B-cell maturation antigen-specific chimeric antigen receptor T cells for multiple myeloma: Clinical experience and future perspectives

Despite major advances in the treatment of multiple myeloma (MM), it remains a largely incurable disease with long-term control often dependent on continuous therapy. More effective, better tolerated treatments are therefore required to achieve durable remissions and to improve the quality of life of MM patients. Adoptive immunotherapy employing T cells expressing chimeric antigen receptors (CAR) is currently among the most promising treatment approaches in cancer. Within the target portfolio for MM immunotherapy, B-cell maturation antigen (BCMA) is among the most widely studied target antigens. BCMA is consistently expressed on MM cells and, importantly, is not expressed in critical healthy tissue. For this reason, it is an ideal target for MM immunotherapy. Several clinical trials evaluating different BCMA-targeting CAR constructs have been initiated and early results are very promising. However, in this rapidly developing clinical landscape, the ultimate role of BCMA-specific CAR-T cell therapy remains unclear. In this review, we will summarize currently available clinical data on BCMA-directed CAR-T cells and discuss potential future perspective for this promising treatment approach in MM.     

A genome wide association study identifies new genes potentially associated with eyelid sagging

Sagging eyelid is considered as an outward of skin ageing and may cause medical issues. However, little is known about the factors involved in sagging eyelid. The study, which aims at determining genetic risk factors for eyelid sagging, was conducted in a cohort of 502 unrelated Caucasian women living in the Paris region. All included participants were aged between 44 and 70 years old (mean age, 57.6 years old). The severity of sagging eyelid was graded in 6 categories by a dermatologist using standardized photographs of the face. A genome wide association study adjusted on potential risk factors (including age and smoking habits) was conducted to identify genetic associations. Two single nucleotide polymorphisms in total linkage disequilibrium on chromosome 10, rs16927253 (P = 7.07 × 10^‐10) and rs4746957 (P = 1.06 × 10^‐8), were significantly associated with eyelid sagging severity. The rs16927253‐T and rs4746957‐A alleles showed a dominant protective effect towards eyelid sagging. These polymorphisms are located in intronic parts of the H2AFY2 gene which encodes a member of the H2A histone family and very close to the AIFM2 gene that induces apoptosis. Additionally, single nucleotide polymorphisms with a false discovery rate below 0.25 were located nearby the type XIII collagen COL13A1 gene on chromosome 10 and in the ADAMTS18 gene on chromosome 16. Several relevant genes were identified by the genome wide association study for their potential role in the sagging eyelid severity.     

Perceptual rivalry across animal species

This review in memoriam of Jack Pettigrew provides an overview of past and current research into the phenomenon of multistable perception across multiple animal species. Multistable perception is characterized by two or more perceptual interpretations spontaneously alternating, or rivaling, when animals are exposed to stimuli with inherent sensory ambiguity. There is a wide array of ambiguous stimuli across sensory modalities, ranging from the configural changes observed in simple line drawings, such as the famous Necker cube, to the alternating perception of entire visual scenes that can be instigated by interocular conflict. The latter phenomenon, called binocular rivalry, in particular caught the attention of the late Jack Pettigrew, who combined his interest in the neuronal basis of perception with a unique comparative biological approach that considered ambiguous sensation as a fundamental problem of sensory systems that has shaped the brain throughout evolution. Here, we examine the research findings on visual perceptual alternation and suppression in a wide variety of species including insects, fish, reptiles, and primates. We highlight several interesting commonalities across species and behavioral indicators of perceptual alternation. In addition, we show how the comparative approach provides new avenues for understanding how the brain suppresses opposing sensory signals and generates alternations in perceptual dominance.     

Constant innervation despite pubertal growth of the mouse penis

The sexual characteristics of the vertebrate body change under the control of sex hormones. In mammals, genitals undergo major changes in puberty. While such bodily changes have been well documented, the associated changes in the nervous system are poorly understood. To address this issue, we studied the growth and innervation of the mouse penis throughout puberty. To this end, we measured length and thickness of the mouse penis in prepubertal (3–4 week old) and adult (8–10 week old) mice and performed fiber counts of the dorsal penile nerve. We obtained such counts with confocal imaging of proximal sections of the mouse penis after paraffin embedding and antibody staining against Protein-Gene-Product-9.5 or Neurofilament-H in combination with antigen retrieval procedures. We find that the mouse penis grows roughly 1.4 times in both thickness and length. Fiber counts in the dorsal penile nerve were not different in prepubertal (1,620 ± 165 fibers per penis) and adult (1,572 ± 383 fibers per penis) mice, however. Antibody staining along with myelin staining by Luxol-Fast-Blue suggested about 57% of penile nerve fibers were myelinated. Quantification of the area of mouse somatosensory penis cortex allowed us to compare cortical magnification of the penile cortex and the whisker-barrel-cortex systems. This comparison suggested that 2 to 4 times less cortical area is devoted to a penile-nerve-fiber than to a whisker-nerve-fiber. The constant innervation of mouse penis through puberty suggests that the pubertal increase of cortical magnification of the penis is not simply a reflection of peripheral change.     

Update PONV – Was gibt es Neues bei der Prophylaxe und Therapie von postoperativer Übelkeit und postoperativem Erbrechen?

Die Anaesthesiologie - Auch wenn für Anästhesiologen über Jahrzehnte die Prophylaxe und Therapie postoperativer Schmerzen im Rahmen des postoperativen Patientenkomforts an vorderster...     

Toilet training in individuals with Angelman syndrome: A case series

Objective: To assess if adapted versions of the response restriction toilet training protocol, based on the behavioral phenotype of Angelman syndrome (AS), were successful in fostering urinary continence in seven individuals with AS.

Method: Data were collected in AB-designs during baseline, training, generalization and follow-up. The response restriction protocol was adapted: individuals were trained in their natural environment, were prompted to void and along with improving continence, the interval between voids was prolonged and time-on-toilet decreased.

Results: During generalization five individuals had less than two accidents and one to six correct voids per day; during baseline more accidents and/or less correct voids occurred. In two participants correct voids increased, but several accidents still occurred. Three participants maintained positive results after 3–18 months.

Conclusion: Despite their intellectual and behavioral challenges, urinary continence can be acquired in AS. Several indications of voiding dysfunctions were found; further research is indicated.     

Anatomical accuracy of brain connections derived from diffusion MRI tractography is inherently limited

Tractography based on diffusion-weighted MRI (DWI) is widely used for mapping the structural connections of the human brain. Its accuracy is known to be limited by technical factors affecting in vivo data acquisition, such as noise, artifacts, and data undersampling resulting from scan time constraints. It generally is assumed that improvements in data quality and implementation of sophisticated tractography methods will lead to increasingly accurate maps of human anatomical connections. However, assessing the anatomical accuracy of DWI tractography is difficult because of the lack of independent knowledge of the true anatomical connections in humans. Here we investigate the future prospects of DWI-based connectional imaging by applying advanced tractography methods to an ex vivo DWI dataset of the macaque brain. The results of different tractography methods were compared with maps of known axonal projections from previous tracer studies in the macaque. Despite the exceptional quality of the DWI data, none of the methods demonstrated high anatomical accuracy. The methods that showed the highest sensitivity showed the lowest specificity, and vice versa. Additionally, anatomical accuracy was highly dependent upon parameters of the tractography algorithm, with different optimal values for mapping different pathways. These results suggest that there is an inherent limitation in determining long-range anatomical projections based on voxel-averaged estimates of local fiber orientation obtained from DWI data that is unlikely to be overcome by improvements in data acquisition and analysis alone.The creation of a comprehensive map of the connectional neuroanatomy of the human brain would be a fundamental achievement in neuroscience. However, despite the numerous efforts to date (for a historical review, see ref. 1), creating this map remains a challenge. A major limitation is that the current gold-standard technique for mapping structural connections, which requires the injection of axonal tracers, cannot be used in humans. The introduction of diffusion-weighted MRI (DWI) (2–4) and the subsequent advent of diffusion tensor MRI (DTI) (5) opened the possibility of exploring the structural properties of white matter in the living human brain (6). Local DWI measures are used clinically for the early detection of stroke and for the characterization of neurological disorders such as multiple sclerosis, epilepsy, and brain gliomas, among others (7). In addition, tractography approaches (8–12) that can infer structural brain connectivity based on brain-wide local DWI measurement have been developed (for reviews, see refs. 13 and 14). The success of DWI tractography as a method for studying fiber trajectories has led to a systematic characterization of large white-matter pathways of the living human brain (e.g., ref. 15), and now it is used routinely to provide a structural explanation for aspects of human brain function (16).A major limitation of DWI tractography is that its characterization of axonal pathways is based on indirect information and numerous assumptions. Local white matter orientation profiles are based on the statistical displacement profile (i.e., diffusion propagator) of water molecules in brain tissue on the coarse scale of a voxel, and fiber trajectories are inferred based on the adjacency of similar diffusion profiles. This approach differs fundamentally from conventional tract-tracing approaches in animals, which involve the physical transport of traceable molecules through the cells’ axoplasm over a large distance. Because these molecules occupy positions within the axon, it sometimes is possible to reconstruct the trajectory of individual neurons through the white matter (e.g., ref. 17). Given the inherent coarseness of DWI tractography, it can be argued that the prospect of using this method to reconstruct complex axonal pathways accurately in the human brain, in a manner similar to that used for molecular tracers in animals, is likely to be intrinsically problematic. Indeed, the limitations of DWI tractography techniques have been noted since their inception (8), and the anatomical accuracy of results from tractography based on the tensor model has been shown to be mixed (18). This inaccuracy has been attributed to two main factors. The first relates to the assumptions underlying tractography algorithms. For example, it has long been recognized that a simple tensor model (19) of local diffusion leads to problems in certain white matter regions where fibers cross within individual voxels. As a remedy, high angular resolution diffusion imaging (HARDI) methods (e.g., refs. 20–24) have been developed to enable better characterization of the diffusion displacement profile and to improve the accuracy of tractography. The second factor limiting accuracy stems from the low quality of clinical DWI data because of various sources of noise. Eddy current distortions, subject motion, physiological noise (see ref. 25 for a review), and susceptibility artifacts from echo planar imaging (EPI) (26) all lead to poor local characterization of diffusion and, consequently, to incorrect tractography results. Continuing advances in sequence design, MRI gradient hardware, and postprocessing correction schemes have overcome many of the initial problems (27) and have led to the belief that further acquisition improvements will result in more precise mapping of structural connections in the human brain (28). In fact, the assumption underlying many recent initiatives to map structural brain connectivity from DWI data is that improved image data quality and sophisticated diffusion modeling approaches will result in anatomically accurate maps of white matter connections (29). The goal of the present study is to investigate the validity of this assumption.To achieve this goal, we acquired high angular resolution DWI data from a normal adult rhesus macaque brain, ex vivo, at a spatial resolution of 250 microns (isotropic). This dataset is ideal for exploring the limits of DWI tractography because of its high signal-to-noise ratio (SNR) (for SNR computation, see SI Materials and Methods) and the almost complete absence of experimental confounds and artifacts such as those originating from patient motion, noise, cardiac pulsation, and EPI distortion that are typically encountered in in vivo studies. Using the axonal tracer results from a well-known atlas (17) as reference, we measured the sensitivity (i.e., the ability to detect true connections) and specificity (i.e., the ability to avoid false connections) of several DWI tractography implementations representative of the current state of the art. This approach allowed us to investigate whether sophisticated diffusion modeling techniques, when applied to DWI data of exceptional quality, would yield accurate maps of axonal connections.     

Free fatty acids exert a greater effect on ocular and skin blood flow than triglycerides in healthy subjects

BACKGROUND: Free fatty acids (FFAs) and triglycerides (TGs) can cause vascular dysfunction and arteriosclerosis. Acute elevation of plasma FFA and TG concentration strongly increase ocular and skin blood flow. This study was designed to discriminate whether FFA or TG independently induce hyperperfusion by measuring regional and systemic haemodynamics. METHODS: In a balanced, randomized, placebo-controlled, double-blind, three-way, crossover study nine healthy subjects received either Intralipid (Pharmacia and Upjohn, Vienna, Austria) with heparin, Intralipid alone or placebo control. Pulsatile choroidal blood flow was measured with laser interferometry, retinal blood flow and retinal red blood cell velocity with laser Doppler velocimetry, and skin blood flow with laser Doppler flowmetry during an euglycaemic insulin clamp. RESULTS: A sevenfold increase of FFA during Intralipid/heparin infusion was paralleled by enhanced choriodal, retinal, and skin blood flow by 17 +/- 4%, 26 +/- 5% (P < 0.001), and 47 +/- 19% (P = 0.03) from baseline, respectively. In contrast, a mere threefold increase of FFA by infusion of Intralipid alone did not affect outcome parameters, despite the presence of plasma TG levels of 250-700 mg dL(-1); similar to those obtained during combined Intralipid/heparin infusion. Systemic haemodynamics were not affected by drug infusion. CONCLUSIONS: Present findings demonstrate a concentration-dependent increase in ocular and skin blood flow by FFA independently of elevated TG plasma concentrations. As vasodilation of resistance vessels occur rapidly, FFA may play a role in the development of continued regional hyperperfusion and deteriorate microvascular function.