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

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

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

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

Early Results From GLASS-JWST. XVII: Building the First Galaxies -- Chapter 1. Star Formation Histories at 5<z < 7

JWST observations of high redshift galaxies are used to measure their star formation histories - the buildup of stellar mass in the earliest galaxies. Here we use a novel analysis program, SEDz*, to compare near-IR spectral energy distributions for galaxies with redshifts 5 < z < 7 to combinations of stellar population templates evolved from z = 12. We exploit NIRCam imaging in 7 wide bands covering 1-5 mu m, taken in the context of the GLASS-JWST-ERS program, and use SEDz* to solve for well-constrained star formation histories for 24 exemplary galaxies. In this first look we find a variety of histories, from long, continuous star formation over 5 < z < 12 to short but intense starbursts - sometimes repeating, and, most commonly, contiguous mass buildup lasting ~ 0.5 Myr,possibly the seeds of today's typical, M* galaxies.Comment: ApJL in press (accepted on October 30, 2022

Differential kinetic profiles and metabolism of primaquine enantiomers by human hepatocytes

BACKGROUND: The clinical utility of primaquine (PQ), used as a racemic mixture of two enantiomers, is limited due to metabolism-linked hemolytic toxicity in individuals with genetic deficiency in glucose-6-phosphate dehydrogenase. The current study investigated differential metabolism of PQ enantiomers in light of the suggestions that toxicity and efficacy might be largely enantioselective. METHODS: Stable isotope (13)C-labelled primaquine and its two enantiomers (+)-PQ, (−)-PQ were separately incubated with cryopreserved human hepatocytes. Time-tracked substrate depletion and metabolite production were monitored via UHPLC–MS/MS. RESULTS: The initial half-life of 217 and 65 min; elimination rate constants (λ) of 0.19 and 0.64 h(−1); intrinsic clearance (Cl(int)) of 2.55 and 8.49 (µL/min)/million cells, which when up-scaled yielded Cl(int) of 6.49 and 21.6 (mL/min)/kg body mass was obtained respectively for (+)- and (−)-PQ. The extrapolation of in vitro intrinsic clearance to in vivo human hepatic blood clearance, performed using the well-stirred liver model, showed that the rate of hepatic clearance of (+)-PQ was only 45 % that of (−)-PQ. Two major primary routes of metabolism were observed—oxidative deamination of the terminal amine and hydroxylations on the quinoline moiety of PQ. The major deaminated metabolite, carboxyprimaquine (CPQ) was preferentially generated from the (−)-PQ. Other deaminated metabolites including PQ terminal alcohol (m/z 261), a cyclized side chain derivative from the aldehyde (m/z 241), cyclized carboxylic acid derivative (m/z 257), a quinone-imine product of hydroxylated CPQ (m/z 289), CPQ glucuronide (m/z 451) and the glucuronide of PQ alcohol (m/z 437) were all preferentially generated from the (−)-PQ. The major quinoline oxidation product (m/z 274) was preferentially generated from (+)-PQ. In addition to the products of the two metabolic pathways, two other major metabolites were observed: a prominent glycosylated conjugate of PQ on the terminal amine (m/z 422), peaking by 30 min and preferentially generated by (+)-PQ; and the carbamoyl glucuronide of PQ (m/z 480) exclusively generated from (+)-PQ. CONCLUSION: Metabolism of PQ showed enantioselectivity. These findings may provide important information in establishing clinical differences in PQ enantiomers

Impact of age at type 2 diabetes mellitus diagnosis on mortality and vascular complications: systematic review and meta-analyses

AIMS/HYPOTHESIS: Few studies examine the association between age at diagnosis and subsequent complications from type 2 diabetes. This paper aims to summarise the risk of mortality, macrovascular complications and microvascular complications associated with age at diagnosis of type 2 diabetes. METHODS: Data were sourced from MEDLINE and All EBM (Evidence Based Medicine) databases from inception to July 2018. Observational studies, investigating the effect of age at diabetes diagnosis on macrovascular and microvascular diabetes complications in adults with type 2 diabetes were selected according to pre-specified criteria. Two investigators independently extracted data and evaluated all studies. If data were not reported in a comparable format, data were obtained from authors, presented as minimally adjusted ORs (and 95% CIs) per 1 year increase in age at diabetes diagnosis, adjusted for current age for each outcome of interest. The study protocol was recorded with PROSPERO International Prospective Register of Systematic Reviews (CRD42016043593). RESULTS: Data from 26 observational studies comprising 1,325,493 individuals from 30 countries were included. Random-effects meta-analyses with inverse variance weighting were used to obtain the pooled ORs. Age at diabetes diagnosis was inversely associated with risk of all-cause mortality and macrovascular and microvascular disease (all p < 0.001). Each 1 year increase in age at diabetes diagnosis was associated with a 4%, 3% and 5% decreased risk of all-cause mortality, macrovascular disease and microvascular disease, respectively, adjusted for current age. The effects were consistent for the individual components of the composite outcomes (all p < 0.001). CONCLUSIONS/INTERPRETATION: Younger, rather than older, age at diabetes diagnosis was associated with higher risk of mortality and vascular disease. Early and sustained interventions to delay type 2 diabetes onset and improve blood glucose levels and cardiovascular risk profiles of those already diagnosed are essential to reduce morbidity and mortality. Graphical abstract

Early results from GLASS-JWST XV: properties of the faintest red sources in the NIRCAM deep fields

We present a first look at the reddest 2-5$\mu\rm m$ sources found in deep images from the GLASS Early Release Science program. We undertake a general search, i.e. not looking for any particular spectral signatures, for sources detected only in bands redder than reachable with the Hubble Space Telescope, and which would likely not have been identified in pre-JWST surveys. We search for sources down to AB $\sim 27$ (corresponding to $>10\sigma$ detection threshold) in any of the F200W to F444W filters,with a $>1$ magnitude excess relative to F090W to F150W bands. Fainter than F444W$>25$ we find 56 such sources of which 37 have reasonably constrained spectral energy distributions to which we can fit photometric redshifts. We find the majority of this population ($\sim$ 65%) as $2<z<6$ star forming low-attenuation galaxies that are faint at rest-frame ultraviolet-optical wavelengths, have stellar masses $10^{8.5}$-$10^{9.5}$M$_\odot$, and have observed fluxes at $>$2$\mu \rm m$ boosted by a combination of the Balmer break and emission lines. The typical implied rest equivalent widths are \sim200\unicode{0x212B} with some extreme objects up to \sim 1000\unicode{0x212B}. This is in contrast with brighter magnitudes where the red sources tend to be $z<3$ quiescent galaxies and dusty star forming objects. Our general selection criteria for red sources allow us to independently identify other phenomena as diverse as extremely low mass ($\sim 10^8$ M$_\odot$) quiescent galaxies at $z<1$, recover recently identified $z>11$ galaxies and a very cool brown dwarf.Comment: Accepted for publication in Astrophysical Journal Letters. 11 pages, 3 figures. Updated with post-flight JWST NIRCAM calibrations leading to significantly revised conclusions. V1 should be discounte

Мониторинг воспроизводства и влияния фекального прогестерона на репродуктивную цикличность циклов самбарского оленя Шри-Ланки (Rusa unicolor unicolor)

Sambar deer hinds, estrus, progesterone, estrous cycle, Sri LankaThis study examines the length of the estrous cycle in 16 Sambar deer hinds in National zoological gardens in Dehiwala and Kegalle, Sri Lanka (NZGDK) assessed with the use of changes in progesterone concentrations, along with the changes in the profile of this hormone and by the visual estrus manifestations. The objectives of the present study were to characterize ovarian activity throughout the estrous cycle and the non-pregnant luteal phase of captive sambar deer in Sri Lanka. These objectives were achieved with the use of radioimmunoassay (RIA) to measure fecal concentrations of progesterone and visual estrus manifestation. Fecal samples were collected from non-pregnant sambar deer hinds (aged 2–4 years)over the period of six months on daily basis, both during breeding and non-breeding seasons. Estrous cycles were recorded in non-pregnant females, based on fecal progesterone concentrations. The average estrous cycle length was 26.1±2.08 days (mean ± SEM) and 2.10 ± 0.51 days in the inter-luteal phase.The average fecal progesterone concentrations attained the peak mid-luteal values of 2.74 ng mL–1. There appeared to be variation in fecal progesterone amplitude between animals and between dates, but the low frequency of sampling prohibited confirmation of trends. Behavioral estrus was detected only when the average progesterone concentrations were less than 0.07 ng mL–1. However, not all periods of depressed progesterone secretion were associated with the observed estrus. Behavioral estrus was detected in hinds when progesterone concentrations were less than 0.07 ng mL–1; a subsequent rise in progesterone indicated ovulation taking place at this time