Epigenetic variation in the serotonin transporter gene predicts resting state functional connectivity strength within the salience‐network

Genetic variation in the serotonin transporter gene (SLC6A4) has been associated with psychopathology and aberrant brain functioning in a plethora of clinical and imaging studies. In contrast, the neurobiological correlates of epigenetic signatures in SLC6A4, such as DNA methylation profiles, have only recently been explored in human brain imaging research. The present study is the first to apply a resting state functional magnetic resonance imaging approach to identify changes in brain networks related to SLC6A4 promoter methylation (N = 74 healthy individuals). The amygdalae were defined as seed regions given that resting state functional connectivity in this brain area is under serotonergic control and relates to a broad range of psychiatric phenotypes. We further used bisulfite pyrosequencing to analyze quantitative methylation at 83 CpG sites within a promoter‐associated CpG island of SLC6A4 from blood‐derived DNA samples. The major finding of this study indicates a positive relation of SLC6A4 promoter methylation and amygdaloid resting state functional coupling with key nodes of the salience network (SN) including the anterior insulae and the dorsal anterior cingulate cortices. Increased intra‐network connectivity in the SN is thought to facilitate the detection and subsequent processing of potentially negative stimuli and reflects a core feature of psychopathology. As such, epigenetic changes within the SLC6A4 gene predict connectivity patterns in clinically and behaviorally relevant brain networks which may in turn convey increased disease susceptibility. Hum Brain Mapp 36:4361–4371, 2015. © 2015 Wiley Periodicals, Inc.     

Adjuvant Therapy‐Related Shortening of Survival (ATRESS): An Underrated Phenomenon

Shortening of survival after dissemination following adjuvant treatment is not understood well enough and is difficult to search for in public databases because of the lack of specific search terms. We suggest using the acronym ATRESS, for “adjuvant therapy-related shortening of survival,” in future literature concerning this issue.In their analysis of docetaxel-containing regimens in metastatic breast cancer, Seidman et al. [1] reported progression-free and overall survival that was one-third better in patients without prior adjuvant taxane treatment than in patients after adjuvant taxane therapy, and they cautiously discussed therapy-induced resistance against these agents. However, they described an important phenomenon: shortening of survival after dissemination following adjuvant treatment. The relevant literature unanimously describes a reduction in survival of ∼30% after dissemination in spite of adjuvant therapy and was recently reviewed by us [2]. In the largest study on this issue, Pierga et al. compared the findings from 446 breast cancer patients with and 984 patients without adjuvant chemotherapy [3]. The disease-free interval from initial therapy to dissemination was identical (42 vs. 44 months). However, with adjuvant pretreatment, the subsequent remission rate (56%) and survival after dissemination (19 months) was lower than without adjuvant therapy (66% and 26 months; p < .0001 for both).Three factors inducing this effect have to be considered. First, adjuvant therapy is given in tumors with higher risk of relapse (e.g., initial N+ stage). Not only is the rate of dissemination in these tumors higher but also metastases are more aggressive, with shorter survival after dissemination [4]. This is the same in colorectal cancer, for which adjuvant chemotherapy remained an independent negative prognostic parameter in multivariate analysis [5]. Second, with adjuvant therapy, the most sensitive tumors are eliminated. Consequently, the recurring tumors are the more aggressive ones. Third, prior adjuvant therapy induced resistance in the relapsing tumors. This was shown in colorectal cancer, using mutation analysis in liver metastases that revealed different potential for inducing resistance among different cytostatics [6].Adjuvant taxanes in breast cancer may induce resistance predominantly against their own class of agents. Miller et al. found that when administering palliative paclitaxel after adjuvant taxane-free treatment, progression-free survival was 7.7 months versus only 3.0 months after adjuvant taxanes [7]. In our study, in agreement with the findings of Seidman et al. [1], overall survival after dissemination was shortened by one-third when patients received adjuvant taxanes compared with a non-taxane-containing adjuvant therapy [2].These mechanisms, which are also relevant for adjuvant hormonal and immunological treatments [2], are not understood well enough and are difficult to search for in public databases because of the lack of specific search terms. We suggest using the acronym ATRESS, for “adjuvant therapy-related shortening of survival,” in future literature concerning this issue.     

Use of polymerase chain reaction for the early detection of HIV infection in the infants of HIV-seropositive women

Forty-two infants of HIV-seropositive women were evaluated to determine the value of polymerase chain reaction (PCR) in the early detection of HIV infection. All infants less than 6 months old had a simultaneous PCR and culture for HIV. There was an 88% concordance between the two techniques. PCR results showed an excellent correlation with clinical outcome; no PCR-negative patient has subsequently been found to be infected. Occasional false-positive or equivocal PCR results did occur. There was one false-negative culture. PCR is a rapid and sensitive diagnostic test for the early diagnosis of HIV infection in infants at risk, but at present it should be performed in conjunction with other diagnostic tests and good clinical follow-up.     

Prognostic value of HPV-mRNA in sentinel lymph nodes of cervical cancer patients with pN0-status

Up to 15% of patients with cervical cancer and pN0-status develop recurrent-disease. This may be due to occult metastatic spread of tumor cells. We evaluated the use of human-papillomavirus-(HPV)-mRNA as a molecular marker for disseminated tumor cells to predict the risk of recurrence. For this prospective, multi-center prognostic study, 189 patients free of lymphnode metastases by conventional histopathology could be analyzed. All patients underwent complete lymphadenectomy. Of each sentinel node (SLN) a biopsy was taken for the detection of HPV-E6-E7-mRNA. Median follow-up time after surgery was 8.1 years. HPV-mRNA could be detected in SLN of 52 patients (27.5%). Recurrence was observed in 22 patients. Recurrence-free-survival was significantly longer for patients with HPV-negative SLN (log rank p = 0.002). By Cox regression analysis the hazard ratio (95%CI) for disease-recurrence was 3.8 (1.5 – 9.3, p = 0.004) for HPV-mRNA-positive compared to HPV-mRNA-negative patients. After adjustment for tumor size as the most influential covariate the HR was still 2.8 (1.1 – 7.0, p = 0.030). In patients with cervical cancer and tumor-free lymph nodes by conventional histopathology HPV-mRNA-positive SLN were of prognostic value independent of tumor size. Particularly, patients with tumors larger than 20mm diameter could possibly benefit from further risk stratification using HPV-mRNA as a molecular marker.     

Conversion of recent-onset atrial fibrillation or flutter with ibutilide after amiodarone has failed

OBJECTIVE: To evaluate whether ibutilide can convert atrial fibrillation or flutter in patients in whom amiodarone has failed. DESIGN AND SETTING: Clinical study in a university hospital intensive care unit (ICU). PATIENTS: Twenty-six patients were studied, in whom atrial fibrillation or flutter persisted for a maximum of 6 h at maximum. Patients were monitored continuously during the arrhythmia. Medical conversion was necessary due to symptomatic or hemodynamic causes. INTERVENTIONS: All patients initially received amiodarone (150 mg i.v.) and after 2 h of persistent arrhythmia ibutilide (1 mg or, without success and body weight > 70 kg, 2 mg i.v.). Before the administration of ibutilide 1 g magnesium was administered, and high normal levels of potassium serum levels were achieved (4.5-5.0 mmol/l). RESULTS. After amiodarone atrial flutter persisted in 73% and atrial fibrillation in 27% of patients. After ibutilide the QT interval was prolonged from 327 +/- 61 to 387 +/- 62 ms. The QTc interval increased from 456 +/-32 to 461 +/- 66 ms. Conversion to normal sinus rhythm was achieved in 22 of 27 of cases. Nonsustained torsade de pointes tachycardia was seen in three patients (11%). No patient showed sustained ventricular tachycardia. Patients with proarrhythmic effects were characterized by a decreased left ventricular function. CONCLUSIONS: In ICU patients ibutilide led to conversion to sinus rhythm in 81.5% of patients in whom amiodarone was unsuccessful. Nonsustained tachycardias were seen in 11%; sustained ventricular tachycardia was not seen. Ibutilide seems to be well suitable for conversion of recent onset atrial fibrillation or flutter and had no severe side effects in this study population.