Gene silencing and a novel monoallelic expression pattern in distinct CD177 neutrophil subsets

CD177 presents antigens in allo- and autoimmune diseases on the neutrophil surface. Individuals can be either CD177-deficient or harbor distinct CD177(neg) and CD177(pos) neutrophil subsets. We studied mechanisms controlling subset-restricted CD177 expression in bimodal individuals. CD177(pos), but not CD177(neg) neutrophils, produced CD177 protein and mRNA. Haplotype analysis indicated a unique monoallelic CD177 expression pattern, where the offspring stably transcribed either the maternal or paternal allele. Hematopoietic stem cells expressed both CD177 alleles and silenced one copy during neutrophil differentiation. ChIP and reporter assays in HeLa cells with monoallelic CD177 expression showed that methylation reduced reporter activity, whereas demethylation caused biallelic CD177 expression. HeLa cell transfection with c-Jun and c-Fos increased CD177 mRNA. Importantly, CD177(pos) human neutrophils, but not CD177(neg) neutrophils, showed a euchromatic CD177 promoter, unmethylated CpGs, and c-Jun and c-Fos binding. We describe epigenetic mechanisms explaining the two distinct CD177 neutrophil subsets and a novel monoallelic CD177 expression pattern that does not follow classical random monoallelic expression or imprinting

Light-chain-induced renal tubular acidosis: effect of sodium bicarbonate on sodium-proton exchange

We measured sodium-proton (Na+/H+) exchange in lymphocytes and platelets of a 46-year-old woman with the adult Fanconi syndrome before, during, and after treatment with NaHCO3. Kappa light chains in her urine and unique but rarely observed crystalline structures confirmed the presence of light-chain nephropathy. Her glomerular filtration rate was only moderately impaired at 72 ml/min. NaHCO3 at 1, 3, and 5 mmol/kg/day for 5 days increased her serum HCO3 and pH from 17 to 21 mmol/l and 7.28 to 7.39 respectively. Plasma renin and aldosterone values were decreased by NaHCO3. Na+/H+ exchange (δHi/min) was measured with the fluorescent marker BCECF after acidification of lymphocytes and platelets with sodium propionate at five (10-50mM) doses. Na+/H+ exchange was accelerated in this patient compared to normal controls. NaHCO3 treatment significantly decreased Na+/H+ exchange in lymphocytes, but not in platelets. These findings suggest that Na+/H+ exchange can be influenced by NaHCO3 ingestion at doses that only modestly affect systemic pH. Since Na+/H+ exchange is involved in stimulus response coupling, cell growth regulation, cell differentiation, and perhaps the progression of nephrosclerosis, these observations may have clinical relevanc

Targeting kidney mesangium by nanoparticles of defined size

Nanoparticles are being investigated for numerous medical applications and are showing potential as an emerging class of carriers for drug delivery. Investigations on how the physicochemical properties (e.g., size, surface charge, shape, and density of targeting ligands) of nanoparticles enable their ability to overcome biological barriers and reach designated cellular destinations in sufficient amounts to elicit biological efficacy are of interest. Despite proven success in nanoparticle accumulation at cellular locations and occurrence of downstream therapeutic effects (e.g., target gene inhibition) in a selected few organs such as tumor and liver, reports on effective delivery of engineered nanoparticles to other organs still remain scarce. Here, we show that nanoparticles of ~75 ± 25-nm diameters target the mesangium of the kidney. These data show the effects of particle diameter on targeting the mesangium of the kidney. Because many diseases originate from this area of the kidney, our findings establish design criteria for constructing nanoparticle-based therapeutics for targeting diseases that involve the mesangium of the kidney

(23)Na magnetic resonance imaging of the lower leg of acute heart failure patients during diuretic treatment

OBJECTIVE: Na+ can be stored in muscle and skin without commensurate water accumulation. The aim of this study was to assess Na+ and H2O in muscle and skin with MRI in acute heart failure patients before and after diuretic treatment and in a healthy cohort. METHODS: Nine patients (mean age 78 years; range 58-87) and nine age and gender-matched controls were studied. They underwent 23Na/1H-MRI at the calf with a custom-made knee coil. Patients were studied before and after diuretic therapy. 23Na-MRI gray-scale measurements of Na+-phantoms served to quantify Na+-concentrations. A fat-suppressed inversion recovery sequence was used to quantify H2O content. RESULTS: Plasma Na+-levels did not change during therapy. Mean Na+-concentrations in muscle and skin decreased after furosemide therapy (before therapy: 30.7+/-6.4 and 43.5+/-14.5 mmol/L; after therapy: 24.2+/-6.1 and 32.2+/-12.0 mmol/L; p<0.05 and p<0.01). Water content measurements did not differ significantly before and after furosemide therapy in muscle (p = 0.17) and only tended to be reduced in skin (p = 0.06). Na+-concentrations in calf muscle and skin of patients before and after diuretic therapy were significantly higher than in healthy subjects (18.3+/-2.5 and 21.1+/-2.3 mmol/L). CONCLUSIONS: 23Na-MRI shows accumulation of Na+ in muscle and skin in patients with acute heart failure. Diuretic treatment can mobilize this Na+-deposition; however, contrary to expectations, water and Na+-mobilization are poorly correlated

Neural Correlates of Induced Light Experience during Meditation: A Pilot Hyperscanning Study

Certain individuals during deep meditative states can transmitt and give out an aura or ‘light, which is perceived by others through some unknown connections, visual, telepathic or other. Despite various anecdotal, historical accounts of such induced light experience (ILE), its underlying neural mechanism is not known. In this pilot study, we investigated the neural correlates of ILE by simultaneously recording the EEGs of an expert Teacher, who is claimed to elicit ILE, and his Pupil (N=2) during joint sessions under various instructions, given separately to the Teacher (transmit/ do not transmit) and to the Pupil (receive/ do not receive). In a further condition both teacher and pupil wear opaque goggles during transmit/receive instruction, limiting the visual/outputinput. We observed a robust increase in the high frequency beta (12-30 Hz) and gamma oscillations (30-70 Hz) in the Teacher’s brain whenever he was instructed to transmit. Electric field tomography analysis localized these effects over several brain regions including the fusiform gyrus, angular gyrus and the cerebellum. Finally, we found that the Teacher’s and Pupil’s brain responses were synchronized, especially in the alpha band (8-12 Hz) during transmit/receive condition, and the information flow was directional, i.e. from the Teacher to the Pupil; interestingly, this enhanced interbrain synchrony disappeared with opaque goggles. These results were interpreted in terms of heightened internally selective attention as manifested by high frequency beta-gamma oscillations and of joint attention as manifested by interbrain alpha synchrony. Altogether, our results provide the first neuroscientific evidence underlying the phenomenological experience of induced light

Health maintenance insurance: Toward an optimal HMO

The financial incentive structure of today's health maintenance organizations addresses certain problems attributed to fee-for-service medical care, but at a theoretical level it does not induce optimal provider behavior. Health maintenance insurance—a combined package of medical, morbidity/disability, and life insurance—encourages providers to compete for the health dollar, and not simply the medical care dollar, thereby remedying deficiencies in prepayment and promoting true health maintenance. The principle underlying health maintenance insurance emphasizes the need to search for effective means of preventing disability, morbidity, and premature death.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45439/1/11077_2004_Article_BF00136030.pd

Correction to: Characterization of stroke-related upper limb motor impairments across various upper limb activities by use of kinematic core set measures

BACKGROUND Upper limb kinematic assessments provide quantifiable information on qualitative movement behavior and limitations after stroke. A comprehensive characterization of spatiotemporal kinematics of stroke subjects during upper limb daily living activities is lacking. Herein, kinematic expressions were investigated with respect to different movement types and impairment levels for the entire task as well as for motion subphases. METHOD Chronic stroke subjects with upper limb movement impairments and healthy subjects performed a set of daily living activities including gesture and grasp movements. Kinematic measures of trunk displacement, shoulder flexion/extension, shoulder abduction/adduction, elbow flexion/extension, forearm pronation/supination, wrist flexion/extension, movement time, hand peak velocity, number of velocity peaks (NVP), and spectral arc length (SPARC) were extracted for the whole movement as well as the subphases of reaching distally and proximally. The effects of the factors gesture versus grasp movements, and the impairment level on the kinematics of the whole task were tested. Similarities considering the metrics expressions and relations were investigated for the subphases of reaching proximally and distally between tasks and subgroups. RESULTS Data of 26 stroke and 5 healthy subjects were included. Gesture and grasp movements were differently expressed across subjects. Gestures were performed with larger shoulder motions besides higher peak velocity. Grasp movements were expressed by larger trunk, forearm, and wrist motions. Trunk displacement, movement time, and NVP increased and shoulder flexion/extension decreased significantly with increased impairment level. Across tasks, phases of reaching distally were comparable in terms of trunk displacement, shoulder motions and peak velocity, while reaching proximally showed comparable expressions in trunk motions. Consistent metric relations during reaching distally were found between shoulder flexion/extension, elbow flexion/extension, peak velocity, and between movement time, NVP, and SPARC. Reaching proximally revealed reproducible correlations between forearm pronation/supination and wrist flexion/extension, movement time and NVP. CONCLUSION Spatiotemporal differences between gestures versus grasp movements and between different impairment levels were confirmed. The consistencies of metric expressions during movement subphases across tasks can be useful for linking kinematic assessment standards and daily living measures in future research and performing task and study comparisons. TRIAL REGISTRATION ClinicalTrials.gov Identifier NCT03135093. Registered 26 April 2017, https://clinicaltrials.gov/ct2/show/NCT03135093

Characterization of stroke-related upper limb motor impairments across various upper limb activities by use of kinematic core set measures

BACKGROUND Upper limb kinematic assessments provide quantifiable information on qualitative movement behavior and limitations after stroke. A comprehensive characterization of spatiotemporal kinematics of stroke subjects during upper limb daily living activities is lacking. Herein, kinematic expressions were investigated with respect to different movement types and impairment levels for the entire task as well as for motion subphases. METHOD Chronic stroke subjects with upper limb movement impairments and healthy subjects performed a set of daily living activities including gesture and grasp movements. Kinematic measures of trunk displacement, shoulder flexion/extension, shoulder abduction/adduction, elbow flexion/extension, forearm pronation/supination, wrist flexion/extension, movement time, hand peak velocity, number of velocity peaks (NVP), and spectral arc length (SPARC) were extracted for the whole movement as well as the subphases of reaching distally and proximally. The effects of the factors gesture versus grasp movements, and the impairment level on the kinematics of the whole task were tested. Similarities considering the metrics expressions and relations were investigated for the subphases of reaching proximally and distally between tasks and subgroups. RESULTS Data of 26 stroke and 5 healthy subjects were included. Gesture and grasp movements were differently expressed across subjects. Gestures were performed with larger shoulder motions besides higher peak velocity. Grasp movements were expressed by larger trunk, forearm, and wrist motions. Trunk displacement, movement time, and NVP increased and shoulder flexion/extension decreased significantly with increased impairment level. Across tasks, phases of reaching distally were comparable in terms of trunk displacement, shoulder motions and peak velocity, while reaching proximally showed comparable expressions in trunk motions. Consistent metric relations during reaching distally were found between shoulder flexion/extension, elbow flexion/extension, peak velocity, and between movement time, NVP, and SPARC. Reaching proximally revealed reproducible correlations between forearm pronation/supination and wrist flexion/extension, movement time and NVP. CONCLUSION Spatiotemporal differences between gestures versus grasp movements and between different impairment levels were confirmed. The consistencies of metric expressions during movement subphases across tasks can be useful for linking kinematic assessment standards and daily living measures in future research and performing task and study comparisons. TRIAL REGISTRATION ClinicalTrials.gov Identifier NCT03135093. Registered 26 April 2017, https://clinicaltrials.gov/ct2/show/NCT03135093

How to return to subjectivity? Natorp, Husserl, and Lacan on the limits of reflection

This article discusses the recent call within contemporary phenomenology to return to subjectivity in response to certain limitations of naturalistic explanations of the mind. The meaning and feasibility of this call is elaborated by connecting it to a classical issue within the phenomenological tradition concerning the possibility of investigating the first-person perspective through reflection. We will discuss how this methodological question is respectively treated and reconfigured in the works of Natorp, Husserl, and Lacan. Finally, we will lay out some possible consequences of such a cross-reading for the conception of subjectivity and the concomitant effort to account for this dimension of first-person experience in response and in addition to its omission within the standard third-person perspective of psychological research

The changing nature of risk and risk management: the challenge of borders, uncertainty and resilience

No abstract available