Corrigendum: Impact of climate change on non-communicable diseases due to increased ambient air pollution.

[This corrects the article on p. 103-121 in vol. 8, PMID: 37799533.].

Predictors of low voltage areas in persistent atrial fibrillation: is it really a matter of time?

BACKGROUND: Time has been postulated as an important factor for electrical remodeling of the left atrium (LA) in persistent atrial fibrillation (AF) ('AF begets AF'). However, it is still a matter of debate if structural changes are the cause or consequence of AF. We sought to determine the clinical and invasive parameters, which correlate with LA scar as determined by voltage mapping, in patients with persistent AF. METHODS: Seventy consecutive patients undergoing ablation of persistent (49%) or long-standing persistent AF (51%), between January 2013 and February 2014, were enrolled in the study. Besides clinical parameters, 2D echocardiographic assessment of LA size and LA pressure (LAP) after transseptal puncture was also considered. Bipolar endocardial signals with a mean voltage amplitude < 0.1 mV during AF were defined as LA scar. RESULTS: In the univariable analysis, LA scar was associated with age, gender, coronary artery disease (CAD), glomerular filtration rate (GFR), LA size and LAP. Arrhythmia duration, mild to moderate mitral regurgitation (MR), left ventricular dysfunction and left ventricular hypertrophy showed no significant correlation with atrial scar (all p > 0.05). In a multivariable regression model, LA scar area was independently associated with age, female gender and LA area. AF duration was not associated with LA scar. CONCLUSIONS: In this study, older age, greater LA area and female gender predicted the degree of LA scar, while other variables tested did not. In particular, we found no significant association between AF duration and LA scar.

3D printed dielectric rectangular waveguides, splitters and couplers for 120 GHz.

We use a 3D printer to fabricate rectangular dielectric single mode waveguides for 120 GHz. The rectangular waveguides consisting of polystyrene showed an attenuation of 6.3 dB/m, which is low enough for short devices. We also characterize 3D printed Y-splitters and a 1x3-splitter based on multimode interference. Further, we construct and measure a variable planar waveguide coupler which can be used as a 3-dB coupler, a cross-coupler and no coupler at all.

Resting state default mode network connectivity in children and adolescents with ADHD after acute tryptophan depletion.

OBJECTIVE: Alterations of the default mode network (DMN) have been described in patients with neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), and the neurotransmitter serotonin (5-HT) is known to modulate DMN activity. This study aimed to explore the role of 5-HT on the DMN and its functional connectivity (FC) in young patients with ADHD. METHODS: Young male patients with ADHD (n = 12) and healthy controls (n = 10) (both aged 12-17 years) were subjected to acute tryptophan depletion (ATD) and subsequently diminished brain 5-HT synthesis. Three hours after challenge intake (ATD or a balanced control condition, BAL), resting state fMRI scans were obtained. RESULTS: In patients, ATD led to attenuated FC of the right superior premotor cortex (BA 6) with the DMN, comparable to the extent found in controls after BAL administration. ATD lowered FC of the left somatosensory cortex (BA 3) with the DMN, independently of the factor group, but with stronger effects in controls. CONCLUSIONS: Data reveal a serotonergic modulation of FC between BA 6 and 3, known to be relevant for motor planning and sensory perception, and the DMN, thereby possibly pointing toward ATD acting beneficially on neural planning of motor activity in patients with ADHD.

Structural Characterization of Lecithin-Stabilized Tetracosane Lipid Nanoparticles. Part I: Emulsions.

The structure of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)-stabilized colloidal tetracosane emulsions was investigated by photon correlation spectroscopy and small-angle X-ray and neutron scattering, using emulsions with different neutron scattering contrasts. Special emphasis was placed on the structure of the DMPC stabilizer layer covering the emulsion droplets. A monolayer, structurally similar to a half DMPC bilayer, with a thickness of 16 Å is found. Thereby, the phosphocholine headgroups arrange flat at the oil-water interface. A deep penetration of the tetracosane oil into the stabilizer layer can be ruled out.

Structural Characterization of Lecithin-Stabilized Tetracosane Lipid Nanoparticles. Part II: Suspensions.

Using photon correlation spectroscopy, transmission electron microscopy, microcalorimetry, wide-angle X-ray scattering (WAXS), and small-angle X-ray and neutron scattering (SAXS, SANS), the structure of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)-stabilized colloidal tetracosane suspensions was studied from the molecular level to the microscopic scale as a function of the temperature. The platelike nanocrystals exhibit for tetracosane an unusual orthorhombic low-temperature crystal structure. The corresponding WAXS pattern can be reproduced with a predicted orthorhombic unit cell (space group Pca21), which usually occurs only for much longer even-numbered n-alkanes. Special emphasis was placed on the structure of the DMPC stabilizer layer covering the nanocrystals. Their structure was investigated by SAXS and SANS, using suspensions with different neutron scattering contrasts. As for the emulsions in Part I , the crystallized nanoparticles are covered by a DMPC monolayer. Their significant smaller thickness of 10.5 Å (for the emulsions in Part I : 16 Å) could be related to a more tilted orientation of the DMPC molecules to cover the expanded surface of the crystallized nanoparticles.

A randomised crossover trial of minimising medical terminology in secondary care correspondence in patients with chronic health conditions: impact on understanding and patient reported outcomes.

BACKGROUND: There is little existing research on the role that secondary care letters have in ensuring patient understanding of chronic health conditions. AIM: To determine whether minimising the use of medical terminology in medical correspondence improved patient understanding and anxiety/depression scores. METHODS: A single-centre, non-blinded, randomised crossover design assessed health literacy, EQ-5D scores and the impact of the 'translated' letter on the doctor's professionalism, the patient's relationship with their general practitioner (GP) and their perceived impact on chronic disease management. Patients were crossed over between their 'translated' and original letter. RESULTS: Sixty patients were recruited. Use of a 'translated' letter reduced mean terms not understood from 7.78 to 1.76 (t(58) = 4.706, P < 0.001). Most patients (78.0%) preferred the 'translated' letter, with 69.5% patients perceiving an enhancement in their doctor's professionalism (z = 2.864, P = 0.004), 69.0% reporting a positive influence on relationship with their GP (z = 2.943, P = 0.003) and 79.7% reporting an increase in perceived ability to manage their chronic health condition with the 'translated' letter (z = 4.601, P < 0.001). There was no effect on EQ-5D depression/anxiety scores. CONCLUSION: Minimising the use of medical terminology in medical correspondence significantly improved patient understanding and perception of their ability to manage their chronic health condition. Although there was no impact on EQ-5D depression/anxiety scores, overwhelming patient preference for the 'translated' letter indicates a need for minimisation of medical terminology in medical correspondence for patients with chronic health conditions.

Serotonergic modulation of resting state default mode network connectivity in healthy women.

The default mode network (DMN) plays a central role in intrinsic thought processes. Altered DMN connectivity has been linked to diminished cerebral serotonin synthesis. Diminished brain serotonin synthesis is further associated with a lack of impulse control and various psychiatric disorders. Here, we investigated the serotonergic modulation of intrinsic functional connectivity (FC) within the DMN in healthy adult females, controlling for the menstrual cycle phase. Eighteen healthy women in the follicular phase (aged 20-31 years) participated in a double-blind controlled cross-over study of serotonin depletion. Acute tryptophan depletion (ATD) and a balanced amino acid load (BAL), used as the control condition, were applied on two separate days of assessment. Neural resting state data using functional magnetic resonance imaging (fMRI) and individual trait impulsivity scores were obtained. ATD compared with BAL significantly reduced FC with the DMN in the precuneus (associated with self-referential thinking) and enhanced FC with the DMN in the frontal cortex (associated with cognitive reasoning). Connectivity differences with the DMN between BAL and ATD in the precentral gyrus were significantly correlated with the magnitude of serotonin depletion. Right medial frontal gyrus and left superior frontal gyrus connectivity differences with the DMN were inversely correlated with trait impulsivity. These findings partially deviate from previous findings obtained in males and underline the importance of gender-specific studies and controlling for menstrual cycle to further elucidate the mechanism of ATD-induced changes within intrinsic thought processes.

Neural correlates of reactive aggression in children with attention-deficit/hyperactivity disorder and comorbid disruptive behaviour disorders.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is often linked with impulsive and aggressive behaviour, indexed by high comorbidity rates between ADHD and disruptive behaviour disorders (DBD). The present study aimed to investigate underlying neural activity of reactive aggression in children with ADHD and comorbid DBD using functional neuroimaging techniques (fMRI). METHOD: Eighteen boys with ADHD (age 9-14 years, 10 subjects with comorbid DBD) and 18 healthy controls were administered a modified fMRI-based version of the 'Point Subtraction Aggression Game' to elicit reactive aggressive behaviour. Trials consisted of an 'aggression phase' (punishment for a fictitious opponent) and an 'outcome phase' (presentation of the trial outcome). RESULTS: During the aggression phase, higher aggressive responses of control children were accompanied by higher activation of the ventral anterior cingulate cortex and the temporoparietal junction. Patients displayed inverted results. During the outcome phase, comparison between groups and conditions showed differential activation in the dorsal striatum and bilateral insular when subjects gained points. Losing points was accompanied by differential activation of regions belonging to the insula and the middle temporal sulcus. CONCLUSION: Data support the hypothesis that deficient inhibitory control mechanisms are related to increased impulsive aggressive behaviour in young people with ADHD and comorbid DBD.

Terahertz meets sculptural and architectural art: Evaluation and conservation of stone objects with T-ray technology.

Conservation of cultural heritage is an area where novel scientific techniques are having enormous impact. Given the value and uniqueness of art pieces, non-invasive diagnostic methods are highly appreciated by conservators. Terahertz radiation has shown enormous potential as non-contact probe that can be used for the three-dimensional reconstruction of internal structure of stone-made objects. In this article we report the evaluation of the internal damage state of two art pieces, a medallion from the Castle of Celle and a window sill from the St. Peter of Trier Cathedral. We also used terahertz radiation to follow and assess the restoration process of the window sill. We found that terahertz spectroscopy is an excellent non-destructive evaluation method for stone artwork that shows enormous potential as a tool for conservation.

Effects of serotonin depletion on punishment processing in the orbitofrontal and anterior cingulate cortices of healthy women.

Diminished synthesis of the neurotransmitter serotonin (5-HT) has been linked to disrupted impulse control in aversive contexts. However, the neural correlates underlying a serotonergic modulation of female impulsivity remain unclear. The present study investigated punishment-induced inhibition in healthy young women. Eighteen healthy female subjects (aged 20-31) participated in a double-blinded, counterbalanced, placebo-controlled, within subjects, repeated measures study. They were assessed on two randomly assigned occasions that were controlled for menstrual cycle phase. In a randomized order, one day, acute tryptophan depletion (ATD) was used to reduce 5-HT synthesis in the brain. On the other day, participants received a tryptophan-balanced amino acid load (BAL) as a control condition. Three hours after administration of ATD/BAL, neural activity was recorded during a modified Go/No-Go task implementing reward or punishment processes using functional magnetic resonance imaging (fMRI). Neural activation during No-Go trials in punishment conditions after BAL versus ATD administration correlated positively with the magnitude of central 5-HT depletion in the ventral and subgenual anterior cingulate cortices (ACC). Furthermore, neural activation in the medial orbitofrontal cortex (mOFC) and the dorsal ACC correlated positively with trait impulsivity. The results indicate reduced neural sensitivity to punishment after short-term depletion of 5-HT in brain areas related to emotion regulation (subgenual ACC) increasing with depletion magnitude and in brain areas related to appraisal and expression of emotions (mOFC and dorsal ACC), increasing with trait impulsivity. This suggests a serotonergic modulation of neural circuits related to emotion regulation, impulsive behavior, and punishment processing in females.

Amino acid challenge and depletion techniques in human functional neuroimaging studies: an overview.

Imbalances of neurotransmitter systems, particularly serotonin (5-HT) and dopamine (DA), are known to play an essential role in many neuropsychiatric disorders. The transient manipulation of such systems through the alteration of their amino acid precursors is a well-known research tool. Among these methods are alterations of tryptophan, the essential amino acid (AA) precursor of 5-HT, as well as manipulations of tyrosine and phenylalanine, the AA precursors of DA, which can be metabolized into norepinephrine and subsequently into epinephrine. These systems can be loaded by applying a large dose of these AAs or depleted by applying an amino acid mixture lacking the respective AAs serving as precursors. Functional neuroimaging has given insights into differential brain activation patterns and functions depending on the tasks performed, pharmacological treatments or specific disorders. Such research has shed light on the function of many brain areas as well as their interactions. The combination of AA challenge approaches with neuroimaging techniques has been subject of numerous studies. Overall, the studies conducted in this particular field of research have shown that AA challenge techniques are valid and effective research tools that allow the investigation of serotonergic and dopaminergic systems without causing serious side effects or long-term damage to the subjects. In this review, we will present an overview of the results obtained so far and discuss the implications of these findings as well as open questions that remain to be answered.

Effects of a short-term reduction in brain serotonin synthesis on the availability of the soluble leptin receptor in healthy women.

Serotonin (5-HT) and the hormone leptin have been linked to the underlying neurobiology of appetite regulation with evidence coming from animal and cellular research, but direct evidence linking these two pathways in humans is lacking. We examined the effects of reduced brain 5-HT synthesis due to acute tryptophan depletion (ATD) on levels of soluble leptin receptor (sOb-R), the main high-affinity leptin binding protein, in healthy adults using an exploratory approach. Women, but not men, showed reduced sOb-R concentrations after ATD administration. With females showing reduced baseline levels of central 5-HT synthesis compared to males diminished brain 5-HT synthesis affected the leptin axis through the sOb-R in females, thereby potentially influencing their vulnerability to dysfunctional appetite regulation and co-morbid mood symptoms.

TGF-beta receptor type-2 expression in cancer-associated fibroblasts regulates breast cancer cell growth and survival and is a prognostic marker in pre-menopausal breast cancer.

Transforming growth factor-beta (TGF-ß) is a pleiotropic cytokine with the capability to act as tumour suppressor or tumour promoter depending on the cellular context. TGF-beta receptor type-2 (TGFBR2) is the ligand-binding receptor for all members of the TGF-ß family. Data from mouse model experiments demonstrated that loss of Tgfbr2 expression in mammary fibroblasts was linked to tumour initiation and metastasis. Using a randomised tamoxifen trial cohort including in total 564 invasive breast carcinomas, we examined TGFBR2 expression (n=252) and phosphorylation level of downstream target SMAD2 (pSMAD2) (n=319) in cancer-associated fibroblasts (CAFs) and assessed links to clinicopathological markers, prognostic and treatment-predictive values. The study revealed that CAF-specific TGFBR2 expression correlated with improved recurrence-free survival. Multivariate analysis confirmed CAF-TGFBR2 to be an independent prognostic marker (multivariate Cox regression, hazard ratio: 0.534, 95% (CI): 0.360-0.793, P=0.002). CAF-specific pSMAD2 levels, however, did not associate with survival outcome. Experimentally, TGF-ß signalling in fibroblasts was modulated using a TGF-ß ligand and inhibitor or through lentiviral short hairpin RNA-mediated TGFBR2-specific knockdown. To determine the role of fibroblastic TGF-ß pathway on breast cancer cells, we used cell contact-dependent cell growth and clonogenicity assays, which showed that knockdown of TGFBR2 in CAFs resulted in increased cell growth, proliferation and clonogenic survival. Further, in a mouse model transfected CAFs were co-injected with MCF7 and tumour weight and proportion was monitored. We found that mouse xenograft tumours comprising TGFBR2 knockdown fibroblasts were slightly bigger and displayed increased tumour cell capacity. Overall, our data demonstrate that fibroblast-related biomarkers possess clinically relevant information and that fibroblasts confer effects on breast cancer cell growth and survival. Regulation of tumour-stromal cross-talk through fibroblastic TGF-ß pathway may depend on fibroblast phenotype, emphasising the importance to characterise tumour microenvironment subtypes.

[First audiological results of the concha-worn bone conduction instrument C.A.I. BC811]. / Erste audiologische Ergebnisse des im Ohr getragenen Knochenleitungshörgeräts C.A.I. BC811.

BACKGROUND: Diverse forms of bone conduction devices (BCD; percutaneous or transcutaneous) provide successful and well-established therapies for conductional hearing loss (CHL). For patients in whom a surgical procedure is to be avoided for medical or personal reasons, instruments with head straps or bands, and bone conduction glasses are available. The current article presents and examines the audiological results of a newly developed, nonsurgical bone conducting device (C.A.I. BC811, bruckhoff hannover; C.A.I: Concha Anchored Instrument) that is fixed in the concha and transfers the sound to the cheekbone. METHODS: In this cross-over study, 4 CHL patients with minimal sensorineural components and existing treatment with a BCD were supplied with a BC811. Audiological outcomes with the optimized existing device and the BC811 were evaluated and compared at 2-weekly intervals. In addition to the aided versus unaided sound field thresholds, the monosyllabic Freiburg intelligibility test, hearing in noise (OlSa) and the subjective benefit of the treatment (APHAB questionnaire) were investigated. RESULTS: No significant differences between BC811 and the optimized existing devices were found in terms of aided thresholds in sound field, functional gain or monosyllabic intelligibility tests. The average aided improvement of the threshold was PTA4 = 29.4 ± 11.1 dB (mean ± standard deviation) with the BC811. The improvements in the monosyllabic intelligibility and hearing in noise tests were significant for both types of device and comparison between the device types revealed no significant differences. The subjective ratings of the perceived improvement reflected by the global APHAB score were positive and similar: 36.4 (control) and 33.4 (BC811). CONCLUSION: The comparison with BCDs demonstrated that the BC811 is a realistic and audiologically sufficient alternative to surgical solutions using percutaneous devices for patients with CHL.

A continuous mixture of two different dimers in liquid water.

It is hitherto thought that liquid water is composed of tetrahedrally coordinated molecules with an asymmetric interaction of the central molecule with neighboring molecules. Kühne et al., Nat. Commun., 2013, 4, 1450 suggested that this asymmetry, energetic rather than geometric, is the cornerstone to reconcile the homogeneous and inhomogeneous viewpoints of liquid water. In order to investigate the geometric origin of that asymmetry, we have scrutinized Molecular Dynamics (MD) simulations of water through a careful analysis of the five-dimensional probability distribution function of Euler angles in which the relative positions and orientations of water molecules are obtained. We demonstrate that, beyond the ubiquitous tetrahedral structure with well-defined molecular dimers, there is a series of possible molecular orientations that define the structure. These orientations are generated by rotating the neighboring molecule around the O-H axis that is involved in the hydrogen bond scheme. Two of the possible orientations have a higher probability, giving rise to two kinds of dimers: one close to the lowest energy of a water dimer in vacuum with an almost perpendicular alignment of the dipole moment, and another one with a parallel orientation of the dipole moment which is less tightly bound. These two different dimers have an effect on the orientation of further water dipole moments up to a distance of ≈6 Å. Liquid water can therefore be described as a continuous mixture of two kinds of dimers where the hydrogen bonds have the same geometry but the interaction energies are different due to a different mutual orientation of the dipoles of the participating water molecules.

Cost-efficient delay generator for fast terahertz imaging.

We present a fast and low-cost delay generator for terahertz (THz) waves that transfers a rotational motion of a transparent dielectric cube into an effective THz delay. The device is easily implemented in the THz beam path and allows for coherent sampling over 40 ps with a scan rate of hundreds of hertz. Furthermore, we show that our approach is particularly suitable for fast THz imaging.

ARF inhibits the growth and malignant progression of non-small-cell lung carcinoma.

Non-small-cell lung carcinoma (NSCLC) is among the deadliest of human cancers. The CDKN2A locus, which houses the INK4a and ARF tumor suppressor genes, is frequently altered in NSCLC. However, the specific role of ARF in pulmonary tumorigenesis remains unclear. KRAS and other oncogenes induce the expression of ARF, thus stabilizing p53 activity and arresting cell proliferation. To address the role of ARF in Kras-driven NSCLC, we compared the susceptibility of NIH/Ola strain wild-type and Arf-knockout mice to urethane-induced lung carcinogenesis. Lung tumor size, malignancy and associated morbidity were significantly increased in Arf(-/-) compared with Arf(+/+) animals at 25 weeks after induction. Pulmonary tumors from Arf-knockout mice exhibited increased cell proliferation and DNA damage compared with wild-type mice. A subgroup of tumors in Arf(-/-) animals presented as dedifferentiated and metastatic, with many characteristics of pulmonary sarcomatoid carcinoma, a neoplasm previously undocumented in mouse models. Our finding of a role for ARF in NSCLC is consistent with the observation that benign adenomas from Arf(+/+) mice robustly expressed ARF, while ARF expression was markedly reduced in malignant adenocarcinomas. ARF expression also frequently colocalized with the expression of p21(CIP1), a transcriptional target of p53, arguing that ARF induces the p53 checkpoint to arrest cell proliferation in vivo. Taken together, these findings demonstrate that induction of ARF is an early response in lung tumorigenesis that mounts a strong barrier against tumor growth and malignant progression.

Development of a human three-dimensional organotypic skin-melanoma spheroid model for in vitro drug testing.

Despite remarkable efforts, metastatic melanoma (MM) still presents with significant mortality. Recently, mono-chemotherapies are increasingly replenished by more cancer-specific combination therapies involving death ligands and drugs interfering with cell signaling. Still, MM remains a fatal disease because tumors rapidly develop resistance to novel therapies thereby regaining tumorigenic capacity. Although genetically engineered mouse models for MM have been developed, at present no model is available that reliably mimics the human disease and is suitable for studying mechanisms of therapeutic obstacles including cell death resistance. To improve the increasing requests on new therapeutic alternatives, reliable human screening models are demanded that translate the findings from basic cellular research into clinical applications. By developing an organotypic full skin equivalent, harboring melanoma tumor spheroids of defined sizes we have invented a cell-based model that recapitulates both the 3D organization and multicellular complexity of an organ/tumor in vivo but at the same time accommodates systematic experimental intervention. By extending our previous findings on melanoma cell sensitization toward TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) by co-application of sublethal doses of ultraviolet-B radiation (UVB) or cisplatin, we show significant differences in the therapeutical outcome to exist between regular two-dimensional (2D) and complex in vivo-like 3D models. Of note, while both treatment combinations killed the same cancer cell lines in 2D culture, skin equivalent-embedded melanoma spheroids are potently killed by TRAIL+cisplatin treatment but remain almost unaffected by the TRAIL+UVB combination. Consequently, we have established an organotypic human skin-melanoma model that will facilitate efforts to improve therapeutic outcomes for malignant melanoma by providing a platform for the investigation of cytotoxic treatments and tailored therapies in a more physiological setting.

Studies in rodents with the dipeptidyl peptidase-4 inhibitor vildagliptin to evaluate possible drug-induced pancreatic histological changes that are predictive of pancreatitis and cancer development in man.

AIM: The present report summarizes rodent studies with vildagliptin, relevant to predicting pancreatitis or pancreatic cancer in man. METHODS: As part of the regulatory development program for vildagliptin, a rodent toxicity program included two 104-week rodent (mouse and rat) carcinogenicity studies that were conducted according to guidelines assigned in Food and Drug Administration's Draft Guidance for Industry. RESULTS: Vildagliptin exposure in animals was evaluated for its effects on endocrine and exocrine pancreas. Two-year carcinogenicity studies were conducted in rats at oral doses up to 900 mg/kg (approximately 200 times the human exposure at the maximum recommended dose) and in mice at oral doses up to 1000 mg/kg (up to 240 times the human exposure at the maximum recommended dose). The results from these studies show the expected preservation and growth of the endocrine ß-cells with no significant findings in the exocrine acinar pancreas. There was no evidence of inflammatory infiltrates characteristic of pancreatitis, no palpable mass detection based on gross examination or any microscopic findings indicative of pancreatic islet cell (endocrine), acinar cell (exocrine) or ductal (exocrine) neoplasia in rat or mouse. CONCLUSIONS: Evaluation of vildagliptin in 2-year preclinical carcinogenicity studies in both rats and mice indicates that while vildagliptin results in pharmacological benefits to the endocrine pancreas, this was not associated with any evidence of pancreatitis, pancreatic islet cell, acinar cell or ductal neoplasia. These data predict no increased risk of pancreatic cancer in man.