) and the biological exposure index (BEI). Significantly higher SCE frequency rate and DNA damage were observed in exposed workers, but MN frequency was not markedly modified by exposure. With respect to the effect of genetic polymorphisms on different exposure and effect biomarkers studied, an increase in SCE levels with elevated microsomal epoxide hydrolase activity was noted in exposed workers, suggesting a possible exposure-genotype interaction.