Self-reported long-term cardiac morbidity in breast cancer patients: a retrospective cohort study in Germany (PASSOS Heart Study)

Purpose

Improved survival after locoregional breast cancer has increased the concern about late adverse effects after therapy. In particular, radiotherapy was identified as a risk factor for major cardiac events in women treated until the 1990s. While modern radiotherapy with computerized planning based on 3D-imaging can help spare organs at risk, heart exposure may remain substantial. In a retrospective cohort study of women treated for locoregional breast cancer, we investigated whether current radiotherapy is associated with an elevated long-term cardiac morbidity risk.

Methods

The study included 11,982 women diagnosed with breast cancer in Germany in 1998–2008. After an individual mortality follow-up, 9338 questionnaires on cardiac events before or after therapy and on associated risk factors were sent out in 2014. Based on 4434 questionnaires from women with radiotherapy, we used Cox regression to analyze the association between self-reported cardiac morbidity and breast cancer laterality as a surrogate measure of radiation exposure.

Results

After a median follow-up of 8.3 years, there was no significant association of tumor laterality with cardiac morbidity in irradiated patients (458 events, hazard ratio for left-sided vs. right-sided tumors 1.07, 95% CI 0.89–1.29). Significant risk factors for any cardiac event included age at diagnosis, chemotherapy, hypertension, hypercholesteremia, and chronic kidney disease.

Conclusions

For contemporary radiotherapy, we found no evidence for a significantly elevated cardiac morbidity risk in left-sided versus right-sided breast cancer. Possible reasons for failing to confirm earlier reports on increased risk include shorter follow-up, application of newer radiotherapy techniques, and improved health monitoring.

     

Self-reported dietary adherence,disease-specific symptoms,and quality of life are associated with healthcare provider follow-up in celiac disease

Background

The only treatment for celiac disease (CeD) is a lifelong gluten-free diet (GFD). The restrictive nature of the GFD makes adherence a challenge. As an integral part of CeD management, multiple professional organizations recommend regular follow-up with a healthcare provider (HCP). Many CeD patients also participate in patient advocacy groups (PAGs) for education and support. Previous work found that follow-up of CeD patients is highly variable. Here we investigated the self-reported factors associated with HCP follow-up among individuals diagnosed with CeD who participate in a PAG.

Methods

We conducted a survey of members of Beyond Celiac (a PAG), collecting responses from 1832 U.S. adults ages 19–65 who reported having CeD. The survey queried HCP follow-up related to CeD and included validated instruments for dietary adherence (CDAT), disease-specific symptoms (CSI), and quality of life (CD-QOL).

Results

Overall, 27% of respondents diagnosed with CeD at least five years ago reported that they had not visited an HCP about CeD in the last five years. The most frequent reason for not visiting an HCP was “doing fine on my own” (47.6%). Using multiple logistic regression, we identified significant associations between whether a respondent reported visiting an HCP about CeD in the last five years and the scores for all three validated instruments. In particular, as disease-specific symptoms and quality of life worsened, the probability of having visited an HCP increased. Conversely, as dietary adherence worsened, the probability decreased.

Conclusions

Our results suggest that many individuals with CeD manage their disease without ongoing support from an HCP. Our results thus emphasize the need for greater access to high quality CeD care, and highlight an opportunity for PAGs to bring together patients and HCPs to improve management of CeD.

     

Cerebellar cortical output encodes temporal aspects of rhythmic licking movements and is necessary for normal licking frequency

Rodents consume water by performing stereotypic, rhythmic licking movements that are believed to be controlled by brainstem pattern‐generating circuits. Previous work has shown that synchronized population activity of inferior olive neurons was phase‐locked to the licking rhythm in rats, suggesting a cerebellar involvement in temporal aspects of licking behavior. However, what role the cerebellum has in licking behavior and whether licking is represented in the high‐frequency simple spike output of Purkinje cells remains unknown. We recorded Purkinje cell simple and complex spike activity in awake mice during licking, and determined the behavioral consequences of loss of cerebellar function. Mouse cerebellar cortex contained a multifaceted representation of licking behavior encoded in the simple spike activities of Purkinje cells distributed across Crus I, Crus II and lobus simplex of the right cerebellar hemisphere. Lick‐related Purkinje cell simple spike activity was modulated rhythmically, phase‐locked to the lick rhythm, or non‐rhythmically. A subpopulation of lick‐related Purkinje cells differentially represented lick interval duration in their simple spike activity. Surgical removal of the cerebellum or temporary pharmacological inactivation of the cerebellar nuclei significantly slowed the licking frequency. Fluid licking was also less efficient in mice with impaired cerebellar function, indicated by a significant decline in the volume per lick fluid intake. The gross licking movement appeared unaffected. Our results suggest a cerebellar role in modulating the frequency of the central pattern‐generating circuits controlling fluid licking and in the fine coordination of licking, while contributing little to the coordination of the gross licking movement.     

Gene expression profiling in human whole blood samples after controlled testosterone application and exercise

Doping with anabolic agents is regulated within a number of sports. Testosterone and its functional analogs are popular compounds for increasing muscle mass, physical performance, recovery, and reducing body fat. While routine tests for anabolic drugs exist (e.g. hair, urine, and blood analysis), the aim of the present study is to determine specific gene expression profiles (induced by testosterone and exercise) which may be used as effective biomarkers to determine the use of anabolic drugs. In this study, whole blood samples of 19 male volunteers were analyzed by semi‐quantitative real‐time polymerase chain reaction (RT‐PCR) for gene expression profiles in the context of exercise and transdermal testosterone application (1.5 mg/kg body weight). The hormone application was monitored by urine and saliva analysis for testosterone. Both urinary and saliva levels indicate that transdermal testosterone application leads to an increase of testosterone, especially after exercise. RT‐PCR results showed a clear variation in the expression of target genes as well as established housekeeping genes. Only one of the nine common housekeeping genes, cyclophilin b (PPIB), appears to be independent of both exercise and testosterone. Out of 14 candidate genes, five are unregulated; all others were more or less influenced by the mentioned variables. Only interleukin‐6 appeared to be exclusively dependent on long‐term testosterone application. This study indicates that many genes are not influenced by testosterone alone while exercise modulates gene expression in whole blood samples. As such, exercise must be considered when validating gene expression techniques for doping analysis. Copyright © 2011 John Wiley & Sons, Ltd.     

Expression and function of C/EBP homology protein (GADD153) in podocytes

Podocytes are crucial for the permeability of the glomerular filtration barrier. In glomerular disease, however, reactive oxygen species (ROS) may be involved in podocyte injury and subsequent proteinuria. Here, we describe ROS-dependent gene induction in differentiated podocytes stimulated with H(2)O(2) or xanthine/xanthine-oxidase. Superoxide anions and H(2)O(2) increased mRNA and protein expression of GAS5 (growth arrest-specific protein 5) and CHOP (C/EBP homology protein). Cultured podocytes overexpressing CHOP showed increased generation of superoxide anions compared to controls. In addition, the expression of alpha(3)/beta(1) integrins, crucial for cell-matrix interaction of podocytes, was down-regulated, leading to increased cell-matrix adhesion and cell displacement. The altered cell-matrix adhesion was antagonized by the ROS scavenger 1,3-dimethyl-2-thiourea, and the increase in cell displacement could be mimicked by stimulating untransfected podocytes with puromycin, an inductor of ROS. We next performed immunohistochemical staining of human kidney tissue (normal, membranous nephropathy, focal segmental glomerulosclerosis, and minimal change nephropathy) as well as sections from rats with puromycin nephrosis, a model of minimal change nephropathy. CHOP was weakly expressed in podocytes of control kidneys but up-regulated in most proteinuric human kidneys and in rat puromycin nephrosis. Our data suggest that CHOP-via increased ROS generation-regulates cell-matrix adhesion of podocytes in glomerular disease.     

Perioperative complication rate in 1706 patients after a standardized laparoscopic supracervical hysterectomy technique

STUDY OBJECTIVE: The aim of the study was to determine perioperative morbidity and complication rate after a standardized technique of laparoscopic supracervical hysterectomy (LASH). DESIGN: Retrospective analysis of consecutive patients (Canadian Task Force classification II-3). SETTING: Private hospital. PATIENTS: Seventeen hundred and six consecutive patients with symptomatic uterine myomata, dysfunctional uterine bleeding, dysmenorrhea, or chronic pelvic pain. INTERVENTION: Laparoscopic supracervical hysterectomy using a unipolar hook for dissection of the body of the uterus followed by electric morcellation. MEASUREMENTS AND MAIN RESULTS: The main indications for LASH were uterine myomata with dysfunctional uterine bleeding (31.1%) or without (45.4%) and therapy-resistant dysfunctional uterine bleeding (21%). The mean uterine weight was 226.4 +/- 193.9 g (95% CI 217.1-235.6), the mean duration of surgery was 91.4 +/- 33.3 minutes (95% CI 89.9-93.0), and the mean duration of hospital stay was 2.15 +/- 0.63 days (95% CI 2.12-2.18). Nine hundred two (52.9%) of the patients had a history of at least one laparotomy. In 14 patients (0.82%), a conversion to laparotomy was necessary. Of these, 11 were due to the size and immobility of the uterus, one was due to severe adhesions, and two because of intraoperative complications. In total, five (0.3%) intraoperative and 20 (1.2%) postoperative complications occurred. The mean weight of the uterus in the five patients with intraoperative complications (three bladder injuries, one ureter injury, and one severe intraoperative bleed) was 818.4 +/- 911.9 g (95% CI -313.9-1950.7). In two patients who suffered trauma to the bladder, there was a history of cesarean sections (two and three, respectively). The most common postoperative complications were bleeding from the cervix and pain caused by adhesions or postoperative infection. CONCLUSION: Laparoscopic supracervical hysterectomy is a minimally invasive surgical method that should be regarded as an alternative to all other methods of total hysterectomy in benign conditions of the uterus (uterine myomata, dysfunctional uterine bleeding, uterine adenomyosis) as it is associated with a low perioperative morbidity and a rapid period of convalescence. Of special significance is that LASH can be performed on nulliparous patients, patients who have not previously had vaginal delivery, and patients who have had previous abdominal surgery.     

Unusual clinical presentation and possible rescue of a novel claudin-16 mutation

CONTEXT: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is caused by a dysfunction of Claudin-16 (CLDN16) and characterized by renal wasting of Mg(2+) and Ca(2+). OBJECTIVE: The objectives of this study were to study the clinical parameters in suspected FHHNC patients, identify mutations in the CLDN16 gene, and analyze molecular defects associated with the mutant protein. DESIGN, SETTING, AND PARTICIPANTS: CLDN16 genes from two siblings diagnosed with FHHNC were sequenced. Expression and characterization of the mutant protein in renal MDCK cells were studied. OUTCOME MEASURES: Standard urine and serum parameters to diagnose FHHNC were determined. Mutations in the CLDN16 gene were identified. The subcellular distribution of the mutant protein was analyzed by immunofluorescence microscopy. RESULTS: Urine and blood analysis showed signs typical for FHHNC. One patient, in addition, presented with hypocalcemic tetany, a phenomenon so far not described for FHHNC. Both siblings carry a novel mutation in CLDN16, Y207X. The review of medical records showed that hypocalcemia is not uncommon in the early childhood of FHHNC patients. Expressed in MDCK cells, the Y207X mutant is not detected at tight junctions but instead is found in lysosomes and, to a lesser extent, the endoplasmic reticulum. Surface expression can be rescued by inhibiting clathrin-mediated internalization. CONCLUSIONS: We propose that mutations in CLDN16 are considered in childhood hypocalcemia. CLDN16 Y207X is transiently delivered to the plasma membrane but not retained and is rapidly retrieved by internalization. Inhibitors of endocytosis may provide novel therapeutic strategies.     

Parametric modulation of cortical activation during smooth pursuit with and without target blanking. an fMRI study

Smooth pursuit eye movements (SPEM) are performed to track slowly moving visual targets and are accompanied by saccades whenever foveal representation is lost. In the present study, we correlated the cerebral activation as assessed by functional magnetic resonance imaging with parameters of eye movement performance in order to determine the cortical areas involved in the retinal and extraretinal processing of maintaining smooth pursuit velocity (SPV) and generating saccades in 16 healthy males. The stimulus consisted of a target moving at a constant velocity of 10 degrees/s with and without target blanking. During constant target presentation, SPV was positively correlated with the BOLD signal in the right V5 complex and negatively correlated with the BOLD response in the left dorsolateral prefrontal cortex (DLPFC). In the condition with target blanking, additional negative correlations with SPV were found in the left frontal eye field (FEF), the left parietoinsular vestibular cortex (PIVC) and the left angular gyrus. Saccadic frequency was negatively correlated with activations of the right mesial intraparietal sulcus (IPS) during both conditions and the right premotor area during continuous target presentation. We conclude that V5 is directly related to the maintenance of an optimal smooth pursuit velocity during visual feedback, whereas the FEF, PFC, angular gyrus and PIVC are involved in reconstitution and prediction whenever SPV decreases, especially during maintenance of smooth pursuit in the absence of a visual target. Furthermore, we suggest that parietal areas are related to the suppression of saccades during smooth pursuit.     

An assessment of the potential value of elevated homocysteine in predicting alcohol-withdrawal seizures

PURPOSE: Higher homocysteine levels were found in actively drinking patients with alcohol dependence. Recent studies have shown that high homocysteine levels are associated with alcohol-withdrawal seizures. The aim of the present study was to calculate the best predictive cutoff value of plasma homocysteine levels in actively drinking alcoholics (n = 88) with first-onset alcohol-withdrawal seizures. METHODS: The present study included 88 alcohol-dependent patients of whom 18 patients had a first-onset withdrawal seizure. All patients were active drinkers and had an established diagnosis of alcohol dependence, according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Sensitivity and specificity were calculated by using every homocysteine plasma level found in the study population as cut-off value. A Bayes theorem was used to calculate positive (PPV) and negative (NPV) predictive values for all cutoff values used. RESULTS: The highest combined sensitivity and specificity was reached at a homocysteine plasma cutoff value of 23.9 microM. Positive predictive values ranged from 0.23 to 0.745; the maximum was reached at a homocysteine plasma level of 41.7 microM. Negative predictive values ranged from 0.50 to 0.935, with a maximum at a homocysteine plasma level of 15.8 microM. CONCLUSIONS: Homocysteine levels above this cutoff value on admission are a useful screening tool to identify actively drinking patients at higher risk of alcohol-withdrawal seizures. This pilot study gives further hints that biologic markers may be helpful to predict patients at risk for first-onset alcohol-withdrawal seizures.     

A low-cost solution to measure mouse licking in an electrophysiological setup with a standard analog-to-digital converter

Licking behavior in rodents is widely used to determine fluid consumption in various behavioral contexts and is a typical example of rhythmic movement controlled by internal pattern-generating mechanisms. The measurement of licking behavior by commercially available instruments is based on either tongue protrusion interrupting a light beam or on an electrical signal generated by the tongue touching a metal spout. We report here that licking behavior can be measured with high temporal precision by simply connecting a metal sipper tube to the input of a standard analog/digital (A/D) converter and connecting the animal to ground (via a metal cage floor). The signal produced by a single lick consists of a 100-800 mV dc voltage step, which reflects the metal-to-water junction potential and persists for the duration of the tongue-spout contact. This method does not produce any significant electrical artifacts and can be combined with electrophysiological measurements of single unit activity from neurons involved in the control of the licking behavior.