[Clinical practise guideline of the special interest group in allergy of the ÖGDV - Drug provocation testing in the diagnosis of cutaneous drug reactions].
Nowadays, clinical and evidence based guidelines are considered one of the major efforts to improve patient care in medical practices as well as hospital settings. In the literature, clinical guidelines have been defined as "systematically developed statements to assist practitioner and patient decisions about appropriate healthcare for specific clinical circumstances", which promote both clinically effective standards and cost-effective care. Despite controversial discussion about the clinical impact of guidelines, they may provide workable recommendations that may thus be important for improving the individual patient's care. Adverse drug reactions (drug allergies, drug hypersensitivities) often represent a major hazard for the affected patient, and a definite diagnosis is important for further drug therapies in most cases. In this context, any diagnostic procedure must be preceded by an individual risk-benefit assessment. Drug provocation testing is regarded as the gold standard, but this kind of testing should be performed in accordance with established criteria and, in the vast majority of cases, in a hospital setting. In this paper we present a clinical guideline for drug provocation testing in Austria.


Damage accrual in Behçet disease: Behçet's Syndrome Overall Damage Index (BODI) versus Behçet's Disease Damage Index (BDI).
To assess the validity of Behçet's Syndrome Overall Damage Index (BODI) and Behçet's Disease Damage Index (BDI) as tools for the detection of damage accrual in Behçet's patients compared to Vasculitis Damage Index (VDI). Also, to evaluate the correlation and the interclass correlation among the 3 indices to find out their consistency. A prospective cohort study was carried out on 102 adult Behçet's disease (BD) patients who were diagnosed according to the International Study Group criteria for BD. Disease severity and organ damage were assessed for each patient by VDI, BDI and BODI at baseline and 1-year follow-up visits. Damage accrual for each index was defined when there was an increase of at least 1 point (∆ ≥ 1) among the baseline and the follow-up visits. Correlations among the 3 indices were significant, with (r = 0.835, P < 0.001) between VDI and BODI, (r = 0.835, P < 0.001) between VDI and BDI, and (r = 0.844, P < 0.001) between BODI and BDI scores. A highly significant positive correlation existed between the 3 indices and age and disease duration. In contrast, the correlation with the BD Current Activity Form was non-significant, which indicates good discriminative validity of the 3 indices. Neuropsychiatric and ocular systems showed a strong interclass correlation among the 3 indices. Regarding detecting damage accrual, BDI was more sensitive than BODI and showed more agreement with VDI. BD damage indices, VDI, BODI and BDI, had good convergent and discriminative validity for the assessment of BD damage. BDI had more sensitivity than BODI to the detection of damage accrual.


The quantitative determination of apolipoprotein A-I (apo-lp-Gln I) in human serum by radial immunodiffusion assay (RID).
A radial immunodiffusion (RID) assay was developed to determine the concentration of the major apolipoprotein (apolipoprotein A-I, apo-lp-Gln I) of human high density lipoproteins (HDL): (1) In a random population sample of apparently healthy persons (104 women, 95 men) aged 40-49 years, serum levels of apo A-I were determined. For both women and men a value of 137 +/- 23 mg/dl was found. (2) Values of 139 +/- 21 mg/dl were found in a group of 31 women taking oral contraceptives, i.e. an insignificant increase in apo A-I level. (3) In two volunteers, apo A-I levels showed no significant variation in a 24-h period.


Increase of placental sensitivity to melatonin and the alteration to its local synthesis in hypertensive syndromes in pregnancy.
To evaluate the relation between hypertensive syndromes and melatonin, and its possible protective role against lesions due to hypertension. Placentas were classified into gestational hypertension (GH), chronic hypertension (CH), pre-eclampsia (PE) and pre-eclampsia superimposed on chronic hypertension, and morphologically examined by hematoxylin-eosin and periodic acid Schiff methods. Immunohistochemistry was performed to detect tryptophan hydroxylase (TH) and melatonin receptor 1A (MR-1A). MR-1A expression was higher in all types of hypertensive syndromes in pregnancy (HSP), mainly in cases with GH, in Caesarean section delivery, preterm placentas and in the cases with alterations in the placental morphology, particularly those presenting inflammation. The expression of TH was higher in cases with CH when compared with the control. This expression was lower in primigestas, in the cases of inflammation and with PE. HSP therapies should be considered and studied, especially in the cases of HSP associated with PE, in which the placenta is more sensitive as it has more receptors, but its synthesis ability is reduced. As for GH and CH, the possible benefits should be evaluated, since the local placental ability to produce melatonin still exists.


Phytotoxicity and mammalian cytotoxicity of macrocyclic trichothecene mycotoxins from Myrothecium verrucaria.
Macrocyclic trichothecene toxins produced by Myrothecium verrucaria (a phytopathogen of interest in biological weed control) and the non-trichothecene toxin atranone B from Stachybotiys atra were tested for phytotoxicity in duckweed (Lemna pausicostata L.) plantlet cultures and kudzu (Pueraria lobata L.) leaf disc assays, and for mammalian cytotoxicity in four cultured cell lines. Roridin E and H, epi-isororidin E, and verrucarin A and J were phytotoxic (half-maximal effect in the concentration range 0.1-9.7 microM on duckweed and 1.5->80 microM on kudzu) and cytotoxic to mammalian cell lines (half-maximal inhibition of proliferation in the concentration range 1-35 nM). Trichoverrins A and B and atranone B were moderately phytotoxic (half-maximal effect in the concentration range 1 9-69 microM on duckweed and 13->80 microM on kudzu) and weakly cytotoxic with mammalian cell lines (half-maximal inhibition of proliferation in the concentration range 0.3->2 microM).


Implementation of neonatal phototherapy with the BiliCocoon Bag® device in the maternity ward and impact on mother-infant separation.
Free bilirubin jaundice is a frequent pathology in the neonatal period. The major complication is neurological toxicity, the most severe form of which is kernicterus. Overall, 5%-10% of jaundiced neonates require treatment. The first-line treatment is phototherapy, with intensive phototherapy being the gold standard. Other equipment is also available, including the BiliCocoon Bag®. It is a safe and controlled therapy that can be performed in the mother's room in the maternity ward, thereby avoiding separation and allowing for breast- or bottle-feeding during treatment. It is easy to install and does not require protective glasses, thus no scope or hospitalization. In our maternity ward, all neonates requiring intensive phototherapy are hospitalized in the neonatology ward. The objective of our study was to evaluate the number of avoided hospitalizations in neonatology for free bilirubin jaundice since the introduction, according to a strict protocol, of the BiliCocoon Bag® device. This was a single-center retrospective cohort study using data of newborns usually collected as part of standard care. Children born in our maternity ward during an 18-month period (August 1, 2020 to January 31, 2022) were included. Causes of jaundice, age at the beginning and mode of treatment, number of sessions for each device, and length of stay were compared. Results are presented as number and percentage with median (25th-75th) or mean (extremes) values for categorical and continuous variables, respectively. A t-test was used to compare the means of the independent groups. A total of 316 newborns were included. Physiological jaundice was the main cause of jaundice. The median age for the first phototherapy treatment was 54.5 h (30-68). The 316 neonates needed 438 phototherapy sessions: 235 (74%) neonates required only one phototherapy session, 85 (36%) of them were treated with the BiliCocoon Bag®. For the 81 children who needed two or more phototherapy sessions, 19 children (23.5%) were treated by tunnel phototherapy and then the BiliCocoon Bag®, and eight children (10%) by BiliCocoon Bag® alone. The BiliCocoon Bag® enabled a relative reduction in the hospitalization rate of 38% and avoided hospitalization for approximately one third of the newborns treated. The BiliCocoon Bag® failure rate was 3.6% and the average length of stay was comparable between the two types of treatment. Following a strict protocol of use, the BiliCocoon Bag® is a reliable method and a good alternative to intensive phototherapy for newborns in the maternity ward, as it avoids hospitalization and mother-infant separation.


The effects of exogenous CCK-8 on the acquisition and expression of morphine-induced CPP.
Cholecystokinin octapeptide (CCK-8) is the most potent endogenous anti-opioid peptide and regulates a variety of physiological processes. In our previous study, we found that exogenous CCK-8 attenuated naloxone-induced withdrawal symptoms, but the possible regulative effects of CCK-8 on the rewarding effects of morphine were not examined. In the present study, we aimed to determine the exact effects of exogenous CCK-8 at various doses on the rewarding action of morphine by utilizing the unbiased conditioned place preference (CPP) paradigm. We therefore examined the effects of CCK-8 on the acquisition, expression and extinction of morphine-induced CPP and on locomotor activity. The results showed that CCK-8 (0.01-1μg, i.c.v.), administered alone, induced neither CPP nor place aversion, but blocked the acquisition of CPP when administered with 10mg/kg morphine. The highest dose of CCK-8 (1μg) administered before CPP testing increased CPP and, along with lower doses (0.1μg), reduced its extinction. In addition, the highest dose (1μg) of CCK-8 suppressed locomotor activity. Our study provides the first behavioral evidence for the inhibitory effects of exogenous CCK-8 on rewarding activity and reveals significant effects of exogenous CCK-8 on various stages of place preference and the development of opioid dependence.


Exercise improves motor deficits and alters striatal GFAP expression in a 6-OHDA-induced rat model of Parkinson's disease.
Astrocytic changes have been demonstrated in several neurodegenerative diseases, showing that these cells play an important role in functional recovery/maintenance against brain damage. Physical exercise is known to contribute to this process; however, the cellular mechanisms involved are not fully understood. This study investigated the effects of physical exercise on motor deficits and the expression of glial fibrillary acidic protein (GFAP) in a model of Parkinson's disease (PD). Rats were divided into four groups: sham sedentary (SS) and sham trained (ST); lesioned sedentary (LS) and lesioned trained (LT). 6-OHDA was infused unilaterally into the medial forebrain bundle. Behavioral tasks were applied to evaluate motor abilities. Tyrosine hydroxylase (TH-in substantia nigra) and GFAP (in striatum) immunoreactivities (ir) were semi-quantified using optical density. The animals submitted to treadmill training completed fewer pharmacological-induced rotations when compared with sedentary animals and they also showed ameliorated motor impairments. Interestingly, although no change in TH-ir, the exercise led to restored striatal GFAP expression in the LT group while there was no effect in the ST group. This study is the first study to show data indicating the recovery of GFAP expression post-exercise in this model and further research is necessary to determine the precise action mechanisms of exercise on astrocytes in the PD.


Recovery of distal changes after nerve constriction by a ligature.
When ligatures were used to constrict the proximal tibial nerve in rabbits, nerve fibres distal to the site of constriction underwent a reduction in axonal and external fibre diameter, and in conduction velocity. Distal changes could be detected within 7-12 days of the onset of constriction; removal of the ligatures was followed by partial recovery. When paranodal myelin damage occurred in the distal tibial nerve, it showed the typical non-random distribution of secondary demyelination, with multiple paranodal defects on some fibres and complete sparing of others. These findings emphasize the role of the axon in the genesis of paranodal demyelination.


Nanoscale actuation of electrokinetic flows on thermoreversible surfaces.
We report on a novel approach for controlling nanohydrodynamic properties at the solid-liquid interfaces through the use of stimuli-responding polymer coatings. The end-tethered polymers undergo a phase separation upon external activation. The reversible change in the thickness and polarity of the grafted polymers yields in a dynamic control of the surface-generated, electrokinetic phenomena. Nonactivated, swollen polymers are thicker than the electrical double layer (EDL) and prohibit the development of an EOF even on charged surfaces. On the other hand, activated polymer chains shrink and become thinner than the EDL and allow for the EOF to build up unimpeded. We show here that, for given experimental conditions, the EOF velocity on the shrunken surface is 35 times greater than the one on the nonactivated surface. Furthermore, we reveal that coupling of such surfaces with dense arrays of thermal actuators developed in our laboratory can lead to novel micro- and nanofluidic devices.


Management of idiopathic sleep bruxism in children and adolescents: A systematic review of the literature.
Primary sleep bruxism (SB) affects between 6 and 30% of children and adolescents. Its frequency increases with age, reaching a peak at 10-14 years of age, after which it drops until adulthood. The treatment of SB has not been extensively documented, resulting in a lack of reference points and legitimate concerns for dentists in their everyday practice. The aim of this literature review was to summarize the available evidence on the management of SB in children and adolescents and the efficacy of the different approaches. A systematic literature search was conducted according to PRISMA guidelines from January 2006 to December 2020 using the PubMed, The Cochrane Library, Science Direct, and Google Scholar databases. All types of SB treatment were accepted. Eight studies were selected for their protocol quality, according to the PICOS tool. Several treatment methods were assessed from the eight clinical studies selected, such as occlusal splint, palatal expansion, and pharmacological treatment. Assessment of the treatment methods was difficult because only eight studies were selected, and both the treatment methods and the study protocols used were different. The therapeutic strategies found in the literature were based on the general condition of the case. Treatment approaches were distinguished into treatments for isolated SB and those for SB associated with ventilatory disorders. The current study shows the need to define diagnostic criteria adapted to SB in children in order to improve epidemiological surveys and subsequently clinical practice. To overcome the difficulties related to SB diagnostic criteria, a multidisciplinary approach, involving pediatricians, otorhinolaryngologists, and dental practitioners, is essential for a better management and follow-up of young patients. A case-by-case approach, taking into account the specificities of each young patient, seems the most appropriate management today.


Smooth muscle 22α deficiency impairs oxytocin-induced uterine contractility in mice at full-term pregnancy.
Smooth muscle 22α (SM22α, namely Transgelin), as an actin-binding protein, regulates the contractility of vascular smooth muscle cells (VSMCs) by modulation of the stress fiber formation. However, little is known about the roles of SM22α in the regulation of uterine contraction during parturition. Here, we showed that contraction in response to oxytocin (OT) was significantly decreased in the uterine muscle strips from SM22α knockout (Sm22α-KO) mice, especially at full-term pregnancy, which may be resulted from impaired formation of stress fibers. Furthermore, serious mitochondrial damage such as the mitochondrial swelling, cristae disruption and even disappearance were observed in the myometrium of Sm22α-KO mice at full-term pregnancy, eventually resulting in the collapse of mitochondrial membrane potential and impairment in ATP synthesis. Our data indicate that SM22α is necessary to maintain uterine contractility at delivery in mice, and acts as a novel target for preventive or therapeutic manipulation of uterine atony during parturition.


Referral rate and false-positive rates in a hearing screening program among high-risk newborns.
More studies exploring referral rates and false-positive rates are needed to make hearing screening programs in newborns better and cost-effective. Our aim was to study the referral and false-positivity rates among high-risk newborns in our hearing screening program and to analyze the factors potentially associated with false-positive hearing screening test results. A retrospective cohort study was done among the newborns hospitalized at a university hospital from January 2009 to December 2014 that underwent hearing screening with a two-staged AABR screening protocol. Referral rates and false-positivity rates were calculated and possible risk factors for false-positivity were analyzed. 4512 newborns were screened for hearing loss in the neonatology department. The referral rate for the two-staged AABR-only screening was 3.8% with false-positivity being 2.9%. Our study showed that the higher the birthweight or gestational age of the newborn, the lower the odds of the hearing screening results being false-positive, and the higher the chronological age of the infant at the time of screening, the higher the odds of the results being false-positive. Our study did not show a clear association between the mode of delivery or gender and false-positivity. Among high-risk infants, prematurity and low-birthweight increased the rate of false-positivity in the hearing screening, and the chronological age at the time of the test seems to be significantly associated with false-positivity.


1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads.
1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aβ levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease.


Dissemination of IncF group F1:A2:B20 plasmid-harbouring multidrug-resistant Escherichia coli ST131 before the acquisition of blaCTX-M in Japan.
The Escherichia coli O25-ST131 clone is responsible for global dissemination of the blaCTX-M gene. However, the prevalence of this clone in the digestive tract, devoid of antimicrobial selection, and its molecular epidemiology remain unclear. In this study, we examined the origin of blaCTX-M-positive E. coli O25-ST131 and its distribution. We separately sequenced the chromosomal and plasmid genomes of 50 E. coli O25 isolates obtained from faecal samples of patients with diarrhoea in Japan. Although 36 (72%) of 50 E. coli O25 isolates were ST131, only 6 harboured blaCTX-M. According to the fimH and ybbW sequences and fluoroquinolone susceptibility, H30R1 isolates were dominant (27/36; 75%) and possessed IncFII-FIA-FIB with FAB formula subtype F1:A2:B20 plasmids at a high frequency (24/27; 89%). The F1:A2:B20 plasmids possessed more resistance genes such as blaTEM-1, aminoglycoside resistance genes and trimethoprim/sulfamethoxazole resistance genes compared with non-F1:A2:B20 plasmids. In contrast, only one blaCTX-M-14 gene was located on the F1:A2:B20 plasmids, whereas the other three were located on IncFII (F4:A-:B-) (n = 1) and IncZ (n = 2) plasmids. Two H30Rx-ST131 isolates harboured blaCTX-M-15: one was on the chromosome and the other on the IncFIA-R plasmid. The stability and conjugation ability of the F1:A2:B20 plasmids were compared with those of non-F1:A2:B20 plasmids, which revealed higher stability but lower conjugative ability. These results suggest that E. coli H30R1-ST131 is a multidrug-resistant clone containing several resistance genes in the F1:A2:B20 plasmid, which were widely distributed before the acquisition of blaCTX-M.


Malassezia-derived indoles activate the aryl hydrocarbon receptor and inhibit Toll-like receptor-induced maturation in monocyte-derived dendritic cells.
The aryl hydrocarbon receptor (AhR) is a nuclear receptor and transcriptional regulator with pleiotropic effects. The production of potent AhR ligands by Malassezia yeasts, such as indirubin, indolo[3,2-b]carbazole (ICZ), tryptanthrin and malassezin, has been associated with the pathogenesis of seborrhoeic dermatitis and pityriasis versicolor. Antigen-presenting cells in the skin can encounter microbes in the presence of these bioactive metabolites that could potentially modulate their function. To study the effects of the aforementioned naturally occurring ligands on AhR activation and Toll-like receptor (TLR)-induced maturation in human monocyte-derived dendritic cells (moDCs). These indoles were screened for AhR activation capacity in moDCs employing CYP1A1 and CYP1B1 induction as read out and for their effects on the function of moDCs after TLR-ligand stimulation. Indirubin and ICZ were the most potent AhR ligands and were selected for subsequent experiments. Concurrent exposure of moDCs to indirubin or ICZ together with TLR agonists significantly augmented the AhR-mediated CYP1A1 and CYP1B1 gene expression. Additionally, mature DCs that were subsequently stimulated with AhR ligands showed increased AhR target gene expression. Moreover, these ligands limited TLR-induced phenotypic maturation (CD80, CD83, CD86, MHC II upregulation) of moDCs, reduced secretion of the inflammatory cytokines interleukin (IL)-6 and IL-12, and decreased their ability to induce alloreactive T-lymphocyte proliferation. These results demonstrate that AhR agonists of yeast origin are able to inhibit moDC responses to TLR ligands and that moDCs can adapt through increased transcription of metabolizing enzymes such as CYP1A1 and CYP1B1.


Improved adherence to test, treat, and track (T3) malaria strategy among Over-the-Counter Medicine Sellers (OTCMS) through interventions implemented in selected rural communities of Fanteakwa North district, Ghana.
Prompt diagnosis and treatment of malaria prevents a mild case from developing into severe disease and death. Unfortunately, parasitological testing of febrile children is greater in the public and formal private sector than in the informal private sector where many patients with malaria-like symptoms first seek treatment. This study was aimed at improving implementation of the T3 policy among OTCMS using some interventions that could be scaled-up easily at the national level. Interventions were evaluated using a two-arm, cluster randomized trial across 8 rural communities (4 clusters per arm), in two adjacent districts of Ghana. A total of 7 OTCMS in the intervention arm and 5 OTCMS in the control arm in the selected communities participated in the study. Five interventions were implemented in the intervention arm only. These were acquisition of subsidized malaria rapid diagnostic test (RDT) kits, training of OTCMS, supportive visits to OTCMS, community sensitization on malaria, and introduction of malaria surveillance tool. The primary outcome was the proportion of children under 10 years with fever or suspected to have malaria visiting OTCMS and getting tested (using RDT) before treatment. Secondary outcomes included OTCMS adherence to national malaria treatment guidelines and the recommended RDT retail price. Outcomes were measured using mystery client (an adult who pretends to be a real patient) surveys supplemented by a household survey. Proportions were compared using chi-square test or Fisher exact test. Following deployment of interventions, mystery client survey showed that OTCMS' adherence to malaria protocol in the intervention arm increased significantly (p < 0.05) compared to the control arm. Household surveys in the intervention arm showed that caregivers self-treating their children or visiting drug vendors significantly decreased in favour of visits to OTCMS shops for treatment (p < 0.001). End-line malaria testing rate was higher compared with the baseline rate, though not statistically significant (30.8% vs 10.5%; p = 0.1238). OTCMS in the intervention arm also adhered to the subsidized RDT retail price of GHc2.40. Interventions targeting OTCMS in rural communities have the potential of improving adherence to the T3 malaria policy and subsequently improving management of uncomplicated malaria in Ghana. ISRCTN registry ISRCTN77836926. Registered on 4 November 2019.


Effect of haloperidol, suckling, oxytocin and hand milking on plasma relaxin and prolactin concentrations in cyclic and lactating pigs.
Prolactin secretion was stimulated in 5 cyclic gilts during the luteal phase (Day 10-13) with 5 mg haloperidol given i.v. Stimulation of prolactin secretion was also attempted by inducing milk let-down by suckling (4 sows), or by the injection of 1 mg oxytocin i.v. followed by hand milking (3 sows). Plasma prolactin concentrations increased significantly 1-2 h after haloperidol injection, and in 3 of 4 sows during suckling (P = 0.001); plasma relaxin concentrations did not change significantly at these times. No change was observed in plasma prolactin or relaxin concentrations at 15 min or 1-2 h after oxytocin injection and hand milking. Plasma relaxin concentrations ranged from below the sensitivity of the assay (100 pg/ml) to 450 pg/ml in lactating sows and from 100 to 2000 pg/ml in cyclic gilts. The results suggest that in cyclic gilts treated in the luteal phase with a dopaminergic receptor blocker, and in lactating sows during suckling, elevations in plasma prolactin concentrations were not accompanied, during the same period, by detectable changes in relaxin concentrations.


Amino terminal acetylation and protein synthesis in eukaryotes.
The amino terminal residue in many proteins is N-acetylated. Available evidence indicates that acetylation occurs during translation whilst the nascent polypeptide is still attached to the ribosome; with some proteins, like the actins, an additional acetylation step occurs which may be catalysed by cytoplasmic enzymes. Studies of protein synthesis in heterologous cell-free systems show that the enzymes which catalyse amino terminal acetylation are ubiquitous and such studies have provided insights into the effects of limitations in the supply of acetyl CoA in vitro. Evidence that availability of acetyl groups in vivo may in part determine the cellular concentration of N-acetylated proteins is examined in terms of the relative amounts of the aceylated fraction of foetal haemoglobin and carbonic anhydrase I in human erythrocytes. Tissue and developmental differences in the concentration of the muscle isoenzyme, carbonic anhydrase III, are considered in terms of changes in the activity and distribution of mitochondria in muscle. Finally, the possibility is discussed that differential effects of thyroid hormone on protein concentration might be partly due to an effect of the hormone on acetyl CoA availability via its action on mitochondria.


Use of BRASS in sedated critically-ill patients as a predictable mortality factor: BRASS-ICU.
Objectives: To demonstrate that a BRASS score≥ 3 at admission of intubated, ventilated and sedated patients is predictive of mortalityMethods: we have realized an Observational prospective multicenter study.All Major patients without neurological history, admitted to ICU for a non-neurological cause, sedated and admitted under mechanical ventilation were included.Results: One hundred and ten patients were included, the BRASS score as well as the FOUR and RASS scores were collected.At day 28, patients with a BRASS score ≥ 3 had an excess mortality (OR 3.29 - CI 95% [1.42-7.63], p = 0.005) as well as day 90 (OR 2.65 - CI 95% [1.19-5.88], p = 0.02), without impact on the delirium measured by CAM-ICU (OR 1.8 - CI 95% [0.68-4.77], p = 0.023). After adjustment with SAPS II, FOUR and RASS, difference in mortality was not any more different.It is also noted that patients with BRASS ≥ 3 are more sedated (RASS: -5 [-5 - -5] vs -4 [-5 - -3], p < 0.0001) and more comatose (FOUR: 2 [1-4] vs 6 [4-9], p < 0.0001), and have higher doses of midazolam (10 mg/h [5-15] vs 7.5 mg/h [5-10], p = 0.02) and sufentanil (20 μg/h [15-22.5] vs 10 [10-12.5], p = 0.01).Conclusions: The early alteration of brainstem reflexes measured by the BRASS score was not independently predictable in terms of mortality in the non-neurological ICU patients, admitted under sedation and mechanical ventilation.Trial registration: ClinicalTrials.gov Identifier: NCT03835091,Registered 8 February 2019 - prospectively registered, https://clinicaltrials.gov/ct2/show/NCT03835091.


Platelet-derived growth factor stimulates non-mitochondrial Ca2+ uptake and inhibits mitogen-induced Ca2+ signaling in Swiss 3T3 fibroblasts.
Changes in intracellular free Ca2+ concentration [( Ca2+]i) were used to study the interaction between mitogens in Swiss 3T3 fibroblasts. Platelet-derived growth factor (PDGF) produced an increase in [Ca2+]i and markedly decreased the increases in [Ca2+]i caused by subsequent addition of bradykinin and vasopressin. If the order of the additions was reversed the [Ca2+]i response to PDGF was not inhibited by bradykinin or vasopressin. Inhibition of protein kinase C by staurosporine or chronic treatment of the cells with phorbol 12-myristate 13-acetate prevented the inhibitory effect of PDGF on the [Ca2+]i response to vasopressin but not bradykinin. PDGF did not decrease the receptor binding of bradykinin and produced only a small decrease in the receptor binding of vasopressin. PDGF decreased the rise in [Ca2+]i caused by the Ca2+ ionophores 4-bromo-A23187 and ionomycin and by a membrane perturbing ether lipid, 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine, both in the presence and absence of external Ca2+. There was no change in cell 45Ca2+ influx caused by PDGF, vasopressin, or bradykinin. 45Ca2+ efflux from cells exposed to PDGF and vasopressin mirrored the changes in [Ca2+]i caused by the agents, that is, PDGF added after vasopressin produced a further increase in 45Ca2+ efflux but vasopressin did not increase 45Ca2+ efflux after PDGF. PDGF but not vasopressin caused an increase in the uptake of 45Ca2+ into an inositol 1,4,5-trisphosphate-insensitive non-mitochondrial store in permeabilized cells. The results suggest that the decreased [Ca2+]i response to mitogens after PDGF represents an action of PDGF at a point beyond the release of intracellular Ca2+ and the influx of external Ca2+, caused by an increase in the rate of removal of cytoplasmic free Ca2+. This increased removal of cytoplasmic Ca2+ by PDGF is not due to the increased export of Ca2+ from the cell but results from increased Ca2+ uptake into non-mitochondrial stores.


cis-Diamminedichloroplatinum and 5-fluorouracil are potent inducers of the cytokines and natural killer cell activity in vivo and in vitro.
It has been reported that certain chemotherapeutic agents exhibit effects that enhance the antitumor host responses in the patients with malignant diseases. In the present study, we investigated whether cis-diamminedichloroplatinum (cisplatin) and 5-fluorouracil (5-FU) may induce cytokines and effector cells with antitumor efficacy in vivo and in vitro. The cultivation of human peripheral blood mononuclear cells (PBMC) in the presence of cisplatin (0-1.0 microg/ml) or 5-FU (0-5.0 microg/ml) resulted in the significant augmentation of natural killer (NK) and lymphokine-activated killer (LAK) cell activities as well as generation of interferon (IFN) gamma, tumor necrosis factor (TNF) alpha, beta interleukin(IL)-1beta, IL-6 and IL-12 in vitro. In addition, all of these activities were almost completely neutralized by addition of anti-asialoGM1 antibody and complement (P < 0.05). In an in vivo model, the administration of anti-asialoGM1 antibody significantly shortened the survival time extended by the treatment with cisplatin or 5-FU (P < 0.05), both on nude mice bearing salivary gland tumors and on syngeneic MethA-tumor-bearing BALB/c mice. Furthermore, high levels of NK and LAK activities and significant increases of the numbers of cells positive for asialoGM1, IFNgamma, TNFalpha, or IL-1beta were detected in the spleen cells derived from animals given cisplatin or 5-FU as compared with those given saline (P < 0.001-0.05). These findings clearly indicate that cisplatin and 5-FU are potent inducers of several types of cytokines and effector cells carrying antitumor activity mediated by asialoGM1-positive cells (mainly NK cells) for the most part, and that these abilities are closely associated with the in vivo antitumor effect of these agents.


Long-term patient survival and kidney allograft survival in post-transplant diabetes mellitus: a single-center retrospective study.
A decade ago, observations suggested that post-transplant diabetes mellitus (PTDM) was linked to allograft loss and shorter patient survival. Increasing awareness, improvements in care, and changes in the immunosuppressive regimen may have modified this association. Single-center analysis of 1990 (age>18; transplantation date 1996-2012) primary kidney recipients (KTR). Patients with <12 months follow-up were excluded. Diabetes was diagnosed according to ADA criteria and characterized as follows: No diabetes, PTDM in the first post-transplant year not treated with glucose-lowering medications (GLM) at 12 months, PTDM in the first post-transplant year treated with GLM at 12 months, and pretransplant diabetes. Cox proportional hazards models were used to examine the relationship of PTDM with allograft and patient survival. Mean follow-up time was 6.8 years for allograft survival and 7.4 years for patient survival. PTDM treated with medication at year one was not associated with allograft survival (HR 1.28, 95% CI 0.97-1.69), but was significantly associated with overall mortality and death with functioning graft (DWFG) (HR overall: 1.81, 95% CI 1.36-2.39; HR DWFG: 1.59 95% CI 1.05-2.38). In this cohort, KTR with PTDM being treated with glucose-lowering medication at 12 months experienced significantly shorter overall survival and survival with functioning graft.


Functional network dynamics between the anterior thalamus and the cortex in deep brain stimulation for epilepsy.
Owing to its unique connectivity profile with cortical brain regions, and its suggested role in the subcortical propagation of seizures, the anterior nucleus of the thalamus (ANT) has been proposed as a key deep brain stimulation (DBS) target in drug-resistant epilepsy. However, the spatio-temporal interaction dynamics of this brain structure, and the functional mechanisms underlying ANT DBS in epilepsy remain unknown. Here, we study how the ANT interacts with the neocortex in vivo in humans and provide a detailed neurofunctional characterization of mechanisms underlying the effectiveness of ANT DBS, aiming at defining intraoperative neural biomarkers of responsiveness to therapy, assessed at 6 months post-implantation as the reduction in seizure frequency. A cohort of 15 patients with drug-resistant epilepsy (n = 6 males, age = 41.6 ± 13.79 years) underwent bilateral ANT DBS implantation. Using intraoperative cortical and ANT simultaneous electrophysiological recordings, we found that the ANT is characterized by high amplitude θ (4-8 Hz) oscillations, mostly in its superior part. The strongest functional connectivity between the ANT and the scalp EEG was also found in the θ band in ipsilateral centro-frontal regions. Upon intraoperative stimulation in the ANT, we found a decrease in higher EEG frequencies (20-70 Hz) and a generalized increase in scalp-to-scalp connectivity. Crucially, we observed that responders to ANT DBS treatment were characterized by higher EEG θ oscillations, higher θ power in the ANT, and stronger ANT-to-scalp θ connectivity, highlighting the crucial role of θ oscillations in the dynamical network characterization of these structures. Our study provides a comprehensive characterization of the interaction dynamic between the ANT and the cortex, delivering crucial information to optimize and predict clinical DBS response in patients with drug-resistant epilepsy.


Pharmacodynamics, pharmacokinetics and safety of revefenacin (TD-4208), a long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD): Results of two randomized, double-blind, phase 2 studies.
Revefenacin (TD-4208) is a potent, lung-selective, long-acting muscarinic antagonist currently in development as a once-daily nebulized therapy for chronic obstructive pulmonary disease (COPD). We evaluated the pharmacodynamics (bronchodilator activity), pharmacokinetics (PK) and safety of single- and multiple-dose administrations of revefenacin in two clinical trials (Study 0059 and Study 0091) in patients with moderate to severe COPD. In Study 0059, 32 patients were randomized to receive a single dose of revefenacin (350 or 700 μg), active control ipratropium (500 μg) or placebo inhalation solution administered via standard jet nebulizer in a double-blind, crossover fashion. In Study 0091, 59 patients were randomized to receive once-daily inhalations of revefenacin (22, 44, 88, 175, 350 or 700 μg) or placebo for 7 days in a double-blind, incomplete block, five-way crossover design. The primary efficacy endpoint was change from baseline in peak (0-6 h) forced expiratory volume in 1 s (FEV1) in Study 0059, and trough FEV1 after the final dose (Day 7) in Study 0091. In both studies, secondary endpoints included area under the FEV1-time curve (FEV1 AUC) values from time 12-24 h post dose and FEV1 AUC values from time zero to 24 h post dose. Revefenacin demonstrated a rapid onset and sustained duration of bronchodilator action in both studies. In Study 0059, mean peak FEV1 was significantly higher (p < 0.001) for revefenacin and ipratropium compared to placebo, with differences of 176.8 mL for 350 μg revefenacin, 162.2 mL for 700 μg revefenacin and 190.6 mL for ipratropium. In Study 0091, mean trough FEV1 on Day 7 was significantly higher (p < 0.006) for all revefenacin doses compared to placebo, with differences ranging from 53.5 mL (22 μg dose) to 114.2 mL (175 μg dose). The results for the other spirometry endpoints were consistent with the primary endpoint for each study, demonstrating that the bronchodilator effect of revefenacin lasted more than 24 h following nebulized administration. Revefenacin was rapidly absorbed and extensively metabolized, followed by a slow apparent terminal elimination and minimal accumulation with repeated dosing. In both studies, adverse events were generally mild and occurred with similar frequencies in all groups, with no indication of significant systemic anti-muscarinic activity at any dose. Following single or multiple nebulized-dose administration in patients with COPD, revefenacin demonstrates a rapid onset and sustained duration of bronchodilator effect over 24 h following once-daily administration, with a PK profile that is commensurate with low systemic exposure.


Thermoelectric properties of PbSe₀.₅Te₀.₅: x (PbI₂) with endotaxial nanostructures: a promising n-type thermoelectric material.
In the present investigation, we report on the thermoelectric properties of PbSe₀.₅Te₀.₅: x (PbI₂) from room temperature to 625 K. High-resolution transmission electron micrographs of the samples reveal endotaxial nanostructures embedded in a PbSe₀.₅Te₀.₅ matrix. The combined effect of mass fluctuation and nanostructures reduces the thermal conductivity to a great extent compared to PbTe and PbSe, without affecting the carrier mobility. As a result, a thermoelectric figure of merit with a value of 1.5 is achieved at 625 K. This value is significantly higher than that of the available state-of-the-art n-type materials.


Correction to: Deciphering cellular transcriptional alterations in Alzheimer's disease brains.
An amendment to this paper has been published and can be accessed via the original article.


Differential quantitative analysis of MHC ligands by mass spectrometry using stable isotope labeling.
Currently, no method allows direct and quantitative comparison of MHC-presented peptides in pairs of samples, such as transfected and untransfected, tumorous and normal or infected and uninfected tissues or cell lines. Here we introduce two approaches that use isotopically labeled reagents to quantify by mass spectrometry the ratio of peptides from each source. The first method involves acetylation and is both fast and simple. However, higher peptide recoveries and a finer sensitivity are achieved by the second method, which combines guanidination and nicotinylation, because the charge state of peptides can be maintained. Using differential acetylation, we identified a beta catenin-derived peptide in solid colon carcinoma overpresented on human leucocyte antigen-A (HLA-A)(*)6801. Guanidination/nicotinylation was applied to keratin 18-transfected cells and resulted in the characterization of the peptide RLASYLDRV (HLA-A(*)0201), exclusively presented on the transfectant. Thus, we demonstrate methods that enable a pairwise quantitative comparison leading to the identification of overpresented MHC ligands.


General practitioner experiences in delivering early medical abortion services to women from culturally and linguistically diverse backgrounds: A qualitative-descriptive study.
General practitioners (GPs) are ideally placed to deliver early medical abortion (EMA), yet little is known about how GPs deliver this care to women from culturally and linguistically diverse (CALD) backgrounds. We explored GP experiences in providing EMA to women from CALD backgrounds and their recommendations for service improvements. This was a qualitative study involving telephone interviews with 18 Australian GPs who provide EMA to women from CALD backgrounds. Data were thematically analysed using the Capability, Opportunity and Motivation Behaviour model. GPs experienced challenges in communication and cultural competency when delivering EMA to women from CALD backgrounds due to insufficient training, lack of multilingual resources and difficulties accessing interpreters. In addition, the stigma surrounding abortion and concerns around reproductive coercion made engaging these women challenging. Upskilling GPs in culturally competent care, improving access to multilingual resources and enabling efficient interpreter use can optimise EMA delivery to women from CALD backgrounds.


Psychometric Properties of the Caregiver Strain Questionnaire in a Chinese Sample of Caregivers of Children with Autism Spectrum Disorder.
The Caregiver Strain Questionnaire assesses the three dimensions of caregiver strain, namely the objective, subjective externalized and subjective internalized strain. It was validated among caregivers of children with Autism Spectrum Disorder (ASD) in the United States and Mainland China with promising psychometric properties.This study aimed to develop and validate the Chinese (traditional script) version of the Caregiver Strain Questionnaire (C-CGSQ) among 198 caregivers of children with ASD in Hong Kong. The C-CGSQ showed excellent internal consistency (α = 0.958) and test-retest reliability (Spearman's r = 0.966). Concurrent, convergent, divergent validity and a three-factor structure (consistent with previous studies) were established. The C-CGSQ demonstrated promising psychometric properties in measuring caregiver strain among caregivers of Chinese ASD children in Hong Kong.


Predictive value of a diagnostic block in focal nerve injury with neuropathic pain when surgery is considered.
In patients with focal nerve injury and neuropathic pain cutting the nerve to obtain permanent pain reduction can be considered. Surgery is indicated only if a diagnostic nerve block provides temporary pain relief. We evaluated the predictive value of a block on the outcome of surgery. In total, three blocks were performed at two week intervals. Patients were blinded to injections containing lidocaine 1% and a placebo was included. Surgery was offered regardless of the effect of the blocks. Twenty-four patients received 72 blocks. Sixteen patients opted for surgery, 5 patients refrained from surgery, and in 3 the blocks provided permanent pain relief. The predictive ability of the block on the outcome of surgery was assessed by calculating the area under a Receiver Operating Characteristic curve (AUC). The AUC of the first lidocaine block was 0.35 with a 95% confidence interval from 0.077 to 0.62. At 95% confidence (two-sided), the AUC is less than 0.62, and hence the predictive ability of the block was poor. The outcome of the second lidocaine block and saline block did not change the conclusion of the first block. We conclude that the use of blocks to select patients for surgery should be critically appraised. A pain relieving response to one open block is currently considered mandatory before patients with focal nerve injury and neuropathic pain are offered surgery. Blinded blocks including a placebo show that responses for selection should be carefully interpreted because they may not be as predictive as generally presumed.


MRI tagging of colonic chyme mixing in healthy subjects: Inter-observer variability and reliability of the measurement with time.
Magnetic resonance imaging (MRI) tagging techniques have been applied to the GI tract to assess bowel contractions and content mixing. We aimed to evaluate the dependence of a tagging measurement (for assessing chyme mixing) on inter-observer variability in both the ascending colon (AC) and descending colon (DC) and to investigate the temporal variation and hence reliability of the colonic tagging technique by acquiring multiple measurements over time on healthy participants. Two independent datasets of healthy adults were used for the retrospective inter-observer variability (Study 1: 13 datasets and Study 2: 31 datasets), and ten participants were scanned for the prospective temporal variation study following a 1 L mannitol oral preparation. All colonic tagging data were acquired on 3 T MRI scanners. The mean and the standard deviation (SD) maps were generated pixel-by-pixel using custom-written software in MATLAB. The colonic regions of interest were defined using MIPAV software. Bland-Altman plots and scatter plots were used for the inter-observer variability. The mean and SD of all repeated measures for each subject were calculated along with a one-way ANOVA to test for variations with time. Scatter plots and Bland-Altman plots showed a large range of data with low variation and small limits of agreements (<5% CoV). The intraclass correlation coefficient of inter-rater reliability was excellent and 0.97 or above for the AC and DC measurements for both datasets. The temporal variation study shows that there was no significant difference found between the multiple measures with time (p = 0.53, one-way repeated measures ANOVA test). MRI tagging technique can provide an assessment of colonic chyme mixing. The inter-observer study data showed high inter-rater agreement. The temporal variation study showed some individual variations with time suggesting multiple measurements may be needed to increase accuracy.


Nuclear relaxation studies on human methemoglobin. Observation of cooperativity and alkaline Bohr effect with inositol hexaphosphate.
Ehanced spin-lattice relaxation (1/t1) of water protons induced by the heme iron of human aquomethemoglobin is exchanged-limited (koff = 1.4 times 10-4 per s at 30 degrees, H+ =7.5 Cal per mol) as indicated by the temperature and frequencey dependencies. A comparison of deuteron and proton relaxation rates revealed an order of magnitude primary isotope effect and a small inverse secondary isotope effect on the escape rate of protons from the heme iron into bulk water establishing the exchange of protons and not the exchange of the entire water molecule to be the chemical mechanism of the entire water molecule to be the chemical mechanism of the exchange process. With fluoromethemoglobin, the relaxation rate is in the fast exchange region. The results can be understood in terms of a water molecule interacting with the heme iron at an iron to proton distance less than 3.4 A in aquomethemoglobin and a single proton at a distance of 4.11 A assignable to the NH proton of the distal histidine imidazole group in fluoromethemoglobin. The relaxation rates are pH-dependent and normal titrations with Hill coefficients n = 1 are observed. The pKa is less than or equal to 6. 7 with aquomethemoglobin and 8.5 with fluoromethemoglobin at 30 degrees C. The binding of inositol hexaphosphate in stoichiometric amounts has no significant effect on the magnetic susceptibility of solutions of aquomethemoglobin and fluoromethemoglobin, but in the former case it increases koff to 3.8 times 10-4 per s by lowering the H+ barrier to 6.8 Cal per mol. In fluoromethemoglobin, inositol hexaphosphate decreases the iron to distal histidine NH distance by 0.17 A and the electron relaxation time taus by 10% as determined by the frequency dependence of 1/T1. In the aquomethemoglobin system, inositol hexaphosphate induces a Bohr effect, raising the pKa of the ionization responsible for the 1/T1 titration to 7.2, and induces cooperativity in the pH titration with a Hill coeffocoemt n = 2.8 plus or minus 0.1. With fluoromethemoglobin, the normal pH titration curve is unaffected by inositol hexaphosphate (n approximately equal to 1). Further, relaxivity titrations with varying amounts of azide and fluoride near neutral pH show normal behavior (n = 1) with and without inositol hexaphosphate. These results indicated that inositol hexaphosphate alters the quaternary structure of methemoglobin to the deoxy conformation without causing a change in the spin state of the heme iron...


A comparison of nalbuphine and meperidine in treatment of postoperative pain.
The analgesic efficacy and side effect profile of nalbuphine 20 mg IV and of nalbuphine 40 mg IV were compared to those of meperidine 75 mg IM in the immediate postoperative period. Pain intensity, pain relief, additional analgesic requirements and the overall acceptability of the treatment were recorded for 150 patients. No significant differences were found between the groups for any of the efficacy variables. Peak analgesic effects occurred at 15 minutes in both nalbuphine groups and at 30 minutes in the meperidine group. The mean time to additional analgesic medication was approximately 207 minutes in each group. The incidence of nausea and vomiting with meperidine was 22 per cent (95 per cent confidence interval 10 to 34 per cent) and with nalbuphine 20 mg the incidence was two per cent (95%CI -2 to 6 per cent). This difference was significant (p less than 0.01). The difference between nalbuphine 40 mg (10 per cent, 95%CI 1 to 19 per cent) and meperidine, was not considered statistically significant (p = 0.17). The analgesic efficacy of nalbuphine 20 mg was indistinguishable from that of nalbuphine 40 mg and from that of meperidine 75 mg. The significantly lower incidence of nausea and vomiting with nalbuphine is a major advantage for a recovery room analgesic.


Postpneumonectomy syndrome: recognition and management.
Postpneumonectomy syndrome (PPS) results from extreme shift and rotation of the mediastinum after pneumonectomy producing symptomatic proximal airway obstruction and air trapping. Herein, we review our experience in the treatment of PPS. Five patients with PPS were treated at our institution between 1991 and 1997. Four patients had previous right pneumonectomy; one patient had left pneumonectomy. Dyspnea was the presenting symptom in all five patients. The time interval to onset of symptoms and to surgical correction ranged from 6 months to 9 years (median: 6 months) and 9 months to 29 years (median, 21 months) after pneumonectomy, respectively. The clinical diagnosis of PPS was confirmed with chest radiograph, two-dimensional echocardiography, pulmonary function tests, CT scan, and awake fiberoptic bronchoscopy. Correction of PPS required reexploration of the pneumonectomy space followed by anterior pericardiorrhaphy and insertion of a saline solution-filled Silastic prosthesis (Dow Corning; Midland, MI) for the purpose of correcting the overshift of the mediastinum. There was no morbidity or mortality. All patients had relief of dyspnea. Corrective repositioning of the mediastinum was confirmed by chest radiograph, CT scan, and awake fiberoptic bronchoscopy. There was a mean increase in the cross-sectional diameter, as measured by CT scan, of the obstructed bronchus by 166.7% (range, 100 to 300%) in four patients. One patient had no change in the measured diameter. Postoperatively, the peak expiratory flow rate increased by a mean of 44.2% (range, 40 to 49%) in all five patients. The presence of PPS should be considered in all patients presenting with progressive dyspnea after pneumonectomy. Repositioning of the mediastinum with a saline solution-filled prosthesis and anterior pericardiorrhaphy is easily performed and provides immediate and lasting symptomatic relief.


Assessment of Costs of Avoidable Delays in Intensive Care Unit Discharge.
Delays in transfer for discharge-ready patients from the intensive care unit (ICU) are increasingly described and contribute to strained capacity. To describe the epidemiological features and health care costs attributable to potentially avoidable delays in ICU discharge in a large integrated health care system. This population-based cohort study was performed in 17 adult ICUs in Alberta, Canada, from June 19, 2012, to December 31, 2016. Participants were patients 15 years or older admitted to a study ICU during the study period. Data were analyzed from October 19, 2018, to May 20, 2020. Avoidable time in the ICU, defined as the portion of total ICU patient-days accounted for by avoidable delay in ICU discharge (eg, waiting for a ward bed). The primary outcome was health care costs attributable to avoidable time in the ICU. Secondary outcomes were factors associated with avoidable time, in-hospital mortality, and measures of use of health care resources, including the number of hours in the ICU and the number of days of hospitalization. Multilevel mixed multivariable regression was used to assess associations between avoidable time and outcomes. In total, 28 904 patients (mean [SD] age, 58.3 [16.8] years; 18 030 male [62.4%]) were included. Of these, 19 964 patients (69.1%) had avoidable time during their ICU admission. The median avoidable time per patient was 7.2 (interquartile range, 2.4-27.7) hours. In multivariable analysis, male sex (odds ratio [OR], 0.92; 95% CI, 0.87-0.98), comorbid hemiplegia or paraplegia (OR 1.47; 95% CI, 1.23-1.75), liver disease (OR 1.20; 95% CI, 1.04-1.37), admission Acute Physiology and Chronic Health Evaluation II score (OR, 1.03; 95% CI, 1.02-1.03), surgical status (OR, 0.90; 95% CI, 0.82-0.98), medium community hospital type (OR, 0.12; 95% CI, 0.04-0.32), and admission year (OR, 1.16; 95% CI, 1.13-1.19) were associated with avoidable time. The cumulative avoidable time was 19 373.9 days, with estimated attributable costs of CAD$34 323 522. Avoidable time accounted for 12.8% of total ICU bed-days and 6.4% of total ICU costs. Patients with avoidable time before ICU discharge showed higher unadjusted in-hospital mortality (1115 [5.6%] vs 392 [4.4%]; P < .001); however, in multivariable analysis, avoidable time was associated with reduced in-hospital mortality (adjusted hazard ratio, 0.74; 95% CI, 0.64-0.85). Results were similar in sensitivity analyses. In this study, potentially avoidable discharge delay occurred for most patients admitted to ICUs across a large integrated health system and translated into substantial associated health care costs.


Heparin: An old drug for new clinical applications.
Heparin, an old but first-line anticoagulant, has been used over a century. It is a heterogeneous, linear, highly sulfated, anionic glycosaminoglycan with a broad distribution in relative molecular weight and charge density. These structural properties allow heparin to selectively interact with multiple proteins, leading to heparin's various pharmacological functions, such as anticoagulant, anti-viral, anti-tumor and anti-inflammatory activities. Clinical data suggest that unfractionated heparin or low molecule weight heparin could decrease mortality in COVID-19 patients with sepsis-induced hypercoagulation through the anticoagulant, anti-viral and anti-inflammatory activities of these drugs. Thus, the non-anticoagulant activity of heparin has again aroused attention. This review highlights recent advances in the preparation of heparin-derived drugs and clinical research on its non-anticoagulant properties over the past decade, to further the development and utilization of these important drugs.


Malaria eradication in Portugal.
Research on malaria, which was endemic in several parts of Portugal at the beginning of this century, was intensified in the 1940's and led to the development of better control methods, especially in the rice-growing areas of the country. In the 1950's residual DDT spraying was introduced and followed by extensive detection of cases of malaria and their treatment. Plans for eradication of the disease were made, and by 1958 the transmission of the infection was interrupted in nearly all areas of European Portugal. The country was placed in the maintenance phase of malaria eradication and the certification of malaria eradication was confirmed by the WHO in 1973. The political and military events of the past five years greatly increased the number of cases of malaria imported into Portugal from tropical Africa and indicated the need for much vigilance to prevent the resumption of transmission by the local vectors. It appears that the measures put into action have succeeded in this respect. This was due to the high degree of effective surveillance and also to the fact that Anopheles atroparvus does not readily transmit the exotic strains of Plasmodium falciparum and P. vivax. However, further vigilance must be maintained and intensified.


Attitudes toward the Legalization of Euthanasia or Physician-Assisted Suicide in South Korea: A Cross-Sectional Survey.
This study aimed to investigate the general South Korean public attitudes toward the legalization of euthanasia or physician-assisted suicide (EAS) and examine the reasons underpinning these attitudes. From March-April 2021, we conducted a cross-sectional survey of a representative national sample of 1000 South Koreans aged 19 years or older. Three in four participants (76.4%) expressed positive attitudes toward the legalization of EAS. Participants who agreed with this legalization reported "meaninglessness of the rest of life" and "right to a good death" as their main reasons. Participants who disagreed with the legalization of EAS reported "respect for life", "violation of the right to self-determination", "risk of abuse or overuse", and "violation of human rights" as theirs. In the multivariate logistic regression analyses, participants with poor physical status (adjusted odds ratio [aOR]: 1.41, 95%; confidence interval [CI]: 1.02-1.93) or comorbidity (aOR: 1.84, 95%; CI: 1.19-2.83) showed positive attitudes toward the legalization of EAS. In summary, most of the general South Korean population regards the legalization of EAS positively, especially participants with poor physical status or comorbidity.


Comments on "Novel molecularly imprinted polymer based on β-cyclodextrin@graphene oxide: Synthesis and application for selective diphenylamine determination".
This comment mainly deals with a mistake of applying pseudo-first-order kinetic model for testing the kinetic behaviors of adsorption.


Lower body positive pressure affects systemic but not cerebral haemodynamics during incremental hyperthermia.
Hyperthermia produces profound redistribution of blood and circulatory reflex function. We investigated the potential for lower body positive pressure (LBPP) to maintain or restore haemodynamics during graded hyperthermia. Eight healthy adults rested supine in a custom-made LBPP box, sealed distal to the iliac crest. Following 5 min of normothermic rest, 20 mmHg of LBPP was applied and repeated when core temperature (Tcore ) had increased passively by +0.5 and +1°C. Primary dependent variables included mean middle cerebral artery blood velocity (MCAvmean , transcranial Doppler), mean arterial blood pressure (MAP, finger photoplethysmography), heart rate (HR) and partial pressure of end-tidal carbon dioxide (PET CO2 ). The absolute increase in MAP during LBPP was lower at Tcore +1°C (2 ± 3 mmHg), compared with normothermia (7 ± 3 p = .01). The modest increase in MCAvmean was unchanged by Tcore (normothermia, 2 ± 3 cm/s; +0.5°C, 3 ± 3 cm/s and +1°C, 3 ± 4 cm/s, p = .74). By design, PET CO2 was unchanged in all conditions from normothermic baseline (42 ± 1, p = .81). LBPP-induced changes in HR were greater at +0.5°C (-13 ± 4 b/min) and +1°C (-12 ± 6 b/min) compared with normothermia (-3 ± 3 b/min, p = .01 and p = .01, respectively). These data indicate that despite a significant attenuation in MAP to LBPP with moderate hyperthermia, MCAvmean dynamics were unchanged among the thermal manipulations.


Cryptosporidium species from common edible bivalves in Manila Bay, Philippines.
Manila Bay is one of the major propagation sites of edible bivalves in the Philippines. Studies have shown that bivalves might be contaminated with human pathogens like the protozoan parasite Cryptosporidium, one of the major causes of gastroenteritis in the world. In this study, Cryptosporidium from four species of edible bivalves were isolated using a combination of sucrose flotation and immunomagnetic separation. Using direct fluorescent antibody test, Cryptosporidium oocysts were found in 67 out of 144 samples collected. DNA sequence analysis of the 18S rRNA gene of the isolates detected C. parvum and C. hominis (major causes of human cryptosporidiosis) and C. meleagridis (causes infection in avian species). Analysis of the 60kDa glycoprotein gene further confirmed the genotypes of the Cryptosporidium isolates. This study is the first to provide baseline information on Cryptosporidium contamination of Manila Bay where bivalves are commonly cultured.


New technique for pancreaticojejunostomy using a biological adhesive.
A new technique of pancreaticojejunostomy using a fibrin glue biological adhesive system (BAS) after pancreaticoduodenectomy is reported. Pancreaticojejunostomy was performed on 112 patients between 1971 and 1985. Forty-two of the patients received BAS application (Group I), but the remaining seventy did not (Group II). To evaluate more precisely the effectiveness of BAS, 22 patients in Group I (Group I-ST) and 26 patients in Group II (Group II-ST) who were operated upon by the same surgeon during the same period were reviewed retrospectively. The selection of patients for the use of BAS was randomized. In Group I-ST, one patient had a minor leak; no major leaks or operative deaths occurred. Two of the twenty-six patients in Group II-ST had minor leaks and one patient had a major leak causing death. This new technique for pancreaticojejunostomy using a biological adhesive system may be useful for preventing anastomotic leaks, especially in a patient with a normal pancreas.


A topological data analysis study on murine pulmonary arterial trees with pulmonary hypertension.
Pulmonary hypertension (PH), defined by a mean pulmonary arterial blood pressure above 20 mmHg in the main pulmonary artery, is a cardiovascular disease impacting the pulmonary vasculature. PH is accompanied by chronic vascular remodeling, wherein vessels become stiffer, large vessels dilate, and smaller vessels constrict. Some types of PH, including hypoxia-induced PH (HPH), also lead to microvascular rarefaction. This study analyzes the change in pulmonary arterial morphometry in the presence of HPH using novel methods from topological data analysis (TDA). We employ persistent homology to quantify arterial morphometry for control and HPH mice characterizing normalized arterial trees extracted from micro-computed tomography (micro-CT) images. We normalize generated trees using three pruning algorithms before comparing the topology of control and HPH trees. This proof-of-concept study shows that the pruning method affects the spatial tree statistics and complexity. We find that HPH trees are stiffer than control trees but have more branches and a higher depth. Relative directional complexities are lower in HPH animals in the right, ventral, and posterior directions. For the radius pruned trees, this difference is more significant at lower perfusion pressures enabling analysis of remodeling of larger vessels. At higher pressures, the arterial networks include more distal vessels. Results show that the right, ventral, and posterior relative directional complexities increase in HPH trees, indicating the remodeling of distal vessels in these directions. Strahler order pruning enables us to generate trees of comparable size, and results, at all pressure, show that HPH trees have lower complexity than the control trees. Our analysis is based on data from 6 animals (3 control and 3 HPH mice), and even though our analysis is performed in a small dataset, this study provides a framework and proof-of-concept for analyzing properties of biological trees using tools from Topological Data Analysis (TDA). Findings derived from this study bring us a step closer to extracting relevant information for quantifying remodeling in HPH.


Comparison of clinical features and prognosis in patients with cryptogenic and secondary organizing pneumonia.
Organizing pneumonia (OP) can be diagnosed pathologically, and cryptogenic OP (COP) and secondary OP (SOP) have been classified by cause and particular underlying context. Because it is clinically difficult to differentiate between COP and SOP, this study investigated characteristics that could distinguish between COP and SOP. The medical records of patients who underwent lung biopsy for a diagnosis of OP at a single tertiary hospital from January 2016 to December 2018 were retrospectively reviewed. Eighty-five patients had pathologically proven OP, including 16 diagnosed with COP and 69 diagnosed with SOP. The most common cause of SOP was infectious pneumonia, observed in 57 (82.6%) of the 69 patients, followed by cancer and radiation pneumonitis. The pathogens causing infectious pneumonia were identified in 45 (65.2%) patients. There were no differences in age, sex, and lung function between the COP and SOP groups. Median body mass index was significantly lower (P = 0.030), and median time from symptom onset to hospital admission significantly shorter (P = 0.006), in the SOP than in the COP group. Fever was more common in the SOP group (P = 0.024), and CURB 65, an index of pneumonia severity, tended to be higher in the SOP group (P = 0.017). Some laboratory results differed significantly between the two groups. Lymphocyte counts in bronchoalveolar lavage (BAL) fluid were significantly higher in the COP than in the SOP group (P = 0.012). Radiologic findings showed that effusion was more common in the SOP group (P = 0.036). There were no between-group differences in steroid use, 30 day and in-hospital mortality rates, and rates of OP outcomes and recurrences. Pneumonia recurrence rate was significantly higher in SOP patients who were than were not treated with steroids (P = 0.035). Infection is the main cause of SOP. Symptom onset is more rapid in patients with SOP than with COP. Some blood and BAL fluid test results differed significantly in the COP and SOP groups. Pleural effusion was more common in the SOP group but there were no differences in clinical course. Recurrence in patients with SOP was more common in those who were than were not treated with steroids.


The development of a classification system for maternity models of care.
A lack of standard terminology or means to identify and define models of maternity care in Australia has prevented accurate evaluations of outcomes for mothers and babies in different models of maternity care. As part of the Commonwealth-funded National Maternity Data Development Project, a classification system was developed utilising a data set specification that defines characteristics of models of maternity care. The Maternity Care Classification System or MaCCS was developed using a participatory action research design that built upon the published and grey literature. The study identified the characteristics that differentiate models of care and classifies models into eleven different Major Model Categories. The MaCCS will enable individual health services, local health districts (networks), jurisdictional and national health authorities to make better informed decisions for planning, policy development and delivery of maternity services in Australia.


Concerns of nursing students beginning clinical courses: A descriptive study.
Students harbor fears related to the clinical environment that influence their participation and learning. Some studies have addressed general anxieties in undergraduate nursing students, but few have asked students to report their fears and concerns prior to entering the clinical environment. Therefore, this study examined the fears and concerns of undergraduate nursing students beginning clinical courses as well as their continued concerns upon completion of the first year of instruction. The study also assessed their confidence in physical assessment skills. Ninety-six junior nursing students enrolled in a generic baccalaureate nursing program completed a survey, two items of which asked about their fears and concerns related to beginning clinical experiences and their confidence in physical assessment. A follow up survey was completed at the end of the junior year by 72 students. Making a mistake, lack of course success, and not knowing how to do something were students' major concerns prior to the start of clinical experiences. Bad experiences with a nurse or instructor, freezing up, and uncomfortable patient/family experiences were also concerns. Not knowing how to do something persisted as a concern at the completion of the first year. Fears about being/feeling left alone in a clinical setting as well as concern about the senior year also emerged on the post survey. Confidence in physical assessment was a mean of 60.46 on a scale of 0-100 at the beginning of clinical instruction and 71.28 at the end of the junior year. Faculty should structure learning activities that decrease anxiety and enhance students' confidence prior to initial clinical experiences. Opportunities might include in-depth orientation to clinical settings and various simulations that allow practice of skills and communication. Awareness of predominant student fears and concerns can also guide staff nurses to provide a welcoming environment and enhance learning.


The circulation of fluid at the limbus (flow and diffusion at the limbus).
Diffusion of molecules, e.g. ions, proteins, etc. and flow of water takes place across the physiological limbus. This 'structure' is estimated to be a zone approximately 1 mm in width and to bridge the anatomical limbus. The source of most molecules that diffuse into the corneal stroma across the limbus under normal circumstances is the perilimbal vascular system with its rich capillary bed. Small ions are lost within 2-3 mm of movement into the stroma, whereas larger molecules may diffuse to the centre of the cornea. Diffusion or flow may be bidirectional; however, it is anticipated that the majority of the flow, albeit small, is inward toward the cornea. The sclera, compared to the corneal stroma, has been found to be less resistant to fluid flow, but more resistant to diffusion of ions and larger molecules. Under normal circumstances, there have been few substances identified of importance that diffuse or flow across the limbus in either direction. There are a number of substances that traverse the limbus that are of importance in disease states, e.g. Wilson's disease, with the corneal Kaiser-Fleischer ring and angiogenic factors stimulating corneal neovascularisation. Under normal circumstances, the limbus would, therefore, seem to be more important as a zone that restricts flow and diffusion rather than an area of active molecular movement.


Optimal Antithrombotic Treatment of Patients with Atrial Fibrillation Early after an Acute Coronary Syndrome-Triple Therapy, Dual Antithrombotic Therapy with an Anticoagulant… Or, Rather, Temporary Dual Antiplatelet Therapy?
The combination of atrial fibrillation (AF) and acute coronary syndrome (ACS) is a complex situation in which a three-dimensional risk-cardioembolic, coronary, and hemorrhagic-has to be carefully managed. Triple antithrombotic therapy (TAT) is burdened with a high risk of serious bleeding, while dual antithrombotic therapy with an anticoagulant (DAT) likely provides only suboptimal coronary protection early after stent implantation. Moreover, TAT precludes the advantages provided by the use of the latest and more potent P2Y12 inhibitors in ACS patients. Here, we aimed to simulate and compare the expected coronary, cardioembolic, and hemorrhagic outcomes offered by DAT, TAT, or modern dual antiplatelet therapy (DAPT) with aspirin plus one of the latest P2Y12 inhibitors in AF patients early after an ACS. The comparison of numbers needed to treat to prevent major adverse events with the various antithrombotic regimens suggests that AF-ACS patients at high ischemic and hemorrhagic risk and at moderately low embolic risk (CHA2DS2VASc score 2-4) might safely withhold anticoagulation after revascularization for one month taking advantage of a modern DAPT, with a favorable risk-to-benefit ratio. In conclusion, this strategy, not sufficiently addressed in recent European and North American guidelines or consensus documents, adds to the spectrum of treatment options in these difficult patients; it might be the best choice in a substantial number of patients; and should be prospectively tested in a randomized controlled trial.


Educating educators about alcoholism and drug addiction: the role of employee assistance programmes.
The historical development of employee assistance programmes (EAPs) from occupational alcoholism programmes is outlined. Services for the three prevention levels of a 'broad brush' programme are described. The 'at-risk' characteristics of academia in potentiating alcoholism and addiction are noted, including several intrinsic characteristics of academics which could predispose to substance abuse. Ways in which EAPs enhance organizational goals are noted and several crucial steps in designing an academic EAP are suggested.


Intensive upper extremity training for children with hemiplegia: from science to practice.
For children with hemiplegic cerebral palsy, bimanual abilities are central to independent function. Over the last decade, considerable attention has been given to 2 forms of extended practice therapy for the upper limb, constraint-induced movement therapy and intensive bimanual training. This article reviews the varying nature of these 2 approaches and the existing scientific rationale supporting them. Comparisons between these 2 intensive upper extremity training approaches indicate similar improvements in unimanual capacity and bimanual performance outcomes; however, when considering participant and caregiver goal achievement, evidence favors a bimanual approach. Careful selection of either therapy for this population requires consideration of individual and contextual factors in relation to treatment goals. The key ingredients and dose responses remain unknown. Treatment intensity, intrinsic motivation, and individualization of treatment are hypothesized as requisite in either approach.


Do negative life experiences predict the health-care-seeking of adolescents? A study of 10th-year students in Oslo, Norway.
To analyze associations among the negative life experiences and health-care-seeking of adolescents during the 12 months before the study. Cross-sectional questionnaire study among 10th-year students at all secondary schools in Oslo. In 2000 and in 2001, 7329 (88%) of Oslo's 8316 secondary-school students responded to the questionnaire. Some contacts with primary health care during the previous year were reported by 71% of respondents, and 6% had seen a mental health practitioner (psychologist or psychiatrist). Health care utilization was not correlated with the family's financial situation as reported by the student (boys = 1019; girls = 1258), or with a parent's unemployment (boys = 253; girls = 325). The 2112 boys (59% of all) and 2378 girls (64%) who reported feeling strong pressure from others to succeed, had more contacts with all primary health care services. Girls, but not boys, who reported being bullied by others reported more psychologist or psychiatrist visits than did their nonbullied peers. Exposure to physical violence was associated with a significant increase in visits to the School Health Service, family physician, and emergency medical service, and was related to more than doubling the probability of visiting a mental health practitioner. Being sexually violated during the previous year increased the likelihood of boys visiting mental health practitioner more than four times (odds ratio [OR] 4.6; 95% confidence interval [CI] 1.7-12.2); and visiting School Health Service by nearly four times, (OR 3.7; 95% CI 1.0-13.5). Variation in adolescent health care seeking can, by and large, be predicted by negative life experiences.


miR-425 regulates cell proliferation, migration and apoptosis by targeting AMPH-1 in non-small-cell lung cancer.
MicroRNAs (miRNAs) have been proved to act as vital roles on non-small-cell lung cancer (NSCLC), and miR-425 has been proven to serve an important function in several tumors. However, the functional role of miR-425 on NSCLC is still unclear. The mRNA and protein expression of miR-425 and AMPH-1 were determined by qRT-PCR and western blot analysis, respectively. NSCLC cells (SK-MES-1 and A549) proliferation and migration were measured by CCK-8 and transwell assay, respectively. Cell apoptosis was assessed by flow cytometry and western blotting, In addition, luciferase reporter assay was carried out to confirm the direct targeting of AMPH-1 by miR-425. Xenograft experiments were performed to observe the tumorigenesis of miR-425 in vivo. The results showed that miR-425 was overexpressed and AMPH-1 expression was downregulated in SK-MES-1 and A549 cells. Silencing miR-425 inhibited proliferation, migration and promoted apoptosis of NSCLC cells. Moreover, we proved that miR-425 could target AMPH-1. The expression of AMPH-1was upregulated in A549 with miR-425 inhibitor. Moreover, miR-425 knockdown were less tumorigenic than the control in vivo. Taken together, miR-425 could promote the proliferation, invasion and suppress apoptosis by targeting AMPH-1 in NSCLC cells. miR-425/AMPH-1 axis may represent a potential therapeutic strategy or novel prognostic biomarkers to NSCLC.


Quick self-healing and thermo-reversible liposome gel.
Self-assembled liposome gel from liposome and cholesterol-end capped polyethylene glycol, was systematically investigated by rheological method, especially in the aspect of its recovery ability upon either mechanical deformation or temperature change. The liposome gel was found to have rheological behavior similar to that of Maxwell model. The dynamic shear modulus of the liposome gel was dependent on both the liposome concentration and the polymer concentration. At low liposome concentration range (5-20 mM), dynamic shear modulus decreased considerably with the liposome concentration, implying the decrease of effective cross-linking density inside gel network due to the addition of liposome. The liposome gel network had a fast, self-healing ability even after high deformation, and the injectability of the gel was confirmed by injection experiment in vitro. The liposome gel also exhibited temperature stimuli responsive behavior and thermo-reversibility. Dynamic light scattering studies proved that the particle size of liposome remained almost unchanged before and after the addition of the polymer.


[Biomechanical aspects of vertebral augmentation].
With increasing age, bone mass decreases and the structure of the cancellous bone in the vertebral body changes. Especially in osteoporotic patients, but also with metastases in the vertebral body, this leads to decreased strength and, thus, to an increased risk of vertebral fractures. It is expected that this problem will increase significantly because of demographic developments. To treat or to prevent such vertebral fractures, different augmentation techniques have been developed. They can mainly be divided into vertebroplasty or kyphoplasty procedures. The goal of this paper is to summarize biomechanical aspects of these augmentations procedures and to present some alternative methods. With vertebroplasty, the loss of bone mass is balanced by injecting bone cement which improves the failure strength of the affected vertebral body. With kyphoplasty, cavities are created and these are filled with bone cement. Disadvantages of vertebroplasty are uncontrollable cement extrusion and increased fracture risk in the adjacent vertebral bodies. With balloon kyphoplasty, the adjacent cancellous bone is compacted during dilation and, thus, does not allow good integration with the remaining trabeculae. In addition, this method is associated with an increased risk of fracture in the adjacent vertebrae. To counter these disadvantages, a number of new types of cement and alternative augmentation methods are being developed, with which the vertebral body may be filled or distracted. The efficacy of these new methods should be tested in appropriate experimental biomechanical studies before they are used in patients.


A comparison of treatment with metformin and gliclazide in patients with non-insulin-dependent diabetes.
Twenty-seven obese non-insulin-dependent diabetic patients, treated with dietary carbohydrate restriction and metformin, were recruited from the diabetic outpatient clinic and entered into an open crossover study with gliclazide. Twenty-one patients completed the study. During three months observation on metformin, the mean weight of the group fell by 1.0 kg with 14 patients losing a mean of 1.8 kg with 14 patients losing a mean of 1.8 kg, 3 remaining unchanged and 4 gaining a mean weight of 1.1 kg. Over the subsequent three months on gliclazide, the mean weight of the group rose by 1.4 kg with 16 patients gaining a mean of 2.2 kg, two remaining unchanged and 3 losing a mean of 2.0 kg. In addition, 10 patients were heavier after gliclazide than at the time of recruitment (mean 2.6 kg), 3 were unchanged and 8 had lost weight since commencing the trial (mean 2.1 kg), mostly due to greater loss on metformin than gain on gliclazide. Glycaemic control did not improve significantly during the observed period on metformin but lower concentrations of fasting glucose and total glycosylated haemoglobin were achieved with gliclazide. Mean plasma insulin concentration was significantly higher and mean serum lactate was significantly lower during treatment with gliclazide. In conclusion, gliclazide does not support weight loss in obese non-insulin-dependent diabetic patients to the same extent as metformin but the difference between the two drugs is small. Gliclazide is a suitable oral hypoglycaemic agent for use in the obese diabetic who cannot be controlled by diet alone.


Hyperthermic modulation of macrophage-tumor cell interactions.
Hyperthermia in the febrile (less than or equal to 41 degrees C) or tumor therapeutic (greater than or equal to 42 degrees C) ranges is known to alter tumor-host interactions: there are reports of either inhibitory or enhancing effects on tumor metastasis and various host defense mechanisms. Historically, this has been an area of conflicting and often anecdotal reports, and there are still significant gaps in our knowledge of the effects of temperature on tumor-host interactions. However, we believe that the tools are now available to further our understanding of the complex relationships between febrile episodes or therapeutically applied heat and various tumor-host cytotoxic mechanisms, and that potentially important and exploitable relationships can be defined. In this review we give an overview of the current status of this field and the factors that have shaped it. We also describe our recent experimental work with macrophages and their monokines, primarily tumor necrosis factor (TNF), which we feel offers new scientific and clinical opportunities for future studies.


BIM (BCL-2 interacting mediator of cell death) SAHB (stabilized α helix of BCL2) not always convinces BAX (BCL-2-associated X protein) for apoptosis.
The interaction of BAX (BCL-2-associated X protein) with BIM (BCL-2 interacting mediator of cell death) SAHB (stabilized α helix of BCL2) directly initiates BAX-mediated mitochondrial apoptosis. This molecular dynamics study reveals that BIM SAHB forms a stable complex with BAX but it remains in a non-functional conformation. N terminal of BAX folds towards the core which has been reported exposed in the functional monomer. The α1-α2 loop, which has been reported in open conformation in functional BAX, acquires a closed conformation during the simulation. BH3/α2 remains less exposed as compared to initial structure. The hydrophobic residues of BIM accommodates in the rear pocket of BAX during the simulation. A steep decrease in radius of gyration and solvent accessible surface area (SASA) indicates the complex folding to acquire a more stable but inactive conformation. Further the covariance matrix reveals that the backbone atoms' motions favour the inactive conformation of the complex. This is the first report on the non-functional BAX-BIM SAHB complex by molecular dynamics simulation in the best of our knowledge.


Biocompatible superparamagnetic sub-micron vaterite particles for thermo-chemotherapy: From controlled design to in vitro anticancer synergism.
A promising candidate for the development of controlled and targeted nanoscale drug delivery system but less studied so far is calcium carbonate (CaCO3) in the form of porous polycrystalline vaterite spheres. Vaterite has been shown to exhibit various beneficial properties such as excellent biocompatibility, high drug loading capacity, and pH-sensitive decomposition under mild conditions. However, fabricating vaterite particles with improved porosity, high surface area and loading a payload into the common synthesis method is still a challenge. Here we report on the synthesis of a highly porous, spherical superparamagnetic vaterite particles (PMVP) of size ∼800 nm encapsulating Iron oxide nanoparticles (IONPs) in a one-step reaction and loaded with DOX molecules through electrostatic attractions and physisorption for cancer thermo-chemotherapy application. The main advantage of the PMVP-DOX is that it can be magnetically targeted into the tumor region and once exposed to the tumor tissues characteristic acidic pH, the PMVP nanoparticle dissociates, releasing the DOX and intelligently converts the pH-triggered drug release into a tumor triggered drug release. Simultaneous application of alternating magnetic field (AMF) generates localized heat of the tumor tissues due to the hyperthermic capability of the IONPs in the PMVP and results in the synergistic tumoricidal activities.


HMGB binding to DNA: single and double box motifs.
High mobility group (HMG) proteins are nuclear proteins believed to significantly affect DNA interactions by altering nucleic acid flexibility. Group B (HMGB) proteins contain HMG box domains known to bind to the DNA minor groove without sequence specificity, slightly intercalating base pairs and inducing a strong bend in the DNA helical axis. A dual-beam optical tweezers system is used to extend double-stranded DNA (dsDNA) in the absence as well as presence of a single box derivative of human HMGB2 [HMGB2(box A)] and a double box derivative of rat HMGB1 [HMGB1(box A+box B)]. The single box domain is observed to reduce the persistence length of the double helix, generating sharp DNA bends with an average bending angle of 99+/-9 degrees and, at very high concentrations, stabilizing dsDNA against denaturation. The double box protein contains two consecutive HMG box domains joined by a flexible tether. This protein also reduces the DNA persistence length, induces an average bending angle of 77+/-7 degrees , and stabilizes dsDNA at significantly lower concentrations. These results suggest that single and double box proteins increase DNA flexibility and stability, albeit both effects are achieved at much lower protein concentrations for the double box. In addition, at low concentrations, the single box protein can alter DNA flexibility without stabilizing dsDNA, whereas stabilization at higher concentrations is likely achieved through a cooperative binding mode.


Lower Limb Strength Is Significantly Impaired in All Muscle Groups in Ambulatory People With Chronic Stroke: A Cross-Sectional Study.
To measure the strength of the major muscle groups of the affected and intact lower limbs in people with stroke compared with age-matched controls. Cross-sectional study. University laboratory. Ambulatory stroke survivors (n=60; mean age, 69±11y), who had had a stroke between 1 and 6 years previously, and age-matched controls (n=35; mean age, 65±9y) (N=95). Not applicable. The maximum isometric strength of 12 muscle groups (hip flexors and extensors, hip adductors and abductors, hip internal rotators and external rotators, knee flexors and extensors, ankle dorsiflexors and plantarflexors, ankle invertors and evertors) of both lower limbs was measured using handheld dynamometry. All strength measurements were taken in standardized positions by 1 rater. The affected lower limb of the participants with stroke was significantly weaker than that of the control participants for all muscle groups (P<.01). Strength (adjusted for age, sex, and body weight) was 48% (range, 34%-62%) of that of the control participants. The most severely affected muscle groups were hip extensors (34% of controls), ankle dorsiflexors (35%), and hip adductors (38%), and the least severely affected muscle groups were ankle invertors (62%), ankle plantarflexors (57%), and hip flexors (55%). The intact lower limb of the participants with stroke was significantly weaker than that of the control participants for all muscle groups (P<.05) except for ankle invertors (P=.25). Strength (adjusted for age, sex, and body weight) was 66% (range, 44%-91%) of that of the control participants. The most severely affected muscle groups were hip extensors (44% of controls), ankle dorsiflexors (52%), and knee flexors (54%). Ambulatory people with chronic stroke have a marked loss of strength in most of the major muscle groups of both lower limbs compared with age-matched controls.


Evaluation of antibacterial photodynamic therapy effects on human dental pulp cell cultures.
The antibacterial photodynamic therapy (aPDT) has been used in dentistry against oral microorganisms because of its excellent biocide effect. However, for carious lesions applications, there is little evidence that this therapy is safe for the pulp tissue. This study evaluates the effects of an aPDT protocol on human pulp cells in vitro. Pulp cells isolated from dental pulp were exposed to an aPDT protocol associating methylene blue (MB) at concentrations of 0.0125, 0.025 and 0.050mg/ml and red laser irradiation using a continuous-wave indium-gallium-aluminum-phosphide (InGaAlP) diode laser (λ=660nm, 40mW, 2.4J, 60J/cm(2) for 1min). Pre-irradiation time was 5min for each MB concentration. Cell viability was determined by MTT assay and activity of alkaline phosphatase was assessed by BCIP-NBT assay. Type of aPDT-induced cell death was assessed by flow cytometry. Data was statistically compared (ANOVA followed by Tukey' or Bonferroni's post hoc tests). aPDT was able to kill pulp cells in a dye concentration-dependent manner. The cellular viability was significantly reduced when used MB at 0.025 or 0.050mg/ml concentrations (p<0.0001). At these concentrations, aPDT-induced cell death occurred mostly by necrosis. Alkaline phosphatase activity was significantly reduced in all experimental groups (p<0.001). Pulp cells showed suitable viability when MB at 0.0125mg/ml was exposed to laser irradiation. aPDT with MB at 0.0125mg/ml may represent a low-risk therapy for restorative dentistry applications. aPDT protocol using concentrations above 0.025mg/ml of MB associating red laser irradiation may be harmful for dental pulp cells.


Eyelid sebaceous gland carcinoma: An assessment of the T classification of the American Joint Committee of Cancer TNM staging system 8th versus 7th edition.
To assess the prognostic values of the T classification of the 8th edition of the American Joint Committee of Cancer staging system and compare it to the 7th edition. Multicenter retrospective study of patients with eyelid sebaceous gland carcinoma. The primary outcome measure was the differences between outcomes when tumors were staged with either 7th or 8th edition. The measures evaluated included presenting features, management, histopathology, metastasis, recurrence, and mortality. Of the 60 patients (median age 73 years), 31 (51.7%) were females. A change in T staging occurred in 39 patients (65%) when the 8th edition was applied. Advanced categories (T3/T4) were significantly associated with nodal metastasis (p = 0.037) using the 8th edition criteria but not with the 7th edition (p = 0.066). The 8th edition T categorization significantly correlated with eye survival (p = 0.022) while the 7th edition did not (p = 0.058). Applying the 8th edition, category T4 at presentation was associated with a higher risk of nodal metastasis (p = 0.037) but not associated with local recurrence, distant metastasis, or tumor-related death (p = 0.281, p = 0.737, p = 0.319, respectively). T3/T4 category tumors were significantly associated with poor tumor differentiation (p = 0.001), and papillary histologic pattern (p = 0.024) but not with pagetoid spread (p = 0.056). The application of the 8th edition AJCC staging system for eyelid SGC may accurately predict nodal metastasis. Local recurrence and distant metastasis were not significantly associated with T classification, using either edition. Poor tumor differentiation and papillary pattern were associated with T3/T4 categories suggesting that pathological features may assist in determining prognosis.


Raman spectroscopic analysis of the interaction between squaric acid and dimethylsulfoxide.
The investigation of solutions of squaric acid in dimethylsulfoxide (DMSO) by Raman spectroscopy has facilitated the observation of the presence of different species derived from squaric acid such as the squarate dianion in solutions of 0.3M and 0.5M concentration and the hydrogen-squarate ion in solution concentrations greater than 2.0M. The method described by Alía and coworkers was used to calculate the two pK values corresponding to the ions produced by squaric acid interacting with DMSO: the hydrogen squarate (pK1=0.80) ion and the squarate dianion (pK2=0.84). From the spectroscopic data it has been also possible to determine the complex formation between associated squaric acid/DMSO in the proportion squaric acid 1:1 DMSO in which the associated squaric acid is hydrogen-bonded to the S atom in the DMSO structure.


Ginsenosides for therapeutically targeting inflammation through modulation of oxidative stress.
Ginsenosides are steroid glycosides derived from ginseng plants such as Panax ginseng, Panax quinquefolium, and Panax notoginseng. Advances in recent studies have identified numerous physiological functions of each type of ginsenoside, i.e., immunomodulatory, antioxidative, and anti-inflammatory functions, in the context of inflammatory diseases. Accumulating evidence has revealed the molecular mechanisms by which the single or combined ginsenoside(s) exhibit anti-inflammatory effects, although it remains largely unclear. It is well known that excessive production of reactive oxygen species (ROS) is associated with pathological inflammation and cell death in a variety of cells, and that inhibition of ROS generation ameliorates the local and systemic inflammatory responses. The mechanisms by which ginsenosides attenuate inflammation are largely unknown; however, targeting ROS is suggested as one of the crucial mechanisms for the ginsenosides to control the pathological inflammation in the immune and non-immune cells. This review will summarize the latest progress in ginsenoside studies, particularly in the context of antioxidant mechanisms for its anti-inflammatory effects. A better understanding of the distinct types and the combined action of ginsenosides will pave the way for developing potential preventive and therapeutic modalities in treating various inflammation-related diseases.


The role of firefly luciferase C-terminal domain in efficient coupling of adenylation and oxidative steps.
The N-terminal domain (N-domain) of the firefly luciferase from Photinus pyraris has weak luminescence activity, and shows a unique light emitting profile with very long rise time of more than several minutes. Through a sensitive assay of the reaction intermediate luciferyl-adenylate (LH2-AMP), we found that the slow increase in the N-domain luminescence faithfully reflected the concentration of dissociated LH2-AMP. No such correlation was observed for wild-type or mutant enzymes with short rise time, except one with longer rise time. The results suggest that the C-terminal domain plays an indispensable role in efficiently coupling adenylation and oxidative steps.