KLLN epigenotype–phenotype associations in Cowden syndrome

Germline KLLN promoter hypermethylation was recently identified as a potential genetic etiology of the cancer predisposition syndrome, Cowden syndrome (CS), when no causal PTEN gene mutation was found. We screened for KLLN promoter methylation in a large prospective series of CS patients and determined the risk of benign and malignant CS features in patients with increased methylation both with and without a PTEN mutation/variant of unknown significance. In all, 1012 CS patients meeting relaxed International Cowden Consortium criteria including 261 PTEN mutation-positive CS patients, 187 PTEN variant-positive CS patients and 564 PTEN mutation-negative CS patients, as well as 111 population controls were assessed for germline KLLN promoter methylation by MassARRAY EpiTYPER analysis. KLLN promoter methylation was analyzed both as a continuous and a dichotomous variable in the calculation of phenotypic risks by stepwise logistic regression and Kaplan–Meier/standardized incidence ratio methods, respectively. Significantly increased KLLN promoter methylation was seen in CS individuals with and without a PTEN mutation/VUS compared with controls (P<0.001). Patients with high KLLN promoter methylation have increased risks of all CS-associated malignancies compared with the general population. Interestingly, KLLN-associated risk of thyroid cancer appears to be gender and PTEN status dependent. KLLN promoter methylation associated with different benign phenotypes dependent on PTEN status. Furthermore, increasing KLLN promoter methylation is associated with a greater phenotype burden in mutation-negative CS patients. Germline promoter hypermethylation of KLLN is associated with particular malignant and benign CS features, which is dependent on the PTEN mutation status.     

Prospective Evaluation of Transseptal TMVR for Failed Surgical Bioprostheses: MITRAL Trial Valve-in-Valve Arm 1-Year Outcomes

ObjectivesThe aim of this study was to assess 1-year clinical outcomes among high-risk patients with failed surgical mitral bioprostheses who underwent transseptal mitral valve-in-valve (MViV) with the SAPIEN 3 aortic transcatheter heart valve (THV) in the MITRAL (Mitral Implantation of Transcatheter Valves) trial.BackgroundThe MITRAL trial is the first prospective study evaluating transseptal MViV with the SAPIEN 3 aortic THV in high-risk patients with failed surgical mitral bioprostheses.MethodsHigh-risk patients with symptomatic moderate to severe or severe mitral regurgitation (MR) or severe mitral stenosis due to failed surgical mitral bioprostheses were prospectively enrolled. The primary safety endpoint was technical success. The primary THV performance endpoint was absence of MR grade ≥2+ or mean mitral valve gradient ≥10 mm Hg (30 days and 1 year). Secondary endpoints included procedural success and all-cause mortality (30 days and 1 year).ResultsThirty patients were enrolled between July 2016 and October 2017 (median age 77.5 years [interquartile range (IQR): 70.3 to 82.8 years], 63.3% women, median Society of Thoracic Surgeons score 9.4% [IQR: 5.8% to 12.0%], 80% in New York Heart Association functional class III or IV). The technical success rate was 100%. The primary performance endpoint in survivors was achieved in 96.6% (28 of 29) at 30 days and 82.8% (24 of 29) at 1 year. Thirty-day all-cause mortality was 3.3% and was unchanged at 1 year. The only death was due to airway obstruction after swallowing several pills simultaneously 29 days post-MViV. At 1-year follow-up, 89.3% of patients were in New York Heart Association functional class I or II, the median mean mitral valve gradient was 6.6 mm Hg (interquartile range: 5.5 to 8.9 mm Hg), and all patients had MR grade ≤1+.ConclusionsTransseptal MViV in high-risk patients was associated with 100% technical success, low procedural complication rates, and very low mortality at 1 year. The vast majority of patients experienced significant symptom alleviation, and THV performance remained stable at 1 year.     

Association of mitochondrial deoxyribonucleic acid 16189 variant (T->C transition) with metabolic syndrome in Chinese adults

OBJECTIVE: A common variant in mitochondrial DNA (mtDNA) at bp 16189 (T-->C transition) has been associated with small birth size, adulthood hyperglycemia, and insulin resistance in Caucasians. In this study, we investigated whether mtDNA 16189 variant is associated with metabolic syndrome in Chinese subjects. METHODS: Six hundred fifteen Chinese adults, aged 40 yr or older, were recruited in this study. The 16189 variant of mtDNA was detected using PCR and restriction enzyme digestion. Metabolic syndrome was diagnosed on modified National Cholesterol Education Program Adult Treatment Panel III guidelines, using body mass index (BMI) instead of waist circumference. An association study was performed with chi2 test and logistic regression analysis. RESULTS: The prevalence of the 16189 variant was higher in patients with metabolic syndrome than in those without: 44% (125 of 284) vs. 33.2% (110 of 331) (P = 0.006). The association between this 16189 variant of mtDNA and metabolic syndrome (P = 0.021) remained significant even after correcting for age and BMI. As to the individual traits, the prevalence of fasting plasma glucose of at least 110 mg/dl (> or =6.1 mmol/liter) [(51.5% (121 of 235) vs. 42.1% (160 of 380); P = 0.023], type 2 diabetes mellitus [48.1% (113 of 235) vs. 39.2% (149 of 380); P = 0.031], and hypertriglyceridemia [44.3% (104 of 235) vs. 35.8% (136 of 380); P = 0.037] were significantly higher in subjects harboring the 16189 variant of mtDNA than those with the wild type. However, the prevalence of hypertension [53.2% (125 of 235) vs. 47.6% (181 of 380); P = 0.180], BMI greater than 25 kg/m2 [48.5% (114 of 235) vs. 43.9% (167 of 380); P = 0.270], and low high-density lipoprotein cholesterol [61.3% (144 of 235) vs. 54.7% (208 of 380); P = 0.111] did not reach a significant difference between the two groups. Furthermore, there was a trend of increasing frequency of occurrence of the 16189 variant in individuals having an increasing number of components of metabolic syndrome (Ptrend < 0.005). CONCLUSION: Our data strongly suggest that mtDNA 16189 variant underlies susceptibility to metabolic syndrome in the Chinese population.     

The Effects of Intravenous Levofloxacin on the QT Interval and QT Dispersion

The QT dispersion (QT_d) is a non-invasive means of identifying those patients at an increased risk of developing sudden cardiac death (SCD). Although levofloxacin has a minimal effect on the QT_c interval, isolated reports of QT prolongation, polymorphic ventricular tachycardia with a normal QT interval and TdP have been reported. The purpose of this study was to examine the effect of intravenous levofloxacin on the QT interval and QT_d. Of the 50 patients who were deemed candidates to receive intravenous levofloxacin, 29 met the eligibility criteria and were enrolled in this study. A 12-lead ECG was performed before the initiation of levofloxacin (baseline), and on days 3 and 5. The QT^c _min, QT^c _max and the QT_d were calculated. Measurements where made by two independent observers blinded to the patients’ clinical status. The QT_d increased significantly on days 3 and 5 following the initiation of therapy [QT_d (baseline) 33.3 ± 20 ms, QT_d (day 3) 64.4 ± 31.3 ms (p = 0.023), QT_d (day 5) 66.8 ± 20.3 ms, (p = 0.008)]. The increase in the QT_d was significantly longer in men than women. Although women had a shorter baseline QT_d compared to men, this did not achieve statistical significance. Intravenous levofloxacin was found to significantly increase the QT_d, which was more pronounced in men compared to women. Its effect on the QT_d may increase the risk of developing a potentially fatal ventricular arrhythmia. Therefore, care must be taken when prescribing this medication to patients with a pre-existing risk of developing SCD.     

The Long-Term Impact of Neurofeedback on Symptom Burden and Interference in Patients With Chronic Chemotherapy-Induced Neuropathy: Analysis of a Randomized Controlled Trial

Context

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment and may adversely affect quality of life (QOL) for years.

Drug-Induced Esophagitis

Drug-induced esophagitis is being recognized increasingly in the past few years. We have reviewed 175 cases with a view to classifying this disease based on pathology. Drug-induced esophageal injury tends to occur at the anatomical site of narrowing, with the middle third behind the left atrium predominating. The disease is classified broadly into two groups. The first group is transient and self-limiting, as exemplified by tetracycline- and emepronium-induced injury (57.3%). The second is the persistent esophagitis group, often with stricture with two distinct entities: 1) patients on nonsteroidal antiinflammatory agents whose injury is aggravated by gastroesophageal reflux (26.2%) (reflux aggravated), and 2) patients with potassium chloride and quinidine sulfate-induced injury (16.2%) (persisting drug injury). We report a case that highlights the pathophysiology (delayed transit, persisting potassium within the stricture) of this type of injury which is not reflux aggravated.     

Seroprevalence of Chlamydia pneumoniae infection in Taiwan

OBJECTIVES: To survey the seroprevalence of Chlamydia pneumoniae (C. pneumoniae) infection in healthy subjects in Taiwan. MATERIALS AND METHODS: We used microimmunofluorescence antibody assay to survey the prevalence of antibodies to C. pneumoniae in 620 serum samples from healthy subjects aged 6 months to 86 years in Taiwan. RESULTS: The mean prevalence (+/-SD) of IgG antibodies against C. pneumoniae at titer greater than or equal 1:16 was 55.8% (range 7.8-81.8%). The antibody prevalence was low in children under the age of 10 years (7.8%), and increased rapidly with age. Most individual acquired infection during the second and third decades of life with highest antibody prevalence reached up to 81.8% at fifth decade of life and remained high (70%) thereafter. CONCLUSIONS: Chlamydia pneumoniae infection is highly endemic in Taiwan. These data contribute to the understanding of asymptomatic infections with C. pneumoniae in general population and should serve as a basis for studies on the role of C. pneumoniae infections and their related diseases.     

Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats

The present study explores the potential utility of peripheral versus central administration of glucagon-like peptide-1 (GLP-1) receptor agonists in the regulation of feeding behavior in Wistar and Zucker obese rats. Acute central (intracerebroventricular [i.c.v.]) and peripheral (subcutaneous [s.c.]) administration of both GLP-1 (7-36) amide and exendin-4 resulted in a reduction in food intake for at least 4 hours, exendin-4 being much more potent than GLP-1 (7-36) amide, especially after peripheral administration. Both Zucker obese rats (fa/fa) and their lean littermates (Fa/-) responded to acute central and peripheral administration of exendin-4. Moreover, in situ hybridization revealed specific labeling for the mRNA for GLP-1 receptors in several brain areas of both the obese and lean rats. The presence of this receptor was also detected by affinity cross-linking assays. Long-term s.c. administration of exendin-4 (1 single injection per day, 1 hour prior to the onset of the dark phase of the cycle) decreased daily food intake and practically blocked weight gain in obese rats. In contrast to previous studies, these findings show that peripheral (s.c.) administration of both GLP-1 receptor agonists also induces satiety and weight loss in rats, and suggest the potential usefulness of exendin-4 as a therapeutic tool for the treatment of diabetes and/or obesity.