Machine learning enabled multiple illumination quantitative optoacoustic oximetry imaging in humans.

Optoacoustic (OA) imaging is a promising modality for quantifying blood oxygen saturation (sO2) in various biomedical applications - in diagnosis, monitoring of organ function, or even tumor treatment planning. We present an accurate and practically feasible real-time capable method for quantitative imaging of sO2 based on combining multispectral (MS) and multiple illumination (MI) OA imaging with learned spectral decoloring (LSD). For this purpose we developed a hybrid real-time MI MS OA imaging setup with ultrasound (US) imaging capability; we trained gradient boosting machines on MI spectrally colored absorbed energy spectra generated by generic Monte Carlo simulations and used the trained models to estimate sO2 on real OA measurements. We validated MI-LSD in silico and on in vivo image sequences of radial arteries and accompanying veins of five healthy human volunteers. We compared the performance of the method to prior LSD work and conventional linear unmixing. MI-LSD provided highly accurate results in silico and consistently plausible results in vivo. This preliminary study shows a potentially high applicability of quantitative OA oximetry imaging, using our method

Na(V)1.5 sodium channel window currents contribute to spontaneous firing in olfactory sensory neurons

Olfactory sensory neurons (OSNs) fire spontaneously as well as in response to odor; both forms of firing are physiologically important. We studied voltage-gated Na+ channels in OSNs to assess their role in spontaneous activity. Whole cell patch-clamp recordings from OSNs demonstrated both tetrodotoxin-sensitive and tetrodotoxin-resistant components of Na+ current. RT-PCR showed mRNAs for five of the nine different Na+ channel α-subunits in olfactory tissue; only one was tetrodotoxin resistant, the so-called cardiac subtype NaV1.5. Immunohistochemical analysis indicated that NaV1.5 is present in the apical knob of OSN dendrites but not in the axon. The NaV1.5 channels in OSNs exhibited two important features: 1) a half-inactivation potential near −100 mV, well below the resting potential, and 2) a window current centered near the resting potential. The negative half-inactivation potential renders most NaV1.5 channels in OSNs inactivated at the resting potential, while the window current indicates that the minor fraction of noninactivated NaV1.5 channels have a small probability of opening spontaneously at the resting potential. When the tetrodotoxin-sensitive Na+ channels were blocked by nanomolar tetrodotoxin at the resting potential, spontaneous firing was suppressed as expected. Furthermore, selectively blocking NaV1.5 channels with Zn2+ in the absence of tetrodotoxin also suppressed spontaneous firing, indicating that NaV1.5 channels are required for spontaneous activity despite resting inactivation. We propose that window currents produced by noninactivated NaV1.5 channels are one source of the generator potentials that trigger spontaneous firing, while the upstroke and propagation of action potentials in OSNs are borne by the tetrodotoxin-sensitive Na+ channel subtypes.This work was aided by support from Boston University, the Rocky Mountain Taste and Smell Center Core for Cellular Visualization and Analysis [National Institute on Deafness and Other Communication Disorders (NIDCD) P30 DC-04657; D. Restrepo, principal investigator], and NIDCD Grants DC-04863 to V. Dionne and DC-006070 to D. Restrepo and T. E. Finger. (Boston University; P30 DC-04657 - Rocky Mountain Taste and Smell Center Core for Cellular Visualization and Analysis [National Institute on Deafness and Other Communication Disorders (NIDCD)]; DC-04863 - Rocky Mountain Taste and Smell Center Core for Cellular Visualization and Analysis [National Institute on Deafness and Other Communication Disorders (NIDCD)]; DC-006070 - Rocky Mountain Taste and Smell Center Core for Cellular Visualization and Analysis [National Institute on Deafness and Other Communication Disorders (NIDCD)])https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122723/Accepted manuscrip

Subdermal solar energy harvesting – A new way to power autonomous electric implants

Subdermal solar harvesting has the potential to obviate the need for the periodic battery replacements as required in patients with cardiac pacemakers. The achievable power output of the subdermal solar module depends on implantation depth, optical skin properties and to an important part on solar cell characteristics. Monte Carlo simulations of light distribution in human skin were used to estimate the power output of subdermal solar cells under midday sunlight exposure in geographical mid-latitudes as a function of implantation depth and solar panel size. For the darkest skin type, the daily energy demand of a modern cardiac pacemaker (0.864 J at a power demand of 10 uW) can be provided by a 2 cm2 solar cell implanted subdermally at a depth of 3 mm when exposed to just 11 min of midday, clear sky irradiance. Our study reveals that solar harvesting with relatively small solar cells if optimized for the spectral subdermal fluence has the potential to power cardiac pacemakers in all skin types within reasonable irradiation exposure times. Solar energy harvesting is very promising to power electronic implants

Pulse-echo speed-of-sound imaging using convex probes.

Computed ultrasound tomography in echo mode (CUTE) is a new ultrasound (US)-based medical imaging modality with promise for diagnosing various types of disease based on the tissue's speed of sound (SoS). It is developed for conventional pulse-echo US using handheld probes and can thus be implemented in state-of-the-art medical US systems. One promising application is the quantification of the liver fat fraction in fatty liver disease. So far, CUTE was using linear array probes where the imaging depth is comparable to the aperture size. For liver imaging, however, convex probes are preferred since they provide a larger penetration depth and a wider view angle allowing to capture a large area of the liver. With the goal of liver imaging in mind, we adapt CUTE to convex probes, with a special focus on discussing strategies that make use of the convex geometry in order to make our implementation computationally efficient. We then demonstrate in an abdominal imaging phantom that accurate quantitative SoS using convex probes is feasible, in spite of the smaller aperture size in relation to the image area compared to linear arrays. A preliminary in vivo result of liver imaging confirms this outcome, but also indicates that deep quantitative imaging in the real liver can be more challenging, probably due to the increased complexity of the tissue compared to phantoms

Impaired Glucose Tolerance in Sleep Disorders

BACKGROUND: Recent epidemiological and experimental data suggest a negative influence of shortened or disturbed night sleep on glucose tolerance. Due to the high prevalence of sleep disorders this might be a major health issue. However, no comparative studies of carbohydrate metabolism have been conducted in clinical sleep disorders. METHODOLOGY/PRINCIPAL FINDINGS: We performed oral glucose tolerance tests (OGTT) and assessed additional parameters of carbohydrate metabolism in patients suffering from obstructive sleep apnea syndrome (OSAS, N = 25), restless legs syndrome (RLS, N = 18) or primary insomnia (N = 21), and in healthy controls (N = 33). Compared to controls, increased rates of impaired glucose tolerance were found in OSAS (OR: 4.9) and RLS (OR: 4.7) patients, but not in primary insomnia patients (OR: 1.6). In addition, HbA1c values were significantly increased in the same two patient groups. Significant positive correlations were found between 2-h plasma glucose values measured during the OGTT and the apnea-arousal-index in OSAS (r = 0.56; p<0.05) and the periodic leg movement-arousal-index in RLS (r = 0.56, p<0.05), respectively. Sleep duration and other quantitative aspects of sleep were similar between patient groups. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that some, but not all sleep disorders considerably compromise glucose metabolism. Repeated arousals during sleep might be a pivotal causative factor deserving further experimental investigations to reveal potential novel targets for the prevention of metabolic diseases

Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia

Acute myeloid leukemia (AML) is an attractive entity for the development of chimeric antigen receptor (CAR) T-cell immunotherapy because AML blasts are susceptible to T-cell–mediated elimination. Here, we introduce sialic acid–binding immunoglobulin-like lectin 6 (Siglec-6) as a novel target for CAR T cells in AML. We designed a Siglec-6–specific CAR with a targeting domain derived from the human monoclonal antibody JML-1. We found that Siglec-6 is commonly expressed on AML cell lines and primary AML blasts, including the subpopulation of AML stem cells. Treatment with Siglec-6 CAR T cells confers specific antileukemia reactivity that correlates with Siglec-6 expression in preclinical models, including induction of complete remission in a xenograft AML model in immunodeficient mice (NSG/U937). In addition, we confirmed Siglec-6 expression on transformed B cells in chronic lymphocytic leukemia (CLL), and specific anti-CLL reactivity of Siglec-6 CAR T cells in vitro. Of particular interest, we found that Siglec-6 is not detectable on normal hematopoietic stem and progenitor cells (HSPCs) and that treatment with Siglec-6 CAR T cells does not affect their viability and lineage differentiation in colony-formation assays. These data suggest that Siglec-6 CAR T-cell therapy may be used to effectively treat AML without the need for subsequent allogeneic hematopoietic stem cell transplantation. In mature normal hematopoietic cells, we detected Siglec-6 in a proportion of memory (and naïve) B cells and basophilic granulocytes, suggesting the potential for limited on-target/off-tumor reactivity. The lack of expression of Siglec-6 on normal HSPCs is a key to differentiating it from other Siglec family members (eg, Siglec-3 [CD33]) and other CAR target antigens (eg, CD123) that are under investigation in AML, and it warrants the clinical investigation of Siglec-6 CAR T-cell therapy