Substitution scanning identifies a novel, catalytically active ibrutinib-resistant BTK cysteine 481 to threonine (C481T) variant.
Irreversible Bruton tyrosine kinase (BTK) inhibitors, ibrutinib and acalabrutinib have demonstrated remarkable clinical responses in multiple B-cell malignancies. Acquired resistance has been identified in a sub-population of patients in which mutations affecting BTK predominantly substitute cysteine 481 in the kinase domain for catalytically active serine, thereby ablating covalent binding of inhibitors. Activating substitutions in the BTK substrate phospholipase Cγ2 (PLCγ2) instead confers resistance independent of BTK. Herein, we generated all six possible amino acid substitutions due to single nucleotide alterations for the cysteine 481 codon, in addition to threonine, requiring two nucleotide substitutions, and performed functional analysis. Replacement by arginine, phenylalanine, tryptophan or tyrosine completely inactivated the catalytic activity, whereas substitution with glycine caused severe impairment. BTK with threonine replacement was catalytically active, similar to substitution with serine. We identify three potential ibrutinib resistance scenarios for cysteine 481 replacement: (1) Serine, being catalytically active and therefore predominating among patients. (2) Threonine, also being catalytically active, but predicted to be scarce, because two nucleotide changes are needed. (3) As BTK variants replaced with other residues are catalytically inactive, they presumably need compensatory mutations, therefore being very scarce. Glycine and tryptophan variants were not yet reported but likely also provide resistance.


Appearance of retinal arterial macroaneurysms in patients using swept-source optical coherence tomographic angiography.
Retinal arterial macroaneurysm (RAM) is a common clinical disease leading to vision loss in elderly individuals. The appropriate interpretation of swept-source optical coherence tomographic angiography (SS-OCTA), a noninvasive examination, is easy and convenient for detecting the status of RAMs and guiding treatment. The objectives of this study were to describe the morphologic characteristics of RAMs using SS-OCTA and to observe whether there are differences in the morphologies of RAMs between SS-OCTA and fundus fluorescein angiography (FFA), before and after treatment. We retrospectively evaluated twenty-two eyes of 22 patients who were diagnosed with RAMs. All patients underwent a complete ophthalmologic examination, including a review of medical records, best-corrected visual acuity (BCVA), fundus photography, FFA and SS-OCTA. RAMs were recorded by SS-OCTA before any treatment or observation decisions were made. The morphologic findings of the RAMs on SS-OCTA were investigated. On SS-OCTA, RAMs can show local dilatation or an irregular linear blood flow signal, and the dilated cystic lumen may show thrombosis with a low reflection signal. After treatment, the shape of the RAMs will show reactive changes. The findings on SS-OCTA are not very consistent with those on FFA. The same RAM may have different manifestations on OCTA and FFA, and OCTA can more conveniently reflect the changes in blood flow signals and treatment response of RAMs.


Does affirming children's autonomy and prosocial intentions help? A microtrial into intervention component effects to improve psychosocial behavior.
Prior research has related children's prosocial behavior to overall well-being, and stimulating prosocial behavior is the aim of many social-emotional skills interventions. This study assessed if affirming children's autonomy stimulates their psychosocial behavior. We conducted a three-arm microtrial with four repeated measures to assess if a social-emotional skills intervention with an autonomy affirmation component had an additive effect on children's behavior as compared to a "regular" intervention focused exclusively on teaching social-emotional skills and a no-treatment control condition. Our sample consisted of 779 children in Grades 4-6 (Mage = 10.61, SD = 0.93). Findings from latent change modeling demonstrated that the social-emotional skills intervention with an autonomy affirmation component yielded superior effects as compared to the "regular" intervention and the no-treatment control condition on the improvement of internalizing and externalizing problem behavior in the three-month period after the intervention. The intervention with autonomy affirmation did not yield superior effects on prosociality and social skills, self-efficacy, and self-esteem or self-perceived competence. The absence of these effects may be attributed to the dosage of the interventions implemented-the affirmation of children's autonomy may require more than four sessions to sort observable effects. Overall, however, the findings of this study provide an initial suggestion that it may be beneficial to affirm children's autonomy and prosocial intentions when enhancing children's behavior.


Geriatric rehabilitation.
Rehabilitation of elderly persons is accompanied by unique challenges, as the physiologic changes with aging may be compounded by a multitude of psychologic, social, and genetic factors. In this chapter we present an overview of the impairments that develop with aging. We discuss factors to consider when evaluating a patient with functional complaints and opportunities for treatment. We provide an overview of common injuries encountered in the elderly, prognostication, and general strategies employed for rehabilitation. New treatment options and areas of ongoing research are also discussed.


Depression after diagnosis of advanced non-small cell lung cancer and survival: a pilot study.
Major depressive disorder is estimated to occur in 10%-25% of people with cancer, and it has been inconsistently linked to increased mortality. This pilot study investigates the association of depression and survival in advanced non-small cell lung cancer (NSCLC) patients. Forty-three recently-diagnosed advanced NSCLC patients completed the Hospital Anxiety and Depression Scale and were followed prospectively. Patients with depression had poorer survival. Median survival was four times shorter than those without depression. Controlling for baseline performance status, depression predicted 6-month mortality, but was not significant for overall survival. Although depression after advanced-NSCLC diagnosis was associated with poorer survival at 6 months, this association was not present for overall survival; however, further research with larger samples should be pursued.


Altered putamen and cerebellum connectivity among different subtypes of Parkinson's disease.
Impairment of basal ganglia (BG)-thalamo-cortical circuit causes various symptoms of Parkinson's disease (PD). We investigated the functional connectivity (FC) patterns of putamen among PD subtypes and healthy control (HC) and explored their clinical significance. A total of 16 patients with tremor-dominant (TD) PD, 23 patients with postural instability and gait difficulty-dominant (PIGD) PD, and 31 HC that underwent functional magnetic resonance imaging were observed. Voxel-wise FC analysis was performed by computing correlation between bilateral putamen and other voxels within the brain. Correlation analysis was performed between FC strength and clinical symptoms. Compared with PIGD group, TD group showed increased FC between left putamen and right cerebellum lobule VI and cerebellum crus I, then we compared the cerebellum FC difference among the three groups. The cerebellum lobule VI FC difference was mainly involved in motor related cortex, and the cerebellum crus I FC difference was related to cognition areas. While compared with HC, TD and PIGD groups both had significant FC difference brain areas correlated with motor and cognition symptoms. The connectively of putamen and right cerebellum lobules VI and I showed positive correlation with tremor and Montreal Cognitive Assessment degree of scores, respectively. The connectivity of putamen and sensorimotor cortex had negative correlation with PIGD scores. The altered connectivity of BG-cortical circuit in patients with PD was related to PIGD symptoms. Motor and cognitive impairments declined slower in patients with TD PD, which may be related to increased functional connectivity between putamen and cerebellum.


A comparison between fibronectin and Matrigel pretreated ePTFE vascular grafts.
Two distinct series of experiments were performed to compare the behavior of ePTFE vascular grafts coated with basement membrane gel to that of identical grafts coated with fibronectin. Bilateral carotid interposition grafts (10 cm long) were interposed in 16 conditioned mongrel dogs. In the first series of experiments (n = 10), each graft was seeded with radiolabeled endothelial cells and initial endothelial cell adherence was determined. Following restoration of blood flow in the grafts, endothelial cell retention was measured for 24 hours. Seeding efficiency was 66.48% (+/- 13.2) for fibronectin-coated grafts and 56.58% (+/- 13.51) for gel-coated grafts. There was a slow, constant loss of activity during the first 90 minutes of imaging, and at 24 hours of observation the activity remaining on the fibronectin-coated graft was 13.2 +/- 3.98% of the initial graft activity. Although the basement membrane gel had a higher mean activity at 24 hours (18.9 +/- 7.22%), the difference was not statistically significant at any interval. In the second series of animals (n = 6), radiolabeled platelets were injected within 60 minutes following restoration of flow. Total platelet activity on the explanted grafts was 3.36 (+/- 1.35) x 10(5) counts per gram/0.2 minute for the fibronectin-coated grafts. The gel-coated grafts had 2.74 (+/- 1.33) x 10(5) counts per gram/0.2 minute, a difference that was not statistically significant. Thus, despite its theoretical appeal, basement membrane gel was no better than fibronectin in increasing endothelial cell adherence and retention, and the resulting flow surface of grafts treated with either compound appeared to attract platelets to an equal degree.


Induction of four proteins in chick embryo cells by sodium arsenite.
Four proteins of Mr = 89,000, 73,000, 35,000, and 27,000 are strongly induced in chick fibroblasts by sodium arsenite. Induction of these proteins is discoordinate as a function of arsenite concentration. Kinetically, all species appear 1 h after exposure to 50 microM arsenite, after 24 and 48 h of exposure, the 27,000 protein is still synthesized extensively, whereas normal cell proteins and the three other induced proteins are greatly reduced. The four proteins are unrelated by tryptic peptide-mapping procedures. Multiple subspecies of p89, p73, and p27 were observed in two-dimensional gels. The subspecies of p73 appear to be related as determined by partial proteolytic maps as are those of p27. Two-dimensional gel analysis of in vitro translation products from rabbit reticulocyte lysates primed with mRNA from uninduced and induced cells reveals that the amount of translatable mRNA specific for these proteins is increase by induction. This increase is attributable to new mRNA synthesis since actinomycin D prevent induction and new bands of RNA (Mr = 0.9 X 10(6) and 1.3 X 10(6)) appear in methyl mercury gels of oligo(dT) selected RNA from induced cells. These bands are assigned to p73 and p89 based on translation of electroeluted RNA from a similar preparative gel. A comparison is made between induction of these proteins and the heat shock response in Drosophilla melanogaster.


Greenhouse gas emissions from Canadian peat extraction, 1990-2000: a life-cycle analysis.
This study uses life-cycle analysis to examine the net greenhouse gas (GHG) emissions from the Canadian peat industry for the period 1990-2000. GHG exchange is estimated for land-use change, peat extraction and processing, transport to market, and the in situ decomposition of extracted peat. The estimates, based on an additive GHG accounting model, show that the peat extraction life cycle emitted 0.54 x 10(6) t of GHG in 1990, increasing to 0.89 x 10(6) t in 2000 (expressed as CO2 equivalents using a 100-y time horizon). Peat decomposition associated with end use was the largest source of GHGs, comprising 71% of total emissions during this 11-y period. Land use change resulted in a switch of the peatlands from a GHG sink to a source and contributed an additional 15%. Peat transportation was responsible for 10% of total GHG emissions, and extraction and processing contributed 4%. It would take approximately 2000 y to restore the carbon pool to its original size if peatland restoration is successful and the cutover peatland once again becomes a net carbon sink.


[Psychotherapy of depression].
There are now several well evaluated (psychological) interventions available to treat depressive disorders. A large number of controlled randomized trials have been conducted to establish scientific evidence for treatments' short- and long-term outcome. If the patient meets the diagnostic criteria for depression, a decision has to be made about referral to a psychiatrist or a psychotherapist for specialized treatment. Depending on severity of symptomatology (suicidality) as well as the range of individual problems, supportive counselling or specific psychotherapy is indicated. Specific psychotherapies for depression are in particular cognitive behaviour therapy (CBT) and interpersonal psychotherapy (IPT), to a less extent short-term psychodynamic psychotherapy (STPP) and client centred psychotherapy (CCPT). For these specific psychotherapies, empirical evidence is available about short-term (successful symptom reduction) and long-term (relapse prevention) outcome as monotherapy or in combination with antidepressive medication. Based on available outcome studies, 14 up-to-date treatment recommendations conclude this presentation.


Nutrition care by primary-care physicians: advancing our understanding using the COM-B framework.
To investigate the nutrition education provided by primary-care physicians (PCP). An integrative review was used to examine literature on nutrition care provided by PCP from 2012 to 2018. A literature search was conducted in MEDLINE, PubMed, Cumulative Index of Nursing and Allied Health Literature (CINAHL) and Scopus using key search terms. USA, Netherlands, Germany, Denmark, UK, Lebanon, Australia and New Zealand. Primary-care physicians. Sixteen qualitative and quantitative studies were analysed thematically using meta-synthesis informed by the COM-B model of behaviour (capability, motivation and opportunity), to understand the influences on PCP behaviours to provide nutrition care. PCP perceive that they lack nutrition capability. While PCP motivation to provide nutrition care differs based on patient characteristics and those of their own, opportunity is influenced by medical educators, mentors and policy generated by professional and governmental organisations. The development of PCP capability, motivation and opportunity to provide nutrition care should begin in undergraduate medical training, and continue into PCP training, to create synergy between these behaviours for PCP to become confident providing nutrition care as an integral component of disease prevention and management in contemporary medical practice.


Expression of endothelin 3 by mesenchymal cells of embryonic mouse caecum.
Mutations in endothelin 3 (EDN3) and endothelin B receptor (EDNRB) genes cause terminal colonic aganglionosis in mice, and mutations in these genes have also been linked to the terminal aganglionosis seen in human Hirschsprung's disease. However, details of EDN3 expression during embryogenesis are lacking, and consequently the cellular mechanism by which EDN3 regulates innervation of the terminal gut is unclear. To localise the expression of EDN3 and EDNRB in the embryonic mouse gut. Expression of EDN3 and EDNRB mRNA was analysed by reverse transcription polymerase chain reaction and in situ hybridisation. High levels of EDN3 mRNA expression were restricted to mesenchymal cells of the caecum before and after the arrival of neural crest cells. In contrast, EDNRB expression along the gut displayed a time dependent pattern similar to those of the protein tyrosine kinase ret and the neural crest cell marker PGP9.5. Mesenchymal cells of the caecum express high levels of EDN3 mRNA during embryogenesis and hence the production of EDN3 at the caecum is likely to act on neural crest cells as a paracrine factor necessary for subsequent innervation of the terminal gut.


Molt induction in lobsters (Homarus americanus) by intramuscular injection of ecdysterone triacetate.
The principal component of the successful, molt-inducing ecdysterone acetate mixture was established as ecdysterone triacetate and shown to have the same activity as the acetate mixture. The triacetate induced ecdysis in male lobsters collected in winter and summer and in female lobsters collected in winter. Intramuscular injections of triacetate in ethanol were as effective as those with oil emulsions.


Immunolocalization of VEGF, VEGFR-1 and VEGFR-2 in lung tissues after acute hemorrhage in rats.
In treatment of hypovolemia it is important to reestablish normal tissue hemodynamics after fluid resuscitation. Vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFR) have been identified as important in many physiological and pathological processes. In this study, we aimed to investigate the histo-physiological effects of VEGF, VEGFR-1 (flt-1) and VEGFR-2 (KDR/flk-1) in resuscitation with different plasma substitutes on lung tissues after acute hemorrhage in rats. Male Sprague-Dawley rats (n=25) were used in this study. The left femoral vein and artery were cannulated for the administration of volume expanders and for direct measurement of mean arterial blood pressure (MAP) (Power-Lab) and heart rate (HR). Fifteen rats were bled (5 ml/10 min) and infused (5 ml/5 min) with one of three randomly selected fluids: (a) dextran-70 (Macrodex); (b) gelatin (Gelofusine); or (c) physiological saline (PS, 0.9% isotonic saline) solutions. Five rats were bled and none were infused (hypovolemia group) and five rats were untreated as the control group. At the end of the experiment, rats were sacrificed and lung tissues were removed for routine processing and paraffin wax embedding. Sections of tissue were stained with hematoxylin and eosin (H&E) and selected blocks were then prepared for indirect immunohistochemical labeling for anti-VEGF, anti-VEGFR-1 and anti-VEGFR-2 primary antibodies. It was observed that both MAP and HR decreased parallel to blood withdrawn in this time interval. The MAP and HR were restored in the following periods. In the control rats, positive immunoreactivity of VEGF and its receptors (VEGFR-1 and VEGFR-2) were detected in respiratory epithelial cells, respiratory and vascular smooth muscle cells, alveolar cells and endothelial cells. While strong immunoreactivities of VEGF and VEGFR-1 were observed in the hypovolemia group, only moderate immunoreactivity of VEGFR-2 was seen in this group. Moderately strong immunolabeling of VEGF and VEGFR-1 were observed in the dextran-70, gelatin and PS resuscitated groups, whereas only weak immunolabeling of VEGFR-2 was observed in these groups. In summary, the vascular protecting effects of these factors were observed with fluid resuscitation, contributing to the pathophysiological changes seen in hypovolemia.


Dopamine signaling regulates the projection patterns in the mouse chiasm.
Ocular albinism (OA) is characterized by inadequate L-3, 4-dihydroxyphenylalanine (L-DOPA) and dopamine (DA) in the eyes. This study investigated DA-related signaling pathways in mouse chiasm projection patterns and the potential role of ocular albinism type 1 (OA1) and dopamine 1A (D1A) receptors in the optic pathway. In embryonic day (E) E13-E15 retina, most L-DOPA and OA1-positive cells were distributed among Müller glial cells on E13 and retinal ganglion cells (RGC) on E14. In the ventral diencephalon, OA1 and L-DOPA were strongly expressed on the optic chiasm (OC) and optic tract (OT), respectively, but weak on the optic stalk (OS). At E13-E15, DA and D1A staining was predominately expressed in radially arranged cells with a neuronal expression pattern. In the ventral diencephalon, DA and D1A were strongly expressed on the OC, OT and OS. Furthermore, L-DOPA significantly inhibited retinal axon outgrowth in both the dorsal nasal (DN) and ventral temporal (VT) groups. DA inhibited retinal axon outgrowth, which was abolished by the D1A antagonist SCH23390. Brain slice cultures indicated that L-DOPA inhibited axons that crossed at the OC of E13 embryos, which was not abolished by DA. L-DOPA also inhibited axons that crossed at the OC of albino mice. Albino mice exhibited reduced ipsilateral retinal projections compared with C57 pigmented mice. No significant difference was identified in the uncrossed projections of albino mice following L-DOPA and DA expression. Furthermore, transcription factor Zic family member 2 (Zic2) upregulated OA1 mRNA expression. Our findings provide critical insights into DA-related signaling in retinal development.


Development and applications of ultrasensitive enzyme immunoassays for antigens and antibodies.
Some enzymes can be measured at lower molar concentrations than the radioisotopes used as labels in radioimmunoassay. Therefore, enzyme immunoassay should be capable of higher sensitivity than radioimmunoassay, if appropriate techniques are used for enzyme-labelling of antibodies and formulation of assay protocols. Techniques required for enzyme immunoassay with attomole sensitivity have been developed, and successfully applied to the measurement of clinically important ligands at levels below those possible using radioimmunoassay. In addition, a novel enzyme immunoassay technique (immune complex transfer enzyme immunoassay technique) is being developed to provide higher sensitivity.


Clinical epidemiological analyses of overweight/obesity and abnormal liver function contributing to prolonged hospitalization in patients infected with COVID-19.
During the 2019 coronavirus disease (COVID-19) outbreak, obesity may contribute to COVID-19 transmission and deterioration. In addition, many patients with COVID-19 infection have suffered liver damage which might contribute to a worse prognosis. We conducted a clinical epidemiological analysis to investigate the association of overweight/obesity and abnormal liver function (ALF) with hospitalized duration in patients infected with COVID-19. Fifty-eight patients with diagnosed COVID-19 (22 women & 36 men; average age: 49.2 ± 13.1 yr) were included, and their clinical data were collected at The Second Affiliated and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang. Overweight/obesity was determined as body mass index (BMI) ≥24 kg/m2, ALF was determined as alanine aminotransferase >40 U/L, and prolonged hospitalization was lasting more than the median value of the hospitalized days (19 days) in this population. The proportions of prolonged hospitalization were elevated in patients with overweight/obesity and ALF compared with those without overweight/obesity (62.1% versus 26.1%, P = 0.010) and those without ALF (70.6% versus 41.5%, P = 0.043). Kaplan-Meier analysis showed that the hospitalized duration was increased from the patients with neither overweight/obesity nor ALF to those with either overweight/obesity or ALF, and to those with both of overweight/obesity and ALF (mean with 95% confidence interval: 16.4 [14.5-18.3] versus 25.3 [21.6-29.1] versus 28.3 [24.6-32.0], P for trend = 0.001). Being discharged from hospital in time was inversely and independently associated with BMI (hazard ratio [HR] = 0.75, 95% CI: 0.63-0.90, P for trend = 0.002) and ALT (HR = 0.95, 95% CI: 0.92-0.99, P for trend = 0.007). Present findings suggested that overweight/obesity and/or ALF contributed to predicting a probability of prolonged hospitalization in patients with COVID-19 infection, to whom extra attentions and precautions should be paid during clinical treatments.


Family planning programmes in ten developing countries: cost effectiveness by mode of service delivery.
The cost effectiveness of various modes of family planning service delivery based on the cost per couple-year of protection (CYP) is assessed using 1984 data for 63 projects in ten countries (three each in Africa and Asia, and four in Latin America). More than 4.8 million CYPs were provided through these projects during the year studied. Programmes with the highest volume of services delivered corresponded to lowest average costs: social marketing (2.8 million CYPs) and sterilization projects (960,000 CYPs) cost about $2 per CYP, on average; highest costs were for full service clinics and community-based distribution projects ($13-14 per CYP). Costs of clinics combined with community-based distribution services fell approximately midway between these two extremes.


Cell-surface modification with an iodinatible imidoester to enhance radiolabeling.
A procedure to enhance incorporation of radioactive iodine into cell-surface proteins is described. The effects of chemical modification of cells with the iodinatible haptens N-succinimidyl-3-(4-hydroxyphenyl) propionate (Bolton-Hunter reagent) and methyl-p-hydroxybenzimidate HC1 (Wood reagent) are compared. The Wood reagent, that does not alter the charge of the modified amino group, is superior in retention of cell viability and function. Cell-surface modification with the Wood reagent prior to radiolabeling is particularly useful for detecting antigens not readily iodinated using standard techniques.


Tumor behavior of hepatocellular carcinoma after hepatitis C treatment by direct-acting antivirals: comparative analysis with non-direct-acting antivirals-treated patients.
Scarce reports have commented on hepatocellular carcinoma (HCC) behavior after direct-acting antivirals (DAAs). To analyze differences in tumor behavior between patients with hepatitis C virus (HCV)-induced HCC and were either treated or not using DAAs. This case-control study includes patients with HCV-related HCC who received generic DAAs (group I) and all non-DAA treated patients with HCC who presented to our clinic during the same period (group II). Patient and tumor characteristics, treatment types and outcome were compared between the two groups. Group I included 89 patients and group II included 207 patients. No significant difference was detected between groups regarding HCC number or size. Group I showed a more infiltrative HCC pattern, whereas group II had more circumscribed and delineated lesions. The incidence of portal vein thrombosis and significant lymphadenopathy was significantly higher in group I (P=0.03 and 0.03, respectively). Serum levels of α-fetoprotein were significantly higher in group I (P=0.02). These factors significantly affected the response to HCC management (P=0.03). Incidence of complete responses were 47.2 and 49.8% for groups I and II, respectively, whereas incomplete responses were 12.4 and 25.1%, respectively. Supportive treatment was applied to 40.4% in group I and 25.1% in group II. HCC behavior was more aggressive in DAA-treated patients regarding portal vein thrombosis, malignant lymphadenopathy, and HCC imaging characteristics, which affected the chance of ablation and the treatment response.


Sperm mitochondrial DNA copy numbers in normal and abnormal semen analysis: A systematic review and meta-analysis.
Normal mature sperm have a considerably reduced number of mitochondria, which provide the energy required for progressive sperm motility. Literature suggests that disorders of sperm motility may be linked to abnormal sperm mitochondrial number and function. To summarise the evidence from literature regarding the association of mitochondrial DNA copy numbers and semen quality with a particular emphasis on the sperm motility. Standard methodology recommended by Cochrane. All published primary research reporting on the association between mitochondrial DNA copy numbers and semen quality. Using standard methodology recommended by Cochrane we pooled results using a random effects model and the findings were reported as a standardised mean difference. We included ten studies. The primary outcome was sperm mitochondrial DNA copy numbers. A meta-analysis including five studies showed significantly higher mitochondrial DNA copy numbers in abnormal semen analysis compared with normal semen analysis (standardised mean difference 1.08, 95% CI 0.74-1.43). Seven studies included in the meta-analysis showed a significant negative correlation between mitochondrial DNA copy numbers and semen parameters. The quality of evidence was assessed as good to very good in 60% of studies. Our review demonstrates significantly higher mitochondrial DNA in human sperm cells of men with abnormal semen analysis in comparison to men with normal semen analysis. There is significantly higher mitochondrial DNA in sperm cells of men with abnormal semen analysis in comparison to men with normal semen analysis.


Overview of current noninodilator therapies for acute heart failure syndromes.
Several treatment strategies exist for patients hospitalized with acute heart failure syndromes (AHFS). These therapies traditionally focus on improving hemodynamics and relieving congestion. This review focuses on noninodilator therapies, including diuretics, nitrovasodilators (nitroprusside and nitroglycerin), vasodilators (nesiritide), digoxin, and intravenous angiotensin-converting enzyme inhibitors. These agents are used based on their associated symptomatic improvements alone. In the hospitalized setting, none of these agents have demonstrated benefits on long-term outcomes. Future work in AHFS should strive to understand the influence of conventional and new pharmacologic therapies on the underlying pathophysiology of AHFS, the processes that lead to myocardial injury and progressive heart failure, and measurable clinical outcomes.


Cerebrovascular endothelial dysfunction induced by mercury exposure at low concentrations.
Mercury (Hg) has many harmful vascular effects by increasing oxidative stress, inflammation and vascular/endothelial dysfunction, all of which may contribute to cerebrovascular diseases development. We aimed to explore the effects of chronic low-mercury concentration on vascular function in cerebral arteries and the mechanisms involved. Basilar arteries from control (vehicle-saline solution, im) and mercury chloride (HgCl2)-treated rats for 30 days (first dose 4.6μg/kg, subsequent dose 0.07μg/kg/day, im, to cover daily loss) were used. Vascular reactivity, protein expression, nitric oxide (NO) levels and superoxide anion (O2(-)) production were analyzed. HgCl2 exposure increased serotonin contraction and reduced the endothelium-dependent vasodilatation to bradykinin. After NO synthase inhibition, serotonin responses were enhanced more in control than in mercury-treated rats while bradykinin-induced relaxation was abolished. NO levels were greater in control than Hg-treated rats. Tiron and indomethacin reduced vasoconstriction and increased the bradykinin-induced relaxation only in HgCl2-treated rats. Vascular O2(-) production was greater in mercury-treated when compared to control rats. Protein expressions of endothelial NO synthase, copper/zinc (Cu/Zn), Manganese (Mn) and extracellular-superoxide dismutases were similar in cerebral arteries from both groups. Results suggest that Hg treatment increases cerebrovascular reactivity by reducing endothelial negative modulation and NO bioavailability; this effect seems to be dependent on increased reactive oxygen species and prostanoids generation. These findings show, for the first time, that brain vasculature are also affected by chronic mercury exposure and offer further evidence that even at small concentration, HgCl2 is hazardous and might be an environmental risk factor accounting for cerebral vasospasm development.


Daunomycin-TFO Conjugates for Downregulation of Gene Expression.
Daunomycin has shown interesting properties as a stabilizing agent for the antigene methodology.This approach consists of targeting a polypurine region of a given gene, with a triplex formingoligonucleotide (TFO), realizing a triple helix complex (triplex), with the aim of down-regulatinggene expression. This chapter describes the basic principles of the triplex approach, the chemistry underliningthe binding of daunomycin to oligonucleotides, and some results of gene-inhibition obtained with daunomycin-TFOconjugates with different targets.


Trypanosomal immune evasion, chronicity and transmission: an elegant balancing act.
During their life cycle, trypanosomes must overcome conflicting demands to ensure their survival and transmission. First, they must evade immunity without overwhelming the host. Second, they must generate and maintain transmission stages at sufficient levels to allow passage into their tsetse vector. Finally, they must rapidly commit to onward development when they enter the tsetse fly. On the basis of recent quantification and modelling of Trypanosoma brucei infection dynamics, we propose that the interplay between immune evasion and development achieves both infection chronicity and transmissibility. Moreover, we suggest that a novel form of bistable regulation ensures developmental commitment on entry into the tsetse fly midgut.


A methodological review finds mismatch between overall and pairwise overlap analysis in a sample of overviews.
Overlap of primary studies is a key methodological challenge for overviews. There are limited reports of methods used to address overlap, and there is no detailed assessment of the corrected covered area (CCA) of a representative sample of overviews. To describe the approaches used to address overlap, and to estimate the overall and pairwise CCA. We searched PubMed for overviews published in 2018. Two authors conducted the screening process. We described the strategy used for assessing overlap, and calculated overall and pairwise CCA for each overview. We analyzed a random sample of 30 out of 89 eligible articles. Eleven did not address the overlap. Of the remainder, most frequent strategies were visual assessment and discussion of overlap as a limitation. Median overall CCA among the included overviews was 6.7%. The pairwise analysis showed that 52.8% of SR pairs had slight overlap, while 28.3% had very high overlap. Reported strategies for addressing overlap vary considerably among overview authors. The pairwise approach for assessing the CCA revealed highly overlapped pairs of SRs in overviews with overall slight overlap and vice versa. We encourage authors to complement the overall CCA assessment with a pairwise approach.


Risedronate for the prevention and treatment of postmenopausal osteoporosis: results from recent clinical trials.
Postmenopausal osteoporosis is a widespread condition that affects the physical and emotional well-being of millions of women worldwide. In the clinical trials reviewed here, antiresorptive therapy using the bisphosphonate, risedronate, significantly reduced the incidence of vertebral and nonvertebral fractures, increased BMD in both early and late menopausal women, and decreased biochemical measures of bone resorption. The safety profile of risedronate appears comparable to placebo. These findings demonstrate that risedronate is effective and well tolerated for the prevention and treatment of postmenopausal osteoporosis.


Three Consecutive Episodes of Thunderstorm Asthma in Ahvaz, Iran: the Possible Role of Conocarpus Pollen.
The aim of this study is to evaluate the clinical pattern of thunderstorm asthma (TA) and the possible environmental hypotheses involved in the escalation of these epidemics. This retrospective descriptive study examined patients with respiratory problems referred to the clinics and emergency departments in Ahvaz, Iran during 2013-2016 periods following the first episodes of rainfall in autumn. The seasonal profile of airborne pollens and fungal spores in Ahvaz were characterized and clinical and spirometry findings of 443 patients were evaluated. Of 56,000 people referred to the emergency department due to respiratory problems associated with the first rainfall in Khuzestan province, 91.4% displayed asthma-like symptoms and 71.3% had a history of allergic rhinitis. According to the results of spirometry test 38%, 52.9%, and 9.1% of patients had normal, obstructive, and restrictive patterns, respectively. Our results highlight the importance of allergic rhinitis as risk factors of TA epidemics. In terms of pollen, seasonal pollen integral was much higher in autumn than in winter. Our results highlight the importance of seasonal allergy and rhinitis as risk factors for thunderstorm asthma epidemics.


Dewatering and granulation of sewage sludge by biophysical drying and thermo-degradation performance of prepared sludge particles during succedent fast pyrolysis.
A novel two-step technology, fast biophysical drying (BPD) coupling with fast pyrolysis (FP), was investigated for moisture removal and energy recovery from sewage sludge. For BPD, combined operations of extreme thermophilic amendment (with accelerated increasing and controllable maintenance of substrate temperature) and enhanced convective evaporation were conducted, both beneficial for moisture removal (moisture content reaching 23.1% for 7d) and organic preservation. Biophysical-dried sludge (BPDS) was characterized by homogeneous fine-particle morphology and well-developed porous microstructure. The synthesized BPDS particle preserved most organic components (92% volatile matters and 79% HHV of traditional thermal-dried sludge [TTDS]) attributable to the inhibitory effect of BPD adjustment, presenting considerable capacity for subsequent residue-derived energy. For FP, the distribution of products from BPDS pyrolysis indicated that syngas and char yields were higher than those of TTDS. The syngas from BPDS is a type of hydrogen-rich gas composed of 42.6 vol.% H(2) at 900°C.


Inverse associations between perceived racism and coronary artery calcification.
To evaluate whether racial discrimination is associated with coronary artery calcification (CAC) in African-American participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study. The study included American Black men (n = 571) and women (n = 791) aged 33 to 45 years in the CARDIA study. Perceived racial discrimination was assessed based on the Experiences of Discrimination scale (range, 1-35). CAC was evaluated using computed tomography. Primary analyses assessed associations between perceived racial discrimination and presence of CAC using multivariable-adjusted logistic regression analysis, adjusted for age, gender, socioeconomic position (SEP), psychosocial variables, and coronary heart disease (CHD) risk factors. In age- and gender-adjusted logistic regression models, odds of CAC decreased as the perceived racial discrimination score increased (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.90-0.98 per 1-unit increase in Experiences of Discrimination scale). The relationship did not markedly change after further adjustment for SEP, psychosocial variables, or CHD risk factors (OR, 0.93; 95% CI, 0.87-0.99). Perceived racial discrimination was negatively associated with CAC in this study. Estimation of more forms of racial discrimination as well as replication of analyses in other samples will help to confirm or refute these findings.


Causes and Predictability of the Negative Indian Ocean Dipole and Its Impact on La Niña During 2016.
In the latter half of 2016 Indonesia and Australia experienced extreme wet conditions and East Africa suffered devastating drought, which have largely been attributed to the occurrence of strong negative Indian Ocean Dipole (IOD) and weak La Niña. Here we examine the causes and predictability of the strong negative IOD and its impact on the development of La Niña in 2016. Analysis on atmosphere and ocean reanalyses and forecast sensitivity experiments using the Australian Bureau of Meteorology's dynamical seasonal forecast system reveals that this strong negative IOD, which peaked in July-September, developed primarily by the Indian Ocean surface and subsurface conditions. The long-term trend over the last 55 years in sea surface and subsurface temperatures, which is characterised by warming of the tropical Indian and western Pacific and cooling in the equatorial eastern Pacific, contributed positively to the extraordinary strength of this IOD. We further show that the strong negative IOD was a key promoter of the weak La Niña of 2016. Without the remote forcing from the IOD, this weak La Niña may have been substantially weaker because of the extraordinarily long-lasting warm surface condition over the dateline from the tail end of strong El Niño of 2015-16.


A pyrene fluorescence technique and microchamber for measurement of oxygen consumption of single isolated axons.
Pyrene fluorescence is quenched by oxygen in an inverse and linear manner related to the partial pressure of O2 in solution. We have developed a microchamber for measuring QO2 of a single isolated axon, monitoring the change in fluorescence of a pyrene probe. The probe consists of a Spectra/Por dialysis hollow fiber filled with 2.5 mM pyrene in paraffin oil. The probe is inserted into a 1-mm-i.d. 2-cm-long quartz capillary tube with a freshly isolated crayfish medial giant axon. The capillary is mounted in an apparatus that forms an air- and water-tight seal except for a 0.2-mm-i.d. stainless steel tube at both ends permitting the exchange of solutions. An Olympus inverted microscope, equipped with epifluorescence optics and a 150-W xenon lamp, is used to view the preparation, generate the excitation light, and monitor the emitted fluorescence with a photomultiplier tube placed in the microscope TV port. A dichroic filter unit is utilized to select an excitation wavelength of 350 nm and collect emitted light above 420 nm. The signal is amplified with a Keithley 480 picoammeter and recorded on a strip chart. QO2 of isolated axons was 552 +/- 70 X 10(-6) mol O2/liter tissue X min. Following sequential treatment with 2 mM ouabain and 2 mM NaCN, QO2 decreased by 22 and 82%, respectively. These data are consistent with QO2 measurements of whole nerve cord made with a Clark electrode O2 monitor.(ABSTRACT TRUNCATED AT 250 WORDS)


Improvement in persistent idiopathic facial pain with comorbid ADHD using the combination of a dopamine system stabilizer and psychostimulant: A case report.
Persistent idiopathic facial pain (PIFP) and attention-deficit/hyperactivity disorder (ADHD) may coexist and can be improved with ADHD medications. Thus, clinicians should screen for ADHD by a multidisciplinary approach when treating PIFP and differentiate between other odontogenic disorders. We report a case of a woman with persistent idiopathic facial pain (PIFP) and attention-deficit/hyperactivity disorder (ADHD) that markedly improved with the administration of a combination of aripiprazole (APZ) and methylphenidate (MP) treatment. Screening for ADHD and administration of APZ and/or MP may be considered in treating PIFP.


Multifocal retinal contraction in macular pucker analyzed by combined optical coherence tomography/scanning laser ophthalmoscopy.
To characterize the topography of macular pucker using coronal plane imaging in vivo, and correlate this with transverse optical coherence tomography (OCT) to assess the relationship between topographic features and severity of disease. Forty-four eyes with macular pucker underwent full ophthalmologic evaluation including B-scan ultrasonography as well as coronal and transverse plane imaging with combined OCT/scanning laser ophthalmoscopy (SLO). Posterior vitreous detachment was present in 37/44 eyes (84.1%) by ultrasound. Multiple foci of retinal contraction were detected in 20/44 eyes (45.5%) by coronal plane OCT/SLO. Intraretinal cysts were present in 6/9 (66.7%) eyes with three or four contraction centers as compared to 10/35 (28.6%) eyes with one or two contraction centers (P = 0.05). Eyes with three or four contraction centers had significantly (P = 0.05) thicker maculae (369 +/- 98 microm) compared to those with one or two contraction centers (297 +/- 110 microm). Coronal plane imaging detected multifocality in nearly half of eyes with macular pucker. Eyes with multiple retinal contraction centers had greater retinal damage compared to eyes with one or two contraction centers. Multifocal retinal contraction may have clinical significance in that it may impact on prognosis and management.


Prevention of esophageal strictures in a caustic burn model using halofuginone, an inhibitor of collagen type I synthesis.
Esophageal strictures caused by caustic injury continue to be a plaguing problem. Halofuginone (HF) has been proven to inhibit the formation of fibrosis in various animal models and human diseases. Its mechanism appears to be through the suppression of the production of collagen alpha1(I) and transforming growth factor-beta signaling pathway. We tried to assess whether HF would have an effect on the formation of strictures after inducing caustic esophageal. Esophageal injury was caused by injecting 25% NaOH to an isolated esophageal segment. Study group rats were treated with HF orally for 3 consecutive days before the injury and afterward. Control group rats received regular chow. The results were evaluated by upper gastrointestinal series (UGI) and through pathologic studies. HF treatment resulted in marked improvement in the esophageal strictures. The UGI series showed esophageal patency of 73% (45%-100%) in the treated animals (n = 7) as compared with almost no patency, 11% (5-16%), in the controls (n = 4) (P = .018). The histologic examination showed significantly less stricture and scarring in the treated group. Whereas the ratio between the esophageal wall thickness to mucosal thickness was 2.34 +/- 0.23 in the study group, the control group had a ratio of 9.56 +/- 0.69 (P = .0044). Finally, whereas 86% of the study group survived, all the rats in the control group died by day 20. HF modulated the wound healing reaction caused by caustic injury of the esophagus in a rat model, resulting in increased esophageal patency, reduction in esophageal wall thickness, and increased survival.


Repression of platelet-derived growth factor A-chain gene transcription by an upstream silencer element. Participation by sequence-specific single-stranded DNA-binding proteins.
Platelet-derived growth factor A-chain is a potent mitogen expressed in a restricted number of normal and transformed cells. Transient transfection and deletion analysis in BSC-1 (African green monkey, renal epithelial) cells revealed that the -1680 to -1374 region of the A-chain gene repressed homologous and heterologous promoter activities by 60-80%. An S1 nuclease-hypersensitive region (5'SHS) was identified within this region (-1418 to -1388) that exhibited transcriptional silencer activity in BSC-1 and a variety of human tumor cell lines (U87, HepG2, and HeLa). Electrophoretic mobility shift assays conducted with 5'SHS oligodeoxynucleotide probes revealed several binding protein complexes that displayed unique preferences for binding to sense, antisense, and double-stranded forms of the element. Southwestern blot analysis revealed that the antisense strand of 5'SHS binds to nuclear proteins of molecular mass 97, 87, 44, and 17 kDa, whereas the double-stranded form of 5'SHS is recognized by a 70-kDa factor. Mutations within 5'SHS element indicated the necessity of a central 5'-GGGGAGGGGG-3' motif for protein binding and silencer function, while nucleotides flanking both sides of the motif were also critical for repression. These results support a model in which silencer function of 5'SHS is mediated by antisense strand binding proteins, possibly by stabilizing single-stranded DNA conformations required for interaction with enhancer sequences in the proximal promoter region of the A-chain gene.


Validity of the Measure of Intensive Mothering Ideology (MIMI).
The aim of this study was to test the validity of the Measure of Intensive Mothering Ideology (MIMI), a French scale assessing beliefs about mothering and childcare. The MIMI was submitted online to Mothers/mothers-to-be (n=249) and Childless women (n=231). To test structural validity, confirmatory factor analyses were conducted in both groups. Then, to test known-groups validity, means comparisons were conducted according to parity (mothers/mothers-to-be and childless women) and employment status (full-time, part-time and housewives). It was also hypothesized that MIMI scores would be negatively correlated with education. Model fit was satisfactory for Mothers/mothers-to-be (X2/df=2.52, AGFI=.957, NFI=.937 RMR=.087) and, to a lesser extent, for Childless women (X2/df=3.31, AGFI=.948, NFI=.907, RMR=.104). In both groups, most dimensions were moderately correlated (.22-.70). As hypothesized, Mothers/mothers-to-be and Housewives had higher score than Childless women and Employed women. MIMI scores were also negatively and moderately correlated with education. The MIMI shows good structural validity and known-groups validity. This scale offers interesting research avenues notably regarding perinatal parental adaptation.


Soft tissue stretching with magnets.
Various clinical conditions require soft tissue elongation that can later host a bone graft. The possibility of stretching the soft tissues by magnetic force was tested on the forearm of dogs. The results are encouraging, provided certain precautions are taken and the pull exerted is not too great.


The synthesis of 13-cis-dl-erythro-15,16-dihydroxyprostaglandins.
Both pairs of dl-11-desoxy- and dl-13-cis-erythro-15,16-dihydroxyprostaglandins have been synthesized via 1,4-conjugate additions of an appropriately functionalized cis-vinyl cuprate to the requisite cyclopentenone. These prostaglandin analogs are considerably less potent than PGE2 as gastric secretion inhibitors or as bronchodilators.


[Preparation and identification of monoclonal antibodies against Pla protein of Yersinia pestis].
To prepare the monoclonal antibody of Pla with recombinant Pla (rPla) by hybridoma cell technology, which will lay the foundation for related research work. Purified rPla was collected by washing repeatedly with urea, and BALB/c mice were immunized by them. Hybridoma cells were achieved by Sp2/0 cell fusion with mouse spleen cells from successfully immunized mice. Monoclonal antibody was screened by indirect ELISA and Western blots with rPla, natural crude Pla and GST respectively. Three strains of hybridoma cells (named 15B8, 14H4 and 19A4 respectively) which secreted stably the monoclonal antibody of Pla were obtained. Their subclasses were IgG2a and IgG1 in heavy chains and κ chains in light chains. The ELISA titers of ascites were 10(6); respectively.Three of monoclonal antibody can react with natural crude Pla tested by western blots. Monoclonal antibody of natural Pla of Yersinia pestis were successfully got, which has laid the foundation for further study of the Pla protein and development diagnosis reagent.


Rhodium-catalyzed carbonylative [2+2+1] cycloaddition reactions: catalytic formation of bicyclic cyclohexenones [corrected].
The rhodium-catalyzed carbonylative [3+2+1] cycloaddition of trienes into bicyclohexenones has been developed. The carbonylated cycloaddition products have a high regioselectivity. This catalytic system tolerates functionalities including ether, sulfonamide, and ester.


Convergent evolution led ribosome inactivating proteins to interact with ribosomal stalk.
Ribosome-inactivating proteins (RIPs) inhibit protein synthesis by depurinating an adenine on the sarcin-ricin loop (SRL) of the large subunit ribosomal RNA. Several RIPs interact with the C-terminal end of ribosomal stalk P proteins, and this interaction is required for their full activity. In contrast, the activity of Pokeweed Antiviral Protein is not affected by blocking this stalk component. Here, we provide evidence from phylogenetic analyses and sequence alignments suggesting that the interaction with the C-terminal end of P proteins evolved independently in different RIPs by convergent evolution.


Pan-genome of Citrullus genus highlights the extent of presence/absence variation during domestication and selection.
The rich genetic diversity in Citrullus lanatus and the other six species in the Citrullus genus provides important sources in watermelon breeding. Here, we present the Citrullus genus pan-genome based on the 400 Citrullus genus resequencing data, showing that 477 Mb contigs and 6249 protein-coding genes were absent in the Citrullus lanatus reference genome. In the Citrullus genus pan-genome, there are a total of 8795 (30.5%) genes that exhibit presence/absence variations (PAVs). Presence/absence variation (PAV) analysis showed that a lot of gene PAV were selected during the domestication and improvement, such as 53 favorable genes and 40 unfavorable genes were identified during the C. mucosospermus to C. lanatus landrace domestication. We also identified 661 resistance gene analogs (RGAs) in the Citrullus genus pan-genome, which contains 90 RGAs (89 variable and 1 core gene) located on the pangenome additional contigs. By gene PAV-based GWAS, 8 gene presence/absence variations were found associated with flesh color. Finally, based on the results of gene PAV selection analysis between watermelon populations with different fruit colors, we identified four non-reference candidate genes associated with carotenoid accumulation, which had a significantly higher frequency in the white flesh. These results will provide an important source for watermelon breeding.


Distal Radioulnar Joint Reaction Force Following Ulnar Shortening: Diaphyseal Osteotomy Versus Wafer Resection.
To compare how ulnar diaphyseal shortening and wafer resection affect distal radioulnar joint (DRUJ) joint reaction force (JRF) using a nondestructive method of measurement. Our hypothesis was that ulnar shortening osteotomy would increase DRUJ JRF more than wafer resection. Eight fresh-frozen human cadaveric upper limbs were obtained. Under fluoroscopic guidance, a threaded pin was inserted into the lateral radius orthogonal to the DRUJ and a second pin was placed in the medial ulna coaxial to the radial pin. Each limb was mounted onto a mechanical tensile testing machine and a distracting force was applied across the DRUJ while force and displacement were simultaneously measured. Data sets were entered into a computer and a polynomial was generated and solved to determine the JRF. This process was repeated after ulnar diaphyseal osteotomy, ulnar re-lengthening, and ulnar wafer resection. The JRF was compared among the 4 conditions. Average baseline DRUJ JRF for the 8 arms increased significantly after diaphyseal ulnar shortening osteotomy (7.2 vs 10.3 N). Average JRF after re-lengthening the ulna and wafer resection was 6.9 and 6.7 N, respectively. There were no differences in JRF among baseline, re-lengthened, and wafer resection conditions. Distal radioulnar joint JRF increased significantly after ulnar diaphyseal shortening osteotomy and did not increase after ulnar wafer resection. Diaphyseal ulnar shortening osteotomy increases DRUJ JRF, which may lead to DRUJ arthrosis.


[Trauma and pregnancy: Is the Kleihauer-Betke test really useful?]
To evaluate the pertinence of Kleihauer-Betke (KB) test, in case of abdominal trauma during pregnancy in forecast of fetal outcomes, according to trauma severity. A single-center retrospective study conducted between January 2014 and April 2016 in a maternity type III and a trauma center, which included the pregnant women admitted for abdominal trauma. The trauma's severity was assessed using the guidelines of the Society of Obstetricians and Gynaecologists of Canada. The impact of a positive KB test, defined as>0.1%, was analyzed. Adverse outcome was defined as one or more of the following complications: intrauterine fetal death, placental abruption, pre-term birth<37 weeks of gestation, and fetal or neonatal anemia. During the study period, 265 pregnancies involved into an abdominal trauma were included: 69% with a minor trauma and 31% with a severe trauma. Of all patients, 5.6% presented a positive KB test, among then 15.4% had an adverse outcome. There was no significant difference in the rate of adverse outcomes in the positive KB group and the KB negative group either in the overall population (P=0.16), in the minor trauma population (P=1) or in the major trauma population (P=0.14). The predictive positive values were respectively in the global population, in the minor trauma group and in the severe trauma group 15.4%, 0% and 25%. The KB test does not seem to be useful in case of trauma during pregnancy to define adverse outcome.


Signaling to nuclear transport.
In a recent issue of Molecular Cell, Yoon et al. provide evidence for the control of nucleocytoplasmic transport by protein kinase signaling pathways through phosphorylation of RanBP3, an accessory factor in the Ran GTPase system. This mechanism may coordinate nucleocytoplasmic transport with other mitogenic effects of these pathways.


[Discharges in the white rami communicantes evoked by stimulation of different fields of the limbic system].
Electrical responses to stimulation of different areas of the cingulate gyrus were studied in L2-L3 white rami in anesthetized and immobilized cats. The stimulation evoked a sympathetic discharge mostly consisting of a wave with a mean latency of 71.2 +/- 2.3 ms. In a few cases, the main wave was preceded by a short-latency component. Thresholds for eliciting sympathetic discharges were lower in case of stimulation of the ventral region of area 25 in comparison to those of the dorsal region of the same area. A comparative study showed that the lowest were the thresholds of hypothalamic evoked discharges, somewhat higher were the thresholds of amygdala stimulation and the highest were those of the cingulate cortex evoked discharges. In experiments with simultaneous recording of arterial pressure and cingulo-sympathetic discharges, after 10-sec period of tetanic (100/sec) stimulation of the limbic cortex, the early components were facilitated while the late component of the cingulo-sympathetic discharges was depressed. The duration of this inhibition corresponded to the period of pressure reaction and, therefore, was of a baroreceptor origin. Possible mechanisms of cingulate cortex regulation of the activity of sympathetic preganglionic neurons, are discussed.


Afterload mismatch in aortic and mitral valve disease: implications for surgical therapy.
In the management of patients with valvular heart disease, an understanding of the effects of altered loading conditions on the left ventricle is important in reaching a proper decision concerning the timing of corrective operation. In acquired valvular aortic stenosis, concentric hypertrophy generally maintains left ventricular chamber size and ejection fraction within normal limits, but in late stage disease function can deteriorate as preload reserve is lost and aortic stenosis progresses. In this setting, even when the ejection fraction is markedly reduced (less than 25%), it can improve to normal after aortic valve replacement, suggesting that afterload mismatch rather than irreversibly depressed myocardial contractility was responsible for left ventricular failure. Therefore, patients with severe aortic stenosis and symptoms should not be denied operation because of impaired cardiac function. In chronic severe aortic and mitral regurgitation, operation is generally recommended when symptoms are present, but whether to recommend operation to prevent irreversible myocardial damage in patients with few or no symptoms has remained controversial. In aortic regurgitation, left ventricular function generally improves postoperatively, even if it is moderately impaired preoperatively, indicating correction of afterload mismatch. Most such patients can be carefully followed by echocardiography. However, in some patients, severe left ventricular dysfunction fails to improve postoperatively. Therefore, when echocardiographic studies in the patient with severe aortic regurgitation show an ejection fraction of less than 40% (fractional shortening less than 25%) plus enlarging left ventricular end-diastolic diameter (approaching 38 mm/m2 body surface area) and end-systolic diameter (approaching 50 mm or 26 mm/m2), confirmation of these findings by cardiac catheterization and consideration of operation are advisable even in patients with minimal symptoms. In chronic mitral regurgitation, maintenance of a normal ejection fraction can mask depressed myocardial contractility. Pre- and postoperative studies in such patients have shown a poor clinical result after mitral valve replacement, associated with a sharp decrease in the ejection fraction after operation. This response appears to reflect unmasking of decreased myocardial contractility by mitral valve replacement, with ejection of the total stroke volume into the high impedance of the aorta (afterload mismatch produced by operation).(ABSTRACT TRUNCATED AT 400 WORDS)


Unawareness of memory impairment in dementia: a population-based study.
Unawareness of cognitive deficit in people with dementia (PwD) has wide clinical implications, impacting on help-seeking behavior, treatment compliance, and patient safety. Most studies on unawareness among PwD have been conducted in small clinical samples. This study investigated the frequency of unawareness of memory impairment in dementia, exploring regional differences and sociodemographic and health status correlates in large population-based surveys. Community samples (total n = 15,022) from three world regions (Latin America, China, and India) were obtained using cross-sectional population-based surveys. Out of these, 897 (5.97%) PwD with memory impairment were identified using standardized interviews, diagnostic algorithms (DSM-IV or 10/66 criteria), and neuropsychological memory assessment. Unawareness of memory deficits was ascertained from the participants' subjective report. The frequency of unawareness was calculated for each region and associations with demographic variables and health status were investigated using prevalence ratios and Poisson regressions. Regional differences in frequency of unawareness were found, from 63% in China to 81% in India. Unawareness was associated with depression in China and Latin America, dementia severity in India and Latin America, and education and socioeconomic level in Latin America. Unawareness of memory impairment in PwD varies across international regions. Our data support the notion that unawareness should be seen not only as a common neurobiological feature of dementia, increasing with severity of dementia, but also as a phenomenon influenced by social and cultural factors.


Polymorphism of apolipoprotein E. II. Genetics of hyperlipoproteinemia type III.
Apolipoprotein E from human serum shows a genetic polymorphism determined by two autosomal codominant alleles, Apo En and Apo Ed. Homozygosity for the gene Apo Ed (phenotype Apo E-D) results in primary dysbetalipoproteinemia, but only some individuals with this phenotype develop gross hyperlipidemia (hyperlipoproteinemia type III). Vertical transmission of dysbetalipoproteinemia represents pseudodominance due to the high frequency of the gene Apo Ed. Dysbetalipoproteinemia is already expressed in childhood. To assess the influence of other genes on the expression of hyperlipidemia in phenotype Apo E-D, comparative studies were carried out in kindreds of hypercholesterolemic (group A) and normo- or hypocholesterolemic probands with dysbetalipoproteinemia (group B). This demonstrated the occurrence of familial (non-type III) forms of hyperlipidemia in group A but not in group B kindreds. Distribution of lipoprotein phenotypes in five of the group A kindreds was consistent with the occurrence of familial combined hyperlipidemia. Apo E phenotypes and hyperlipidemia segregated independently. It is concluded that primary dysbetalipoproteinemia is a frequent monogenic variant of lipoprotein metabolism, but not a disease. Coincidence in one individual of genes for this specific dyslipoproteinemia with any of the genes for monogenic or polygenic forms of familial hyperlipidemia results in hyperlipoproteinemia type III. Hence hyperlipoproteinemia type III is caused by at least two non-allelic genes and is a polygenic disorder.


Evidence-based somatic treatment of depression in adults.
The efficacy of antidepressants has become a contentious topic over the last decade, and yet a review of the literature shows that they are consistently more effective than placebo. Although the average magnitude of this effect is unclear, many individual patients respond well to a course of antidepressants, and relapse when the medication is discontinued. Choosing the right antidepressant for a given patient remains more art than science, but the studies reviewed here provide some helpful guidance. Table 4 lists the second-generation antidepressants along with potential reasons for choosing one over the other (based on side effects, costs, or possible therapeutic advantages.) Based on these data, the following conclusions can be drawn: • For an all-around first-line antidepressant, sertraline is hard to beat, given its combination of efficacy, tolerability, and low expense. Once escitalopram becomes generic, it will join sertraline in this category. • Bupropion is often a first-line alternative to sertraline, because of its lack of sexual side effects; although it has less efficacy for anxiety disorders, it is helpful for other comorbidities, such as tobacco dependence and attention-deficit/ hyperactivity disorder. • Both paroxetine and mirtazepine are often maligned because of side effects of sedation and weight gain; however, these side effects may be advantageous for those whose depressive symptoms include insomnia and excessive weight loss. • Although not specifically reviewed in this article, certain antidepressants are liable to cause more drug–drug interactions than others; the most prominent of these are fluoxetine, paroxetine, and fluvoxamine.


The social smile in infants during the COVID-19 pandemia.
The emergency created by Coronavirus disease 2019 (COVID-19) has inevitably changed human normal social and relational habits. The use of personal protective equipment, like surgical masks, by healthcare workers has been recommended to prevent human-to-human transmission of the novel coronavirus infection. However, the use of these masks could cause slight to considerable and reproducible changes in the infant's attitude towards the operator and health taker during routine clinical assessments. We reported a brief report on the impact of to the use of the surgical masks on the affective behaviour in 40 infants of age 2-9 months (study group) by using a scale to assess pain and distress among pediatric patients, the Face, Legs, Activity Cry and Consolability Scale (FLACC), and in 40 infants with the same ages and characteristics assessed before the COVID-19 pandemia onset (control group). Thirty-seven of the 40 infants in the study group had some signs of discomfort and appeared irritable and less prone to be engaged by the examiner with a different pattern of responses related to age with better responses for younger infants. These infants reported higher significant scores (p < 0.001) in the FLACC scale than those assessed before the COVID-19 onset. Infants appear to react negatively to the use of the surgical mask by the health operator. A different way to assess paediatric patients in early infancy with longitudinal studies should be proposed.


Proatlantal intersegmental artery and trigeminal artery associated with an aneurysm. Case report.
A case of coexisting proatlantal intersegmental artery and primitive trigeminal artery is described. These anomalies were incidental findings in a patient with hemiparesis due to occlusion of the middle cerebral artery. The primitive trigeminal artery had an asymptomatic aneurysm at its origin from the internal carotid artery.


Risk factors for metabolic bone disease in Crohn's disease patients.
The aim was to evaluate the presence of metabolic bone disease (MBD) in patients with Crohn's disease (CD) and to identify potential etiologic factors. The case-control study included 99 patients with CD and 56 controls with a similar age and gender distribution. Both groups had dual-energy x-ray absorptionmetry and a nutritional evaluation. Single nucleotide polymorphisms at the IL1, TNF-α, LTα, and IL-6 genes were analyzed in patients only. Statistical analysis was performed using SPSS software. The prevalence of MBD was significantly higher in patients (P = 0.006). CD patients with osteoporosis were older (P < 0.005), small bowel involvement and surgical resections were more frequent (P < 0.005), they more often exhibited a penetrating or stricturing phenotype (P < 0.05), duration of disease over 15 years (P < 0.005), and body mass index (BMI) under 18.5 kg/m(2) (P < 0.01) were more often found. No association was found with steroid use. Patients with a Z-score < -2.0 more frequently had chronic active disease (P < 0.05). With regard to diet, low vitamin K intake was more frequent (P = 0.03) and intake of total, monounsaturated, and polyunsaturated fat was higher in patients with Z-score < -2.0 (P < 0.05). With respect to genetics, carriage of the polymorphic allele for LTα252 A/G was associated with a higher risk of osteoporosis (P = 0.02). Regression analysis showed that age over 40 years, chronic active disease, and previous colonic resections were independently associated with the risk of developing MBD. The prevalence of MBD was significantly higher in CD patients. Besides the usual risk factors, we observed that factors related to chronic active and long-lasting disease increased the risk of MBD.


5-fluorouracil modulation of dihydrofolate reductase RNA levels in methotrexate-resistant KB cells.
Cytotoxicity and growth inhibition by 5-fluorouracil in methotrexate-resistant dihydrofolate reductase gene-amplified KB cells in the presence of 30 microM thymidine correlates with incorporation of this fluorinated pyrimidine into RNA. Growth of these cells over several generations in the presence of inhibitory concentrations of 5-fluorouracil does not depress the steady state levels of either 18 or 28 S RNA but actually causes an increase. Similarly the rates of RNA and protein synthesis in 5-fluorouracil-treated cells are not decreased. The level of dihydrofolate reductase RNA from 5-fluorouracil-treated cells increases in a dose-dependent manner correlated with 5-fluorouracil incorporation into RNA. The qualitative size distribution of the dihydrofolate reductase RNA species is unaffected when examined by the Northern blotting technique indicating an RNA processing lesion is not induced by 5-fluorouracil incorporation into RNA. As the dose of dihydrofolate reductase RNA increases, there is no change in the level of dihydrofolate reductase specific activity, but the level of enzyme activity per cell increases. The relevance of these phenomena to the mechanism of 5-fluorouracil effect on RNA and relevance to combination chemotherapy with methotrexate are discussed.


Towards more efficient testing strategies--analyzing the efficiency of toxicity data requirements in relation to the criteria for classification and labelling.
This contribution is based on the assumption that the aim of toxicity testing as required by chemicals legislation is to identify as many chemicals of concern to human health and the environment as possible, given a limited amount of resources allocated to testing. Based on this assumption we propose a method for the optimization of test systems for industrial chemicals, based on the calculation of efficiency ratios for tests and test systems. The efficiency ratio of a toxicity test depends on the monetary cost of performing the test and the probability that the test will identify a chemical of concern, as estimated by the rules for classification and warning labelling. Efficiency ratios are estimated based on the results of basic standardized toxicity testing for acute toxicity, subacute toxicity, irritation and sensitization of 1409 industrial chemicals notified in the European Union between 1994 and 2004. This careful evaluation of the regulatory consequences of testing indicated that many of these substances are classified based on short-term testing of acute toxicity, irritation and sensitization and that most of the substances classified due to a 28-day study were also classified based on short-term testing. These results indicate that, within the classification and labelling system, it is currently more efficient to perform short-term testing of a larger number of substances rather than to perform subacute toxicity studies on substances already tested for acute toxicity.


Effects of 15-lipoxygenase overexpressing adipose tissue mesenchymal stem cells on the Th17 / Treg plasticity.
15-lipoxygenase (15-LOX) is a critical enzyme that allows the direction of arachidonic acid metabolism to change from inflammation into the resolution. This study aims to reveal how the immunomodulation properties of mesenchymal stem cells (MSC) alter by the 15-LOX overexpression. For this purpose, peripheral blood mononuclear cells (PBMCs) isolated from seven healthy volunteers, and both MSCs and 15-LOX overexpressing MSCs (15-LOXMSCs) were co-cultured at different cell ratios (1/1, 1/5 and 1/10). Alterations of CD4+Tbet+, CD4+Gata3+, CD4+RoRC2+, and CD4+FoxP3+ lymphocyte frequencies were detected by flow cytometry, and IFN-γ, IL-4, IL-6, IL-10, IL-17a, TGF-β and LXA4 levels of medium supernatants were measured by ELISA method. According to our findings, MSC and 15-LOXMSCs have a suppressive effect on PHA activated PBMCs. However, as the ratio of PBMCs increased, the effects of 15-LOXMSCs increased significantly, while the effects of MSCs decreased. The most notable effect of the 15-LOX modification was the significant reduction in IL-6, IL-10 and IL-17a expression and the accompanying increase in TGF-β and LXA4 levels. We also observed a similar situation between CD4+RoRC2+ and CD4+FoxP3+ cell frequencies. These data suggested that the effects of MSCs on the balance of Th17 / Treg could change by the 15-LOX overexpression, and this might be in favor of the Treg cells.


The impact of Enhanced Recovery after Surgery (ERAS) pathways with regard to perioperative outcome in patients with ovarian cancer.
Major surgery for ovarian cancer is associated with significant morbidity. Recently, guidelines for perioperative care in gynecologic oncology with a structured "Enhanced Recovery after Surgery (ERAS)" program were presented. Our aim was to evaluate if implementation of ERAS reduces postoperative complications in patients undergoing extensive cytoreductive surgery for ovarian cancer. 134 patients with ovarian cancer (FIGO I-IV) were included. 47 patients were prospectively studied after implementation of a mandatory ERAS protocol (ERAS group) and compared to 87 patients that were treated before implementation (pre-ERAS group). Primary endpoints of this study were the effects of the ERAS protocol on postoperative complications and length of stay in hospital. Preoperative and surgical data were comparable in both groups. Only the POSSUM score was higher in the ERAS group (11.8% vs. 9.3%, p < 0.001), indicating a higher surgical risk in the ERAS group. Total number of postoperative complications (ERAS: 29.8% vs. pre-ERAS: 52.8%, p = 0.011), and length of hospital stay (ERAS: 11 (6-23) vs pre-ERAS: 13 (6-50) days; p < 0.001) differed significantly. A lower fraction of patients of the ERAS group (87.2%) needed postoperative admission to the ICU compared to the pre-ERAS group (97.7%), p = 0.022). Mortality within the ERAS group was 0% vs. 3.4% (p = 0.552) in the pre-ERAS group. The implementation of a mandatory ERAS protocol was associated with a lower rate of postoperative complications and a reduced length of stay in hospital. If ERAS has influence on long-term outcome needs to be further evaluated.


Effect of celecoxib on Ca2+ movement and cell proliferation in human osteoblasts.
In human osteoblasts, the effect of the widely prescribed cyclooxygenase-2 inhibitor celecoxib on intracellular Ca(2+) concentrations ([Ca(2+)](i)) and cell proliferation was explored by using fura-2 and the tetrazolium assay, respectively. Celecoxib at concentrations greater than 1microM caused a rapid rise in [Ca(2+)](i) in a concentration-dependent manner ( EC 50= 10 microM). Celecoxib-induced [Ca(2+)](i) rise was reduced by 90% by removal of extracellular Ca(2+), and by 30% by l-type Ca(2+) channel blockers. Celecoxib-induced Mn(2+)-associated quench of intracellular fura-2 fluorescence also suggests that celecoxib-induced extracellular Ca(2+) influx. In Ca(2+)-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca(2+)-ATPase, caused a monophasic [Ca(2+)](i) rise, after which the increasing effect of celecoxib on [Ca(2+)](i) was greatly inhibited. Conversely, pretreatment with celecoxib to deplete intracellular Ca(2+) stores totally prevented thapsigargin from releasing more Ca(2+). U73122, an inhibitor of phoispholipase C, abolished histamine (an inositol 1,4,5-trisphosphate-dependent Ca(2+) mobilizer)-induced, but not celecoxib-induced, [Ca(2+)](i) rise. Pretreatment with phorbol 12-myristate 13-acetate and forskolin to activate protein kinase C and adenylate cyclase, respectively, partly inhibited celecoxib-induced [Ca(2+)](i) rise in Ca(2+)-containing medium. Separately, overnight treatment with 1-100microM celecoxib inhibited cell proliferation in a concentration-dependent manner. These findings suggest that in human osteoblasts, celecoxib increases [Ca(2+)](i) by stimulating extracellular Ca(2+) influx and also by causing intracellular Ca(2+) release from the endoplasmic reticulum via a phospholiase C-independent manner. Celecoxib may be cytotoxic at higher concentrations.


The effects of mandible morphology and photosynthetic pathway on selective herbivory in grasshoppers.
In the present study the following hypotheses were tested: 1) Selective herbivory is influenced by the photosynthetic pathway of plants, and 2) selective herbivory is influenced by the mandible morphology of herbivores. To test these hypotheses, grasshoppers with different mandibular patterns were offered C3 and C4 plants in controlled feeding experiments.Mandible morphology was found to be significantly associated with energy assimilation and feeding frequency. Grasshoppers with herbivorous mandibles had greater assimilation efficiencies and fed significantly less often than grasshoppers with forbivorous mandibles. These results indicate grasshoppers (with comparable caloric requirements) feed with a frequency determined, in part, by the functional morphology of their mandibles.Photosynthetic pathway also influenced the foraging behavior of grasshoppers tested. As predicted by the C4 avoidance hypothesis (Caswell et al. 1973), C4 plants were fed upon significantly less often than C3 plants. These results suggest grasshoppers may discriminate between C3 and C4 plants, but apparently not on the basis of available energy.Recent studies of insect herbivory, previously interpreted within the framework of C4 plant avoidance, are reviewed. The results of these studies may be critically dependent on incomplete considerations of mandible morphology and photosynthetic pathway.


Increasing radiation exposure from computed tomography in liver transplant recipients over time.
To evaluate changes in radiation exposure from computed tomography (CT) among patients undergoing liver transplantation in our unit over a 10-year period. We evaluated 134 elective patients, without hepatocellular carcinoma or cholangiocarcinoma who underwent transplantation in 2007-2008 and 2017-2018. CT scans performed in our hospital up to 2 years pre transplant and 1 year post transplant were evaluated. There was an increase in mean estimated effective radiation dose per patient in 2017-2018 compared to 2007-2008 (77.8 mSv ± 6.2 vs 56.7 mSv ± 5.9, p < 0.05). This change was mainly due to an increased number of pre-transplant CT scans per patient (2.9 ± 0.3 vs 1.4 ± 0.14, p = 0.0001). High radiation dose scan protocols were more frequently used in 2017-2018, with 4-phase liver CT accounting for a larger proportion of scans both pre-transplant (61% vs 43%, p = 0.004) and post-transplant (29% vs 13%, p = 0.002). A greater proportion of patients were exposed to > 100 mSv of ionising radiation in the 2017-2018 patients (29% vs 11%, p < 0.01). These figures are likely to be a significant under-estimate as they exclude other imaging modalities and CT scans performed at other institutions. Radiation exposure from diagnostic imaging has increased among liver transplant recipients at our institution over the last decade. This appears to be due to an increase in the number of CT scans performed, and a shift towards higher dose scan protocols.


A standard operating procedure for the physical performance analysis of wheelchair fencer: a scoping review.
Wheelchair fencing (WF) is a very practiced sport within the Paralympic world. A careful analysis of the characteristics and data of a WF athlete can be useful for coaches and movement experts to better plan a training program. The objective of the study was to evaluate physical fitness assessment methods adopted in WF and to propose a standard operating procedures (SOP). Original articles written in English were included in this review, and the population studied was composed of athletes who practiced WF. Studies were searched from PubMed, Web of Science, and Scopus databases using keywords and Boolean operators. Eight studies were included in this review. Most of the studies converge and agree on the physical, physiological, and technical characteristics of a WF athlete. The scientific literature referring to this sport is very scarce, hence the need for new original studies to optimize the SOP proposed.


Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)--report on 370 patients.
An attempt was made to define the role of radiotherapy before operation for AGC. From January 1978 to May 1989, a prospective randomized trial on preoperative radiotherapy (R+S) vs. surgery alone (S) for AGC was carried out in 370 patients. Patients were randomized into a combined group (R+S, 171 patients) or a surgery alone group (S, 199 patients) by the envelope method. 8-MV photon or telecobalt was used for the preoperative radiation therapy, using anterior-posterior opposing parallel fields to deliver 40 Gy to the cardia, lower segment of the esophagus, fundus, lesser curvature, and hepatogastric ligament. Surgery was performed after 2 to 4 weeks rest. The 5- and 10-year survival rates of the R+S Group and the S Alone Group were 30.10% and 19.75%, 20.26% and 13.30%, respectively. The survival curves of these two groups diverged right from the beginning after the operation over the ninth year. Statistics by Kaplan-Meier log rank test proves that the difference is significant (chi2 = 6.74, p = 0.0094). The immediate results were: resection rate 89.5% and 79.4% (p < 0.01); pathologic stage after resection T2 12.9% and 4.5% (p < 0.01), T4 40.3% and 51.3% (p < 0.05), lymph node metastasis rates 64.3% and 84.9% (p < 0.001); operative mortality rates 0.6% and 2.5%; intrathoracic leak rates 1.8% and 4.0%, respectively. The causes of failure were: local uncontrol and recurrence 38.6% vs. 51.7% (p < 0.025), regional lymph node metastasis 38.6% vs. 54.6% (p < 0.005), distant metastasis 24.3% vs. 24.7%. Preoperative radiation therapy is able to improve the results of surgery for adenocarcinoma of the gastric cardia.


An effective uranium removal using diversified synthesized cross-linked chitosan bis-aldehyde Schiff base derivatives from aqueous solutions.
Three new cross-linked chitosan derivatives were yielded through intensification of chitosan with diverse types of bis-aldehydes. The prepared cross-linked chitosan was characterized by FTIR, 1H NMR, XRD, and TGA techniques. TGA indicated an improvement in thermal stability of the cross-linked chitosan compared with pure chitosan. Batch adsorption experiments showed that the three novel cross-linked chitosan bis-aldehyde derivatives possessed good adsorption capacity against U(VI) in the order of BFPA > BFB > BODB (adsorption capacity of the three adsorbents for U(VI) reaches 142, 124, and 114 mg/g respectively) and the adsorption isotherm and kinetic were well described by the Langmuir and the pseudo-second-order kinetic model, respectively. In addition, the prepared cross-linked chitosan bis-aldehyde derivatives were examined as U(VI) catcher from waste solutions.


Differences in the repertoires of basement membrane degrading enzymes in two carcinoma sublines with distinct patterns of site-selective metastasis.
Basement membrane-degrading enzymes of two clonal sublines of the murine Lewis lung carcinoma with distinct patterns of organ-selective metastasis were analyzed. Subline M-27 is highly metastatic to the lung and does not form liver metastases, while subline H-59 is highly metastatic to lymph nodes and liver, but not to lung. Qualitative and quantitative differences in the enzymatic profiles were found. H-59 cells which were significantly more invasive in vitro in the Matrigel invasion assay were found by zymogram analysis to secrete high levels of a 72 kDa gelatinase, while M-27 cells produced low levels of this gelatinase and of a higher molecular weight species which migrated in the 107 kDa region. On the other hand, M-27 cells produced significantly higher levels of urokinase type plasminogen activator (uPA) as indicated by a fibrinolysis assay and by Western blot analysis. Northern blot assays revealed an increase of approx. 3-fold in mRNA for cathepsin B in tumor M-27 which was reflected in a quantitative difference in plasma membrane cathepsin B levels as detected by Western blot analysis. H-59 cells on the other hand expressed approx. 8.5-fold more mRNA for cathepsin L. The quantitative differences in the levels of basement membrane degrading proteinases released by these tumor cells suggest that invasion by these cells is differentially regulated--a possible factor in their distinct patterns of dissemination.


Exploratory Study of 6-Month Pain Trajectories in Individuals With Predominant Patellofemoral Osteoarthritis: A Cohort Study.
Knowledge of patellofemoral osteoarthritis (OA) pain trajectories is vital to helping clinicians and patients make shared disease-specific decisions regarding treatment options and coping strategies. To describe the pain trajectories of people living with patellofemoral OA who present to a chronic care management program, and to explore baseline characteristics associated with different trajectories. In this prospective longitudinal cohort study, 88 participants who presented to a chronic care management program reported their worst pain over the previous week at baseline and at 6, 12, 18, and 26 weeks using a 10-cm visual analog scale. Trajectories (classes) were identified using latent class growth analysis. Demographics, pain, physical performance, strength, quality of life, mental health, and lower limb/foot structural measures obtained at baseline were assessed for association with trajectory class membership. Individuals in class 1 (28%) exhibited high, persistent pain from baseline (7.8 ± 1.7 cm), which continued over time (P = .52). Class 2 (57%) displayed moderate baseline pain (4.8 ± 1.8 cm), which also remained persistent (P = .97). Individuals in class 3 (15%) showed low, improving pain (baseline pain, 2.6 ± 1.2 cm) over time (P = .017). At baseline, poor Knee injury and Osteoarthritis Outcome Score (KOOS) scores, local and proximal sensitivity to pressure, and lower knee extensor strength were associated with increased odds of following the high-pain trajectory (range [95% confidence interval], 1.03 [1.00, 1.07] to 16.24 [2.53, 104.34]). Distinct pain trajectories appear to exist in people with patellofemoral OA presenting to a chronic care management program. Baseline variables may be useful for identifying individuals at risk of poorer prognosis. Larger studies are needed to confirm the efficacy of this finding. Prognosis, level 2b. J Orthop Sports Phys Ther 2019;49(1):5-16. Epub 12 Sep 2018. doi:10.2519/jospt.2019.8354.


Increased serum oestrone and oestradiol following spironolactone administration in hypertensive men.
The present study was undertaken to evaluate long-term effects of spironolactone on basal serum oestrone, oestradiol, testosterone, LH and prolactin concentrations in hypertensive male patients. Serum prolactin response to TRH was also evaluated. Patients were divided into two groups: a conventional-dosage group, consisting of six males with essential hypertension who took 75 to 150 mg of spironolactone daily for 12 weeks, and a high-dosage group, consisting of two males with idiopathic hyperaldosteronism who took 300 mg of spironolactone daily for more than 40 weeks. In the conventional-dosage group, serum oestrone concentrations significantly increased (P less than 0.01) at 12 weeks, serum oestradiol concentrations gradually increased throughout the study period, however, the increments were not statistically significant (P less than 0.2). Basal serum testosterone, LH and prolactin concentrations were not significantly changed throughout the study period. Enhancement of serum prolactin response to TRH was not found in any of the patients in the conventional-dosage group. In the high-dosage group, serum oestrone maintained high levels from the beginning of this study, and serum oestradiol concentrations increased with the development of gynaecomastia. Serum testosterone, LH and prolactin concentrations did not show any definite change throughout the study period. Thus, long-term spironolactone treatment increased the serum levels of oestrone and oestradiol in hypertensive men followed by the development of gynaecomastia. The elevation in circulating oestrogens could well explain the oestrogenic side-effects of spironolactone treatment.


A new feature of the ablepharon macrostomia syndrome: zygomatic arch absence.
The ablepharon macrostomia syndrome is an extremely rare congenital anomaly. It is characterised by bilateral absence or hypoplasia of lower eyelids, macrostomia and multiple other congenital anomalies. Three cases have been reported (McCarthy and West, 1977; Hornblass and Reifler, 1985). In addition to ablepharon and macrostomia, other anomalies common to all patients include auricular deformity, nasal alar deformity, absence of lanugo hair, dry, ichthyotic skin and ambiguous genitalia. A new feature of the syndrome is described--absence of the zygomatic arches. In addition, an expanded and revised classification of the ablepharon macrostomia syndrome and related disorders is presented. Skin graft pigmentation in this black patient has been prevented by prolonged application of sun block.


Free calcium in rat papillary muscle at contraction assessed with Ca-selective microelectrodes.
Direct measurements of free intracellular calcium (Ca)i are needed for an understanding of the regulation of contractility. An on-line measurement of (Ca)i with Ca-selective microelectrodes in intact muscle strips provides a suitable means of investigating this problem, although considerable methodologic difficulties exist. Measurements of (Ca)i concentrations during muscle contraction have been carried out by different methods such as Ca-binding techniques and aequorin luminescence, but remain unsatisfying, since they were not performed on intact muscle strips. The authors' measurements were carried out with Ca-selective microelectrodes on rat papillary muscles (stretched to optimal length in a perfusion bath of 1.54 mL at 30 degrees C). The impalement of electrodes was considered adequate when the heights of Ca-electrode potential and membrane potential remained constant for more than twenty minutes. For provoking contractile responses, the authors replaced the normal Tyrode solution by a caffeine-containing contracture solution (content in mM: 0 NaCl [choline], 4 CaCl2, 30 KCl, 25 caffeine, 1.05 MgCl2). Ca-selective microelectrodes were calibrated before and after each measurement and only those impalements were taken as adequate that showed identical calibration curves before and after the experiment. They measured the (Ca)i at 20%, 50%, and 80% of maximal contractile force and obtained (Ca)i concentrations of 1.1 +/- 0.3 microM (at 20%), 3.6 +/- 1.2 microM (at 50%), and 11.8 +/- 0.27 microM (at 80%) (n = 6, +/- SEM). These results represent the fist on-line measurements of the myocardial (Ca)i concentrations with Ca++-selective microelectrodes in intact muscle strips during various degrees of contraction.(ABSTRACT TRUNCATED AT 250 WORDS)


Virus usurps alternative splicing to clear the decks for infection.
Since invasion, there will be a tug-of-war between host and virus to scramble cellular resources, for either restraining or facilitating infection. Alternative splicing (AS) is a conserved and critical mechanism of processing pre-mRNA into mRNAs to increase protein diversity in eukaryotes. Notably, this kind of post-transcriptional regulatory mechanism has gained appreciation since it is widely involved in virus infection. Here, we highlight the important roles of AS in regulating viral protein expression and how virus in turn hijacks AS to antagonize host immune response. This review will widen the understandings of host-virus interactions, be meaningful to innovatively elucidate viral pathogenesis, and provide novel targets for developing antiviral drugs in the future.


Plasma Thrombomodulin Levels and Ischemic Stroke: A Population-Based Prognostic Cohort Study.
Thrombomodulin has been suggested to be implicated in ischemic stroke because of its anticoagulant, anti-inflammatory, and cytoprotective properties. We aimed to investigate the associations of plasma thrombomodulin levels with clinical outcomes after ischemic stroke in a multicenter prognostic cohort study. Our multicenter prognostic cohort study included 3,532 Chinese ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke. All patients were followed up at 3 months after ischemic stroke onset. The primary outcome was the composite outcome of death and major disability (modified Rankin Scale [mRS] score ≥3) at 3 months after ischemic stroke. Secondary outcomes included major disability (mRS score 3-5), vascular events, and the ordered 7-level categorical score of the mRS. During 3 months of follow-up, 867 participants experienced the primary outcome. After multivariate adjustment, the adjusted odds ratios or hazard ratios associated with the highest quartile of plasma thrombomodulin were 0.75 (95% CI 0.59-0.97; p trend = 0.029) for the primary outcome, 0.73 (95% CI 0.56-0.94; p trend = 0.028) for major disability, and 0.80 (95% CI 0.42-1.51; p trend = 0.232) for vascular events. In addition, a significantly better shift in the distribution of the mRS score was observed with higher thrombomodulin quartiles (p trend = 0.005). A multivariable-adjusted spline regression model showed a linear relationship between plasma thrombomodulin and the risk of primary outcome (p for linearity = 0.027). Subgroup analyses further confirmed these associations. Increased plasma thrombomodulin levels at baseline were associated with decreased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting a protective role of thrombomodulin in the development of ischemic stroke. Further studies from various populations are needed to replicate our findings.


A Chatt-Type Catalyst with One Coordination Site for Dinitrogen Reduction to Ammonia.
With [Mo(N2 )(P2 Me PP2 Ph )] the first Chatt-type complex with one coordination site catalytically converting N2 to ammonia is presented. Employing SmI2 as reductant and H2 O as proton source 26 equivalents of ammonia are generated. Analogous Mo0 -N2 complexes supported by a combination of bi- and tridentate phosphine ligands are catalytically inactive under the same conditions. These findings are interpreted by analyzing structural and spectroscopic features of the employed systems, leading to the conclusion that the catalytic activity of the title complex is due to the strong activation of N2 and the unique topology of the pentadentate tetrapodal (pentaPod) ligand P2 Me PP2 Ph . The analogous hydrazido(2-) complex [Mo(NNH2 )(P2 Me PP2 Ph )](BArF )2 is generated by protonation with HBArF in ether and characterized by NMR and vibrational spectroscopy. Importantly, it is shown to be catalytically active as well. Along with the fact that the structure of the title complex precludes dimerization this demonstrates that the corresponding catalytic cycle follows a mononuclear pathway. The implications of a PCET mechanism on this reactive scheme are considered.