“First experience with JenaValve?: a single-centre cohort”

Aims

Since the introduction of transcatheter aortic valve implantation (TAVI), newer generation and novel devices such as the retrievable JenaValve™ have been developed. We evaluated the procedural and 6-month results of our first experience with implantation of the JenaValve™.

Methods and results

From June 2012 to December 2013, 24 consecutive patients (mean age 80 ± 7 years, 42 % male) underwent an elective transapical TAVI with the JenaValve™. Device success was 88 %. The mortality rate was 4 % at 30 days and 31 % at 6 months. TAVI reduced the mean transvalvular gradient (44.2 ± 11.1 mmHg vs. 12.3 ± 4.3 mmHg, p < 0.001) and increased the mean aortic valve area (0.8 3 ± 0.23 to 1.70 ± 0.44 cm²). A mild paravalvular leakage (PVL) occurred in 4 patients (18 %) and a moderate PVL in 1 patient (4 %). Mean New York Heart Association Functional Class improved from 2.9 ± 0.5 to 2.0 ± 0.8 at 30 days.

Conclusion

TAVI using the JenaValve™ prosthesis seems adequate and safe in this first experience cohort.     

Expression of γ-H2AX and patient prognosis in breast cancer cohort

H2AX phosphorylation is a novel marker of DNA double-stranded breaks. In the present study, we assessed the γ-H2AX expression, its association with other clinicopathologic characteristics, and the prognosis in a cohort of 97 patients with breast cancer. Ninety-seven specimens of tumor tissue and 77 adjacent normal tissues from patients with breast cancer were examined. All patients underwent modified radical mastectomy or local tumor resection without lymph node dissection. γ-H2AX expression was assessed by standard immunohistochemistry. Patients were followed after surgery for a mean duration of 70.1 ± 18.7 months (range, 6-93 months). The γ-H2AX staining was positive in 27 (27.8%) patients. The positive rates of H2AX were 26.0% and 2.6% in tumor tissue and adjacent normal tissues, respectively. γ-H2AX positive status was negatively associated with TNM staging, with 24 positive cases (32.4%) in TNM staging I-II, while no positive cases in TNM staging III-IV (P = 0.026). Sixteen patients (16.5%) died during the follow-up. No significant association between γ-H2AX expression and patient survival was detected. The unadjusted HR (hazard ratio) for γ-H2AX positive was 0.84 (95% CI: 0.27, 2.60). In TNM staging subgroup analysis, death only occurred in γ-H2AX negative patients. Our study is the first study to demonstrate that expression of γ-H2AX is associated with TNM staging. Due to the small sample and limited follow-up time, we did not observe a significant association between γ-H2AX and patient survival. γ-H2AX expression could be a potential biomarker for cancer diagnosis and prediction, and further studies are in need.     

Generation or birth cohort effect on cancer risk in Li–Fraumeni syndrome

Genetic anticipation is the increased incidence, earlier onset, or increased severity of a disease in successive generations. Before the biological basis of anticipation had been demonstrated, the phenomenon was thought to be due to sampling bias, epigenetic effects, gene conversion, or recombinant events. Since then, the biologic basis for anticipation in a number of neurodegenerative disorders has been shown to be attributable to trinucleotide repeat instability, with expansion of repeats clearly correlated with an earlier age of onset. Recently, telomere shortening has been suggested as the mechanism for anticipation in the autosomal dominant form of dyskeratosis congenita, attributable to mutations in the TERC gene, leading to dysfunctional telomeres (Vulliamy et al. 2004). However, the pattern of anticipation has been observed in other disorders, including cancers, for which no genetic defect has been identified. In this study, we assess the apparent generation effect on cancer incidence in ten extended families with P53 germline mutation, identified through probands diagnosed with childhood sarcoma. The probands were from two sets of systematically ascertained sarcoma patients treated at the University of Texas M. D. Anderson Cancer Center between 1944 and 1982. From those overall studies, we have identified ten kindreds having germline P53 mutations in more than one generation. We compared the cancer incidence in members of successive generations of these families with P53 mutations (carriers) and with no P53 mutations (noncarriers). In carriers, cancer incidence increased in succeeding generations; there was no evidence for this effect in noncarriers; however, the noncarrier population was too small to rule it out. The apparent lack of increase in incidence in noncarriers argues against a cohort effect explaining the increase in carriers.     

Radioiodine treatment for graves’ disease: a 10-year Australian cohort study

Background

Radioactive iodine (I¹³¹) is a common definitive treatment for Graves’ Disease. Potential complications include worsening, or new development of Graves’ eye disease and development of a radiation thyroiditis. The purpose of the present study was to assess outcomes of patients treated with I¹³¹ in an Australian tertiary centre over 10 years.

Methods

Data from 101 consecutive patients treated with I¹³¹ for a diagnosis of Graves’ disease between 2005 to 2015 was collected and reviewed retrospectively. Baseline TSH receptor antibody titre, pre-treatment free thyroxine (FT4), technetium scan uptake, initial treatment, duration of treatment, reason for definitive therapy, complications, and time to remission (defined as euthyroidism or hypothyroidism after 12 months) were recorded.

Results

Of the 92 patients with adequate outcome data, 73 (79.3%) patients achieved remission with a single dose of I¹³¹. Of the remaining 19 patients, 12 had a second dose and became hypothyroid. TSH receptor antibody titre at diagnosis was significantly lower in the group that achieved remission with the first dose compared with those who did not (P =?0.0071). There was no difference in technetium uptake, I¹³¹ dose, duration of therapy or pre-treatment free thyroxine (FT4). I¹³¹ was complicated by development of eye disease in 3 patients and 1 (of 11 with pre-existing eye disease) had worsening eye disease. A clinically apparent flare of hyperthyroidism following I¹³¹ was evident in 8 patients (8.6%).

Conclusion

Radioiodine is an effective therapy for Graves’ Disease with few complications. The majority of patients achieve remission with a single dose. Those who require a second dose are more likely to have higher TSH receptor antibody titres at diagnosis. To the best of our knowledge, this is the first study to report outcomes from radioiodine treatment for Graves’ disease in an Australian population.

     

Cancer mortality in a population-based cohort of American Indians – The strong heart study

BackgroundCancer mortality among American Indian (AI) people varies widely, but factors associated with cancer mortality are infrequently assessed.MethodsCancer deaths were identified from death certificate data for 3516 participants of the Strong Heart Study, a population-based cohort study of AI adults ages 45–74 years in Arizona, Oklahoma, and North and South Dakota. Cancer mortality was calculated by age, sex and region. Cox proportional hazards model was used to assess independent associations between baseline factors in 1989 and cancer death by 2010.ResultsAfter a median follow-up of 15.3 years, the cancer death rate per 1000 person-years was 6.33 (95 % CI 5.67–7.04). Cancer mortality was highest among men in North/South Dakota (8.18; 95 % CI 6.46–10.23) and lowest among women in Arizona (4.57; 95 % CI 2.87–6.92). Factors independently associated with increased cancer mortality included age, current or former smoking, waist circumference, albuminuria, urinary cadmium, and prior cancer history. Factors associated with decreased cancer mortality included Oklahoma compared to Dakota residence, higher body mass index and total cholesterol. Sex was not associated with cancer mortality. Lung cancer was the leading cause of cancer mortality overall (1.56/1000 person-years), but no lung cancer deaths occurred among Arizona participants. Mortality from unspecified cancer was relatively high (0.48/100 person-years; 95 % CI 0.32−0.71).ConclusionsRegional variation in AI cancer mortality persisted despite adjustment for individual risk factors. Mortality from unspecified cancer was high. Better understanding of regional differences in cancer mortality, and better classification of cancer deaths, will help healthcare programs address cancer in AI communities.     

Urinary F₂-isoprostanes, obesity, and weight gain in the IRAS cohort

Obesity has been associated with increased F(2)-isoprostane (F(2)-IsoP) levels cross-sectionally. However, the prospective association may be inverse, based on our earlier finding that elevated urinary F(2)-IsoP levels predict lower risk of diabetes. This earlier finding led us to hypothesize that urinary F(2)-IsoPs reflect the intensity of oxidative metabolism and as such predict lower risk of both diabetes and weight gain. We examined cross-sectional relationships with obesity and prospective relationships with weight gain using the data from 299 participants of the Insulin Resistance Atherosclerosis Study (IRAS), all of whom were free of diabetes at baseline. Four urinary F(2)-IsoPs were assayed in stored baseline urine samples using liquid chromatography with tandem mass spectrometry: iPF(2α)-III, 2,3-dinor-iPF(2α)-III, iPF(2α)-VI, and 8,12-iso-iPF(2α)-VI (F(2)-IsoP 1-4, respectively). Baseline F(2)-IsoPs were positively associated with baseline measures of obesity; the strongest associations were found with two F(2)-IsoPs: odds ratios (95% confidence intervals) for overall and abdominal obesity were 1.74 (1.26-2.40) and 1.63 (1.18-2.24) for F(2)-IsoP2 and 1.47 (1.12-1.94) and 1.64 (1.22-2.20) for F(2)-IsoP4. F(2)-IsoP2 showed the strongest and significant inverse association with weight gain during the 5-year follow-up period: increase in F(2)-IsoP2 equal to 1 s.d. was associated with 0.90 kg lower weight gain (P = 0.02) and the odds ratios for relative (≥5%) and absolute (≥5 kg) weight gain were 0.67 (0.47-0.96) and 0.57 (0.37-0.87), respectively. The other three F(2)-IsoPs were consistently inversely associated with weight gain, although not significantly, suggesting that different F(2)-IsoPs vary in their ability to detect the association with weight gain.     

Are mitochondrial haplogroups associated with elite athletic status? A study on a Spanish cohort

There is increasing evidence regarding the association between mitochondrial DNA (mtDNA) and aerobic capacity; however, whether mtDNA haplogroups are associated with the status of being an elite endurance athlete is more controversial. We compared the frequency distribution of mtDNA haplogroups among the following groups of Spanish (Caucasian) men: 102 elite endurance athletes (professional road cyclists, endurance runners), 51 elite power athletes (jumpers, throwers and sprinters), and 478 non-athletic controls. We observed a significant difference between endurance athletes and controls (Fisher exact test = 17.89, P = 0.015; Bonferroni's significant threshold = 0.017), yet not between power athletes and controls (Fisher exact test = 47.99, P = 0.381) or between endurance and power athletes (Fisher exact test = 5.53, P = 0.597). We observed that the V haplogroup was overrepresented in endurance athletes (15.7%) compared with controls (7.5%) (odds ratio: 2.284; 95% confidence interval: 1.237, 4.322). In conclusion, our findings overall support the idea that mtDNA variations could be among the numerous contributors to the status of being an elite endurance athlete, whereas no association was found with elite power athletic status.     

Clinical recognition of acute aortic dissections: insights from a large single-centre cohort study

Aims

Acute aortic dissection (AD) requires immediate treatment, but is a diagnostic challenge. We studied how often AD was missed initially, which patients were more likely to be missed and how this influenced patient management and outcomes.

Methods

A retrospective cohort study including 200 consecutive patients with AD as the final diagnosis, admitted to a tertiary hospital between 1998 and 2008. The first differential diagnosis was identified and patients with and without AD included were compared. Characteristics associated with a lower level of suspicion were identified using multivariable logistic regression, and Cox regression was used for survival analyses. Missing data were imputed.

Results

Mean age was 63 years, 39% were female and 76% had Stanford type A dissection. In 69% of patients, AD was included in the first differential diagnosis; this was less likely in women (adjusted relative risk [aRR]: 0.66, 95% CI: 0.44–0.99), in the absence of back pain (aRR: 0.51, 95% CI: 0.30–0.84), and in patients with extracardiac atherosclerosis (aRR: 0.64, 95% CI: 0.43–0.96). Absence of AD in the differential diagnosis was associated with the use of more imaging tests (1.8 vs. 2.3, p = 0.01) and increased time from admission to surgery (1.8 vs. 10.1 h, p < 0.01), but not with a difference in the adjusted long-term all-cause mortality (hazard ratio: 0.76, 95% CI: 0.46–1.27).

Conclusion

Acute aortic dissection was initially not suspected in almost one-third of patients, this was more likely in women, in the absence of back pain and in patients with extracardiac atherosclerosis. Although the number of imaging tests was higher and time to surgery longer, patient outcomes were similar in both groups.

     

Association between selected cholesterol-related gene polymorphisms and Alzheimer’s disease in a Turkish cohort

Molecular Biology Reports - Numerous genetic evidence has pointed out that variations in cholesterol-related genes may be associated with an Alzheimer’s disease (AD) risk. We aimed to...     

Malformations in a cohort of 284 women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH)

ABSTRACT: BACKGROUND: The aim of this retrospective study was to describe the spectrum of genital and associated malformations in women with Mayer-Rokitansky-Kuster-Hauser syndrome using evaluated diagnostic procedures and the Vagina Cervix Uterus Adnex -- associated Malformation classification system (VCUAM). METHODS: 290 women with MRKH syndrome were clinically evaluated with using clinical examinations, abdominal and perineal/rectal ultrasound, MRI, and laparoscopy. RESULTS: Classification of female genital malformation according to the Vagina Cervix Uterus Adnex -- associated Malformation classification system was possible in 284 women (97.9%). Complete atresia of Vagina (V5b) and bilateral atresia of Cervix (C2b) were found in 284 patients (100%). Uterus: bilateral rudimentary or a plastic uterine horns were found in 239 women (84.2%). Adnexa: normal Adnexa were found in 248 women (87.3%). Malformations: associated malformations were found in 126 of 282 evaluable women (44.7%), 84 women (29.6%) had malformations of the renal system. Of 284 women with Mayer-Rokitansky-Kuster-Hauser syndrome 212 women (74.7%) could be classified as V5bC2bU4bA0. The most frequent classification was V5bC2bU4bA0M0 (46.8%) diagnosed in 133 of 284 women. CONCLUSIONS: Complete atresia of vagina and cervix were found in all patients, variable malformations were found with uterus and adnexa. A variety of associated malformations were present, predominantly of the renal system. It is therefore recommended that all patients with genital malformations should be evaluated for renal abnormalities.     

Mortality from cardiovascular diseases in the German uranium miners cohort study, 1946–1998

An increased risk of cardiovascular diseases after exposure to low doses of ionizing radiation has been suggested among the atomic bomb survivors. Few and inconclusive results on this issue are available from miner studies. A positive correlation between coronary heart disease mortality and radon exposure has been reported in the Newfoundland fluorspar miners study, yet low statistical power due to small sample size was of concern. To get further insight into this controversial issue, data from the German uranium miners cohort study were used, which is by far the largest miner study up to date. The cohort includes 59,001 male subjects who were employed for at least six months between 1946 and 1989 at the former Wismut uranium company in Eastern Germany. Exposure to radon, long-lived radionuclides and external gamma radiation was estimated by using a detailed job-exposure matrix. About 16,598 cohort members were deceased until 31 December 1998, including 5,417 deaths from cardiovascular diseases. Linear Poisson regression models were used to estimate the excess relative risk (ERR) per unit of cumulative radiation exposure after adjusting for attained age and calendar period. No trend in risk of circulatory diseases with increasing cumulative exposure to either radon [ERR per 100 working level month: 0.0006; 95% confidence limit (CI): −0.004 to 0.006], external gamma radiation (ERR per Sv: −0.26, 95% CI: −0.6 to 0.05) or long-lived radionuclides (ERR per 100 kBqh/m³: −0.2, 95% CI: −0.5 to 0.06), respectively, was observed. This was also true for the sub-group heart disease and stroke. Our findings do not support an association between cardiovascular disease mortality and exposure to radiation among miners, yet low doses and uncontrolled confounding hamper interpretation.     

NT-proBNP independently predicts long term mortality after acute exacerbation of COPD – a prospective cohort study

Background

Cardiovascular disease is prevalent and frequently unrecognized in patients with chronic obstructive pulmonary disease (COPD). NT-proBNP is an established risk factor in patients with heart failure. NT-proBNP may also be released from the right ventricle. Thus serum NT-proBNP may be elevated during acute exacerbations of COPD (AECOPD). The prognostic value of NT-proBNP in patients hospitalized with AECOPD is sparsely studied. Our objective was to test the hypothesis that NT-proBNP independently predicts long term mortality following AECOPD.

Methods

A prospective cohort study of 99 patients with 217 admissions with AECOPD. Clinical, electrocardiographic, radiological and biochemical data were collected at index and repeat admissions and analyzed in an extended survival analysis with time-dependent covariables.

Results

Median follow-up time was 1.9 years, and 57 patients died during follow-up. NT-proBNP tertile limits were 264.4 and 909 pg/mL, and NT-proBNP in tertiles 1 through 3 was associated with mortality rates of 8.6, 35 and 62 per 100 patient-years, respectively (age-adjusted log-rank p<0.0001). After adjustment for age, gender, peripheral edema, cephalization and cTnT in a multivariable survival model, the corresponding hazard ratios for dying were 2.4 (0.95-6.0) and 3.2 (1.3-8.1) (with 95% confidence intervals in parentheses, p-value for trend 0.013).

Conclusions

NT-proBNP is a strong and independent determinant of mortality after AECOPD.     

Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome

Birt-Hogg-Dubé syndrome (BHD), a genodermatosis characterized by multiple hamartomas of the hair follicle (fibrofolliculoma), predisposes individuals to an increased risk of developing renal neoplasms and spontaneous pneumothorax. Previously, we localized the BHD locus (also known as FLCN) to chromosome 17p11.2 by linkage analysis and subsequently identified germline mutations in a novel gene in probands from eight of the nine families with BHD in our screening panel. Affected members of five of the families inherited an insertion/deletion of a cytosine in a C8 tract in exon 11. This mutation was also identified by exon 11 screening in probands from 22 of 52 additional families with BHD and therefore represents a hypermutable "hotspot" for mutation in BHD. Here, we screened the remaining 30 families from this large BHD cohort by direct sequence analysis and identified germline BHD mutations in 84% (51/61) of all families with BHD recruited to our study. Mutations were located along the entire length of the coding region, including 16 insertion/deletion, 3 nonsense, and 3 splice-site mutations. The majority of BHD mutations were predicted to truncate the BHD protein, folliculin. Among patients with a mutation in the exon 11 hotspot, significantly fewer renal tumors were observed in patients with the C-deletion than those with the C-insertion mutation. Coding-sequence mutations were not found, however, in probands from two large families with BHD whose affected members shared their family's BHD-affected haplotype. Of the 53 families with BHD whose members inherited either a germline mutation or the affected haplotype, 24 (45%) had at least one member with renal neoplasms. Three families classified with familial renal oncocytoma were identified with BHD mutations, which represents the first disease gene associated with this rare form of renal neoplasm. This study expands the BHD-mutation spectrum and evaluates genotype-phenotype correlations among families with BHD.     

β-thymosins and interstitial lung disease: study of a scleroderma cohort with a one-year follow-up

Background

β-thymosins play roles in cytoskeleton rearrangement, angiogenesis, fibrosis and reparative process, thus suggesting a possible involvement in the pathogenesis of systemic sclerosis. The aim of the study was to investigate the presence of thymosins β₄, β₄ sulfoxide, and β₁₀ in bronchoalveolar lavage fluid of scleroderma patients with interstitial lung disease and the relation of these factors with pulmonary functional and radiological parameters.

Methods

β-thymosins concentrations were determined by Reverse Phase-High Performance Liquid Chromatography-Electrospray-Mass Spectrometry in the bronchoalveolar lavage fluid of 46 scleroderma patients with lung involvement and of 15 controls.

Results

Thymosin β_4, β₄ sulfoxide, and β₁₀ were detectable in bronchoalveolar lavage fluid of patients and controls. Thymosin β₄ levels were significantly higher in scleroderma patients than in controls. In addition, analyzing the progression of scleroderma lung disease at one-year follow-up, we have found that higher thymosin β₄ levels seem to have a protective role against lung tissue damage. Thymosin β₄ sulfoxide levels were higher in the smokers and in the scleroderma patients with alveolitis.

Conclusions

We describe for the first time β-thymosins in bronchoalveolar lavage fluid and their possible involvement in the pathogenesis of scleroderma lung disease. Thymosin β₄ seems to have a protective role against lung tissue damage, while its oxidation product mirrors an alveolar inflammatory status.     

Age–period–cohort analysis of colorectal cancer in East Anglia, 1971–2005

Background: This study aimed to investigate the incidence trends of colorectal cancer by sex and subsite, in East Anglia from 1971 to 2005. Methods: Using data from the Eastern Cancer Registration and Information Centre, we examined the time trends and the effect of age, period of diagnosis and birth cohort on the incidence of colorectal cancer by sex and subsite. Results: Between 1971 and 2005, 23 875 males and 22 651 females were registered with colorectal cancer in East Anglia. During this period, the increase in the incidence trends was higher among males, more recent periods of diagnosis, and proximal colon. Cohort effects were statistically significant in distal and rectal cancers in males (p < 0.001 and p = 0.05, respectively), and in proximal colon in females (p < 0.001). Period effects were statistically significant across all subsites and both sexes (p < 0.001 for all). Conclusions: Period effects were significant across all subsites for both sexes, whereas cohort effects varied in their significance levels depending on subsite and sex. We suggest that the period effect may be due to an increase in the use of colonoscopy for diagnostic or opportunistic screening, and the cohort effect may be due to aetiological differences in CRC between sexes and subsites.     

Gene–smoking interactions in multiple Rho-GTPase pathway genes in an early-onset coronary artery disease cohort

We performed a gene–smoking interaction analysis using families from an early-onset coronary artery disease cohort (GENECARD). This analysis was focused on validating and expanding results from previous studies implicating single nucleotide polymorphisms (SNPs) on chromosome 3 in smoking-mediated coronary artery disease. We analyzed 430 SNPs on chromosome 3 and identified 16 SNPs that showed a gene–smoking interaction at P < 0.05 using association in the presence of linkage—ordered subset analysis, a method that uses permutations of the data to empirically estimate the strength of the association signal. Seven of the 16 SNPs were in the Rho-GTPase pathway indicating a 1.87-fold enrichment for this pathway. A meta-analysis of gene–smoking interactions in three independent studies revealed that rs9289231 in KALRN had a Fisher’s combined P value of 0.0017 for the interaction with smoking. In a gene-based meta-analysis KALRN had a P value of 0.026. Finally, a pathway-based analysis of the association results using WebGestalt revealed several enriched pathways including the regulation of the actin cytoskeleton pathway as defined by the Kyoto Encyclopedia of Genes and Genomes.     

Human serum elements’ levels and leukemia: A first pilot study from an adult Greek cohort

BackgroundThe present study focuses on the evaluation of potential relationships between trace elements and acute and chronic types of leukemia, via the determination of their levels in human blood serum.MethodsA total of 199 serum samples from a Greek cohort were examined, including both leukemia cases and controls. Elements’ analysis was carried out using inductively coupled plasma mass spectrometry (ICP-MS) and demographic features such as age, gender, smoking habits and area of residence were recorded and statistically treated applying Shapiro-Wilk, Kolmogorov-Smirnov, Mann Whitney and Kruskal Wallis tests (p < 0.05). Spearman correlation and principal component analysis (PCA) were also performed to investigate possible associations.ResultsThe results demonstrated significantly higher (p < 0.05) trace elements concentrations in cases’ serum compared to that of controls excluding Ba, with Cu (median concentration 1295 μg L⁻¹) being the most abundant in cases. Additionally, concentration of toxic Pb and Cd were found at seven and four fold higher concentrations in cases, respectively. Among the trace elements examined, only Rb (164 μg L⁻¹) was detected in higher concentrations in controls. Ba, Cd and Co presented the lowest concentrations (lower than 1 μg L⁻¹). PCA was performed for overall and classified data, indicating a stronger relation among the toxic As, Cd, Ni and Pb in cases than controls, particularly referring to smokers and industrial sites’ residents. Hematological parameters and factors such as age and gender did not present any significant outcome or correlation.ConclusionsThe findings from this pilot study suggest a potential relationship between metals and leukemia, especially concerning the toxic ones. Results from the employed source apportionment tools imply that smoking and atmospheric degradation may be positively related with higher metal serum levels in leukemia patients.