Leishmanicidal activity in vitro of Musa paradisiaca L. and Spondias mombin L. fractions.
Visceral leishmaniasis (VL) is a zoonotic disease characterized by infection of mononuclear phagocytes by Leishmania chagasi. The primary vector is Lutzomyia longipalpis and the dog is the main domestic reservoir. The control and current treatment of dogs using synthetic drugs have not shown effectiveness in reducing the incidence of disease in man. In attempt to find new compounds with leishmanicidal action, plant secondary metabolites have been studied in search of treatments of VL. This study aimed to evaluate the leishmanicidal activity of Musa paradisiaca (banana tree) and Spondias mombin (cajazeira) chemical constituents on promastigotes and amastigotes of L. chagasi. Phytochemical analysis by column chromatography was performed on ethanol extracts of two plants and fractions were isolated. Thin layer chromatography was used to compare the fractions and for isolation the substances to be used in vitro tests. The in vitro tests on promastigotes of L. chagasi used the MTT colorimetric method and the method of ELISA in situ was used against amastigotes besides the cytotoxicity in RAW 264.7 cells. Of the eight fractions tested, Sm1 and Sm2 from S. mombin had no action against promastigotes, but had good activity against amastigotes. The fractions Mp1 e Mp4 of M. paradisiaca were very cytotoxic to RAW 264.7 cells. The best result was obtained with the fraction Sm3 from S. mombin with IC(50) of 11.26 μg/ml against promastigotes and amastigotes of 0.27 μg/ml. The fraction Sm3 characterized as tannic acid showed the best results against both forms of Leishmania being a good candidate for evaluation in in vivo tests.


Effectiveness of Immune Checkpoint Inhibitors in Transplant Recipients with Progressive Multifocal Leukoencephalopathy.
Antibodies against PD1 have been used to treat progressive multifocal leukoencephalopathy (PML), a rare brain disease caused by JC virus. We used these antibodies (nivolumab) to treat PML in 3 kidney transplant recipients. All died within 8 weeks of diagnosis. Hence, nivolumab did not improve PML outcome after solid organ transplantation.


Teleost fish genomes contain a diverse array of L1 retrotransposon lineages that exhibit a low copy number and high rate of turnover.
Retrotransposable elements exhibit a wide range of variation in population dynamics, abundance, and lineage diversity among host genomes across taxa. This range of diversity is illustrated by a single well-defined constituent monophyletic clade of L1 non-LTR retrotransposons that is shared between mammalian and teleost fish genomes. Despite the clear phylogenetic relationships that exist between mammalian and teleost L1 sequences, these elements exhibit markedly different dynamics within their respective taxa. While mammalian genomes typically contain a single, abundant lineage of L1 elements that traces millions of years of evolution, the zebraflsh genome was recently shown to exhibit a high diversity of ancient lineages coexisting at a very low copy number and apparently exhibiting a high rate of turnover. In the present study, a combination of degenerate PCR, lineage-specific PCR, and genomic Southern blot analysis is utilized to demonstrate high L1 lineage diversity, low copy number, and a high proportion of polymorphic inserts in the genomes of the killifish species, Fundulus heteroclitus. Additional species surveyed by degenerate PCR include Cyprinodon variegatus, Rivulus marmoratus, and Menidia beryllina. These results further support the generality of the differences that exist in host-element dynamics between teleost fish and mammalian genomes with regard to L1 retrotransposons.


Lung lobe torsion in dogs: 52 cases (2005-2017).
To report outcomes and risk factors for mortality in dogs that underwent surgical management of lung lobe torsion. Retrospective case series from 5 veterinary teaching hospitals (2005-2017). Fifty dogs with 52 instances of lung lobe torsion. Data collected from medical records included signalment, clinical findings, results of clinicopathologic testing and diagnostic imaging, surgical treatment, lung lobe affected, intraoperative and postoperative complications, histopathologic and microbiologic findings, and outcome. Follow-up was obtained from medical records and telephone contact with primary care veterinarians. Fifty-two instances of lung lobe torsion were identified in 50 dogs, with a median follow-up of 453 days (range, 0-3075). Forty-six (92%) dogs survived to discharge. Dogs with concurrent torsion of the right cranial and middle lung lobes were less likely to survive (2/4) than those with torsion of the left cranial lung lobe (22/22). No other risk factors for mortality prior to hospital discharge were identified. Overall median survival time after hospital discharge was 1369 days. Four dogs had >1 episode of lung lobe torsion. The percentage of dogs surviving to discharge after surgical treatment of lung lobe torsion was higher than previously reported. The short- and long-term prognosis was excellent with surgical treatment of lung lobe torsion. Surgery should be recommended when lung lobe torsion is suspected because of the high survival to discharge rate and excellent long-term prognosis.


In situ binding assay to detect Myosin-1c interactions with hair-cell proteins.
Myosin-1c is an unconventional myosin involved in hair-cell mechanotransduction, a process that underlies our senses of hearing and balance. To study the interaction of myosin-1c with other components of the hair-cell transduction complex, we have developed an in situ binding assay that permits visualization of myosin-1c binding to hair-cell proteins. In this chapter we describe in detail the methods needed for the expression and purification of recombinant myosin-1c fragments and their use in the in situ binding assay.


Japanese encephalitis vaccine in travellers. Is wider use prudent?
Vaccination against Japanese encephalitis has been carried out extensively in many Asian countries for the past 20 years and is also increasingly recommended for travellers to endemic areas. Although the currently available vaccine, manufactured from mouse brain, is generally considered to be highly effective and of low reactogenicity, approximately 50% of vaccinees report experiencing usually mild adverse effects following vaccination. Concern has been raised regarding potential neurological adverse effects but the incidence of such effects appears to be very low (around 1 to 2.3 per 1000000 vaccinations). Routine vaccination of all travellers to endemic areas is clearly not beneficial at this moment and use of the vaccine should remain restricted to persons spending a month or longer in endemic areas, especially rural areas, during the transmission season. However, when counselling individual travellers, it has to be kept in mind that the possibility of Japanese encephalitis can never be ruled out completely when travelling to endemic areas, and that such an infection can prove disastrous for the individual concerned.


Magnetic resonance imaging-controlled results of the pectoralis major tendon transfer for irreparable anterosuperior rotator cuff tears performed with standard and modified fixation techniques.
Irreparable ruptures of the subscapularis tendon lead to impaired function of the shoulder joint. In such cases, transfer of the pectoralis major tendon has led to encouraging results. The procedure fails periodically, typically associated with insufficient in-growth of the transferred tissue. We hypothesized that tendon harvest with chips of cancellous bone would improve the tendon-bone interface. Of 62 consecutive pectoralis tendon transfers, 54 shoulders were followed-up at an average of 35 months. In all shoulders, the transferred tendon was rerouted behind the conjoint tendon and fixed by transosseous sutures. In 29 shoulders, the tendon was harvested with a cuff of cancellous bone. In 25 shoulders, the conventional technique with sharp detachment of the tendon was used. Apart from detailed clinical examination of all shoulders, a magnetic resonance image (MRI) was available in 52 shoulders. The overall Constant score had improved from an average of 38.8 points preoperatively to 63.4 points at follow-up. Shoulders treated with the new fixation technique scored 64.4 compared with 62.2 for the conventional fixations. The MRI showed intact tendons and muscles in 80.8% of shoulders. In 7 shoulders (13.5%), the transferred tendon was ruptured. Two of these were treated with the new fixation technique. Mean patient satisfaction score was 8.2 points. A secure method of fixation that avoids secondary ruptures despite insufficiency of the transferred tendon is of great importance. Also the rerouting of the transferred tendon under the conjoined tendon is essential to imitate the natural force vector and the function of an intact subscapularis tendon. Patients in this investigation were also monitored by MRI to verify the integrity of the transferred tendon. As a salvage procedure, the pectoralis major tendon transfer provides good results in most cases. Sufficient in-growth of the transferred tissue is essential for the success of the procedure. This seems to be facilitated by both methods.


Assessment of kidney function in chronic kidney disease by combining diffusion tensor imaging and total kidney volume.
This study aimed to investigate the value and feasibility of combining fractional anisotropy (FA) values from diffusion tensor imaging (DTI) and total kidney volume (TKV) for the assessment of kidney function in chronic kidney disease (CKD). Fifty-one patients were included in this study. All MRI examinations were performed with a 3.0 T scanner. DTI was used to measure FA values, and TKV was obtained from DTI and T2-weighted imaging (T2WI). Patients were divided into three groups (mild, moderate, severe) according to eGFR, which was calculated with serum creatinine. Differences in the FA values of the cortex and medulla were analysed among the three groups, and the relationships of FA values, TKV, and the product of the FA values and TKV with eGFR were analysed. Receiver operating characteristic (ROC) curve analysis was used to compare the diagnostic efficiency of the FA values, TKV, and the product of the FA values and TKV for kidney function in different CKD stages. Medullary FA values (m-FA), TKV, and the product of the m-FA values and TKV (m-FA-TKV) were significantly correlated with eGFR (r = 0.653, 0.685, and 0.797, respectively; all P < 0.001). ROC curve analysis showed that m-FA-TKV exhibited better diagnostic performance than m-FA values (P = 0.022). m-FA-TKV obtained by DTI significantly improves the accuracy of kidney function assessment in CKD patients.


The adjuvant activity of a non-toxic, water-soluble glycopeptide present in large quantities in the culture filtrate of Mycobacterium tuberculosis strain DT.
A water-soluble mycobacterial glycopeptide was obtained in large quantities from the culture supernatant fluid of M. tuberculosis strain DT. This glycopeptide was strongly adjuvant-active when injected, in a water-in-oil emulsion contianing ovalbumin, into guinea-pigs. In addition, it was devoid of cord factor toxicity in mice, polyarthritogenic activity in rats and cavity stimulating activity in rabbit lungs.


Activated protein C protects against myocardial ischemic/reperfusion injury through AMP-activated protein kinase signaling.
Activated protein C (APC) is a vitamin K-dependent plasma serine protease that down-regulates clotting and inflammatory pathways. It is known that APC exerts a cardioprotective effect by decreasing apoptosis of cardiomyocytes and inhibiting expression of inflammatory mediators after myocardial ischemia. The objective of this study was to understand the mechanism of the APC-mediated cardioprotection against ischemic injury. Cardioprotective activities of wild-type APC and two derivatives, having either dramatically reduced anticoagulant activity or lacking signaling activity, were monitored in an acute ischemia/reperfusion injury model in which the left anterior descending coronary artery (LAD) was occluded. APC reduced the myocardial infarct size by a mechanism that was largely independent of its anticoagulant activity. Thus, the non-anticoagulant APC-2Cys mutant, but not the non-signaling APC-E170A mutant, attenuated myocardial infarct size by EPCR and PAR-1-dependent mechanisms. Further studies revealed that APC acts directly on cardiomyocytes to stimulate the AMP-activated protein kinase (AMPK) signaling pathway. The activation of AMPK by APC ameliorated the post-ischemic cardiac dysfunction in isolated perfused mouse hearts. Moreover, both APC and APC-2Cys inhibited production of TNFα and IL-6 in vivo by attenuating the ischemia/reperfusion-induced JNK and NF-κB signaling pathways. APC exerts a cardioprotective function in ischemic/reperfusion injury through modulation of AMPK, NF-κB and JNK signaling pathways.


Ocular application of chitosan.
A major problem in ocular therapeutics with classical formulations is the maintenance of an effective drug concentration at the site of action for a long period of time. Enhancement of ocular bioavailability with increased dose penetration and longer retention time at desired sites can be achieved by recent formulations. Chitosan stands out with its unique structural advantageous characteristics for different types of formulations like in situ gelling systems, micro- and nanoparticles, inserts, etc. In this review, the authors focus on ocular therapeutics and the characteristics that make chitosan more acceptable in ocular applications. Chitosan seems to be one of the most promising polymeric carriers for both hydrophilic and lipophilic drugs for ocular application.


Biological Evaluation of Different Extracts of Aerial Parts of Nepeta deflersiana and Standardization of Active Extracts Using 8-Epi-7-Deoxyloganic Acid and Ursolic Acid by Validated HPTLC Method.
Nepeta deflersiana (Lamiaceae) is a well-known medicinal plant that grows in Saudi Arabia. This plant is used in Saudi and Yemeni folk medicine as an anti-inflammatory, carminative, and antirheumatic agent. In order to prove its use in folk medicine, four different extracts from the aerial parts of the plant: petroleum ether, chloroform, ethyl acetate, and n-butanol extracts were subjected to biological assays to screen PPARα and PPAR ϒ agnostic, antioxidant, anti-inflammatory, and cytotoxic activities. Ethyl acetate and n-butanol extracts of N. deflersiana NDEE and NDBE, respectively, showed a decrease in oxidative stress and inhibition of both NF-kB and iNOS activities with no cytotoxic effects on four human cancer cell lines. Both active extracts were standardized using two bioactive metabolites which were isolated from the aerial parts of the same plant [8-epi-7-deoxyloganic acid (compound 1) and Ursolic acid (compound 2)] by developing a validated HPTLC method. It was found to provide a sharp and compact band of compound 1 at Rf = 0.07 and Rf = 0.57 for compound 2, using chloroform, methanol, and formic acid (8.9:0.8:0.3, v/v/v) as mobile phase at 550 nm. Compounds 1 and 2 were found in NDEE by 9.59 %, w/w, and 84.63 %, w/w, respectively, and by 11.97 %, w/w, and 21.26 %, w/w, respectively, in NDBE.


Corticocortical and collateral thalamocortical connections of postcentral somatosensory cortical areas in squirrel monkeys: a double-labeling study with radiolabeled wheatgerm agglutinin and wheatgerm agglutinin conjugated to horseradish peroxidase.
Experiments were performed to determine whether thalamic neurons send collaterals to more than one subdivision of postcentral somatosensory cortex, and to evaluate the fidelity of somatotopic connections between cortical representations of the body surface. After microelectrode recordings identified the locations of the representations of the fingertips along the border of area 3b with area 3a and along the border of area 1 with area 2, one tracer, tritiated N-acetyl wheatgerm agglutinin ([3H]WGA), was injected into the rostral representation at the 3a-3b border, and another, wheatgerm agglutinin conjugated to horseradish peroxidase (WGA:HRP), was injected into the caudal representation at the 1-2 border. The results indicate that three thalamic regions are interconnected with both border zones. Regions of overlapping retrograde and anterograde label included the ventromedial portion of the lateral division of the ventroposterior nucleus (VPL), which is known to represent the digits; the medial extent of a dorsal capping zone of VPL that we term the ventroposterior superior nucleus (VPS); and the anterior pulvinar (Pa). Cells labeled with one or the other tracer, as well as cells labeled with both tracers, were found in VPL, VPS, and Pa. Our procedures necessarily underestimated the numbers of cells projecting to both rostral and caudal injection zones, but at least 15-20% of VPL and 20-40% of VPS neurons that were autoradiographically labeled appeared to have such collaterals. While only a few cells in Pa were autoradiographically labeled from injections at the 3a-3b border, the presence of several double-labeled cells suggests that at least some Pa neurons project to both injected zones. By relating the present results to those from studies where connections were determined for single architectonic fields, we conclude that many neurons in VP project to both areas 3b and 1, and that many neurons in VPS project to both areas 3a and 2. In addition, both areas 3a and 2 appear to have interconnections with Pa. Connections of Pa with area 2 have only recently been reported (Pons and Kaas, in press), and connections of Pa with area 3a have not been described. The results imply that, in part, the same information from cutaneous receptors is relayed to areas 3b and 1, and the same information from deep receptors is relayed to areas 3a and 2.(ABSTRACT TRUNCATED AT 400 WORDS)


[Treatment of inoperable liver metastases: preliminary results with intrahepatic chemotherapy via a new type of indwelling catheter (author's transl)].
Intra-arterial liver perfusion of cytostatic drugs via an indwelling double-lumen polyurethane catheter was undertaken in 17 patients with diffuse metastases involving 50-70% of the liver and previously treated by radical local resections. Treatment continued over 3-20 months (mean 8.4 months). In ten patients with colorectal carcinoma treatment lasted for 7 months, follow-up for a mean of 14 months (range 5-24 months), and the one-year survival time (using the actuarial method) was 79 +/- 26%. The toxicity was well controllable. It is concluded that this form of treatment improves quality of life in such patients.


Interfacial mechanical properties of tetrahydrofuran hydrate-solid surfaces: Implications for hydrate management.
Understanding the interfacial mechanical properties between hydrate and solids is vital to designing and fabricating surfaces for hydrate management. Herein, the role of the surface wettability, the type of solid substrate and temperature on the interfacial adhesion properties of tetrahydrofuran (THF) hydrate and ice were examined by force analysis based shearing measurements and molecular dynamics (MD) simulations. The results showed that the adhesion strength of THF hydrate and ice on silica varies with the compositions of coating, and the adhesion strength of ice is larger than that of THF hydrate for all investigated solid substrates. Particularly, in contrast to a linear relationship between 1 + cosθr and hydrate adhesion on organic silanes/thiols/polymer surfaces, the hydrate adhesion on the coated inorganic glass surfaces is enhanced as a function of 1 + cosθr, in which θr is the receding contact angle. MD simulations uncovered that the adhesion strength of ice on solid substrates is dominated by the quasi-liquid water layer, however, that of hydrate is governed not only by the quasi-liquid layer but also newly formed unconventional clathrate cages. This study provides new insights and perspectives into the hydrate adhesion on solid surfaces, which is of help to develop hydrate-phobic coatings for advanced hydrate management.


Weak feature enhancement in machinery fault diagnosis using empirical wavelet transform and an improved adaptive bistable stochastic resonance.
Machinery vibration signal is a typical multi-component signal and fault features are often submerged by some interference components. To accurately extract fault features, a weak feature enhancement method based on empirical wavelet transform (EWT) and an improved adaptive bistable stochastic resonance (IABSR) is proposed. This method makes full use of the signal decomposition performance of EWT and the signal enhancement of the IABSR to achieve the purpose of fault feature enhancement in low frequency band of FFT spectrum. Firstly, EWT is used as the preprocessing program of bistable stochastic resonance (BSR) to decompose the machinery vibration signal into a set of sub-components. Then, the sensitive component that contains main fault information is further input into BSR system to enhance fault features with the assistance of residual noises. Finally, the fault features are identified from fast Fourier transform (FFT) spectrum of the BSR output. To achieve the optimal BSR output, the IABSR method based on salp swarm algorithm (SSA) is presented. Compared with the tradition adaptive BSR (ABSR), the IABSR optimizes not only the BSR system parameters but also the calculation step size. Two case studies on machinery fault diagnosis demonstrate the effectiveness and superiority of the proposed method. In addition, the proposed method is easy to implement and is robust to noise to some extent.


An in vitro tumorigenesis model based on live-cell-generated oxygen and nutrient gradients.
The tumor microenvironment (TME) is multi-cellular, spatially heterogenous, and contains cell-generated gradients of soluble molecules. Current cell-based model systems lack this complexity or are difficult to interrogate microscopically. We present a 2D live-cell chamber that approximates the TME and demonstrate that breast cancer cells and macrophages generate hypoxic and nutrient gradients, self-organize, and have spatially varying phenotypes along the gradients, leading to new insights into tumorigenesis.


Prevalence of Frailty in Brazilian Older Adults: A Systematic Review and Meta-analysis.
Frailty is characterized by a functioning decline in multiple systems accompanied by an increase in individual's vulnerability to stressors. It appears to be higher in low and middle-income countries compared with high-income ones. This study aimed to evaluate the prevalence of frailty in non-institutionalized Brazilian older adults. a systematic review and meta-analysis study. Cross-sectional and prospective data from Brazil. non-institutionalized adults aged 60 and older. Electronic searches were performed in PubMed/MEDLINE, LILACS, SCOPUS and Web of Science, considering the studies published between March 2001 and July 2018, using a combination of the following terms and correlates: "elder" AND "frail" AND "prevalence" AND "Brazil". Two independent reviewers selected studies according to the inclusion criteria. Disagreements were resolved by a third reviewer (title/abstract) and by consensus. Studies with samples ≥221 subjects were considered for meta-analysis. 28 studies were included, while 18 had the data meta-analyzed. The majority of studies (61%) included older adults only from the Southeastern region. The number of subjects ranged from 53 to 5,532 individuals (N = 17,604) and the average age ranged from 65.6 to 85.5 years. The overall prevalence of frailty was 24%. When considering the different assessment methods, the prevalence was lower for frailty phenotype (16%) compared with other criteria (40%). Regarding sex, the prevalence of frailty was similar for women (28%) and men (25%). The prevalence of frailty was higher in older adults recruited from health care services (30%) compared to community ones (22%). In Brazil, the overall prevalence of frailty in non-institutionalized older adults is higher than observed from more developed countries. However, it may vary according to the assessment methods and settings.


Stimulation of cell division in ectopic kidney grafts following unilateral removal of the lung.
Small fragments of kidney tissue were grafted into the right lung (Xenopus laevis) and the left lung was subsequently removed. This stimulated compensatory hyperplasia (increased mitotic rate) in alveolar tissue of the right lung and in the kidney graft. This suggests that the stimulus to compensatory hyperplasia is location-specific rather than tissue- or organ-specific. After implantation into the lung the kidney grafts are revascularized by the surrounding pulmonary supply. Damage or functional impairment of an organ usually produces a localized increase in the rate of blood flow and we therefore propose that this may lead to an increased rate of cell division in one of two ways: by permitting an increased functional capacity in the tissue concerned, or by causing a more rapid local clearance of mitotic control factors.


Psychiatric role conflicts in the neighborhood health setting.
The current movement of psychiatrists toward the health care system, and away from community mental health, has led to increased psychiatric presence in neighborhood health centers. Neighborhood settings confront the traditionally trained psychiatrist with role and value conflicts, some of which parallel those experienced in community mental health. These conflicts include definition of professionalism, the nature of psychotherapy, and hierarchical power. Other conflicts are specific to the neighborhood health setting, including the place of confidentiality, multidisciplinary relations, and the medical model and remedicalization in psychiatric practice. Residency training must be altered to adequately prepare psychiatrists for these new roles.


New species and new records of Tingidae (Hemiptera. Heteroptera) from Thailand.
Eight species new to science are described from Thailand and 35 species new to Thailand are recorded. The fauna of Thailand, represented formerly by 12 species is increased to 52 species here. Comments on their distribution are added. Most of the species recorded come from material collected in the mid XXth century and deposited in Museums and from recent collecting surveys.


Substituted 4-aminopiperidines having high in vitro affinity and selectivity for the cloned human dopamine D4 receptor.
We have discovered two substituted 4-aminopiperidine compounds having high in vitro affinity and selectivity for the human dopamine D1 receptor. Both compounds, 3-ethoxy-N-methyl-N-[1-(phenylmethyl)-4-piperidinyl]-2-pyridinylamine (U-99363E), and its 3-isopropoxy analog (U-101958), were found through a routine receptor binding screen. The determined affinities (Ki) of these compounds for the cloned human dopamine D4 receptor were 2.2 and 1.4 nM, respectively. They exhibited at least 100-fold lower affinities for dopamine D2 and for other dopaminergic, serotonergic and adrenergic receptors. Both compounds were found to antagonize quinpirole-induced mitogenesis in Chinese hamster ovary cells expressing the human dopamine D4 receptor. In spite of their poor metabolic stability and low bioavailability. U-99363E and U-101958 appear to be among the first high-affinity, highly selective dopamine D4 receptor antagonists reported, and may have utility in in vitro investigations requiring selective tagging or blockade of dopamine D4 sites.


Atypical case of ocular hemosiderosis: leopard cataract.
We present an interventional case report of an 83-year-old woman who developed ocular hemosiderosis secondary to massive retinal and intravitreal bleeding associated with a choroidal neovascular membrane as a result of age-related macular degeneration. Anterior segment manifestations included low-grade inflammation, posterior synechiae, reversible hyperchromic heterochromia, and a mature cataract with "leopard spots." The longstanding vitreous hemorrhage was thought to be the etiology of these findings. At the request of the vitreoretinal surgeon, cataract surgery was performed to provide visualization of the posterior segment. However, the patient's visual potential was limited by her underlying retinal pathology. Neither author has a financial or proprietary interest in any material or method mentioned. Additional disclosure is found in the footnotes.


Prenatal stress: course and interrelation of emotional and physiological stress measures.
Prenatal stress is known to be a potential risk factor for cognitive, behavioural and motor development that even last until adolescence. A consensus of how 'prenatal stress' can be measured, in which trimester of pregnancy women should be studied and whether subjective feelings of being stressed are associated with a hormonal response is still lacking. To close this gap, a prospective longitudinal study was conducted in pregnant women. 108 subjects were asked to fill out questionnaires concerning pregnancy-related anxiety, perceived stress, marital satisfaction, critical life events and to collect salivary cortisol in each trimester of pregnancy. Fear of giving birth increases until the end of pregnancy, and marital satisfaction is highest at the end of pregnancy. Perceived stress is related to a hormonal response in cortisol only in the first (r = 0.18, p < 0.10) and second (r = 0.18, p < 0.10) trimesters of pregnancy. Critical life events are linked to raised cortisol levels in early pregnancy only (r = 0.28, p < 0.01). Prenatal stress can be operationalized by using different subjective as well as physiological stress measures. Only in the first half of pregnancy self-report and physiological stress measures seem to be associated.


Mitochondrial defect drives non-autonomous tumour progression through Hippo signalling in Drosophila.
Mitochondrial respiratory function is frequently impaired in human cancers. However, the mechanisms by which mitochondrial dysfunction contributes to tumour progression remain elusive. Here we show in Drosophila imaginal epithelium that defects in mitochondrial function potently induce tumour progression of surrounding tissue in conjunction with oncogenic Ras. Our data show that Ras activation and mitochondrial dysfunction cooperatively stimulate production of reactive oxygen species, which causes activation of c-Jun amino (N)-terminal kinase (JNK) signalling. JNK cooperates with oncogenic Ras to inactivate the Hippo pathway, leading to upregulation of its targets Unpaired (an interleukin-6 homologue) and Wingless (a Wnt homologue). Mitochondrial dysfunction in Ras-activated cells further cooperates with Ras signalling in neighbouring cells with normal mitochondrial function, causing benign tumours to exhibit metastatic behaviour. Our findings provide a mechanistic basis for interclonal tumour progression driven by mitochondrial dysfunction and oncogenic Ras.


A simple spectrophotometric method for the determination of beta-blockers in dosage forms.
A simple, extraction-free spectrophotometric method is proposed for the analysis of some beta-blockers, namely atenolol, timolol and nadolol. The method is based on the interaction of the drugs in chloroform with 0.1% chloroformic solutions of acidic sulphophthalein dyes to form stable, yellow-coloured, ion-pair complexes peaking at 415 nm. The dyes used were bromophenol blue (BPB), bromothymol blue (BTB) and bromocresol purple (BCP). Under the optimum conditions, the three drugs could be assayed in the concentration range 1-10 microg ml(-1) with correlation coefficient (n = 5) more than 0.999 in all cases. The stoichiometry of the reaction was found to be 1:1 in all cases and the conditional stability constant (K(F)) of the complexes have been calculated. The free energy changes (DeltaG) were determined for all complexes formed. The interference likely to be introduced from co-formulated drugs was studied and their tolerance limits were determined. The proposed method was then applied to dosage-forms the percentage recoveries ranges from 99.12-100.95, and the results obtained were compared favorably with those given with the official methods.


Multi-omics analysis reveals the ontogenesis of basal chichi in Ginkgo biloba L.
Chichi is a unique biological phenomenon observed in Ginkgo biloba L.. In this study, multi-omics analysis was used to compare basal chichi (C) with roots (R) and stems (S) to explore the regulatory mechanisms of basal chichi ontogenesis. The results showed that compared with roots and stems, the tZ, SA and ABA contents in basal chichi were the highest, and the ratio of IAA/tZ was the lowest. Nucleotides and their derivatives in basal chichi were upregulated, and phenylpropane metabolites were downregulated. Some differentially expressed genes (DEGs) strongly correlated to plant hormones were screened. We speculate that auxin and cytokinin are involved in the morphogenesis of basal chichi and that cytokinin plays a major role. The ontogenesis of basal chichi is closely related to environmental stress, and it may be a coping strategy of G. biloba in the face of environmental stress.


[Deinstitutionalization: myth or reality (present-day aspects of returning mentally ill patients to society in the United States].
From a recent journey in the U.S.A. we bring any news about deinstitutionalization. This current is not knew as soon as it must in France and connoted of ideological conceptions, which are very distant from the real practices.


Evaluation of Reliability and Correlations of Quality Measures in Cancer Care.
Measurement of the quality of care is important for alternative payment models in oncology, yet the ability to distinguish high-quality from low-quality care across oncology practices remains uncertain. To assess the reliability of cancer care quality measures across oncology practices using registry and claims-based measures of process, utilization, end-of-life (EOL) care, and survival, and to assess the correlations of practice-level performance across measure and cancer types. This cross-sectional study used the Surveillance, Epidemiology, and End Results (SEER) Program registry linked to Medicare administrative data to identify individuals with lung cancer, breast cancer, or colorectal cancer (CRC) that was newly diagnosed between January 1, 2011, and December 31, 2015, and who were treated in oncology practices with 20 or more patients. Data were analyzed from January 2018 to December 2020. Receipt of guideline-recommended treatment and surveillance, hospitalizations or emergency department visits during 6-month chemotherapy episodes, care intensity in the last month of life, and 12-month survival were measured. Summary measures for each domain in each cohort were calculated. Practice-level rates for each measure were estimated from hierarchical linear models with practice-level random effects; practice-level reliability (reproducibility) for each measure based on the between-measure variance, within-measure variance, and distribution of patients treated in each practice; and correlations of measures across measure and cancer types. In this study of SEER registry data linked to Medicare administrative data from 49 715 patients with lung cancer treated in 502 oncology practices, 21 692 with CRC treated in 347 practices, and 52 901 with breast cancer treated in 492 practices, few practices had 20 or more patients who were eligible for most process measures during the 5-year study period. Patients were 65 years or older; approximately 50% of the patients with lung cancer and CRC and all of the patients with breast cancer were women. Most measures had limited variability across practices. Among process measures, 0 of 6 for lung cancer, 0 of 6 for CRC, and 3 of 11 for breast cancer had a practice-level reliability of 0.75 or higher for the median-sized practice. No utilization, EOL care, or survival measure had reliability across practices of 0.75 or higher. Correlations across measure types were low (r ≤ 0.20 for all) except for a correlation between the CRC process and 1-year survival summary measures (r = 0.35; P < .001). Summary process measures had limited or no correlation across lung cancer, breast cancer, and CRC (r ≤ 0.16 for all). This study found that quality measures were limited by the small numbers of Medicare patients with newly diagnosed cancer treated in oncology practices, even after pooling 5 years of data. Measures had low reliability and had limited to no correlation across measure and cancer types, suggesting the need for research to identify reliable quality measures for practice-level quality assessments.


Image-based deep learning in diagnosing the etiology of pneumonia on pediatric chest X-rays.
Comparing the efficacy of a deep-learning model in classifying the etiology of pneumonia on pediatric chest X-rays (CXRs) with that of human readers. We built a clinical-pediatric CXR set containing 4035 patients to exploit a deep-learning model called Resnet-50 for differentiating viral from bacterial pneumonia. The dataset was split into training (80%) and validation (20%). Model performance was assessed by receiver operating characteristic curve and area under the curve (AUC) on the first test set of 400 CXRs collected from different studies. For the second test set composed of 100 independent examinations obtained from the daily clinical practice at our institution, the kappa coefficient was selected to measure the interrater agreement in a pairwise fashion for the reference standard, all reviewers, and the model. Gradient-weighted class activation mapping was used to visualize the significant areas contributing to the model prediction. On the first test set, the best-performing classifier achieved an AUC of 0.919 (p < .001), with a sensitivity of 79.0% and specificity of 88.9%. On the second test set, the classifier achieved performance similar to that of human experts, which resulted in a sensitivity of 74.3% and specificity of 90.8%, positive and negative likelihood ratios of 8.1 and 0.3, respectively. Contingence tables and kappa values further revealed that expert reviewers and model reached substantial agreements on differentiating the etiology of pediatric pneumonia. This study demonstrated that the model performed similarly as human reviewers and recognized the regions of pathology on CXRs.


An intervention study-the aspirin myocardial infarction study.
The Aspirin Myocaridal Infarction Study is a randomized, double-blind clinical trial designed to study the potential value of aspirin in the reduction of mortality in patients who have had a prior myocardial infarction. This trial is based upon several previously published studies which suggest that aspirin may be valuable iprevention of coronary thrombosis. The requirement of 4200 patients dictates that the study must be multicenter, and good design requires that the study be collaborative with cnetral monitoring and an elaborate committee structure to insure uniformity and comparability.


[Topiramate in chronic daily headache due to migraine].
Chronic daily headache (CDH) includes primary headaches that last more than four hours with a frequency equal or superior to 15 days a month over the last three months. It has a prevalence of 4-5% in the general population and is a frequent reason for visiting the physician in headache units. To evaluate the effectiveness of topiramate, as the primary drug, in CDH due to probable chronic migraine with or without medication abuse. From the 447 patients with migraine in our database, we selected those: a) satisfying Silberstein criteria for CDH; b) that had not followed prior prophylactic treatment; and c) who were treated with topiramate as the primary drug. The mean number of days with headache and bouts of severe migraine in the fourth month of treatment using topiramate as compared to the month preceding treatment, as well as the percentage of responses and the rate of respondents in the fourth month were all analysed. Eighty-three patients (88% females) with a mean age of 38.0 +/- 14.13 years were selected. Medication abuse was reported in 44% of cases. At the fourth month of treatment, the mean number of days with headache dropped significantly from 20.8 to 7.9 (p < 0.0001) and the mean number of bouts of severe migraine diminished from 4.4 to 1.7 (p < 0.0001). The rate of respondents was 72%. Medication abuse continued in 14% of cases. Side effects were produced in 58% of patients and the dropout rate was 24%. Topiramate proved to be effective in the treatment of CDH due to probable chronic migraine and with probable medication abuse in de novo migraine patients.


Extraoral anterior approach for the treatment of os odontoideum: illustrative case.
Os odontoideum is typically treated with instrumented fusion through a posterior cervical approach. When this approach fails, limited options for revision are available. Occipitocervical fusion and transoral anterior fusions have been utilized in the past but are associated with high morbidity and complications. Here the authors report a case of os odontoideum that was treated with an anterior cervical extraoral approach after failed posterior instrumented fusion. They discuss the challenges that can be encountered with the failure of fusion and the limited options when it comes to approach and fixation of os odontoideum. To the authors' knowledge and based on a review of the literature, this case represents the first use of an anterior extraoral prevascular approach to the high cervical spine to address os odontoideum. They demonstrate that this approach can be utilized as a reasonable alternative to transoral surgery and should be considered in cases where additional or alternative fixation is desired without the morbidity and complications associated with occipitocervical fusion or a transoral approach, especially in a younger patient population.


Zinc phthalocyanine conjugated with the amino-terminal fragment of urokinase for tumor-targeting photodynamic therapy.
Photodynamic therapy (PDT) has attracted much interest for the treatment of cancer due to the increased incidence of multidrug resistance and systemic toxicity in conventional chemotherapy. Phthalocyanine (Pc) is one of main classes of photosensitizers for PDT and possesses optimal photophysical and photochemical properties. A higher specificity can ideally be achieved when Pcs are targeted towards tumor-specific receptors, which may also facilitate specific drug delivery. Herein, we develop a simple and unique strategy to prepare a hydrophilic tumor-targeting photosensitizer ATF-ZnPc by covalently coupling zinc phthalocyanine (ZnPc) to the amino-terminal fragment (ATF) of urokinase-type plasminogen activator (uPA), a fragment responsible for uPA receptor (uPAR, a biomarker overexpressed in cancer cells), through the carboxyl groups of ATF. We demonstrate the high efficacy of this tumor-targeting PDT agent for the inhibition of tumor growth both in vitro and in vivo. Our in vivo optical imaging results using H22 tumor-bearing mice show clearly the selective accumulation of ATF-ZnPc in tumor region, thereby revealing the great potential of ATF-ZnPc for clinical applications such as cancer detection and guidance of tumor resection in addition to photodynamic treatment.


Plasminogen activator inhibitor-1 expression and secretion are stimulated by growth hormone and interleukin-6 in 3T3-L1 adipocytes.
Various adipocytokines have been described which influence insulin sensitivity and vascular function profoundly and might, therefore, potentially link obesity, insulin resistance, and atherosclerosis. Among those, plasminogen activator inhibitor (PAI)-1 is an adipose-secreted factor upregulated in obesity and insulin resistance that inhibits fibrinolysis. Furthermore, recent studies in knockout mice suggest that PAI-1 directly impairs insulin sensitivity. In the current study, the impact of growth hormone (GH) and interleukin (IL)-6 on PAI-1 mRNA synthesis and secretion was determined in 3T3-L1 adipocytes. Interestingly, 500 ng/ml GH and 30 ng/ml IL-6 increased PAI-1 secretion five-fold and 3.6-fold, respectively. Furthermore, GH and IL-6 induced PAI-1 mRNA by up to 7.3-fold, and 3.6-fold, respectively, in a time-dependent fashion with significant stimulation seen at concentrations as low as 5 ng/ml GH and 10 ng/ml IL-6. Other insulin resistance-inducing hormones which stimulated PAI-1 synthesis included insulin, TNFalpha, and dexamethasone. Studies using pharmacological inhibitors suggested that basal and GH-induced PAI-1 synthesis were at least in part mediated by p44/42 mitogen-activated protein kinase but not janus kinase 2 and phosphatidylinositol 3-kinase. Taken together, our results show a differential regulation of PAI-1 mRNA by insulin resistance-inducing hormones including GH and IL-6.


Imidazoline derivative templated synthesis of broccoli-like Bi2S3 and its electrocatalysis towards the direct electrochemistry of hemoglobin.
A broccoli-like bismuth sulfide (bBi2S3) was synthesized via a solvothermal method using a self-made imidazoline derivative of 2-undecyl-1-dithioureido-ethyl-imidazoline as the soft template. The morphology and chemical constitution of the product were characterized by scanning electron microscope (SEM), transmission electron microscope (TEM) and X-ray diffraction (XRD). Electrochemical characterization experiments show that the bBi2S3 has the higher specific surface area and standard heterogeneous electron transfer rate constant than the rod-like Bi2S3 (rBi2S3). Hemoglobin (Hb) was then chosen as a protein model to investigate the electrocatalytic property of the synthesized bBi2S3. The results show that Hb entrapped in the composite film of chitosan and bBi2S3 displays an excellent direct electrochemistry, and retains its biocatalytic activity toward the electro-reduction of hydrogen peroxide. The current response in the amperometry shows a linear response to H2O2 concentrations in the range from 0.4 to 4.8µM with high sensitivity (444µAmM(-1)) and low detection limit (0.096µM). The Michaelis-Menten constant (KM(app)) of the fabricated bioelectrode for H2O2 was determined as low as 1µM. These results demonstrate that the synthesized bBi2S3 offers a new path for the immobilization of redox-active protein and the construction of the third-generation biosensors.


Toward a framework for developing an ICF-based documentation system in spinal cord injury-specific rehabilitation based on routine clinical practice: a case study approach.
Case study. To present a framework for developing an International Classification of Functioning, Disability and Health (ICF)-based documentation system in spinal cord injury (SCI)-specific rehabilitation. Data collection took place at Maharaj Hospital, Thailand. The preparatory studies and analysis were performed at Swiss Paraplegic Research, Switzerland. Data collected from interviews and health records of four SCI cases across the continuum of care (acute, post-acute, early and late long term) were linked to ICF categories using established ICF linking rules. The resulting categories were compared with selected ICF sets (ICF Generic-30, ICF core sets for SCI and multiple sclerosis) to determine the extent of coverage. Furthermore, the context of applicable services was described systematically. Less than half of the ICF categories in the defined ICF sets were covered by clinical assessment tools. Low correspondence was found predominantly in acute and late long-term phase. Least well covered were categories of activities and participations and environmental factors. The correspondence of categories increased when considering the additional ICF categories identified from patient interviews. The description of rehabilitation services provided in each case classified according to the dimensions of service provider, funding, and service delivery. There is a need to promote the systematic and standardized assessment of functioning among health professionals working in the field of SCI in developing countries. This study describes basic steps toward developing a standardized ICF-based system for assessing and reporting functioning outcomes in SCI rehabilitation and across the continuum of care.


A novel HLA-DPB1 allele, HLA-DPB1*1447:01, identified by next-generation sequencing.
HLA-DPB1*1447:01 differs from HLA-DPB1*04:01:01 by a single nucleotide in exon 2 from A to C at position 134.


Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors.
Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a GIPR/GLP-1R dual agonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their multiplexed pharmacological actions over monoagonists such as semaglutide, we determine cryo-electron microscopy structures of tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR. The structures reveal both common and unique features for the dual and triple agonism by illustrating key interactions of clinical relevance at the near-atomic level. Retention of glucagon function is required to achieve such an advantage over GLP-1 monotherapy. Our findings provide valuable insights into the structural basis of functional versatility of tirzepatide and peptide 20.


Comparison of liposomal amphotericin B alone and in combination with flucytosine in the treatment of non-HIV Cryptococcal meningitis: A nationwide observational study.
Cryptococcal meningitis (CM) is an opportunistic infectious disease that occurs in immunocompromised hosts, not only in patients living with HIV, but also in patients without HIV. The evidence regarding the treatment for CM in patients without HIV is mainly found in small retrospective studies and is extremely limited. In the present study, we compared the efficacy of liposomal amphotericin B (L-AMB) alone and in combination with flucytosine (5-FC) for the induction treatment of CM in patients without HIV. Data were gathered from the Japanese Diagnosis Procedure Combination database obtained from hospitals throughout Japan. The study included 517 patients without HIV but having CM who fulfilled the inclusion and exclusion criteria. We analysed the average effect of adding 5-FC to L-AMB treatment using the survival time within 14 days of the diagnosis after adjustment of the baseline clinical characteristics with associations with both selections of the treatment and the prognosis. A total of 146 and 217 CM patients received L-AMB and L-AMB with 5-FC, respectively, within 7 days of diagnosis. L-AMB with 5-FC showed better prognosis than L-AMB on day 14 (mortality 6% vs. 11%, hazard ratio, 0.5775; 95% confidence interval, 0.2748-1.213; p = 0.1, Wald test). From the results of this real-world database study, we revealed that the combination therapy of 5-FC on L-AMB for induction therapy might have an advantage on the survival time of NHNT patients with CM as well as PLHIV patients with CM.


Medical versus surgical management of prolactinomas.
Prolactinomas are the most common hormone-secreting pituitary adenomas, comprising 40% of all pituitary tumors. Prolactinomas present a unique challenge for clinicians, as these tumors are amenable to either medical or surgical treatments based on patients' comorbidities, tolerance to medical treatment, and the response of tumors to medical treatment. Rare prolactinomas that are unresponsive to either medical or surgical treatment modalities may be responsive to radiation therapy. This article reviews the recent advancements in the management of prolactinomas.


Centrally mediated effects of neurohypophyseal hormones.
The neurohypophyseal hormones oxytocin and vasopressin cause a variety of biological effects in animals which are mediated by central nervous system mechanisms. Among the best studied of these effects is the modulation of both memory processes and the development of drug tolerance and dependence. Neurohypophyseal hormones have also been shown to alter various physiological parameters such as heart rate and body temperature following central administration. In addition, these peptides can profoundly alter spontaneous, unlearned behavior in several rodent species. Many of the centrally mediated effects of neurohypophyseal hormones have been shown to be elicited at sites within the brain stem and the limbic system where vasopressin and oxytocin occur in cell bodies, axons and nerve terminals, suggesting a physiological role for these peptide effects. The various central effects of neurohypophyseal hormones involve different mechanisms which can be distinguished from one another on the basis of required dose, time-course of action, and structure-activity relationships. Thus, alterations of spontaneous behavior are mediated by putative receptors closely related to vasopressin receptors in blood vessels responsible for the peripheral pressor response while the effects on memory processes are mediated by a mechanism which is not closely related to those involved in the peripheral hormonal effects of the peptides. The influence of neurohypophyseal hormones on memory and attention may be useful clinically. A potential role for these peptides in mental disorders is discussed.


Stability of Lisfranc injury fixation in Thiel Cadavers: Is routine fixation of the 1st and 3rd tarsometatarsal joint necessary?
There is debate as to whether a home run screw (medial cuneiform to 2nd metatarsal base) combined with k-wire fixation of the 4th & 5th tarsometatarsal joints is sufficient to stabilise Lisfranc injuries or if fixation of the 1st and 3rd tarsometatarsal joints is also required. Unlike the 2nd, 4th and 5th tarsometatarsal joints, stabilisation of the 1st and 3rd requires either intra-articular screw or an extra-articular plate which risk causing chondrolysis and/or osteoarthritis. The aims of this cadaveric study were to determine if routine fixation of the 1st and 3rd tarsometatarsal joints is necessary and to determine if a distal to proximal home run screw is adequate. Using 8 Theil-embalmed specimens, measurements of tarsometatarsal joint dorsal displacement at each ray (1st-5th) and 1st-2nd metatarsal gaping were made during simulated weight bearing with sequential ligamentous injury and stabilisation to determine the contribution of anatomical structures and fixation to stability. At baseline, mean dorsal tarsometatarsal joint displacement of the intact specimens during simulated weight bearing (mm) was: 1st: 0.14, 2nd: 0.1, 3rd:0, 4th: 0, 5th: 0.14. The 1st-2nd intermetatarsal gap was 0mm. After transection of the Lisfranc ligament only, there was 1st-2nd intermetatarsal gaping (mean 4.5mm), but no increased dorsal displacement. After additional transection of all the tarsometatarsal joint ligaments, dorsal displacement increased at all joints (1st: 4.5, 2nd: 5.1, 3rd: 3.6, 4th: 2, 5th: 1.3). Stabilisation with the home run screw and 4th and 5th ray k-wires virtually eliminated all displacement. Further transection of the inter-metatarsal ligaments increased mean dorsal displacement of the 3rd ray to 2.5mm. K-wire fixation of the 3rd ray completely eliminated dorsal displacement. The results of this cadaveric study suggest that stabilising the medial cuneiform to the 2nd metatarsal base combined with stabilisation of the 4th and 5th tarsometatarsal joints with K-wires will stabilise the 1st and 3rd tarsometatarsal joints if the inter-metatarsal ligaments are intact. Thus 3rd TMTJ stability should be checked after stabilising the 2nd and 4/5th. Provided the intermetatarsal ligaments (3rd-4th) are intact, the 3rd ray does not need to be routinely stabilised.


The Prince Henry Hospital dementia caregivers' training programme.
To describe the theory, elements and practice of a successful caregiver training programme; and report the 8-year outcome. Prospective, randomized control trial and longitudinal follow-up over approximately 8 years. Psychiatry unit, general teaching hospital, Sydney, Australia. 96 persons less than 80 years old with mild to moderate dementia and their cohabiting caregivers. All patients received a 10-day structured memory retraining and activity programme. Caregivers in the immediate and wait-list caregiver training groups received a structured, residential, intensive 10-day training programme, boosted by follow-ups and telephone conferences over 12 months. Those in the wait-list group entered the programme after waiting 6 months. The third group of caregivers received 10 days' respite (while patients underwent their memory retraining programme) and 12 months booster sessions as for the other groups. Nursing home admission; time until patient death. 64% of patients whose caregivers were in the immediate training group, 53% of wait-list group patients and 70% of memory retraining patients had died. Nursing home admission had occurred in 79% of the immediate training, 83% of the delayed and 90% of the memory retraining group. Eight-year survival analysis indicated that patients whose caregivers received training stayed at home significantly longer (p = 0.037) and tended to live longer (p = 0.08). Caregiver training programmes demonstrably can delay institutionalization of people with dementia.


Encapsulated follicular thyroid tumor with equivocal nuclear changes, so-called well-differentiated tumor of uncertain malignant potential: a morphological, immunohistochemical, and molecular appraisal.
There is a continuous debate regarding the classification of thyroid follicular lesions and the term "well-differentiated tumor of uncertain malignant potential (WDT-UMP)" was recently introduced to cover this problematic spectrum of tumors. The objective of this study was to reappraise WDT-UMP using morphological, immunochemical, and molecular analysis and to shed more light on encapsulated thyroid follicular-patterned tumors. A total of 30 cases of WDT-UMP with equivocal papillary thyroid carcinoma-type nuclear changes (PTC-N) or focal unequivocal PTC-N were examined. As a control, follicular adenoma (n = 29), follicular carcinoma (n = 8), hyalinizing trabecular adenoma (n = 5), and PTC (n = 48) were included. HBME-1, cytokeratin 19, and galectin-3 were positive in 12 (40.0%), 10 (33.3%) and 11 (36.7%) cases of WDT-UMP, respectively. According to the positivity of those markers, significant differences were obtained between WDT-UMP and PTC encapsulated common type (P = 0.028, 0.010, and 0.004, respectively), infiltrative follicular variant (P = 0.020, 0.026, and 0.008, respectively), and infiltrative common type (P = 0.004, 0.001, and 0.005, respectively), but not between WDT-UMP and follicular adenoma or follicular carcinoma. BRAF(V600E) mutation was absent but RET/PTC1 rearrangement was found in only two (6.7%) cases of WDT-UMP. None of the 20 patients with WDT-UMP developed recurrence, with an average follow-up of 80 months. These findings indicate that WDT-UMP has a favorable outcome and is distinct from PTC in morphological, immunohistochemical, and molecular characteristics. We propose that WDT-UMP should be classified as "well-differentiated tumor with uncertain behavior".


[Spermatogenesis in old age--nuclear DNA determination by flow cytophotometry in testicular samples of older men for the quantification of spermatogenesis].
The flow cytometric determination of the nuclear DNA content of testicular samples permits a fast and reliable quantification of spermatogenesis. 70 testicular samples from men over 50 years of age were analysed with this method. 60% of the samples showed a distinct reduction of spermatogenesis. Only three men showed a nonreduced spermatogenesis in both testes. Comparing the results of the measurements of both testes, in nearly half of the testes pairs a reduction of the germ cell number below two thirds of the better side was striking. In one patient, a Leydig cell tumor was detected by chance by an aneuploidy.


Ossification in the wall of a radicular cyst: report of a case.
An unusual case of a maxillary radicular cyst that contained bone in the wall is presented. In our opinion, this finding was the result of a reparative process that started after the extraction of the tooth responsible for the original formation of the cyst.


Potential skin protective effects after UVB irradiation afforded by an antioxidant peptide from Odorrana andersonii.
With increasing demand, the development of new natural antioxidants has become a primary direction of scientific research. We previously identified a short gene-encoded peptide (OA-VI12) from Odorrana andersonii frog skin secretions that exerted direct scavenging capacity against free radicals, suggesting a possible function in protecting skin against photodamage caused by their high-altitude habitat. In the current research, we examined the effects of OA-VI12 on both UVB-irradiation and hydrogen peroxide-induced oxidative stress models established with human immortalized keratinocytes. In addition, we identified the differentially expressed genes (DEGs) in the oxidative stress and OA-VI12 groups and further performed transcriptome as well as functional and pathway enrichment analyses. Results showed that OA-VI12 protected cell viability, promoted the release of catalase, and decreased the levels of lactate dehydrogenase and reactive oxygen species. Moreover, the peptide promoted the production of superoxide dismutase and glutathione, alleviated epidermis and dermis thickness, and decreased the production of light spots and collagen fibers in skin from the photo-injured mouse model. Kyoto Encyclopedia of Genes and Genomes analysis showed mitogen-activated protein kinase (MAPK) to be the most abundant signaling pathway. Gene Ontology (GO) analysis indicated that the top 55 significantly enriched GO terms mainly involved cellular processes, parts, and binding. These results revealed the beneficial role of the small molecule gene-encoding antioxidant peptide (OA-VI12) and its potential application as a protective agent against photodamage.


Fungal colonization of sago starch in Papua New Guinea.
Sago starch is an important source of dietary carbohydrates in lowland Papua New Guinea. Over the past 30 years there have been sporadic reports of severe illness following consumption of sago starch. A common assumption is that fungal metabolites might be associated with the illness, leading to the need for a more thorough investigation of the mycoflora of sago starch. Sago starch was collected from areas of high sago consumption in Papua New Guinea for fungal analysis (69 samples). Storage methods and duration were recorded at the time of collection and pH on arrival at the laboratory. Yeasts were isolated from all samples except two, ranging from 1.2 x 10(3) to 8.3 x 10(7) cfu/g. Moulds were isolated from 65 of the 69 samples, ranging from 1.0 x 10(2) to 3.0 x 10(6) cfu/g. Of 44 samples tested for ergosterol content, 42 samples showed the presence of fungal biomass. Statistical analyses indicated that sago starch stored for greater than five weeks yielded significantly higher ergosterol content and higher numbers of moulds than sago stored for less than five weeks. The method of storage was also shown to influence mould numbers with storage in natural woven fibre containers returning significantly greater numbers than present in other storage methods tested. Potentially mycotoxigenic genera of moulds including Aspergillus and Penicillium were commonly isolated from sago starch, and as such storage factors that influence the growth of these and other filamentous fungi might contribute to the safety of traditional sago starch in PNG.


The future of pediatric US.
Despite advances in other modalities, US remains an essential technology in pediatric imaging. Improvements in technology provide increasingly detailed anatomical images, and new techniques show promise in providing novel anatomical as well as physiological and structural information. Other specialties are recognizing the value of US to their patients and are increasingly performing their own examinations. Economic and social factors are also influencing the development and use of US. This review will evaluate many of these issues and demonstrate that the future of pediatric US is bright and that pediatric radiologists can and should continue to be leaders in its use and development.


Impact of Early Life Antibiotic Exposure and Neonatal Hyperoxia on the Murine Microbiome and Lung Injury.
Cross talk between the intestinal microbiome and the lung and its role in lung health remains unknown. Perinatal exposure to antibiotics disrupts the neonatal microbiome and may have an impact on the preterm lung. We hypothesized that perinatal antibiotic exposure leads to long-term intestinal dysbiosis and increased alveolar simplification in a murine hyperoxia model. Pregnant C57BL/6 wild type dams and neonatal mice were treated with antibiotics before and/or immediately after delivery. Control mice received phosphate-buffered saline (PBS). Neonatal mice were exposed to 95% oxygen for 4 days or room air. Microbiome analysis was performed using 16S rRNA gene sequencing. Pulmonary alveolarization and vascularization were analyzed at postnatal day (PND) 21. Perinatal antibiotic exposure modified intestinal beta diversity but not alpha diversity in neonatal mice. Neonatal hyperoxia exposure altered intestinal beta diversity and relative abundance of commensal bacteria in antibiotic treated mice. Hyperoxia disrupted pulmonary alveolarization and vascularization at PND 21; however, there were no differences in the degree of lung injury in antibiotic treated mice compared to vehicle treated controls. Our study suggests that exposure to both hyperoxia and antibiotics early in life may cause long-term alterations in the intestinal microbiome, but intestinal dysbiosis may not significantly influence neonatal hyperoxic lung injury.


Immune checkpoint inhibitors-induced nephropathy: a French national survey.
Immune checkpoint inhibitors (ICIs), aiming to foster cancer-targeted immune response, proved to be effective in several advanced malignancies at the price of immune-related adverse events affecting various organs, notably the kidneys. Herein, a retrospective descriptive analysis was performed on all biopsy-confirmed cases of ICI-induced nephropathy notified to the French Pharmacovigilance database to date. Data were gathered about patients' characteristics, acute kidney injuries and histopathological features. A total of 63 biopsy-proven cases were included for analysis. Immune-related nephropathy occurred after a mean of 105.5 ± 98.6 (standard deviation) days after the introduction of the ICI. Kidney Disease: Improving Global Outcomes acute kidney injury stage 3 occurred in 36.5% of patients, and the mean peak serum creatinine was 288 µmol/L. Histopathology suggested acute tubule-interstitial nephritis in 52 patients (83%), while signs of acute tubular necrosis were found in 18 (29%) and glomerular involvement in 5 of them (8%). Another immune-related adverse event was documented in 25 patients (39.7%). Patients were treated with corticosteroids in 88.9% of cases. All in all, 27.0% fully recovered, 54.0% partially recovered, 12.7% did not recover. Rechallenge was attempted in 19 patients and one patient relapsed. Three-quarters of patients received a medication known to cause acute tubule-interstitial nephritis. The major limits of this study are those inherent to pharmacovigilance studies, such as its retrospective nature and incomplete data. Although it cannot pretend drawing any pathophysiological conclusion, this study depicts the clinical and histopathological pictures of ICI-induced nephropathies in a large cohort of biopsied patients with all grades of severity.


The use of polyelectrolyte-fractionated porcine factor VIII in the treatment of a spontaneously acquired inhibitor to factor VIII.
Polyelectrolyte-fractionated porcine factor VIII concentrate is a recent addition to the therapeutic choices for treatment of factor VIII inhibitor patients, but cross-reactivity of the inhibitor with porcine factor VIII limits its usefulness in some cases. Hemophilic patients with inhibitor titers greater than or equal to 50 Bethesda units/micromilligrams often demonstrate sufficient cross-reactivity (10-20%) to prevent the achievement of a satisfactory plasma factor VIII level and a therapeutic response with porcine factor VIII. We have studied plasma from five women with high-titer, spontaneously acquired factor VIII inhibitors to determine the degree of cross-reactivity with porcine factor VIII. Four of the five had little or no detectable inhibitor to porcine factor VIII despite high titers to human factor VIII (26-143 Bethesda units/micromilligrams). One of these patients, with a titer of 53 Bethesda units/micromilligrams against human factor VIII, was treated successfully with porcine factor VIII concentrate, given for serious hemorrhagic complications. These studies and other reports support the conclusion that the majority of high-titer spontaneous factor VIII inhibitors exhibit little cross-reactivity with porcine factor VIII and can be treated successfully with this product.


BioID identifies novel c-MYC interacting partners in cultured cells and xenograft tumors.
The BioID proximity-based biotin labeling technique was recently developed for the characterization of protein-protein interaction networks [1]. To date, this method has been applied to a number of different polypeptides expressed in cultured cells. Here we report the adaptation of BioID to the identification of protein-protein interactions surrounding the c-MYC oncoprotein in human cells grown both under standard culture conditions and in mice as tumor xenografts. Notably, in vivo BioID yielded >100 high confidence MYC interacting proteins, including >30 known binding partners. Putative novel MYC interactors include components of the STAGA/KAT5 and SWI/SNF chromatin remodeling complexes, DNA repair and replication factors, general transcription and elongation factors, and transcriptional co-regulators such as the DNA helicase protein chromodomain 8 (CHD8). Providing additional confidence in these findings, ENCODE ChIP-seq datasets highlight significant coincident binding throughout the genome for the MYC interactors identified here, and we validate the previously unreported MYC-CHD8 interaction using both a yeast two hybrid analysis and the proximity-based ligation assay. In sum, we demonstrate that BioID can be utilized to identify bona fide interacting partners for a chromatin-associated protein in vivo. This technique will allow for a much improved understanding of protein-protein interactions in a previously inaccessible biological setting. The c-MYC (MYC) oncogene is a transcription factor that plays important roles in cancer initiation and progression. MYC expression is deregulated in more than 50% of human cancers, but the role of this protein in normal cell biology and tumor progression is still not well understood, in part because identifying MYC-interacting proteins has been technically challenging: MYC-containing chromatin-associated complexes are difficult to isolate using traditional affinity purification methods, and the MYC protein is exceptionally labile, with a half-life of only ~30 min. Developing a new strategy to gain insight into MYC-containing protein complexes would thus mark a key advance in cancer research. The recently described BioID proximity-based labeling technique represents a promising new complementary approach for the characterization of protein-protein interactions (PPIs) in cultured cells. Here we report that BioID can also be used to characterize protein-protein interactions for a chromatin-associated protein in tumor xenografts, and present a comprehensive, high confidence in vivo MYC interactome. This article is part of a Special Issue entitled: Protein dynamics in health and disease. Guest Editors: Pierre Thibault and Anne-Claude Gingras.


Cross protection between a laboratory passaged Chinese strain of Schistosoma japonicum and field isolates of S. japonicum from China.
Our laboratory strain of Schistosoma japonicum has been isolated for 51 years, but is comparable to the indigenous Chinese parasite in terms of its infectivity to both the intermediate and definitive hosts. Vaccination with our strain protects mice against challenge with wild isolates of S. japonicum from China. Thus any defined antigen vaccine developed using our laboratory strain would be expected to protect against S. japonicum in the field in China.


Age-dependent modulation of DNA repair enzymes by covalent modification and subcellular distribution.
Chronic oxidative stress is generally believed to be a major etiologic factor in the aging process. In addition to modulation of signaling processes and oxidation of cellular proteins and lipids, reactive oxygen species (ROS) induce multiple damages in both nuclear and mitochondrial genomes, most of which are repaired via the DNA base excision repair pathway. 8-Oxoguanine (8-oxoG), a major ROS product in the genome, is excised by 8-oxoG-DNA glycosylase (OGG1) and the resulting abasic (AP) site is cleaved by AP-endonuclease (APE1) in the initial steps of repair. Here, we provide data showing that differences between young and aged cells' efficiency in import of OGG1 and APE1 may be responsible for age-associated increase in DNA damage in both nuclear and mitochondrial compartments. It is also evident that age-dependent changes in covalent modifications of APE1 by acetylation regulate its action as a transcriptional repressor of many Ca(2+)-responsive genes by binding to nCaRE, in addition to its endonuclease activity. Thus, ROS-induced altered signaling is responsible for age-dependent changes in post-translational modifications and import of DNA repair enzymes into nuclei and mitochondria (mt), which in turn affect repair of their genomes.


Transethnic adoption and personality traits: a lesson from Japanese orphans returned from China to Japan.
The authors interviewed 25 Japanese who had been left as orphans in China at the end of World War II and who had recently returned to Japan with their Chinese spouses after almost four decades. It was found that even though they had been raised as Chinese culturally for almost their entire lives, most of these subjects had retained certain Japanese personality traits and social behavior from early childhood, and these characteristics distinguished them from their Chinese counterparts.


Touch Research-Quo Vadis? A Plea for High-Quality Clinical Trials.
Recently, the issue of a lack of interpersonal touch has gained much public interest due to the social distancing ordered by the authorities in the present pandemic situation [...].


Anemia associated with extraerythrocytic oxidative stress damage mediated by neutrophil superoxide anion production in chronic renal failure patients undergoing hemodialysis.
Anemia in patients with uremia undergoing hemodialysis (HD) is a complex process that is dependent on erythropoiesis associated with erythropoietin and iron availability. Published information about an extra erythrocytic factor in the data concerning HD and the underlying mechanism by which anemia occurs remain unclear. The aim of this study was to investigate the superoxide anion generation by polymorphonuclear neutrophils and red blood cell (RBC) lipid peroxidizability as well as the possible association between these parameters and anemia in patients undergoing HD. Blood was collected from 15 volunteers prior to and following HD, and hematological data showed significant anemia at both time points. RBC lipid peroxidizability and neutrophil anion superoxide production, as evaluated by kinetics analysis, revealed increased initial and maximal velocity before and after HD. Plasma malondialdehyde (MDA) and antioxidant levels in the patient group were higher than those in the control group. RBC superoxide dismutase and catalase activities did not differ between groups. There was a significant correlation between increased RBC lipid peroxidizability and superoxide anion production and anemia in patients undergoing HD. The individual variation in plasma MDA was accompanied by superoxide anion production. The RBC lipid peroxidizability, mediated by neutrophil-generated superoxide anions, seems to be a plausible mechanism for explaining, in part, the extraerythrocytic damage that leads to anemia in patients on HD.


Low-Cost Endoscope Camera System for Neurosurgical Cadaveric Laboratory Dissections.
Many training institutions in low-income countries do not have the resources to purchase and maintain a clinical-grade endoscopy tower dedicated to the laboratory. This project aimed to create a low-cost endoscope camera system using online-sourced materials to allow the operators to practice endoscopic surgical techniques in a cadaver laboratory setting. A low-cost endoscope system was created using a 34MP camera with recording capabilities and direct streaming to high-definition multimedia interface in full high resolution, with an adjustable focal length coupler and a light-emitting diode light source. The system cost was $443, as the endoscope and the monitor were already in the laboratory. The system was successfully employed to practice endoscopic dissections in 3 cadaveric specimens with good visualization of relevant structures. This article demonstrated how to produce a low-cost endoscope camera system for laboratory training in neuroendoscopy.


Propofol induces oxidative stress and apoptosis in vitro via regulating miR-363-3p/CREB signalling axis.
Propofol, a generally used anaesthetic in patients care, has been proven to induce neurotoxicity. Studies have shown that miR-363-3p was closely related to neurological dysfunction, and the up-regulated miR-363-3p was recognized to be participate in propofol-induced neurotoxicity. However, the mechanisms and functions of miR-363-3p in propofol-induced neurotoxicity remain rarely reported. The aim of our research was to clarify the potential effects of miR-363-3p in neurotoxicity induced by propofol. SH-SY5Y cells were treated with propofol, miR-363-3p inhibitor or sh-CREB. quantitative real-time polymerase chain reaction and western blotting were applied to detect the expression of miR-363-3p, CREB, Bax, Bcl-2, cleaved caspase-9 and cleaved caspase-3 at the mRNA and/or protein level, respectively. The levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdehyde (MDA) in cell supernatant were detected using different kits. Flow cytometry and MTT assay were applied for assessing the functions of miR-363-3p and CREB on cell ability in cellular activity and apoptotic rate. In addition, Bioinformatic analysis and luciferase assay verified the relationship between 3'-UTR of CREB and miR-363-3p. Our data indicated that the cell viability decreased with the increasing propofol concentration. Bioinformatic analysis and luciferase assay suggested that 3'-UTR of transcript of CREB might be a binding site of miR-363-3p, and miR-363-3p could negatively regulate the expression of CREB. The changes in reactive oxygen species, LDH, SOD and MDA suggested that propofol mediates oxidative stress and apoptosis via modulating miR-363-3p/CREB axis. Propofol induces oxidative stress and apoptosis via affecting miR-363-3p/CREB axis in SH-SY5Y cells, suggesting miR-363-3p down-regulation may act as a novel strategy to ameliorate the propofol-induced neurotoxicity. Significance of the study: The present study demonstrated that propofol induces oxidative stress and apoptosis via affecting miR-363-3p/CREB axis in SH-SY5Y cells, suggesting miR-363-3p down-regulation may act as a novel strategy to ameliorate the propofol-induced neurotoxicity.


Lessons Learned From the Comprehensive Care for Joint Replacement Model at an Academic Tertiary Center: The Good, the Bad, and the Ugly.
Our institution participated in the Comprehensive Care for Joint Replacement (CJR) model from 2016 to 2020. Here we review lessons learned from a total joint arthroplasty (TJA) care redesign at a tertiary academic center amid changing: (1) CJR rules; (2) inpatient only rules; and (3) outpatient trends. Quality, financial, and patient demographic data from the years prior to and during participation in CJR were obtained from institutional and Medicare reconciled CJR performance data. Despite an increase in true outpatients and new challenges that arose from changing inpatient-only rules, there was significant improvement in quality metrics: decreased length of stay (3.48-1.52 days, P < .001), increased home discharge rate (70.2-85.5%, P < .001), decreased readmission rate (17.7%-5.1%, P < .001), decreased complication rate (6.5%-2.0%, P < .001), and the Centers for Medicare and Medicaid Services (CMS) Composite Quality Score increased from 4.4 to 17.6. Over the five year period, CMS saved an estimated $8.3 million on 1,486 CJR cases, $7.5 million on 1,351 non-CJR cases, and $600,000 from the voluntary classification of 371 short-stay inpatients as outpatient-a total savings of $16.4 million. Despite major physician time and effort leading to marked improvements in efficiency, quality, and large cost savings for CMS, CJR participation resulted in a net penalty of $304,456 to our institution, leading to zero physician gainsharing opportunities. The benefits of CJR were tempered by malalignment of incentives among payer, hospital, and physician as well as a lack of transparency. Future payment models should be refined based on the successes and challenges of CJR.


De novo revertant fiber formation and therapy testing in a 3D culture model of Duchenne muscular dystrophy skeletal muscle.
The biological basis of Duchenne muscular dystrophy (DMD) pathology is only partially characterized and there are still few disease-modifying therapies available, therein underlying the value of strategies to model and study DMD. Dystrophin, the causative gene of DMD, is responsible for linking the cytoskeleton of muscle fibers to the extracellular matrix beyond the sarcolemma. We posited that disease-associated phenotypes not yet captured by two-dimensional culture methods would arise by generating multinucleated muscle cells within a three-dimensional (3D) extracellular matrix environment. Herein we report methods to produce 3D human skeletal muscle microtissues (hMMTs) using clonal, immortalized myoblast lines established from healthy and DMD donors. We also established protocols to evaluate immortalized hMMT self-organization and myotube maturation, as well as calcium handling, force generation, membrane stability (i.e., creatine kinase activity and Evans blue dye permeability) and contractile apparatus organization following electrical-stimulation. In examining hMMTs generated with a cell line wherein the dystrophin gene possessed a duplication of exon 2, we observed rare dystrophin-positive myotubes, which were not seen in 2D cultures. Further, we show that treating DMD hMMTs with a β1-integrin activating antibody, improves contractile apparatus maturation and stability. Hence, immortalized myoblast-derived DMD hMMTs offer a pre-clinical system with which to investigate the potential of duplicated exon skipping strategies and those that protect muscle cells from contraction-induced injury. STATEMENT OF SIGNIFICANCE: Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disorder that is caused by mutation of the dystrophin gene. The biological basis of DMD pathology is only partially characterized and there is no cure for this fatal disease. Here we report a method to produce 3D human skeletal muscle microtissues (hMMTs) using immortalized human DMD and healthy myoblasts. Morphological and functional assessment revealed DMD-associated pathophysiology including impaired calcium handling and de novo formation of dystrophin-positive revertant muscle cells in immortalized DMD hMMTs harbouring an exon 2 duplication, a feature of many DMD patients that has not been recapitulated in culture prior to this report. We further demonstrate that this "DMD in a dish" system can be used as a pre-clinical assay to test a putative DMD therapeutic and study the mechanism of action.


Pre-thrombectomy prognostic prediction of large-vessel ischemic stroke using machine learning: A systematic review and meta-analysis.
Machine learning (ML) methods are being increasingly applied to prognostic prediction for stroke patients with large vessel occlusion (LVO) treated with endovascular thrombectomy. This systematic review aims to summarize ML-based pre-thrombectomy prognostic models for LVO stroke and identify key research gaps. Literature searches were performed in Embase, PubMed, Web of Science, and Scopus. Meta-analyses of the area under the receiver operating characteristic curves (AUCs) of ML models were conducted to synthesize model performance. Sixteen studies describing 19 models were eligible. The predicted outcomes include functional outcome at 90 days, successful reperfusion, and hemorrhagic transformation. Functional outcome was analyzed by 10 conventional ML models (pooled AUC=0.81, 95% confidence interval [CI]: 0.77-0.85, AUC range: 0.68-0.93) and four deep learning (DL) models (pooled AUC=0.75, 95% CI: 0.70-0.81, AUC range: 0.71-0.81). Successful reperfusion was analyzed by three conventional ML models (pooled AUC=0.72, 95% CI: 0.56-0.88, AUC range: 0.55-0.88) and one DL model (AUC=0.65, 95% CI: 0.62-0.68). Conventional ML and DL models have shown variable performance in predicting post-treatment outcomes of LVO without generally demonstrating superiority compared to existing prognostic scores. Most models were developed using small datasets, lacked solid external validation, and at high risk of potential bias. There is considerable scope to improve study design and model performance. The application of ML and DL methods to improve the prediction of prognosis in LVO stroke, while promising, remains nascent. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021266524, identifier CRD42021266524.


Inhibition of NarL of Mycobacterium Tuberculosis: an in silico approach.
Mycobacterium tuberculosis (MTB) consumes nitrate as the alternate mechanism of respiration in the absence of oxygen, thus increasing its survival and virulence during latent stage of tuberculosis infection. NarL is a nitrate/nitrite response transcriptional regulatory protein of two-component signal transduction system which regulates nitrate reductase and formate dehydrogenase for MTB adaptation to anaerobic condition. Phosphorylation by sensor kinase (NarX) is the primary mechanism behind the activation of NarL although many response regulators get activated by small molecule phospho-donors in the absence of sensor kinase. Virtual screening was performed using Autodock suite for the compounds from ZINC database against NarL and potential inhibitors was identified to inhibit the activation of NarL by affecting its phosphorylation. Molecular dynamics simulation studies predicted the stability of 1-{1-[(3-nitrophenyl) methyl] piperidin-2-yl} ethan-1-amine in the active site of NarL over 10 ns simulation. Phosphorylation of NarL by small molecule phospho-donors is also investigated in the present study. Here we suggest that nitro benzene - amine piperidine moiety can be an effective lead candidate for developing novel anti-tuberculosis drugs.


Recommendations for strengthening the role of embedded researchers to accelerate implementation in health systems: Findings from a state-of-the-art (SOTA) conference workgroup.
Traditional research approaches do not promote timely implementation of evidence-based innovations (EBIs) to benefit patients. Embedding research within health systems can accelerate EBI implementation by blending rigorous methods with practical considerations in real-world settings. A state-of-the-art (SOTA) conference was convened in February 2019 with five workgroups that addressed five facets of embedded research and its potential to impact healthcare. This article reports on results from the workgroup focused on how embedded research programs can be implemented into heath systems for greatest impact. Based on a pre-conference survey, participants indicating interest in accelerating implementation were invited to participate in the SOTA workgroup. Workgroup participants (N = 26) developed recommendations using consensus-building methods. Ideas were grouped by thematic clusters and voted on to identify top recommendations. A summary was presented to the full SOTA membership. Following the conference, the workgroup facilitators (LJD, CDH, NR) summarized workgroup findings, member-checked with workgroup members, and were used to develop recommendations. The workgroup developed 12 recommendations to optimize impact of embedded researchers within health systems. The group highlighted the tension between "ROI vs. R01" goals-where health systems focus on achieving return on their investments (ROI) while embedded researchers focus on obtaining research funding (R01). Recommendations are targeted to three key stakeholder groups: researchers, funders, and health systems. Consensus for an ideal foundation to support optimal embedded research is one that (1) maximizes learning; (2) aligns goals across all 3 stakeholders; and (3) implements EBIs in a consistent and timely fashion. Four cases illustrate a variety of ways that embedded research can be structured and conducted within systems, by demonstrating key embedded research values to enable collaborations with academic affiliates to generate actionable knowledge and meaningfully accelerate implementation of EBIs to benefit patients. Embedded research approaches have potential for transforming health systems and impacting patient health. Accelerating embedded research should be a focused priority for funding agencies to maximize a collective return on investment.


Using stable isotope fractionation factors to identify Cr(VI) reduction pathways: Metal-mineral-microbe interactions.
Microbes interact with metals and minerals in the environment altering their physical and chemical states, whilst in turn metals and minerals impact on microbial growth, activity and survival. The interactions between bacteria and dissolved chromium in the presence of iron minerals, and their impact on Cr isotope variations, were investigated. Cr(VI) reduction experiments were conducted with two bacteria, Pseudomonas fluorescens LB 300 and Shewanella oneidensis MR-1, in the presence of two iron oxide minerals, goethite and hematite. Both minerals were found to inhibit the rates of Cr(VI) reduction by Pseudomonas, but accelerated those of Shewanella. The Cr isotopic fractionation factors generated by Shewanella were independent of the presence of the minerals (ε = -2.3‰). For Pseudomonas, the ε value was the same in both the presence and absence of goethite (-3.3‰); although, it was much higher (ε = -4.3‰) in the presence of hematite. The presence of aqueous Fe(III) in solution had no detectable impact on either bacterial Cr reduction rates nor isotopic fractionation factors. The presence of aqueous Fe(II) induced rapid abiotic reduction of Cr(VI). The different effects that the presence of Fe minerals had on the Cr fractionation factors and reduction rates of the different bacterial species may be attributed to the way each bacteria attached to the minerals and their different reduction pathways. SEM images confirmed that Pseudomonas cells were much more tightly packed on the mineral surfaces than were Shewanella. The images also confirmed that Shewanella oneidensis MR-1 produced nanowires. The results suggest that the dominant Cr(VI) reduction pathway for Pseudomonas fluorescens LB 300 may have been through membrane-bound enzymes, whilst for Shewanella oneidensis MR-1 it was probably via extracellular electron transfer. Since different minerals impact differentially on bacterial Cr(VI) reduction and isotope fractionation, variations of mineralogies and the associated changes of bacterial communities should be taken into consideration when using Cr isotopes to quantify Cr redox behaviour in the environment.


Quokka bites. The first report of bites from an Australian marsupial.
To describe the incidence and natural history of bites from the quokka, a small wallaby. A prospective case series. Rottnest Island Nursing Post, a small hospital staffed by registered nurses on call 24 hours a day, located on Rottnest Island 18 km off the coast of Western Australia near Perth. All patients presenting after a bite from a quokka. Seventy-two patients (30 males and 42 females) presented after a bite. All but two patients were patting or feeding a quokka at the time of being bitten, and all but two were bitten on a finger or the thumb. Sixty-one per cent of patients were followed up; all wounds healed without complications. No wound pathogens were cultured from either wound swabs or swabs of the mouths of quokkas. Bites from quokkas heal without complications, usually in two to three weeks. Simple first aid and tetanus prophylaxis where appropriate are all that is required. Antibiotics are not indicated.


Practical Approaches for Cryo-FIB Milling and Applications for Cellular Cryo-Electron Tomography.
Cryo-electron tomography (cryo-ET) is a powerful technique to examine cellular structures as they exist in situ. However, direct imaging by TEM for cryo-ET is limited to specimens up to ∼400 nm in thickness, narrowing its applicability to areas such as cellular projections or small bacteria and viruses. Cryo-focused ion beam (cryo-FIB) milling has emerged in recent years as a method to generate thin specimens from cellular samples in preparation for cryo-ET. In this technique, specimens are thinned with a beam of gallium ions to gradually ablate cellular material in order to leave a thin, electron-transparent section (a lamella) through the bulk material. The lamella can be used for high-resolution cryo-ET to visualize cells in 3D in a near-native state. This approach has proved to be robust and relatively simple for new users and exhibits minimal sectioning artifacts. In this chapter, we describe a general approach to cryo-FIB milling for users with prior cryo-EM experience, with extensive notes on operation and troubleshooting.


Analysis of cardiac chronotropic responses to some autonomic blocking agents in conscious trained dogs.
The changes of heart rate in response to i.v. administration of methylatropine (0.5 mg/kg) and/or propranolol (2 mg/Kg) or practolol (2.5 mg/Kg) were studied in conscious trained dogs. Cholinergic blockade alone or combined blockade of sympathetic and parasympathetic effector systems resulted in cardiac acceleration. Conversely, beta-adrenoceptor antagonism with either propranolol or practolol reduced heart rate. The data were analysed by means of a new method, whereby the heart (HRN) of the dog is considered to be the product of the intrinsic heart rate (HR0) and 3 further factors: HRN-HR0 times S times V times W (Multiplicative model). 2 of these factors represent the tonic sympathetic (S) and parasympathetic (V) influences, whereas the third (W) represents the sympathetic-parasympathetic interaction. This type of analysis reveals that W was approximately 1, i.e., the sympathetic-parasympathetic interaction did not play any significant role in determining the heart rate of conscious resting dogs (HRN = HRO-S-V-W = HRO-S-V). The change of heart rate due to the action of parasympathetic system (-53% of the intrinsic heart rate) was more important than the change caused by the action of the sympathetic system (26% of the intrinsic heart rate).


Trajectory Inference for Unraveling Dynamic Biological Processes from Raman Spectral Data.
Cell heterogeneity is a crucial parameter for understanding the complexity of numerous biomedical issues. Trajectory inference-based approaches are recent tools developed for single-cell transcriptomics (scRNA-seq) data analysis. They aim to reconstruct evolving pathways from the variety of cell states that coexist simultaneously in a cell population. We propose to expand this concept to Raman spectroscopy, a label-free modality that probes the global molecular nature of a sample, by investigating the dynamics of adipocyte differentiation.


(5,7,7,12,14,14-Hexamethyl-1,4,8,11-tetra-aza-cyclo-tetra-deca-4,11-diene)nickel(II) bis-[O,O'-bis-(4-tert-butyl-phen-yl) dithio-phosphate].
The title salt, [Ni(C(16)H(32)N(4))](C(20)H(26)O(2)PS(2))(2), comprises a centrosymmetric [Ni(Me(6)[14]dieneN(4))](2+) dication (Me(6)[14]dieneN(4) is 5,7,7,12,14,14-hexa-methyl-1,4,8,11-tetra-aza-cyclo-tetra-deca-4,11-diene) and two O,O'-bis-(4-tert-butyl-phen-yl) dithio-phosphate anions. The Ni(II) ion lies on an inversion centre and displays a slightly distorted NiN(4) square-planar chelation arrangement with four N atoms from the Me(6)[14]dieneN(4) macrocycle. Two S atoms from symmetry-related anions are located in pseudo-axial positions with respect to the Ni(II) ion, with Ni⋯S distances of 3.2991 (7) Å. Inter-molecular N-H⋯S and C-H⋯S hydrogen bonds link the complex cation and pair of anions into a 1:2 type salt.


A combination of a microemulsion and a phospholipid complex for topical delivery of oxymatrine.
Oxymatrine (OMT), a water-soluble drug, has a very low oral bioavailability because of its low membrane permeability and its biotransformation in the gastrointestinal tract. Formulated as an oxymatrine-phospholipid complex (OMT-PLC) can improve the lipid solubility and effectiveness of OMT. The purpose of this study was to explore the utility of the combination of a microemulsion and an OMT-PLC as a topical delivery vehicle for enhancing the absorption and efficacy of OMT. The solubility of OMT-PLC was determined and phase diagrams of microemulsions were constructed. Various microemulsion formulations were developed and characterized by their physicochemical properties, and their in vitro and in vivo permeability through skin. An optimal microemulsion (ME4), which presented as spherical droplets and consisted of 10.0% OMT-PLC, 8.0% isopropyl myristate, 30.0% Cremophor RH40/polyethylene glycol 400 (1:1) and 52.0% water, was selected. It possessed an average droplet size of 32.4 nm, a low viscosity of 113.7 mPa · s, and a high cloud point of 88°C. Compared to the control solution, ME4 provided better skin permeability in vitro and a higher retention ratio of OMT in skin in vivo. Moreover, ME4 significantly enhanced the antiproliferative activity of OMT on scar fibroblasts. These results indicate that the combination of a microemulsion and a phospholipid complex represents an effective vehicle for topical delivery of OMT.