A Variable Stiffness Robotic Probe for Soft Tissue Palpation

During abdominal palpation diagnosis, a medical practitioner would change the stiffness of their fingers in order to improve the detection of hard nodules or abnormalities in soft tissue to maximize the haptic information gain via tendons. Our recent experiments using a controllable stiffness robotic probe representing a human finger also confirmed that such stiffness control in the finger can enhance the accuracy of detecting hard nodules in soft tissue. However, the limited range of stiffness achieved by the antagonistic springs variable stiffness joint subject to size constraints made it unsuitable for a wide range of physical examination scenarios spanning from breast to abdominal examination. In this letter, we present a new robotic probe based on a variable lever mechanism able to achieve stiffness ranging from 0.64 to 1.06 N ⋅m/rad that extends the maximum stiffness by around 16 times and the stiffness range by 33 times. This letter presents the mechanical model of the novel probe, the finite element simulation as well as experimental characterization of the stiffness response for lever actuation

Conditioned haptic perception for 3D localization of nodules in soft tissue palpation with a variable stiffness probe

This paper provides a solution for fast haptic information gain during soft tissue palpation using a Variable Lever Mechanism (VLM) probe. More specifically, we investigate the impact of stiffness variation of the probe to condition likelihood functions of the kinesthetic force and tactile sensors measurements during a palpation task for two sweeping directions. Using knowledge obtained from past probing trials or Finite Element (FE) simulations, we implemented this likelihood conditioning in an autonomous palpation control strategy. Based on a recursive Bayesian inferencing framework, this new control strategy adapts the sweeping direction and the stiffness of the probe to detect abnormal stiff inclusions in soft tissues. This original control strategy for compliant palpation probes shows a sub-millimeter accuracy for the 3D localization of the nodules in a soft tissue phantom as well as a 100% reliability detecting the existence of nodules in a soft phantom

Enantioselective interactions of anti-infective 8-aminoquinoline therapeutics with human monoamine oxidases a and b

8-Aminoquinolines (8-AQs) are an important class of anti-infective therapeutics. The monoamine oxidases (MAOs) play a key role in metabolism of 8-AQs. A major role for MAO-A in metabolism of primaquine (PQ), the prototypical 8-AQ antimalarial, has been demonstrated. These investigations were further extended to characterize the enantioselective interactions of PQ and NPC1161 (8-[(4-amino-1-methylbutyl) amino]-5-[3, 4-dichlorophenoxy]-6-methoxy-4-methylquinoline) with human MAO-A and-B. NPC1161B, the (R)-(−) enantiomer with outstanding potential for malaria radical cure, treatment of visceral leishmaniasis and pneumocystis pneumonia infections is poised for clinical development. PQ showed moderate inhibition of human MAO-A and-B. Racemic PQ and (R)-(−)-PQ both showed marginally greater (1.2-and 1.6-fold, respectively) inhibition of MAO-A as compared to MAO-B. However, (S)-(+)-PQ showed a reverse selectivity with greater inhibition of MAO-B than MAO-A. Racemic NPC1161 was a strong inhibitor of MAOs with 3.7-fold selectivity against MAO-B compared to MAO-A. The (S)-(+) enantiomer (NPC1161A) was a better inhibitor of MAO-A and-B compared to the (R)-(−) enantiomer (NPC1161B), with more than 10-fold selectivity for inhibition of MAO-B over MAO-A. The enantioselective interaction of NPC1161 and strong binding of NPC1161A with MAO-B was further confirmed by enzyme-inhibitor binding and computational docking analyses. Differential interactions of PQ and NPC1161 enantiomers with human MAOs may contribute to the enantioselective pharmacodynamics and toxicity of anti-infective 8-AQs therapeutics

An Abdominal Phantom with Tunable Stiffness Nodules and Force Sensing Capability for Palpation Training

Robotic phantoms enable advanced physical examination training before using human patients. In this paper, we present an abdominal phantom for palpation training with controllable stiffness liver nodules that can also sense palpation forces. The coupled sensing and actuation approach is achieved by pneumatic control of positive-granular jammed nodules for tunable stiffness. Soft sensing is done using the variation of internal pressure of the nodules under external forces. This paper makes original contributions to extend the linear region of the neo-Hookean characteristic of the mechanical behavior of the nodules by 140% compared to no-jamming conditions and to propose a method using the organ level controllable nodules as sensors to estimate palpation position and force with a root-means-quare error (RMSE) of 4% and 6.5%, respectively. Compared to conventional soft sensors, the method allows the phantom to sense with no interference to the simulated physiological conditions when providing quantified feedback to trainees, and to enable training following current bare-hand examination protocols without the need to wear data gloves to collect data.This work was supported in part by the Engineering and Physical Sciences Research Council (EPSRC) MOTION grant EP/N03211X/2 and EP/N03208X/1, and EPSRC RoboPatient grant EP/T00603X/

Pathway-specific inhibition of primaquine metabolism by chloroquine/quinine

BACKGROUND: There has been some evidence to suggest that the addition of chloroquine (CQ) or quinine (QN) to 8-aminoquinoline (8-AQ) treatment regimens may increase the therapeutic efficacy of the 8-AQ and simultaneously mitigate against its haemolytic toxicity. However, both CQ and QN are considered effective, although perhaps moderate inhibitors of CYP2D6, an enzyme now regarded as necessary for primaquine (PQ) pharmacologic activity. An understanding of the influence of CQ and QN on the metabolism of PQ may shed light on the potential mechanisms of the beneficial interaction. METHODS: Differential metabolism of PQ enantiomers by recombinant human CYP2D6, monoamine oxidase A (MAO), and cryopreserved human hepatocytes in the presence/absence of CQ and QN. RESULTS: Both CQ and QN significantly inhibited the activity of CYP2D6. PQ depletion by MAO and human hepatocytes was not affected significantly by the presence of CQ and QN. CYP2D6-mediated hydroxylation was largely suppressed by both CQ and QN. The formation of the primary deaminated metabolites, including carboxyprimaquine (CPQ) and cyclized side chain derivative from the aldehyde (m/z 241), was not sensitive to the presence of CQ and QN. However, the appearance of the glucuronides of CPQ and PQ alcohol were significantly suppressed. CQ and QN also inhibited the appearance of the m/z 257 metabolite with a similar pattern, suggesting that it may be derived from the CPQ conjugate. The apparent quinone-imine of CPQ (m/z 289) was only partially suppressed by both QN and CQ, but with a differential pattern of inhibition for the two drugs. The m/z 274 (quinone-imine of a ring-hydroxylated PQ metabolite) and m/z 422 (an apparent glucose conjugate of PQ) metabolites in hepatocytes were strongly suppressed by both QN and CQ, perhaps a reflection of the 2D6 inhibition by these drugs. The formation of the carbamoyl glucuronide of PQ (m/z 480) was not affected by CQ/QN. CONCLUSION: The metabolite-specific interactions in the current studies seem at variance with earlier reports of the dependence of PQ on CYP2D6 metabolism, and enhanced PQ anti-malarial activity/reduced toxicity in the presence of CQ/QN. These results suggest a complex picture in which CQ/QN may shift metabolite pathway balances towards a profile that retains efficacy, while reducing the formation or availability of toxic metabolites to erythrocytes. Alternatively, these drugs may alter transport or distribution of PQ metabolites in a fashion that reduces toxicity while maintaining efficacy against the parasite

EQ-5D-3L Derived Population Norms for Health Related Quality of Life in Sri Lanka

Background Health Related Quality of Life (HRQoL) is an important outcome measure in health economic evaluation that guides health resource allocations. Population norms for HRQoL are an essential ingredient in health economics and in the evaluation of population health. The aim of this study was to produce EQ-5D-3L-derived population norms for Sri Lanka. Method A population sample (n =  780) was selected from four districts of Sri Lanka. A stratified cluster sampling approach with probability proportionate to size was employed. Twenty six clusters of 30 participants each were selected; each participant completed the EQ-5D-3L in a face-to-face interview. Utility weights for their EQ-5D-3L health states were assigned using the Sri Lankan EQ-5D-3L algorithm. The population norms are reported by age and socio-economic variables. Results The EQ-5D-3L was completed by 736 people, representing a 94% response rate. Sixty per cent of the sample reported being in full health. The percentage of people responding to any problems in the five EQ-5D-3L dimensions increased with age. The mean EQ-5D-3L weight was 0.85 (SD 0.008; 95%CI 0.84-0.87). The mean EQ-5D-3L weight was significantly associated with age, housing type, disease experience and religiosity. People above 70 years of age were 7.5 times more likely to report mobility problems and 3.7 times more likely to report pain/discomfort than those aged 18-29 years. Those with a tertiary education were five times less likely to report any HRQoL problems than those without a tertiary education. A person living in a shanty was 4.3 more likely to have problems in usual activities than a person living in a single house. Conclusion The population norms in Sri Lanka vary with socio-demographic characteristics. The socioeconomically disadvantaged have a lower HRQoL. The trends of population norms observed in this lower middle income country were generally similar to those previously reported in high income countries

NPC1161B, an 8-aminoquinoline analog, is metabolized in the mosquito and inhibits Plasmodium falciparum oocyst maturation

© 2019 by the authors. The goal of this study was to investigate the potential for a cannabidiol-rich cannabis extract (CRCE) to interact with the most common over-the-counter drug and the major known cause of drug-induced liver injury–acetaminophen (APAP)–in aged female CD-1 mice. Gavaging mice with 116 mg/kg of cannabidiol (CBD) [mouse equivalent dose (MED) of 10 mg/kg of CBD] in CRCE delivered with sesame oil for three consecutive days followed by intraperitoneally (i.p.) acetaminophen (APAP) administration (400 mg/kg) on day 4 resulted in overt toxicity with 37.5% mortality. No mortality was observed in mice treated with 290 mg/kg of CBD+APAP (MED of 25 mg/kg of CBD) or APAP alone. Following CRCE/APAP co-administration, microscopic examination revealed a sinusoidal obstruction syndrome-like liver injury–the severity of which correlated with the degree of alterations in physiological and clinical biochemistry end points. Mechanistically, glutathione depletion and oxidative stress were observed between the APAP-only and co-administration groups, but co-administration resulted in much greater activation of c-Jun N-terminal kinase (JNK). Strikingly, these effects were not observed in mice gavaged with 290 mg/kg CBD in CRCE followed by APAP administration. These findings highlight the potential for CBD/drug interactions, and reveal an interesting paradoxical effect of CBD/APAP-induced hepatotoxicity

Inhibitory Activity of Machaeridiol-Based Novel Anti-MRSA and Anti-VRE Compounds and Their Profiling for Cancer-Related Signaling Pathways

Corresponding author (NCNPR): Premalatha Balachandran, [email protected]://egrove.olemiss.edu/pharm_annual_posters_2022/1002/thumbnail.jp

Formation primaquine-5, 6-orthoquinone, the putative active and toxic metabolite of primaquine via direct oxidation in human erythrocytes

Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics Short precorneal residence time and poor transocular membrane permeability are the major challenges associated with topical ocular drug delivery. In the present research, the efficiency of the electrolyte-triggered sol-to-gel-forming system of natamycin (NT) transfersomes was investigated for enhanced and prolonged ophthalmic delivery. Transfersomes were optimized by varying the molar ratios of phospholipid, sorbitan monostearate (Span) and tocopheryl polyethylene glycol succinate (TPGS). NT transfersome formulations (FNs) prepared with a 1:1 molar ratio of phospholipid-to-Span and low levels of TPGS showed optimal morphometric properties, and were thus selected to fabricate the in situ gelling system. Gellan gum-based (0.3% w/v) FN-loaded formulations (FNGs) immediately formed an in situ gel in the simulated tear fluid, with considerable viscoelastic characteristics. In vitro cytotoxicity in corneal epithelial cells and corneal histology studies demonstrated the ocular safety and cytocom-patibility of these optimized formulations. Transcorneal permeability of NT from these formulations was significantly higher than in the control suspension. Moreover, the ocular disposition studies of NT, from the FNs and FNGs, in New Zealand male albino rabbits demonstrated the superiority of the electrolyte-sensitive FNGs in terms of NT delivery to the ocular tissues

New Determinations of the UV Luminosity Functions from z~9 to z~2 show a remarkable consistency with halo growth and a constant star formation efficiency

Here we provide the most comprehensive determinations of the rest-frame $UV$ LF available to date with HST at z~2, 3, 4, 5, 6, 7, 8, and 9. Essentially all of the non-cluster extragalactic legacy fields are utilized, including the Hubble Ultra Deep Field (HUDF), the Hubble Frontier Field parallel fields, and all five CANDELS fields, for a total survey area of 1136 arcmin^2. Our determinations include galaxies at z~2-3 leveraging the deep HDUV, UVUDF, and ERS WFC3/UVIS observations available over a ~150 arcmin^2 area in the GOODS North and GOODS South regions. All together, our collective samples include >24,000 sources, >2.3x larger than previous selections with HST. 5766, 6332, 7240, 3449, 1066, 601, 246, and 33 sources are identified at z~2, 3, 4, 5, 6, 7, 8, and 9, respectively. Combining our results with an earlier z~10 LF determination by Oesch+2018a, we quantify the evolution of the $UV$ LF. Our results indicate that there is (1) a smooth flattening of the faint-end slope alpha from alpha~-2.4 at z~10 to -1.5 at z~2, (2) minimal evolution in the characteristic luminosity M* at z>~2.5, and (3) a monotonic increase in the normalization log_10 phi* from z~10 to z~2, which can be well described by a simple second-order polynomial, consistent with an "accelerated" evolution scenario. We find that each of these trends (from z~10 to z~2.5 at least) can be readily explained on the basis of the evolution of the halo mass function and a simple constant star formation efficiency model.Comment: 18 pages, 10 figures, 5 tables, in submission to ApJ, figures 9 and 10 show the main resul