Octahedral Co3O4 particles threaded by carbon nanotube arrays as integrated structure anodes for lithium ion batteries.
Octahedral Co3O4 particles threaded by ultra-long multi-walled carbon nanotube (MWCNT) arrays were prepared by a hydrothermal process and subsequent calcination. The Co3O4 octahedron with the (111) facets attaches to MWCNTs uniformly and closely. The composite can be used as an integrated anode for lithium ion batteries (LIBs) without any other additives (such as conductive additives and polymer binder), which exhibits a high reversible capacity of 725 mA h g(-1) at a current density of 100 mA g(-1), and excellent cyclic stability without capacity degradation over 100 cycles at a current density of 500 mA g(-1). The high performance can be attributed to the unique structure: (i) the ultra-long MWCNT array facilitates fast electron transfer; (ii) the tight adhesion between Co3O4 and MWCNTs prevents particle drifting and agglomeration; (iii) the free space between MWCNTs promotes fast ion transport and alleviates the large volume variation during discharge-charge process. This work demonstrates the great potential of MWCNT arrays as substrate and provides insights for the design and direct use of MWCNT array-based materials in LIBs, which will be helpful for future development of high-performance electrode materials.


Prevention of cellular ROS damage by isovitexin and related flavonoids.
The antioxidant properties of isovitexin and related flavonoids were studied. Isovitexin inhibited xanthine oxidase with an IC50 value of = 15.2 microM. The flavonoid analogues, apigenin, kaempferol, quercetin, myricetin, and genistein also inhibited xanthine oxidase with IC50 values of 0.58, 2.18, 1.09, 9.90, and 4.83 microM, respectively. Isovitexin protected DNA from the Fenton reaction-induced breakage in a dose-dependent manner with an IC50 value of 9.52 microM. Isovitexin also protected HL-60 cells from the ROS damage induced by the xanthine/xanthine oxidase reaction. Isovitexin exhibited the lowest cytotoxicity toward HL-60 cells (LD50 >400 microM) compared to the other flavonoids examined. In addition, excess hydrogen peroxide induced by cadmium in A2780 ovarian cells was significantly suppressed by isovitexin. These results suggest that isovitexin in rice may protect cells from oxidative stress.


Reversal of age-related alterations in synaptic plasticity by blockade of L-type Ca2+ channels.
The role of L-type Ca2+ channels in the induction of synaptic plasticity in hippocampal slices of aged (22-24 months) and young adult (4-6 months) male Fischer 344 rats was investigated. Prolonged 1 Hz stimulation (900 pulses) of Schaffer collaterals, which normally depresses CA3/CA1 synaptic strength in aged rat slices, failed to induce long-term depression (LTD) during bath application of the L-channel antagonist nifedipine (10 microM). When 5 Hz stimulation (900 pulses) was used to modify synaptic strength, nifedipine facilitated synaptic enhancement in slices from aged, but not young, adult rats. This enhancement was pathway-specific, reversible, and impaired by the NMDA receptor (NMDAR) antagonist DL-2-amino-5-phosphonopentanoic acid (AP5). Induction of long-term potentiation (LTP) in aged rats, using 100 Hz stimulation, occluded subsequent synaptic enhancement by 5 Hz stimulation, suggesting that nifedipine-facilitated enhancement shares mechanisms in common with conventional LTP. Facilitation of synaptic enhancement by nifedipine likely was attributable to a reduction ( approximately 30%) in the Ca2+-dependent K+-mediated afterhyperpolarization (AHP), because the K+ channel blocker apamin (1 microM) similarly reduced the AHP and promoted synaptic enhancement by 5 Hz stimulation. In contrast, apamin did not block LTD induction using 1 Hz stimulation, suggesting that, in aged rats, the AHP does not influence LTD and LTP induction in a similar way. The results indicate that, during aging, L-channels can (1) facilitate LTD induction during low rates of synaptic activity and (2) impair LTP induction during higher levels of synaptic activation via an increase in the Ca2+-dependent AHP.


Effectiveness of adult community-based physical activity interventions with objective physical activity measurements and long-term follow-up: a systematic review and meta-analysis.
To identify randomised controlled trials (RCTs) of physical activity (PA) interventions with objective PA outcomes in adults and to evaluate whether intervention effects were sustained beyond 12 months. Systematic review and meta-analysis. Seven databases (Medline, Embase, PsycINFO, Web of Science, Cochrane library, CINAHL (Cumulative Index of Nursing and Allied Health Literature) and ASSIA (Applied Social Sciences Index and Abstracts)) were searched from January 2000 until December 2019. RCTs reporting objective PA outcomes beyond 12 months with community-based participants aged ≥18 years were included; those where controls received active interventions, including advice to increase PA levels, were excluded. Two independent reviewers completed extraction of aggregate data and assessed risk of bias. Meta-analyses used random-effects models at different follow-up points. Primary outcomes were daily steps and weekly minutes of moderate-to-vigorous PA (MVPA). Of 33 282 records identified, nine studies (at generally low risk of bias) were included, five in meta-analyses with 12 months to 4 year follow-up. We observed 12 month increases for intervention vs control participants in steps/day (mean difference (MD)=554 (95% CIs: 384 to 724) p<0.0001, I2=0%; 2446 participants; four studies) and weekly MVPA minutes (MD=35 (95% CI: 27 to 43) p<0.0001, I2=0%; 2647 participants; four studies). Effects were sustained up to 4 years for steps/day (MD=494 (95% CI: 251 to 738) p<0.0001, I2=0%; 1944 participants; four studies) and weekly MVPA minutes (MD=25 (95% CI: 13 to 37) p<0.0001, I2=0%; 1458 participants; three studies). There are few PA interventions with objective follow-up beyond 12 months, more studies are needed. However, this review provided evidence of PA intervention effects beyond 12 months and sustained up to 4 years for both steps/day and MVPA. These findings have important implications for potential long-term health benefits. CRD42017075753.


Isotropic Versus Bipolar Functionalized Biomimetic Artificial Basement Membranes and Their Evaluation in Long-Term Human Cell Co-Culture.
In addition to dividing tissues into compartments, basement membranes are crucial as cell substrates and to regulate cellular behavior. The development of artificial basement membranes is indispensable for the ultimate formation of functional engineered tissues; however, pose a challenge due to their complex structure. Herein, biodegradable electrospun polyester meshes are presented, exhibiting isotropic or bipolar bioactivation as a biomimetic and biofunctional model of the natural basement membrane. In a one-step preparation process, reactive star-shaped prepolymer additives, which generate a hydrophilic fiber surface, are electrospun with cell-adhesion-mediating peptides, derived from major components of the basement membrane. Human skin cells adhere to the functionalized meshes, and long-term co-culture experiments confirm that the artificial basement membranes recapitulate and preserve tissue specific functions. Several layers of immortalized human keratinocytes grow on the membranes, differentiating toward the surface and expressing typical epithelial markers. Fibroblasts migrate into the reticular lamina mimicking part of the mesh. Both cells types begin to produce extracellular matrix proteins and to remodel the initial membrane. It is shown at the example of skin that the artificial basement membrane design provokes biomimetic responses of different cell types and can thus be used as basis for the future development of basement membrane containing tissues.


Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals.
Recently, common noncoding variants in the TCF7L2 gene were strongly associated with increased risk of type 2 diabetes in samples from Iceland, Denmark, and the U.S. We genotyped 13 single nucleotide polymorphisms (SNPs) across TCF7L2 in 8,310 individuals in family-based and case-control designs from Scandinavia, Poland, and the U.S. We convincingly confirmed the previous association of TCF7L2 SNPs with the risk of type 2 diabetes (rs7903146T odds ratio 1.40 [95% CI 1.30-1.50], P = 6.74 x 10(-20)). In nondiabetic individuals, the risk genotypes were associated with a substantial reduction in the insulinogenic index derived from an oral glucose tolerance test (risk allele homozygotes have half the insulin response to glucose of noncarriers, P = 0.003) but not with increased insulin resistance. These results suggest that TCF7L2 variants may act through insulin secretion to increase the risk of type 2 diabetes.


Technology evaluation: ISIS-113715, Isis.
Isis is developing ISIS-113715, an antisense inhibitor of the PTP1B gene, for the potential treatment of type 2 diabetes and obesity. ISIS-113715 is undergoing phase II clinical trials.


Acute intermittent porphyria caused by novel mutation in HMBS gene, misdiagnosed as cholecystitis.
Acute intermittent porphyria (AIP) is an autosomal dominant neurovisceral inherited disorder due to a defect in the heme biosynthesis pathway. Misdiagnosis of the porphyrias is not uncommon. We present a case of a 26-year-old female with suspected acute cholecystitis, mental status changes, and seizures. Biochemical and molecular investigations confirmed the diagnosis of AIP by findings of elevated urinary porphobilinogen, 5-aminolevulinic acid, and total porphyrins. DNA molecular testing showed a novel heterozygous mutation (c. 760delC p.L254X) in the exon11 of the HMBS gene. To the best of our knowledge, this is the first report of a misdiagnosis of AIP presenting with acute cholecystitis. Clinicians are alerted to consider the possibility of AIP in an adult presenting with an acute abdomen, features of cholecystitis, and neuropsychiatric manifestations.


High prevalence of fasciolosis and evaluation of the efficacy of anthelmintics against Fasciola hepatica in buffaloes in Guangxi, China.
Fasciola hepatica is a common parasite of grazing livestock in Guangxi Zhuang Autonomous Region in China, but its prevalence has not been studied. While triclabendazole is commonly used to treat F. hepatica infection in China, oxyclozanide has never been used. This study investigated the prevalence of F. hepatica infections in buffaloes in the Guangxi and evaluated the efficacy of oxyclozanide and triclabendazole as treatments. In the prevalence study, a total of 767 individual faecal samples were obtained from 58 farms in Guangxi to detect the prevalence of F. hepatica, and the total rate of infection was 87.35%. A subset of 277 infected buffaloes from these farms were randomly divided into 3 groups. Group 1 (n = 101) was treated with oxyclozanide at 10 mg/kg.bw; group 2 (n = 94) was treated with triclabendazole (12 mg/kg.bw); and group 3 (n = 82) was untreated. Faecal samples were taken on days 0, 7, 14, 21 and 28. Whole blood and serum were collected on days 0 and 14. Anthelmintic efficacy was assessed using faecal egg count reduction (FECR), buffaloes positive by coprology reduction (BPCR) as well as post-treatment improvement in biochemical and haematological indicators. After 28 days treatment, group 1 and 2 showed FECR% values above 98%, and BPCR% values of 97.03% and 77.66%, respectively. In addition, the biochemical indicators and haematological parameters were improved at 14 days post-treatment compared with those before treatment. These results indicate a high prevalence of F. hepatica in Guangxi, demonstrate that oxyclozanide and triclabendazole are effective against F. hepatica infection in buffaloes, and indicate that oxyclozanide could be used in China as an alternative drug.


CD8+ T cells from feline immunodeficiency virus (FIV) infected cats suppress exogenous FIV replication of their peripheral blood mononuclear cells in vitro.
Feline immunodeficiency virus (FIV) isolates from domestic cats have been classified into five subtypes, designated A, B, C, D and E. Although many FIV-infected cats may have frequent contact with multiple strains of FIV, they usually become infected with a single FIV subtype. In the present study, we demonstrate that peripheral blood mononuclear cells (PBMC) of FIV infected cats were resistant to exogenous FIV (second virus) replication in vitro and that the resistance of these PBMC was mediated by CD8+ T cells. In cats with a low anti-FIV activity of CD8+ T cells, the proviral DNA of the second virus inoculated into PBMC was detected intracellularly, and both the second and the originally infecting strain (original virus) were produced in the culture supernatant. In contrast, in cats with a high anti-FIV activity of CD8+ T cells, both the proviral DNA of the second virus and the original virus were detected in PBMC intracellularly, but neither virus was produced in the culture supernatant. However, when PBMCs from these cats were depleted of CD8+ T cells, the RNA of both viruses was detected in the culture supernatant. These results suggest that CD8+ T cells inhibit the late phase of FIV replication after viral integration. Moreover, the inhibition was also effective against FIV strains of different subtypes from that of the original strain. It appears that the CD8+ T cell-mediated immune response plays important roles in the maintenance of an asymptomatic state in FIV-infected cats and their resistance to superinfection.


Supratentorial gliomas: surgical considerations and immediate postoperative results. Gross total resection versus partial resection.
Forty-two patients with supratentorial gliomas not involving the basal ganglia (extraganglionic) were studied pre- and postoperatively with computed tomographic (CT) scans to evaluate the effect of the extent of surgical resection on the immediate postoperative results. Thirty-three patients (79%) had malignant astrocytic gliomas (glioblastoma or anaplastic astrocytoma), 4 patients (10%) had well-differentiated astrocytomas, and 5 (12%) had oligodendrogliomas. The median age was 58 years, and the median Karnofsky rating was 70. There was no operative mortality. Six patients (14%) had surgical complications. A gross total resection was defined as the absence of any abnormal enhancement on the postoperative CT scan. A nearly gross total resection had been accomplished when less than 10% of the preoperatively enhancing mass was still seen. A partial resection was indicated by the presence of more than 10% of the enhancing lesion on the postoperative CT scan. A gross total or nearly gross total resection was accomplished in 36 patients (86%), and an improved or stable postoperative neurological status was present in 35 of these patients (97%). In contrast, the rate of neurological morbidity after a partial resection was 40%. Supratentorial extraganglionic gliomas, regardless of their histological type, generally were well-circumscribed lesions except at the level of the ventricular wall, where glioblastomas and anaplastic astrocytomas blended with the subependymal white matter from which they seemed to arise.


Adult congenital heart disease: Past, present and future.
The diagnosis and management of congenital heart disease (CHD), the most common inborn defect, has been a tremendous success story of modern medicine. In the 1950s, survival of children born with CHD was only approximately 15%, whereas nowadays more than 90% of these children survive well into adulthood. Consequently, the prevalence of patients with CHD has shifted away from infancy and childhood towards adulthood. Adult CHD cardiology is now encompassing not only young or middle-aged adults but also patients with CHD over 60 years old. Many adult patients are afflicted by residual haemodynamic lesions and also face additional opportunities and/or challenges such as pregnancy, acquired heart disease, non-cardiac pathology etc., necessitating integrated care and all medical disciplines. We are faced with a "tsunami" in terms of adult CHD numbers, disease heterogeneity and complexity of work and interventions needed. We need to secure resources, welcome more people in our field, learn from "marching with our patients", and educate better patients, public and ourselves so that every single patient with CHD, born anywhere in the world, may reach their full life potential.


OGTT results in obese adolescents with normal HOMA-IR values.
To investigate insulin resistance (IR) with OGTT in obese adolescents who have normal fasting insulin and homeostasis model assessment for insulin resistance (HOMA-IR). A total of 97 obese adolescents who had values of HOMA-IR <3.16 and insulin levels <18 μU/mL (125 pmol/L) were included in the study. Oral glucose tolerance test (OGTT) was performed on all cases. Subjects were divided into two groups: subjects with and without IR using an insulin peak of ≥150 μU/mL (1041.8 pmol/L) and/or ≥75 μU/mL (520.9 pmol/L) 120 min after glucose charge and the sum of insulin levels >2083.5 pmol/L (300 μU/mL) in OGTT. IR risk factors were defined as family history of diabetes mellitus, acanthosis nigricans (AN), and hepatic steatosis. IR was detected in 61 (62.9%) patients. The IR group had significantly more frequent AN (p=0.0001). As the number of risk factors increased, the frequency of IR also increased (p=0.01). We advise to perform OGTT in obese adolescents with normal HOMA-IR, if they have risk factors for IR.


[Sensitivity of bacteria exposed to subinhibitory concentrations of antibiotics to the action of serum and liver phagocytes].
Incubation of E.coli and S. aureus with subinhibitory concentration (1/5 MIC) of cefamandole modified bacterial morphology and resistance to host defence mechanisms. In fact, cefamandole induced filamentous forms of E. coli, when added to the perfusing medium of the isolated rat liver system, were phagocytized at a much fortes rate then control bacteria, but appeared less sensitive to serum bactericidal activity. In contrast, S.aureus, after exposure to the antibiotic, was more sensitive to the bactericidal activity of serum then controls, while treated and untreated cells were phagocytized at the some rate. The data suggest that even at low doses some antibiotics may alter bacterial structure and increase their susceptibility to host factors.


Using data derived from cellular phone locations to estimate visitation to natural areas: An application to water recreation in New England, USA.
We introduce and validate the use of commercially available human mobility datasets based on cell phone locations to estimate visitation to natural areas. By combining this data with on-the-ground observations of visitation to water recreation areas in New England, we fit a model to estimate daily visitation for four months to more than 500 sites. The results show the potential for this new big data source of human mobility to overcome limitations in traditional methods of estimating visitation and to provide consistent information at policy-relevant scales. However, the data providers' opaque and rapidly developing methods for processing locational information required a calibration and validation against data collected by traditional means to confidently reproduce the desired estimates of visitation. We found that with this calibration, the high-resolution information in both space and time provided by cell phone location-derived data creates opportunities for developing next-generation models of human interactions with the natural environment.


Preclinical pharmacokinetic evaluation of praziquantel loaded in poly (methyl methacrylate) nanoparticle using a HPLC-MS/MS.
Praziquantel (PZQ) is the drug recommended by the World Health Organization for treatment of schistosomiasis. However, the treatment of children with PZQ tablets is complicated due to difficulties to adapt the dose and the extremely bitter taste of PZQ. For this reason, poly (methyl methacrylate) nanoparticles loaded with Praziquantel (PZQ-NP) were developed for preparation of a new formulation to be used in the suspension form. For this reason, the main aim of the present study was to evaluate the pharmacokinetic (PK) profile of PZQ-NP, through HPLC-MS/MS assays. Analyses were performed with an Omnisphere C18 column (5.0 μm×4.6 mm×150.0 mm), using a mixture of an aqueous solution containing 0.1 wt% of formic acid and methanol (15:85-v/v) as the mobile phase at a flow rate of 0.800mL/min. Detection was performed with a hybrid linear ion-trap triple quadrupole mass spectrometer with multiple reactions monitoring in positive ion mode via electrospray ionization. The monitored transitions were m/z 313.18>203.10 for PZQ and m/z 285.31>193.00 for the Internal Standard. The method was validated with the quantification limit of 1.00 ng/mL, requiring samples of 25 μL for analyses. Analytic responses were calibrated with known concentration data, leading to correlation coefficients (r) higher than 0.99. Validation performed with rat plasma showed that PZQ was stable for at least 10 months when stored below -70 °C (long-term stability), for at least 17 h when stored at room temperature (RT, 22 °C) (short-term stability), for at least 47 h when stored at room temperature in auto-sampler vials (post-preparative stability) and for at least 8 successive freeze/thaw cycles at -70 °C. For PK assays, Wistar rats, weighing between 200 and 300 g were used. Blood samples were collected from 0 to 24 h after oral administration of single doses of 60 mg/kg of PZQ-NP or raw PZQ (for the control group). PZQ was extracted from plasma by liquid-liquid extraction with terc-butyl methyl ether. The values obtained for maximum concentration (C(max)) and area under curve (AUC) for the PZQ-NP group were about 3 times smaller than the respective values obtained for the control group. However, the time for achieving maximum concentration (T(max)), the elimination constant (Ke) and the half-life time of elimination (T(½β)) were not statistically different. These results suggest that PZQ absorption is probably the rate-limiting step for obtainment of better PK parameters for PZQ-NP. Thus, further studies are needed to understand both the PZQ-NP absorption mechanisms and the drug diffusion process through the polymer matrix in vivo, in order to improve the PZQ-NP release profile.


Role of the prostaglandin E2 EP1 receptor in traumatic brain injury.
Brain injuries promote upregulation of so-called proinflammatory prostaglandins, notably prostaglandin E2 (PGE2), leading to overactivation of a class of its cognate G-protein-coupled receptors, including EP1, which is considered a promising target for treatment of ischemic stroke. However, the role of the EP1 receptor is complex and depends on the type of brain injury. This study is focused on the investigation of the role of the EP1 receptor in a controlled cortical impact (CCI) model, a preclinical model of traumatic brain injury (TBI). The therapeutic effects of post-treatments with a widely studied EP1 receptor antagonist, SC-51089, were examined in wildtype and EP1 receptor knockout C57BL/6 mice. Neurological deficit scores (NDS) were assessed 24 and 48 h following CCI or sham surgery, and brain immunohistochemical pathology was assessed 48 h after surgery. In wildtype mice, CCI resulted in an obvious cortical lesion and localized hippocampal edema with an associated significant increase in NDS compared to sham-operated animals. Post-treatments with the selective EP1 receptor antagonist SC-51089 or genetic knockout of EP1 receptor had no significant effects on cortical lesions and hippocampal swelling or on the NDS 24 and 48 h after CCI. Immunohistochemistry studies revealed CCI-induced gliosis and microglial activation in selected ipsilateral brain regions that were not affected by SC-51089 or in the EP1 receptor-deleted mice. This study provides further clarification on the respective contribution of the EP1 receptor in TBI and suggests that, under this experimental paradigm, the EP1 receptor would have limited effects in modulating acute neurological and anatomical pathologies following contusive brain trauma. Findings from this protocol, in combination with previous studies demonstrating differential roles of EP1 receptor in ischemic, neurotoxic, and hemorrhagic conditions, provide scientific background and further clarification of potential therapeutic application of prospective prostaglandin G-protein-coupled receptor drugs in the clinic for treatment of TBI and other acute brain injuries.


Peri-operative deaths in Singapore: a forensic perspective in a study of 132 cases.
A study of 132, largely non-traumatic, peri-operative deaths out of 6605 Coroner's autopsies, conducted over a three-year period from 1989 to 1991, showed a preponderance of males (M:F ratio = 1.36), with almost half (46.3%) being middle-aged subjects between 40 to 59 years, while infants (< one year old) made up about a tenth of the cases. A total of 51 cases (38.6%) were related to cardiothoracic surgery, which also accounted for the majority of deaths that had occurred intra-operatively (11/21 or 8.3% in all) and within the first postoperative day (16/36 or 12.1% in all). The vast majority of cases (81.8%) were pathologically natural deaths, with 15.2% attributable to complications or mishaps of surgery and invasive diagnostic or therapeutic procedures. There were three anaesthetic deaths which accounted for 2.3% of the cases. Out of 124 completed Coroner's inquiries as at the end of June 1993, verdicts of death from natural causes were recorded in 110 (83.3%) cases. General surgery accounted for the highest proportion of unnatural deaths (6.1%), which was twice that for cardiothoracic surgery (3.0%). While there was close agreement between a finding of a pathologically natural death and a similar Coroner's verdict (107/110 or 97.3%), only a total of ten out of 23 pathologically unnatural deaths received verdicts of misadventure at the time of writing. Although a verdict of misadventure usually pertained to an iatrogenic death, this was not invariably the case. Thus far, no findings of medical negligence was made in any of the Coroner's inquiries into these cases.(ABSTRACT TRUNCATED AT 250 WORDS)


Deep learning assisted quantitative assessment of histopathological markers of Alzheimer's disease and cerebral amyloid angiopathy.
Traditionally, analysis of neuropathological markers in neurodegenerative diseases has relied on visual assessments of stained sections. Resulting semiquantitative scores often vary between individual raters and research centers, limiting statistical approaches. To overcome these issues, we have developed six deep learning-based models, that identify some of the most characteristic markers of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). The deep learning-based models are trained to differentially detect parenchymal amyloid β (Aβ)-plaques, vascular Aβ-deposition, iron and calcium deposition, reactive astrocytes, microglia, as well as fibrin extravasation. The models were trained on digitized histopathological slides from brains of patients with AD and CAA, using a workflow that allows neuropathology experts to train convolutional neural networks (CNNs) on a cloud-based graphical interface. Validation of all models indicated a very good to excellent performance compared to three independent expert human raters. Furthermore, the Aβ and iron models were consistent with previously acquired semiquantitative scores in the same dataset and allowed the use of more complex statistical approaches. For example, linear mixed effects models could be used to confirm the previously described relationship between leptomeningeal CAA severity and cortical iron accumulation. A similar approach enabled us to explore the association between neuroinflammation and disparate Aβ pathologies. The presented workflow is easy for researchers with pathological expertise to implement and is customizable for additional histopathological markers. The implementation of deep learning-assisted analyses of histopathological slides is likely to promote standardization of the assessment of neuropathological markers across research centers, which will allow specific pathophysiological questions in neurodegenerative disease to be addressed in a harmonized way and on a larger scale.


Practical aspects of chemometrics for oil spill fingerprinting.
Tiered approaches for oil spill fingerprinting have evolved rapidly since the 1990s. Chemometrics provides a large number of tools for pattern recognition, calibration and classification that can increase the speed and the objectivity of the analysis and allow for more extensive use of the available data in this field. However, although the chemometric literature is extensive, it does not focus on practical issues that are relevant to oil spill fingerprinting. The aim of this review is to provide a framework for the use of chemometric approaches in tiered oil spill fingerprinting and to provide clear-cut practical details and experiences that can be used by the forensic chemist. The framework is based on methods for initial screening, which include classification of samples into oil type, detection of non matches and of weathering state, and detailed oil spill fingerprinting, in which a more rigorous matching of an oil spill sample to suspected source oils is obtained. This review is intended as a tutorial, and is based on two examples of initial screening using respectively gas chromatography with flame ionization detection and fluorescence spectroscopy; and two of detailed oil spill fingerprinting where gas chromatography-mass spectrometry data are analyzed according to two approaches: The first relying on sections of processed chromatograms and the second on diagnostic ratios.


Kinetic analysis of effector cell recycling and effector-target binding capacity in a model of cell-mediated cytotoxicity.
A kinetic analysis of cell-mediated cytotoxicity (CMC) at the population level based on theoretical models has been performed. This analysis considers that the binding process and the kinetics of the lytic process occur through different types of conjugates: LTn, i.e., conjugates containing one effector cell and n target cells, and LmT conjugates which contain m effector cells bound to one target cell. This allowed us to provide a quantitative description of the conjugation process, and of the binding capacities of the effector and target cells. Thus, it has been shown that these processes are governed by an equilibrium in which are involved the unbound effector and target cells, and the conjugates formed. This implies that, when the equilibrium concentrations are reached, the total number of conjugates cannot be increased from the unbound effector and target cells. However, it does not mean that the free effector cells are nonbinding, and so, when the conditions of equilibrium are perturbated (as occurs for example in CMC), all effector cells, virgin and those who have already participated in the lytic process, are able to form new conjugates. The existence of this equilibrium has also important consequences when different subpopulations are separated from an effector-target system. Thus, it explains the observation reported in the literature that, although cytometric techniques can be used to detect and count different types of conjugates, the conjugates formed cannot be separated by cell sorting (unless special precautions are taken). Finally, we have found that the number of target cells killed by one effector cell, which has been previously considered as the recycling capacity of an effector population, is in reality the result of two different mechanisms. One of these mechanisms is due to the recycling process, whereas the other (which has the same effect) is due to the multiple killing capacity of the LTn conjugates which kill more than one target cell. The average number of target cells killed per conjugate has been determined, and this allowed us to obtain the relative contributions of these two mechanisms to the total killing capacity of one effector cell. It appears that the recycling capacities of effector cell populations previously determined had been 1- to 3-fold overestimated.


Correlations between substituent parameters of 4-substituted benzoic acids and their in vitro dissolution and partitioning.
The in vitro dissolution and partitioning of some 4-substituted benzoic acids from nondisintegrating disks was investigated using a water-octanol system. The rates of appearance of benzoic acids in the aqueous phase differed from the rates of appearance in octanol, probably due to back-transfer from the octanol phase. The suitability of the procedure for investigating the influence of molecular modification on in vitro dissolution and partitioning is considered. Correlations among the rates of appearance in octanol, the rates of appearance in an aqueous phase, and substituent parameters of benzoic acids were investigated. The best statistical fit was obtained using molecular orbital substituent indexes.


A systematic review of the supportive care needs of people living with and beyond cancer of the colon and/or rectum.
Gaining a clear understanding of the health needs and concerns of people with cancer of the colon and/or rectum can help identify ways to offer a comprehensive care package. Our aim was to systematically assess the relevant literature and synthesise current available evidence. A systematic review was conducted according to the PRISMA Statement guidelines. Five electronic databases were searched to identify studies employing qualitative and/or quantitative methods. Pre-specified selection criteria were applied to all retrieved records. Findings were integrated in a narrative synthesis. Of 3709 references initially retrieved, 54 unique studies were retained. A total of 136 individual needs were identified and classified into eight domains. Just over half of the needs (70; 51%) concerned information/education or health system/patient-clinician communication issues. Emotional support and reassurance when trying to deal with fear of cancer recurrence featured as the most prominent need regardless of clinical stage or phase of treatment. Information about diet/nutrition and about long-term self-management of symptoms and complications at home; tackling issues relating to the quality and mode of delivery of health-related information; help with controlling fatigue; and on-going contact with a trustworthy health professional also featured as salient needs. Available research evidence is of moderate-to-good quality. Investing time to sensitively inquire about the supportive care needs of this patient population is key, whilst evaluating and re-shaping clinical interactions based on patients' priorities is equally essential. The diverse needs identified require a multi-professional and multi-agency approach to ensure unmet needs are addressed or measures offered.


PTEN inhibitor VO-OHpic attenuates inflammatory M1 macrophages and cardiac remodeling in doxorubicin-induced cardiomyopathy.
Doxorubicin (Doxo) is an effective agent commonly used in cancer therapeutics. Unfortunately, Doxo treatment can stimulate cardiomyopathy and subsequent heart failure, limiting the use of this drug. The role of phosphatase and tensin homolog (PTEN) in apoptosis has been documented in Doxo-induced cardiomyopathy (DIC) and heart failure models. However, whether direct inhibition of PTEN attenuates apoptosis, cardiac remodeling, and inflammatory M1 macrophages in the DIC model remains elusive. Therefore, the present study was designed to understand the effects of VO-OHpic (VO), a potent inhibitor of PTEN, in reducing apoptosis and cardiac remodeling. At day 56, echocardiography was performed, which showed that VO treatment significantly ( P < 0.05) improved heart function. Immunohistochemistry, TUNEL, and histological staining were used to determine apoptosis, proinflammatory M1 macrophages, anti-inflammatory M2 macrophages, and cardiac remodeling. Our data show a significant increase in apoptosis, hypertrophy, fibrosis, and proinflammatory M1 macrophages with Doxo treatment, whereas VO treatment significantly reduced apoptosis, adverse cardiac remodeling, and proinflammatory M1 macrophages significantly ( P < 0.05) compared with the Doxo-treated group. Western blot analysis confirmed the reduction of phosphorylated PTEN and increase in phosphorylated AKT protein expression in the Doxo + VO-treated group. Moreover, VO administration increased anti-inflammatory M2 macrophages. Collectively, our data suggest that VO treatment attenuates apoptosis and adverse cardiac remodeling, a process that is mediated through the PTEN/AKT pathway, resulting in improved heart function in DIC. NEW & NOTEWORTHY Doxorubicin-induced cardiomyopathy (DIC) is still a major issue in patients with cancer. These novel findings on the phosphatase and tensin homolog inhibitor VO-OHpic in DIC is the first report, as per the best of our knowledge, that VO-OHpic significantly decreases apoptosis, fibrosis, hypertrophy, adverse cardiac remodeling, and proinflammatory M1 macrophages and increases anti-inflammatory M2 macrophages along with significantly improved cardiac function. VO-OHpic could be a future therapeutic agent for patients with DIC.


The Connected Steady State Model and the Interdependence of the CSF Proteome and CSF Flow Characteristics.
Here we show that the hydrodynamic radii-dependent entry of blood proteins into cerebrospinal fluid (CSF) can best be modeled with a diffusional system of consecutive interdependent steady states between barrier-restricted molecular flux and bulk flow of CSF. The connected steady state model fits precisely to experimental results and provides the theoretical backbone to calculate the in-vivo hydrodynamic radii of blood-derived proteins as well as individual barrier characteristics. As the experimental reference set we used a previously published large-scale patient cohort of CSF to serum quotient ratios of immunoglobulins in relation to the respective albumin quotients. We related the inter-individual variances of these quotient relationships to the individual CSF flow time and barrier characteristics. We claim that this new concept allows the diagnosis of inflammatory processes with Reibergrams derived from population-based thresholds to be shifted to individualized judgment, thereby improving diagnostic sensitivity. We further use the source-dependent gradient patterns of proteins in CSF as intrinsic tracers for CSF flow characteristics. We assume that the rostrocaudal gradient of blood-derived proteins is a consequence of CSF bulk flow, whereas the slope of the gradient is a consequence of the unidirectional bulk flow and bidirectional pulsatile flow of CSF. Unlike blood-derived proteins, the influence of CSF flow characteristics on brain-derived proteins in CSF has been insufficiently discussed to date. By critically reviewing existing experimental data and by reassessing their conformity to CSF flow assumptions we conclude that the biomarker potential of brain-derived proteins in CSF can be improved by considering individual subproteomic dynamics of the CSF system.


Assembly of Cell Mimicking Supported and Suspended Lipid Bilayer Models for the Study of Molecular Interactions.
Model cell membranes are a useful screening tool with applications ranging from early drug discovery to toxicity studies. The cell membrane is a crucial protective barrier for all cell types, separating the internal cellular components from the extracellular environment. These membranes are composed largely of a lipid bilayer, which contains outer hydrophilic head groups and inner hydrophobic tail groups, along with various proteins and cholesterol. The composition and structure of the lipids themselves play a crucial role in regulating biological function, including interactions between cells and the cellular microenvironment, which may contain pharmaceuticals, biological toxins, and environmental toxicants. In this study, methods to formulate uni-lipid and multi-lipid supported and suspended cell mimicking lipid bilayers are described. Previously, uni-lipid phosphatidylcholine (PC) lipid bilayers as well as multi-lipid placental trophoblast-inspired lipid bilayers were developed for use in understanding molecular interactions. Here, methods for achieving both types of bilayer models will be presented. For cell mimicking multi-lipid bilayers, the desired lipid composition is first determined via lipid extraction from primary cells or cell lines followed by liquid chromatography-mass spectrometry (LC-MS). Using this composition, lipid vesicles are fabricated using a thin-film hydration and extrusion method and their hydrodynamic diameter and zeta potential are characterized. Supported and suspended lipid bilayers can then be formed using quartz crystal microbalance with dissipation monitoring (QCM-D) and on a porous membrane for use in a parallel artificial membrane permeability assay (PAMPA), respectively. The representative results highlight the reproducibility and versatility of in vitro cell membrane lipid bilayer models. The methods presented can aid in rapid, facile assessment of the interaction mechanisms, such as permeation, adsorption, and embedment, of various molecules and macromolecules with a cell membrane, helping in the screening of drug candidates and prediction of potential cellular toxicity.


Vacuum microcasting of 2-methacryloyloxyethyl phosphorylcholine polymer for stable cell patterning.
This study demonstrates the rapid fabrication and utility of 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer film for cell patterning. The film was obtained on a cell culture surface by microcasting MPC polymer ethanol solution into a degassed polydimethylsiloxane mold with a desired pattern. After removal of the mold, 293AD cells were cultured on the surface of the polymer film with the patterned microstructures. Patterned cell adhesion restricted by the film was successfully maintained during at least a 168-h cultivation. The microcast MPC polymer film can be prepared rapidly and used for efficient long-term cell confinement.


Toxoplasmosis in kidney transplant recipients: report of six cases and review.
Six patients with toxoplasmosis complicating renal transplantation are described, and 25 other reported cases are reviewed. The mean age of the 31 patients was 35.16 years. Most of the recipients (25 of 29) showed signs of toxoplasmosis within 3 months post-transplantation, with fever, neurological disturbances, and pneumonia as the main clinical features. Diagnosis was established at autopsy in 15 cases, by serology in 13 cases, and by direct examination, culture, or polymerase chain reaction of biological samples in 5 cases. Seventeen patients also had concomitant infections. The donor was the likely source of transmission to 10 recipients; reactivation was suspected in two cases. The source of transmission could not be determined for the remaining 19 patients. The mortality rate was 64.5%. Ten of the 11 patients given specific treatment survived, indicating that early diagnosis and therapy are essential.


Multifocusing and depth estimation using a color shift model-based computational camera.
This paper presents a novel approach to depth estimation using a multiple color-filter aperture (MCA) camera and its application to multifocusing. An image acquired by the MCA camera contains spatially varying misalignment among RGB color channels, where the direction and length of the misalignment is a function of the distance of an object from the plane of focus. Therefore, if the misalignment is estimated from the MCA output image, multifocusing and depth estimation become possible using a set of image processing algorithms. We first segment the image into multiple clusters having approximately uniform misalignment using a color-based region classification method, and then find a rectangular region that encloses each cluster. For each of the rectangular regions in the RGB color channels, color shifting vectors are estimated using a phase correlation method. After the set of three clusters are aligned in the opposite direction of the estimated color shifting vectors, the aligned clusters are fused to produce an approximately in-focus image. Because of the finite size of the color-filter apertures, the fused image still contains a certain amount of spatially varying out-of-focus blur, which is removed by using a truncated constrained least-squares filter followed by a spatially adaptive artifacts removing filter. Experimental results show that the MCA-based multifocusing method significantly enhances the visual quality of an image containing multiple objects of different distances, and can be fully or partially incorporated into multifocusing or extended depth of field systems. The MCA camera also realizes single camera-based depth estimation, where the displacement between multiple apertures plays a role of the baseline of a stereo vision system. Experimental results show that the estimated depth is accurate enough to perform a variety of vision-based tasks, such as image understanding, description, and robot vision.


A novel matrix metalloproteinase gene (XMMP) encoding vitronectin-like motifs is transiently expressed in Xenopus laevis early embryo development.
To study the role of matrix metalloproteinases (MMPs) in early vertebrate development, we cloned cDNAs for six different MMPs from the frog Xenopus laevis embryos at different stages of development and describe here a novel MMP called XMMP. Xenopus XMMP has 604 amino acids including a putative signal peptide of 22 residues. At the carboxyl-terminal end of the propeptide, XMMP has a 37-amino acid-long insertion domain containing a segment that is 38% identical with a rat vitronectin sequence between residues 108-135. Following this domain is an RRKR motif, a putative cleavage site for intracellular activation by furin proteinases. XMMP lacks a proline-rich linker peptide, or hinge region, typically found in other MMPs between the catalytic domain and carboxyl-terminal "hemopexin/vitronectin-like" domain. In XMMP, the carboxyl-terminal domain is composed of four tandem repeats that are 21-33% identical to a sequence (residues 213-264) encoded by vitronectin exon-5. Interestingly, XMMP gene is transiently expressed during Xenopus embryo development. XMMP mRNA of 3.0 kilobase pairs was undetected in the blastula stage embryo, induced in gastrula embryo, expressed in neurula embryo, and then down-regulated in pretailbud embryo. In comparison, other Xenopus MMP genes that we have cloned show a different developmental regulation. In blastula embryo, the only MMP gene expressed was found to be 92-kDa type IV collagenase, which was also expressed in the gastrula, neurula, and pretailbud embryos. Expression of stromelysin-1, stromelysin-3, and two different membrane type-MMPs was first detected in the neurula and pretailbud embryos. These results suggest that MMPs and the novel XMMP reported here play a role in Xenopus early development.


Acute Myeloid Leukemia Alters Group 1 Innate Lymphoid Cell Differentiation from a Common Precursor.
NK cells are known to be developmentally blocked and functionally inhibited in patients with acute myeloid leukemia (AML), resulting in poor clinical outcomes. In this study, we demonstrate that whereas NK cells are inhibited, closely related type 1 innate lymphoid cells (ILC1s) are enriched in the bone marrow of leukemic mice and in patients with AML. Because NK cells and ILC1s share a common precursor (ILCP), we asked if AML acts on the ILCP to alter developmental potential. A combination of ex vivo and in vivo studies revealed that AML skewing of the ILCP toward ILC1s and away from NK cells represented a major mechanism of ILC1 generation. This process was driven by AML-mediated activation of the aryl hydrocarbon receptor (AHR), a key transcription factor in ILCs, as inhibition of AHR led to decreased numbers of ILC1s and increased NK cells in the presence of AML. These results demonstrate a mechanism of ILC developmental skewing in AML and support further preclinical study of AHR inhibition in restoring normal NK cell development and function in the setting of AML.


[Biological activity of kurilostatin--an unusual alkaloid from sea sponges].
Biological activity of kurilostatin (KS), an unusual alkaloid from the sea sponge was studied. KS was shown to exert a strong cytostatic effect upon tumor cells and activated lymphocytes by mitogen. However it does not display any antitumoral activity in vivo. KS was found to induce release of free [Ca2+] from the above mentioned cells. This process is probably the basis of the cytostatic effect mechanism of KS.


A mutation uncouples the tubulin conformational and GTPase cycles, revealing allosteric control of microtubule dynamics.
Microtubule dynamic instability depends on the GTPase activity of the polymerizing αβ-tubulin subunits, which cycle through at least three distinct conformations as they move into and out of microtubules. How this conformational cycle contributes to microtubule growing, shrinking, and switching remains unknown. Here, we report that a buried mutation in αβ-tubulin yields microtubules with dramatically reduced shrinking rate and catastrophe frequency. The mutation causes these effects by suppressing a conformational change that normally occurs in response to GTP hydrolysis in the lattice, without detectably changing the conformation of unpolymerized αβ-tubulin. Thus, the mutation weakens the coupling between the conformational and GTPase cycles of αβ-tubulin. By showing that the mutation predominantly affects post-GTPase conformational and dynamic properties of microtubules, our data reveal that the strength of the allosteric response to GDP in the lattice dictates the frequency of catastrophe and the severity of rapid shrinking.


Psychomotor speed as a predictor of functional status in older chronic heart failure (CHF) patients attending cardiac rehabilitation.
The association among psychological, neuropsychological dysfunctions and functional/clinical variables in Chronic Heart Failure (CHF) has been extensively addressed in literature. However, only a few studies investigated those associations in the older population. To evaluate the psychological/neuropsychological profile of older CHF patients, to explore the interrelation with clinical/functional variables and to identify potential independent predictors of patients' functional status. This study was conducted with a multi-center observational design. The following assessments were performed: anxiety (Hospital Anxiety and Depression Scale, HADS), depression (Geriatric Depression Scale, GDS), cognitive impairment (Addenbrooke's Cognitive Examination Revised, ACE-R), executive functions (Frontal Assessment Battery, FAB), constructive abilities (Clock Drawing Test, CDT), psychomotor speed and alternated attention (Trail Making Test, TMT-A/B), functional status (6-minute walking test, 6MWT) and clinical variables (New York Heart Association, NYHA; Brain Natriuretic Peptide, BNP; left ventricular ejection fraction, LVEF; left ventricular end diastolic diameter, LVEDD; left ventricular end diastolic volume, LVEDV; tricuspid annular plane systolic excursion, TAPSE). 100 CHF patients (mean age: 74.9±7.1 years; mean LVEF: 36.1±13.4) were included in the study. Anxious and depressive symptoms were observed in 16% and 24,5% of patients, respectively. Age was related to TMT-A and CDT (r = 0.49, p<0.001 and r = -0.32, p = 0.001, respectively), Log-BNP was related to ACE-R-Fluency subtest, (r = -0.22, p = 0.034), and 6MWT was related to ACE-R-Memory subtest and TMT-A (r = 0.24, p = 0.031 and r = -0.32, p = 0.005, respectively). Both anxiety and depression symptoms were related to ACE-R-Total score (r = -0.25, p = 0.013 and r = -0.32, p = 0.002, respectively) and depressive symptoms were related to CDT (r = -0.23, p = 0.024). At multiple regression analysis, Log-BNP and TMT-A were significant and independent predictors of functional status: worse findings on Log-BNP and TMT-A were associated with shorter distance walked at the 6MWT. Psychological and neuropsychological screening, along with the assessment of psychomotor speed (TMT-A), may provide useful information for older CHF patients undergoing cardiac rehabilitation.


[Epidemiological behavior of leprosy in several Latin American countries, 2011-2020Comportamento epidemiológico da hanseníase em vários países da América Latina, 2011-2020].
To describe the epidemiological behavior of leprosy in several Latin American countries during 2011-2020, based on World Health Organization (WHO) indicators. Cross-sectional, descriptive and quantitative study with official data on incidence and prevalence in the general population, children, clinical form and cases with grade 2 disability from WHO records between 2011 and 2020. The eight countries in Latin America that reported most cases were selected and analyses were carried out using simple descriptive and comparative statistics between different variables. During the study period, 301 312 cases of leprosy were reported in the selected countries: Argentina, Brazil, Colombia, Cuba, Dominican Republic, Mexico, Paraguay, and Venezuela. Brazil is the only country in the region with a prevalence greater than 1 per 10 000, representing 93.77% of all cases. Brazil and the Dominican Republic showed an increase in prevalence during 2011-2019, while in other countries the trend was decreasing. The disease is more frequent in men, and multibacillary cases significantly exceed paucibacillary ones. Brazil showed the highest incidences of cases of childhood leprosy and grade 2 disability during the evaluated period. In Latin America, leprosy is only considered a public health problem in Brazil; however, most countries in the region continue to report cases annually, revealing a lack of adequate medical care. This study confirmed the importance of active surveillance, early diagnosis and planning of actions against the disease in all the countries evaluated with the aim of reducing its transmission.


Isoeugenol-functionalized nanogels inhibit peri-implantitis associated bacteria in vitro.
Obligate and facultative anaerobic bacteria adhering to dental implants are a major cause for peri-implant inflammation, which, if left untreated, can lead to implant loss. Previously, our group developed a new route for the synthesis of isoeugenol-functionalized aqueous nanogels for implant coatings. Here, the antimicrobial activity of several new nanogels differing in spacer length (n = 6, 9, 44), radius (60-200 nm), and amount of isoeugenol functional substance (1-20 mol%) was tested against the following peri-implantitis-associated species: Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella intermedia, Aggregatibacter actinomycetemcomitans, Escherichia coli, Actinomyces viscosus, Enterococcus faecalis, Staphylococcus aureus, Streptococcus oralis, S. parasanguinis, and the yeast Candida albicans. The minimal bactericidal concentration (MBC) and fungicidal concentration (MFC) were determined for each combination. In addition, transmission electron microscopy (TEM) and fluorescence microscopy after live-dead-staining (LD-S) were performed to visualize nanogel-microbe interactions. Two nanogels, NG9-3 and NG9-4 (colloids of 80-150 nm, with a spacer length of n = 9 and feeding between 5 and 10 mol% isoeugenol), had an inhibitory effect on all Gram-positive species and on P. gingivalis and P. intermedia with MBC ≥31.25 μg/ml. TEM and LD-S images showed that cellular adhesion and uptake of nanogels resulted in swelling, shedding, or even complete detachment of the cell wall and then to bursting (see graphical abstract). Functional nanogels can be used as building blocks in the design of bioactive coatings on implants to prevent infection and accelerate tissue regeneration, but the concentrations required are higher than for antibiotics.


Retrospective first-in-human use of the LithoVue™ Elite ureteroscope to measure intrarenal pressure.
To report on our first-in-human experience using the LithoVue Elite™ ureteroscope (Boston Scientific Corp., Marlborough, MA, USA) to measure intrarenal pressure (IRP) during flexible ureteroscopy. A single-arm retrospective observational analysis was performed in 50 consecutive patients undergoing ureteroscopic lithotripsy using the LithoVue Elite™ system with pressure sensing capability between April 2022 and February 2023 at two centres. A pressure bag set at 150 mmHg or hand irrigation with a 60-mL syringe was used for irrigation and a ureteric access sheath (UAS) was placed at the physician's discretion. Median and maximum IRPs, and relative cumulative time exceeding 20, 40, 60, 80, 100, 120, 140, 160, and 200 mmHg per total procedure time were analysed. The two-sample Mann-Whitney U-test was used, with statistical significance set at P < 0.05. The median (interquartile range [IQR]) patient age and body mass index (BMI) was 62.5 (46.7-68.2) years and 27.6 (23.3-32.1) kg/m2 , respectively. During the median (IQR) total procedure time of 31.9 (17.4-44.9) min, the median and maximum IRPs were 28.5 (20.0-47.5) and 174.0 (133.5-266.0) mmHg, respectively. IRP remained at <60 mmHg during 92% of the procedure times. Patients with Asian ethnicity, and those without pre-stenting or UAS use exhibited longer cumulative/total durations exceeding pre-defined IRP cut-off values. The smaller 10/12-F UAS did not lower pressures as much as the 11/13-F or 12/14-F UAS (P < 0.001). Age, diabetes, hypertension, preoperative α-blockade, stone size, and BMI did not show any statistically significant associations with IRP. The IRP can now be routinely measured during ureteroscopy. Patients had a median IRP of 28.5 mmHg and a maximum of 174 mmHg. Using a smaller UAS (10/12 F), Asian ethnicity, and tight ureters were found to have higher IRPs.


Influence of Different Patellofemoral Design Variations Based on Genesis II Total Knee Endoprosthesis on Patellofemoral Pressure and Kinematics.
In total knee arthroplasty (TKA), patellofemoral groove design varies greatly and likely has a distinct influence on patellofemoral biomechanics. To analyse the selective influence, five patellofemoral design variations were developed based on Genesis II total knee endoprosthesis (original design, being completely flat, being laterally elevated, being medially elevated, and both sides elevated) and made from polyamide using rapid prototyping. Muscle-loaded knee flexion was simulated on 10 human knee specimens using a custom-made knee simulator, measuring the patellofemoral pressure distribution and tibiofemoral and patellofemoral kinematics. The measurements were carried out in the native knee as well as after TKA with the 5 design prototypes. The overall influence of the different designs on the patellofemoral kinematics was small, but we found detectable effects for mediolateral tilt (p < 0.05 for 35°-80° flexion) and translation of the patella (p < 0.045 for 20°-65° and 75°-90°), especially for the completely flat design. Considering patellofemoral pressures, major interindividual differences were seen between the designs, which, on average, largely cancelled each other out. These results suggest that the elevation of the lateral margin of the patellofemoral groove is essential for providing mediolateral guidance, but smooth contouring as with original Genesis II design seems to be sufficient. The pronounced interindividual differences identify a need for more patellofemoral design options in TKA.


[Studies on antiendotoxin action of total saponins from radix Bupleuri].
To study antiendotoxin activities of total saponins from Radix Bupleuri. The antiendotoxin activities were demonstrated by Limulus Amebocyte Lysate test (LAL test) in vitro, the fever model induced by endotoxin in rabbits and the model induced by LPS in BCG-primed mice. Total saponins from Radix Bupleuri still had antiendotoxin effect even when it (50 mg.ml-1) was diluted to 32 times by LAL test in vitro. The fever experiment results showed the average rising temperature of BCS + LPS, group, model group and BCS group was 0.75 degrees C, -0.25 degrees C and -0.37 degrees C respectively. In the experiment of the poison induced by LPS, fatal rate of model group was 90.0%, that of BCS + LPS group was 13.3%, there was a significant difference (P < 0.01). The result showed that the total saponins in Bupleuri had the strongest antiendotoxin action.


POTENTIAL NEW ROLES OF LEPTIN IN HEALTH AND DISEASE.
Leptin is an adipose-tissue specific cytokine described 20 years ago and classically thought to be involved in regulation of food intake and energy homeostasis. More recently, leptin was proven to exert other multiple roles in carbohydrate and lipid metabolism, reproductive system, and inflammatory and immune reactions. Emerging data propose leptin to be a modulator of bone mass. In some particular circumstances leptin synthesis follow specific patterns in inflammation and sepsis, not being proportional with fat mass. Therefore, it may be used as diagnostic or prognostic marker for critical illness.


Early Childhood Father Absence and Depressive Symptoms in Adolescent Girls from a UK Cohort: The Mediating Role of Early Menarche.
Absence of the biological father in early childhood has been linked to depressive symptoms in mid-adolescent girls. Earlier studies have linked father absence to early timing of menarche, and early menarche is a risk factor for increased depressive symptoms in adolescence. No studies, however, have examined whether the association between father absence and depressive symptoms may be explained by the early onset of menarche. This study investigated whether age at menarche mediates the association between father absence in early childhood (birth to 5 years) and depressive symptoms in adolescent girls aged 14 years. The study sample comprised 7056 girls from a large UK birth cohort (Avon Longitudinal Study of Parents and Children) who provided data on age at onset of menarche and depressive symptoms assessed using the Short Mood and Feelings Questionnaire at 14 years. Mothers provided data on father absence from the birth of the study child up to 10 years. Using structural equation modelling, we found that 15 % of the total estimated association between father absence in early childhood and depressive symptoms at 14 years was explained by early age at menarche. In addition to the mediated effect, father absence was linked to an 11 % increase in depressive symptoms in adolescence. The findings suggest that early age at menarche is one of the pathways linking early childhood father absence and depressive symptoms in mid-adolescent girls. Preventive strategies could be targeting young girls at risk for depressive symptoms as a function of stressful family factors (e.g., biological father absence) and earlier menarche.


Products of vitamin D3 or 7-dehydrocholesterol metabolism by cytochrome P450scc show anti-leukemia effects, having low or absent calcemic activity.
Cytochrome P450scc metabolizes vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,23(OH)(2)D3, as well as 1-hydroxyvitamin D3 to 1alpha,20-dihydroxyvitamin D3 (1,20(OH)(2)D3). It also cleaves the side chain of 7-dehydrocholesterol producing 7-dehydropregnenolone (7DHP), which can be transformed to 20(OH)7DHP. UVB induces transformation of the steroidal 5,7-dienes to pregnacalciferol (pD) and a lumisterol-like compounds (pL). To define the biological significance of these P450scc-initiated pathways, we tested the effects of their 5,7-diene precursors and secosteroidal products on leukemia cell differentiation and proliferation in comparison to 1alpha,25-dihydroxyvitamin D3 (1,25(OH)(2)D3). These secosteroids inhibited proliferation and induced erythroid differentiation of K562 human chronic myeloid and MEL mouse leukemia cells with 20(OH)D3 and 20,23(OH)(2)D3 being either equipotent or slightly less potent than 1,25(OH)(2)D3, while 1,20(OH)(2)D3, pD and pL compounds were slightly or moderately less potent. The compounds also inhibited proliferation and induced monocytic differentiation of HL-60 promyelocytic and U937 promonocytic human leukemia cells. Among them 1,25(OH)(2)D3 was the most potent, 20(OH)D3, 20,23(OH)(2)D3 and 1,20(OH)(2)D3 were less active, and pD and pL compounds were the least potent. Since it had been previously proven that secosteroids without the side chain (pD) have no effect on systemic calcium levels we performed additional testing in rats and found that 20(OH)D3 had no calcemic activity at concentration as high as 1 microg/kg, whereas, 1,20(OH)(2)D3 was slightly to moderately calcemic and 1,25(OH)(2)D3 had strong calcemic activity. We identified novel secosteroids that are excellent candidates for anti-leukemia therapy with 20(OH)D3 deserving special attention because of its relatively high potency and lack of calcemic activity.


Possible nitric oxide modulation in protective effect of (Curcuma longa, Zingiberaceae) against sleep deprivation-induced behavioral alterations and oxidative damage in mice.
Sleep is essential for the physical and mental health of a human being. Problems of sleep deprivation are increasing in modern society nowadays. Recently, various antioxidants have been implicated as neuroprotectants in the treatment of stress and stress related problems. The present study was designed to explore the possible role of nitric oxide in the protective effect of Curcumin (Curcuma longa, Zingiberaceae) against 72-h sleep deprivation-induced behavioral alterations and oxidative damage in mice. 72-h sleep deprivation significantly caused weight loss, anxiety like behavior, impaired locomotor activity and oxidative damage (increased lipid peroxidation, nitrite level and deplete glutathione and catalase activity) in animals. Treatment with Curcumin extract (10 and 20mg/kg, ip) for 5 days significantly prevented weight loss, impairment in locomotor activity, anxiety like effects in all behavioral paradigms tasks (mirror chamber, plus maze, zero maze) as compared to control (72-h sleep-deprived) (P<0.05). Biochemically, Curcumin extract treatment significantly restored depleted reduced glutathione, catalase activity, attenuated raised lipid peroxidation and nitrite level as compared to control (72-h sleep-deprived) animals. Further, pretreatment of l-arginine (50mg/kg, ip), nitric oxide precursor reversed the protective effect of Curcumin (10 mg/kg, ip) (P<0.05). However, pretreatment of l-NAME (5 mg/kg, ip), nitric oxide synthase inhibitor caused a potentiation in the protective effect of Curcumin (P<0.05). The present study suggests that nitric oxide modulation is involved in the protective effect of Curcumin in ameliorating sleep deprivation-induced behavioral alterations and oxidative damage.


An evaluation of the total similarity principle: effects of similarity on frequency judgments.
Memory models that embody the total similarity principle (e.g., Gillund & Shiffrin, 1984; Hintzman, 1988; Murdock, 1982; Ratcliff, 1990) assume that frequency judgments reflect the total similarity of a test item to stimuli that have been studied. In 4 experiments, subjects estimated the frequencies of target words that had been presented in the context of varying numbers of semantically similar words. In a fifth experiment, subjects made forced-choice relative frequency judgments. The results of these experiments supported 1 prediction of total similarity models: Presenting similar words will increase rather than decrease frequency judgments of target words. However, a second prediction of these models was not supported. In particular, similar-word presentations had no effect on the judged frequencies of target words that had not been shown.


Neutralizing antibody spectrum determines the antigenic profiles of emerging mutants of visna virus.
The visna viruses are antigenically related nononcogenic retroviruses of sheep. The original strain was isolated from the brain of a paralyzed sheep in Iceland during the 1940s. The prototype strains has been passed serially in sheep and has undergone progressive antigenic change. Previous reports have shown that such antigenic changes in visna virus can be reproduced in infected cell cultures treated with neutralizing antibody. We now show that the antigenic profiles of the emerging mutants directly reflect the nature of the selecting antibody. Mutants with minor antigenic changes were selected by "early" sera which had a limited neutralization range. Mutants with greater antigenic changes were selected by "late" sera with a wide neutralization range. Mutants selected by early sera emerged rapidly and consistently in cultures, and these were antigenically very similar to one another. Mutants rarely emerged in cultures treated with late sera, but these viruses showed major antigenic changes. The data suggest that the evolution of antigenic mutants of visna virus progresses by a series of minor mutations which accumulate under the selective pressure of antibody.


Recurrence rate of diabetic neurotrophic foot ulcers healed using topical application of growth factors released from platelets.
The purpose of this study was to determine the recurrence rate of diabetic neurotrophic foot ulcers that had healed in a treatment protocol using topically applied growth factors released from platelets. Thirty-six patients with diabetic neurotrophic foot ulcers were entered into a randomized prospective double-blind 20-week trial of topically applied platelet growth factors or buffered saline dressings. Ulcers had been present for 15.5 months (mean, range 2 to 60 months). Sixteen patients (44%) healed and were followed up for as many as 30 months to determine the rate of ulcer recurrence. Eleven patients (68.8%) had ulcers that recurred, including 10 treated with platelet growth factors and one treated with buffered saline solution. These ulcers had been present for 20 months (range 5 to 60 months) before healing. Average time to ulcer recurrence was 2.2 months (range 0.25 to 7 months). Five ulcers (31.2%) remained healed, including four treated with platelet growth factors and one treated with buffered saline solution. These healed, nonrecurring ulcers had been present for 5 months (range 2 to 6 months) before healing. Average follow up was 25 months (range 24 to 30 months). Ulcers were more likely to recur if they had been present longer before healing. If patients were not compliant in wearing footwear to protect the healed ulcer, the ulcers were prone to early recurrence. These data indicate that ulcers healed by using growth factors in the form of a platelet growth factors did not have more durable skin over the ulcer and were prone to early ulcer recurrence.


The Ocular Surface and the Coronavirus Disease 2019: Does a Dual 'Ocular Route' Exist?
Coronavirus disease 2019 (COVID-19) is an important health problem that was defined as a pandemic by the World Health Organization on 11 March 2020. Although great concern has been expressed about COVID-19 infection acquired through ocular transmission, its underlying mechanism has not currently been clarified. In the current work, we analyzed and elucidated the two main elements that should be taken into account to understand the "ocular route", both from a clinical and molecular point of view. They are represented by the dynamism of the ocular surface system (e.g., the tear film turnover) and the distribution of ACE2 receptors and TMPRSS2 protein. Although it seems, at the moment, that there is a low risk of coronavirus spreading through tears, it may survive for a long time or replicate in the conjunctiva, even in absence of conjunctivitis signs, indicating that eye protection (e.g., protective goggles alone or in association with face shield) is advisable to prevent contamination from external droplets and aerosol.


Chiari Type I Malformation Associated With Verbal Fluency Impairment.
Chiari malformation (CM) Type I is a rare disorder that implies an anomaly in the craniocervical junction, where one or both cerebellar tonsils are displaced below the foramen magnum into the cervical spinal channel. Research carried out regarding cognitive symptoms such as verbal fluency is scarce. The aim of this study was to investigate whether verbal fluency is impaired in a CM clinical group compared to a group of healthy control individuals while controlling for depression and anxiety symptomatology. For this purpose, 101 individuals were enrolled to take part in the study (51 CM, 50 healthy controls). The Controlled Oral Word Association Test (Benton, de Hamsher, & Sivan, 1983) and the Hospital Anxiety and Depression Scale (Zigmond & Snaith, 1983) were administered. Results showed significantly lower scores for the CM group in verbal fluency compared to the control group (p < .005). After performing an analysis of covariance to eliminate depression and anxiety symptomatology tendencies, it was observed that verbal fluency could not be predicted by this variable (p > .005). From the results of this study, it can be concluded that people suffering from CM exhibit less verbal fluency than healthy control individuals and that this difference is not caused by depression or anxiety.


What is it to do good ethics?
Much of my work in bioethics over the years has been throwing off ethics as pursued in the analytical tradition. I believe the field should steer clear of the rigid style of hyper-rationalist ethics and a reduction of ethics to a search for rules and principles. It should be open to a full range of influence, in style and substance, of literature, history and the social sciences. It should take in the full range of human life, individual and social.


[Emergencies in neurological patients].
Patients with neurological diseases amount to about one fifth of hospital admissions. Out of the numerous emergency situations three leading presentations are discussed. In an isolated epileptic grand mal seizure immediate treatment is not needed, whereas the different forms of status epilepticus ask for emergency measures. Acute headache may be a sign of subarachnoid hemorrhage or an other dangerous intracranial affection. Several harmless forms of acute headache are discussed. Central paLsies with acute presentation are most often of cerebrovascular origin. Peripheral palsies including Bell's palsy are discussed.


Teratomas in infancy and childhood at Tygerberg Hospital, South Africa, 1973 to 1992.
To document the childhood teratomas at Tygerberg Hospital and compare the profile with other African series. Retrospective review of the clinicopathologic features of 43 cases of childhood teratomas. Tumors were classified according to the World Health Organization criteria for germ cell tumors. Tygerberg Hospital, University of Stellenbosch, Cape Town, South Africa. There were 26 mature, 15 immature, and 2 malignant teratomas. The most common sites were the ovaries and the sacrococcygeal region. Testicular teratomas were absent. The female-to-male ratio for black patients was 5.5:1. There was a peak age incidence in the first 4 years of life, with sacrococcygeal teratomas predominating. A second, smaller peak between 12 and 15 years was seen owing to ovarian teratomas. Immature teratomas presented at an earlier age than mature teratomas. The majority of ovarian teratomas occurred in patients of mixed race, whereas the extragonadal teratomas were distributed more evenly among the race groups. In black patients and patients of mixed race mature teratomas predominated, whereas in white patients immature teratomas were most common. The increased occurrence of teratomas among female patients, the large number of ovarian teratomas, the absence of testicular teratomas, and the low incidence of malignant teratomas correspond to the observations of other African series. Certain differences are apparent among the three race groups, namely, a high ratio of female-to-male patients in the black group, a predominance of ovarian teratomas in the mixed-race and black groups, and a predominance of extragonadal and immature teratomas in the white group.


Successful treatment of pulmonary nocardiosis with fluoroquinolone in bronchial asthma and bronchiectasis.
A 72-year-old Japanese woman was admitted at Saga University Hospital for fever, malaise, and productive cough. Six years ago, she had been diagnosed with bronchial asthma and was treated with inhaled corticosteroids. Chest radiograph and computed tomography on admission showed infiltrates in the right middle lobe, a mass lesion in the left lower lobe, and bronchiectasis in both lower lobes. Sputum examination showed Gram-positive rods with phagocytosis by neutrophils. These bacilli were identified as Nocardia otitidiscaviarum by 16S ribosomal RNA sequencing. Therefore, she was diagnosed with pulmonary nocardiosis and was treated with trimethoprim/sulfamethoxazole (TMP-SMX) and minocycline (MINO). However, she had to discontinue these antibiotics because of severe nausea and anorexia and instead was treated with fluoroquinolone for 6 months. There was resolution of the disease thereafter. Pulmonary nocardiosis with bronchial asthma and bronchiectasis can be successfully treated with fluoroquinolone, an alternative to TMP-SMX or MINO.


BiasViz: visualization of amino acid biased regions in protein alignments.
About a third of all protein sequences have at least one composition biased region (CBR). Such regions might act as linkers between protein domains but often confer specific binding to various molecules; therefore, their characterization in terms of their boundaries and over-represented residues is important. Analysis of CBRs in a particular sequence can be time consuming if several types of biases have to be explored and their position visualized. Assessment of the significance of the detected CBRs can be approached by comparison to homologous protein sequences. To assist this procedure, we have developed BiasViz, a tool that allows to graphically studying local amino acid composition in protein sequences of a multiple sequence alignment.


3-[1-(Ethylamino)ethylidene]-6-methyl-3H-pyran-2,4-dione.
The structural results clearly indicate that 3-[1-(ethylamino)ethylidene]-6-methyl-3H-pyran-2,4-dione exists as a keto-enamine tautomer in the solid state. The H atom bonded to N(9) refines with a normal temperature factor and the bond distance of the keto group [C(4)--O(13)] of 1.263 (1) A is elongated due to resonance. This resonance is also indicated by an averaging of the single bonds [C(2)--C(3), C(3)--C(4), C(4)--C(5) and C(8)--N(9)] and double bonds [C(3)--C(8) and C(4)--O(13)] in the crystal structure and by the fact that not only is the pyran ring planar [r.m.s. deviation 0.0212 (9) A] but also there is planarity for the whole molecule [r.m.s. deviation 0.074 (1) A]. A strong intramolecular hydrogen bond is found between the 4-oxo group and the amine H atom.


Chromosome formation during fertilization in eggs of the teleost Oryzias latipes.
Upon fertilization, eggs shift their cell cycle from the meiotic to the mitotic pattern for embryogenesis. The information on chromosome formation has been accumulated by various experiments using inhibitors to affect formation and behavior of chromosomes in the cycle of cell proliferation. Based on experimental results on meiosis and early stages of development of the teleost Oryzias latipes, we discuss the roles of the activities of histone H1 kinase, microtubule-associated protein kinase, DNA polymerase, DNA topoisomerase, and other cytoplasmic factors that play a crucial role in formation and separation of chromosomes.


Studies on the pyridoxal phosphate site in glycogen phosphorylase b.
It is usually accepted that the adduct formed by reaction of pyridoxal phosphate with amines in aprotic solvents is a good model to stimulate some properties of the pyridoxal phosphate site in glycogen phosphorylase. The chemical structure of this adduct was not very well established. An aldimine structure is supported by the infrared, electronic absorption and nuclear magnetic resonance spectra given in this work. Therefore, we conclude that, at neutral pH, the pyridoxal phosphate is bound to the glycogen phosphorylase through a Schiff base structure and embedded in a hydrophobic environment. The polarographic measurements reported in this paper could explain the fact that, at neutral pH, the pyridoxal phosphate can not be reduced onto phosphorylase by NaBH4.


Targeting VEGFR and FGFR in head and neck squamous cell carcinoma in vitro.
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease characterized by a tumor microenvironment (TME) that overexpresses vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), which can lead to neovascularization, tumor growth and metastasis. Therapeutic strategies inhibiting these signaling pathways might lead to innovative HNSCC treatments. Five HNSCC cell lines were characterized based on VEGFR1-3 and FGFR1-4 expression by sqRT-PCR and treated with three different tyrosine kinase inhibitors (TKIs) (nintedanib, dovitinib and pazopanib), all of which are effective against VEGFR and FGFR family members. Crystal violet assays were performed to analyze the effect of the treatments on cell growth (viability). Additionally, VEGFR1-3 and FGFR1-4 expression data were retrieved from The Cancer Genome Atlas (TCGA), and statistical analyses were performed to investigate the receptor expression level in the different cell lines and the efficacy of the single-agent treatments. A correlation analysis was performed to quantify the degree of relationship between receptor expression and drug efficacy. With the exception of VEGFR2, the targeted receptors were expressed at different levels in all of the cell lines. The cell lines exhibited concentration-dependent responses with cell line-specific differences toward two of the three TKIs (nintedanib and dovitinib). Notably, all of the cell lines were resistant to pazopanib. TKIs have potential as therapeutic agents for HNSCC. Cell line-specific differences were observed in our in vitro experiments. The observed pazopanib resistance could be explained by receptor expression. Further investigation is required to determine TKI efficacy in HNSCC.


Challenges in surgical management of abdominal pain in the neutropenic cancer patient.
Abdominal pain in neutropenic cancer patients presents a unique clinical challenge for surgeons. The purposes of this retrospective study were to characterize the clinicopathologic factors associated with the presentation of neutropenia and abdominal pain, examine the treatment strategies used, and define associated outcomes for these patients. We identified patients with concomitant neutropenia (absolute neutrophil count <1000 cells/microL) and abdominal pain who had been evaluated by surgical oncologists over a period of more than 6 years. A Cox proportional hazards regression model was used to analyze the association between clinicopathologic factors and overall survival time. Sixty patients were included in this analysis. After our clinical and radiographic evaluations, we determined that the most frequent causes of the abdominal pain were neutropenic enterocolitis (28%) and small bowel obstruction (12%); the cause remained uncertain in 35%. Surgical interventions had been performed in 9 patients. The 30- and 90-day mortality rates for all patients were 30% and 52%, respectively. Multivariate analysis revealed that severe sepsis, a relatively long duration of neutropenia, and the lack of surgical intervention were significant adverse prognostic factors for overall survival. Abdominal pain as a symptom in neutropenic patients continues to be a diagnostic and therapeutic challenge and is associated with a high mortality rate. Based on our results, we conclude that efforts should focus on improving neutrophil counts and on treating the frequent and serious comorbidities found in these patients. Surgery should be delayed, when possible, to allow for neutrophil recovery.


Neonatal diethylstilbestrol exposure alters the metabolic profile of uterine epithelial cells.
Developmental exposure to diethylstilbestrol (DES) causes reproductive tract malformations, affects fertility and increases the risk of clear cell carcinoma of the vagina and cervix in humans. Previous studies on a well-established mouse DES model demonstrated that it recapitulates many features of the human syndrome, yet the underlying molecular mechanism is far from clear. Using the neonatal DES mouse model, the present study uses global transcript profiling to systematically explore early gene expression changes in individual epithelial and mesenchymal compartments of the neonatal uterus. Over 900 genes show differential expression upon DES treatment in either one or both tissue layers. Interestingly, multiple components of peroxisome proliferator-activated receptor-γ (PPARγ)-mediated adipogenesis and lipid metabolism, including PPARγ itself, are targets of DES in the neonatal uterus. Transmission electron microscopy and Oil-Red O staining further demonstrate a dramatic increase in lipid deposition in uterine epithelial cells upon DES exposure. Neonatal DES exposure also perturbs glucose homeostasis in the uterine epithelium. Some of these neonatal DES-induced metabolic changes appear to last into adulthood, suggesting a permanent effect of DES on energy metabolism in uterine epithelial cells. This study extends the list of biological processes that can be regulated by estrogen or DES, and provides a novel perspective for endocrine disruptor-induced reproductive abnormalities.


Clinical applications of Trabecular Metal.
Trabecular Metal (porous tantalum) offers a viable solution to several challenges in orthopedic reconstructive surgery, including monoblock acetabular cups, avascular necrosis intervention devices, and total hip reconstruction in situations of massive femoral bone loss. Porous tantalum approaches the ideal biomaterial: it is porous, strong, flexible, and biocompatible. For use in components for total hip arthroplasty, porous tantalum provides a substitute for lost bone, immediate bone loading, bone ingrowth, and soft-tissue attachment. It can be machine-shaped into custom designs in situations of massive bone loss.


Efficacy and Toxicity of Low-Dose versus Conventional-Dose Chemotherapy for Malignant Tumors: a Meta-Analysis of 6 Randomized Controlled Trials
Low-dose chemotherapy has emerged as a new strategy for control of cancer. However, there is a controversy as to whether low-dose chemotherapy is an effective way to manage many human malignancies. To shed light on this controversy, we performed a meta-analysis of relative merits between low-dose and conventional-dose chemotherapy in different carcinomas. Studies published before February 29, 2016 were reviewed for the meta-analysis and selected according to defined criteria. The effect levels of low-dose chemotherapy regarding overall survival (OS), progression-free survival (PFS) and severe adverse events (SAEs) (Grade≥3) were calculated as risk ratios (ORs) or adjusted hazard ratios (HRs). Six randomized controlled studies (RCTs) have provided data for low-dose chemotherapy versus conventional-dose chemotherapy for 838 cases and 833 cases, respectively. Interestingly, low-dose chemotherapy achieved the same desired potency as conventional-dose chemotherapy, with no differences in pooled ORR (RR=1.00, 95%CI [0.89, 1.13]; (P=0.97), OS (HR=1.07, 95%CI [0.90, 1.26]; P=0.44) and PFS (HR=1.02, 95%CI [0.84, 1.23]; P=0.87) values. Furthermore, pooled data for common SAEs showed that, compared with conventional-dose chemotherapy regimen, low-dose chemotherapy regimen resulted in significant less mucositis (P<0.0001), thrombocytopenia (P<0.00001), anemia (P=0.0001) and febrile neutropenia (P=0.004). At the same time, no statistically significant differences were observed with regard to treatment-related death (P=0.36), diarrhea (P=0.49), leucopenia (P=0.11), neutropenia (P=0.74) and nausea/vomiting (ʺPʺ=0.21). Publication bias was assessed by Egger's test and the funnel plot. In conclusion, the meta-analysis seems to support the idea that low-dose chemotherapy may play an important role in achieving the same desired potency as conventional-dose chemotherapy in managing malignant tumors. Moreover, low-dose regimen seems to possess positive advantages of lower toxicity which is a particular concern for most patients.


Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients.
Programmed death-ligand 1 (PD-L1) may be induced by oncogenic signals or can be upregulated via interferon gamma (IFN-γ). We have explored whether the expression of IFNG, the gene encoding IFN-γ, is associated with clinical response to the immune checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE, STAT1 and other associated genes has also been examined. Total RNA from 17 NSCLC and 21 melanoma patients was analyzed by quantitative reverse transcription PCR. STAT3 and Rantes, YAP1 and CXCL5, DNMT1, RIG1 and TET1, EOMES, IFNG, PD-L1 and CTLA4, IKBKE and NFATC1 mRNA were examined. PD-L1 protein expression in tumor and immune cells and stromal infiltration of CD8+ T-cells were also evaluated. Progression-free survival and overall survival were estimated. A total of 17 NSCLC patients received nivolumab and 21 melanoma patients received pembrolizumab. Progression-free survival with nivolumab was significantly longer in NSCLC patients with high versus low IFNG expression (5.1 months versus 2 months, p = 0.0124). Progression-free survival with pembrolizumab was significantly longer in melanoma patients with high versus low IFNG expression (5.0 months versus 1.9 months, p = 0.0099). Significantly longer overall survival was observed for melanoma patients with high versus low IFNG expression (not reached versus 10.2 months p = 0.0183). There was a trend for longer overall survival for NSCLC patients with high versus low IFNG expression. IFN-γ is an important marker for prediction of response to immune checkpoint blockade. Further research is warranted in order to validate whether IFNG is more accurate than PD-L1.


Enhanced performance of NaOH-modified Pt/TiO2 toward room temperature selective oxidation of formaldehyde.
Pt/TiO(2) catalysts with various Pt loadings (0.05-2 wt %) were prepared by a combined NaOH-assisted impregnation of titania with Pt precursor and NaBH(4)-reduction. The thermal catalytic activity was evaluated toward catalytic decomposition of formaldehyde (HCHO) vapor in the presence of toluene under ambient conditions. HCHO could be selectively oxidized into CO(2) and H(2)O over Pt/TiO(2) catalysts and toluene had no change. Pt/TiO(2) catalysts prepared with the assistance of NaOH showed higher HCHO oxidation activity than those without NaOH due to the introduction of additional surface hydroxyl groups, the enhanced adsorption capacity toward HCHO, and larger mesopores and macropores facilitating diffusion and transport of reactants and products. The as-prepared Pt/TiO(2) catalysts with an optimal Pt loading of 1 wt % exhibited high catalytic stability. Considering the versatile combination of noble-metal nanoparticles and supports, this work will provide new insights to the design of high-performance catalysts for indoor air purification.


Nardosinone Alleviates Parkinson's Disease Symptoms in Mice by Regulating Dopamine D2 Receptor.
Nardostachyos Radix et Rhizoma (nardostachys) is the root and rhizome of Nardostachys jatamansi DC. Recent studies have shown that nardostachys may exert an anti-PD effect. In this study, the UHPLC-LTQ-Orbitrap-MS method was used to analyze the brain components of nardostachys in rats. Based on the results of UHPLC-LTQ-Orbitrap-MS analysis, nardosinone was identified to be the most effective anti-PD compound in nardostachys. To further verify this inference, a mouse PD model was established and the effect of nardosinone on PD mice was determined using classic behavioral tests. The results showed that nardosinone was indeed effective for relieving PD symptoms in mice. Moreover, network pharmacology analysis was used to elucidate the mechanism underlying the anti-PD effect of nardosinone. Dopamine receptor D2 (DRD2) was identified as the key target of nardosinone-PD interaction network, which was further verified by molecular docking and Western blotting. The results demonstrated that nardosinone and DRD2 could interact with each other. Furthermore, the expression level of DRD2 was decreased in the brain tissue of PD mice, and nardosinone could restore its expression to a certain extent. In conclusion, our findings suggest that nardosinone may reduce the motor and cognitive symptoms in the animal PD model by regulating DRD2 expression.


Community therapy as a strategy for promoting the mental health of professors in the COVID-19 pandemic.
To understand the perception of university professors about Integrative Community Therapy as a mental health promotion strategy. Qualitative, phenomenological and interventional research, conducted with professors of the Nursing course at the Universidade Estadual do Sudoeste da Bahia, Jequié, Bahia, Brazil. The experiential descriptions were produced through phenomenological interviews, whose resulting material was analyzed based on the Ambiguity Analytical technique. The professors expressed a lack of interaction between them, a fact that has become a reality in everyday academic life and that has worsened in the emergence of the COVID-19 pandemic. In this context, the Community Therapy circles in a virtual environment proved to be effective in sharing psychosocial and physical demands, as well as in the collective discussion of problem situations and the search for joint solutions. The study highlights the potential of Community Therapy as an integrative and complementary practice to the Brazilian public health care model.


Nitrite-nitric oxide control of mitochondrial respiration at the frontier of anoxia.
Actively respiring animal and plant tissues experience hypoxia because of mitochondrial O(2) consumption. Controlling oxygen balance is a critical issue that involves in mammals hypoxia-inducible factor (HIF) mediated transcriptional regulation, cytochrome oxidase (COX) subunit adjustment and nitric oxide (NO) as a mediator in vasodilatation and oxygen homeostasis. In plants, NO, mainly derived from nitrite, is also an important signalling molecule. We describe here a mechanism by which mitochondrial respiration is adjusted to prevent a tissue to reach anoxia. During pea seed germination, the internal atmosphere was strongly hypoxic due to very active mitochondrial respiration. There was no sign of fermentation, suggesting a down-regulation of O(2) consumption near anoxia. Mitochondria were found to finely regulate their surrounding O(2) level through a nitrite-dependent NO production, which was ascertained using electron paramagnetic resonance (EPR) spin trapping of NO within membranes. At low O(2), nitrite is reduced into NO, likely at complex III, and in turn reversibly inhibits COX, provoking a rise to a higher steady state level of oxygen. Since NO can be re-oxidized into nitrite chemically or by COX, a nitrite-NO pool is maintained, preventing mitochondrial anoxia. Such an evolutionarily conserved mechanism should have an important role for oxygen homeostasis in tissues undergoing hypoxia.


A sensitive radioimmunoassay for fentanyl. Plasma level in dogs and man.
Antiserum to fentanyl was obtained in rabbits repeatedly injected with carboxyfentanyl conjugated to bovine serum albumin. Using the antiserum, a highly sensitive radioimmunoassay has been developed, based on the dextran-coated charcoal method. It proved possible to assay the drug directly in plasma, in amounts as small as 30 picogram in 0.5 ml. The antibody was highly specific for fentanyl and no cross-reaction was observed with its major metabolites. This sensitive and specific radioimmunoassay method was employed to determine fentanyl in plasma from six volunteers after an intravenous bolus of 0.2 mg, and in plasma from dogs treated both intravenously and subcutaneously with 0.02 mg/kg. The plasma level of fentanyl could be followed for up to 6 h after a therapeutic dose in dogs and man.


A Comparative Study to Assess the Efficacy of Two Different Estradiol Formulations during In Vitro Fertilization.
Improvements in stimulation protocols, introduction of vitrification, and changes in clinical practices have contributed to improved efficacy and safety of assisted reproductive technology (ART) procedures. This has also led to a concomitant increase in number of cycles requiring hormone replacement therapy (HRT) protocol for performing an embryo transfer. Successful implantation is dependent on endometrial thickness which in turn is regulated by temporal regulation of hormones. Careful control of estrogen levels determines uterine receptivity. One of the most used drugs for achieving appropriate endometrial lining of >7 mm in HRT is estradiol valerate. Although different estrogen formulations with varying physicochemical properties exist, there is not enough literature to support if the differences translate into a discernible clinical outcome in an in vitro fertilization (IVF) setting. Objective and Method. In this study, retrospective in nature, we compare the efficacy of oral estradiol hemihydrate with estradiol valerate in HRT cycles in 2,529 Indian women, undergoing treatment at a center in India between Jan 2017 and May 2019. Results. Our results primarily indicate that between the estradiol valerate and estradiol hemihydrate treatment groups, the implantation rate (IR) was 47.42% and 49.07%, respectively (P value 0.284), and the endometrial thickness (mean ± SEM in mm) that was achieved was 9.25 ± 0.038 mm and 9.57 ± 0.058 mm (P value < 0.001), respectively. There were no significant differences observed in the secondary outcome measures including clinical pregnancy rate, abortion rate, ectopic pregnancy, and live birth rate. Conclusions. Hence, this study concludes that oral estradiol hemihydrate and estradiol valerate are therapeutically equivalent and provide similar clinical outcomes in an IVF setting.