Nitric oxide production and signalling in algae.
Nitric oxide (NO) was the first identified gaseous messenger and is now well established as a major ubiquitous signalling molecule. The rapid development of our understanding of NO biology in embryophytes came with the partial characterization of the pathways underlying its production and with the decrypting of signalling networks mediating its effects. Notably, the identification of proteins regulated by NO through nitrosation greatly enhanced our perception of NO functions. In comparison, the role of NO in algae has been less investigated. Yet, studies in Chlamydomonas reinhardtii have produced key insights into NO production through the identification of NO-forming nitrite reductase and of S-nitrosated proteins. More intriguingly, in contrast to embryophytes, a few algal species possess a conserved nitric oxide synthase, the main enzyme catalysing NO synthesis in metazoans. This latter finding paves the way for a deeper characterization of novel members of the NO synthase family. Nevertheless, the typical NO-cyclic GMP signalling module transducing NO effects in metazoans is not conserved in algae, nor in embryophytes, highlighting a divergent acquisition of NO signalling between the green and the animal lineages.


Normalizing lower-extremity strength data for children without disability using allometric scaling.
To evaluate existing approaches for normalizing lower-extremity strength data and to develop normalization equations using allometric scaling in children without disabilities. Cross-sectional study evaluating traditional mass normalization and allometry as methods of adjusting lower-extremity muscle torques for the influence of body mass. Motion analysis laboratory. Thirty-nine children without disability (age range, 4-17y). Not applicable. Maximum torque generated during hip abduction and adduction, knee extension and flexion, and ankle dorsiflexion and plantarflexion. Linear regressions of torque/mass(1.0) versus body mass and age produced slopes that differed significantly from zero (P<.001) for all muscle groups except the ankle plantarflexors versus body mass (P=.28). Regressions for torque/body mass index also produced slopes that differed significantly from zero (P<.001). Regressions of torque/(mass x height) produced slopes that differed from zero in some cases but not others. Allometric scaling exponents (exponent b) differed significantly from the theoretical value of 1.0 for all muscle groups except the ankle plantarflexors (1.32; 95% confidence interval, 0.98-1.67). Linear regressions performed using torque/mass(b) produced slopes that did not differ significantly from zero for all muscle groups (P>/=.10). Regressions performed using torque/mass(1.6) for the hip and knee and torque/mass(1.4) for the ankle also produced slopes that did not differ significantly from zero. Traditional mass normalization does not effectively adjust for the influence of body mass. Allometric scaling performed using torque/mass(1.6) for the hip and knee or torque/mass(1.4) for the ankle provides more appropriate normalization.


P-cadherin and beta-catenin are useful prognostic markers in breast cancer patients; beta-catenin interacts with heat shock protein Hsp27.
The cadherin-catenin proteins have in common with heat shock proteins (HSP) the capacity to bind/interact proteins of other classes. Moreover, there are common molecular pathways that connect the HSP response and the cadherin-catenin protein system. In the present study, we have explored whether in breast cancer the HSP might interact functionally with the cadherin-catenin cell adhesion system. Beta-catenin was immunoprecipitated from breast cancer biopsy samples, and the protein complexes isolated in this way were probed with antibodies against HSP family members. We are thus the first to demonstrate a specific interaction between beta-catenin and Hsp27. However, beta-catenin did not bind Hsp60, Hsp70, Hsp90, gp96, or the endoplasmic reticulum stress response protein CHOP. To confirm the finding of Hsp27-beta-catenin interaction, the 27-kDa immunoprecipitated band was excised from one-dimensional polyacrylamide gel electrophoresis gels and submitted to liquid chromatography-tandem mass spectrometry with electrospray ionization, confirming a role for Hsp27. In addition, beta-catenin interacted with other proteins including heat shock transcription factor 1, P-cadherin, and caveolin-1. In human breast cancer biopsy samples, beta-catenin was coexpressed in the same tumor areas and in the same tumor cells that expressed Hsp27. However, this coexpression was strong when beta-catenin was present in the cytoplasm of the tumor cells and not when beta-catenin was expressed at the cell surface only. Furthermore, murine breast cancer cells transfected with hsp25 showed a redistribution of beta-catenin from the cell membrane to the cytoplasm. When the prognostic significance of cadherin-catenin expression was examined by immunohistochemistry in breast cancer patients (n = 215, follow-up = >10 years), we found that the disease-free survival and overall survival were significantly shorter for patients expressing P-cadherin and for patients showing expression of beta-catenin in the cytoplasm only (not at the cell surface). The interactions of beta-catenin with Hsp27 and with HSF1 may explain some of the molecular pathways that influence tumor cell survival and the clinical significance in the prognosis of the breast cancer patients.


IL-39 promotes chronic graft-versus-host disease by increasing T and B Cell pathogenicity.
Chronic graft-versus-host disease (cGVHD) remains a major complication during the late phase of allogeneic hematopoietic stem cell transplantation (allo-HSCT). IL-39, a newly described pro-inflammatory cytokine belonging to the IL-12 family, plays a role in lupus development. Recently, IL-39 has been identified as a pathogenic factor in acute GVHD (aGVHD). However, the role of IL-39 in the pathogenesis of cGVHD remains unclear. We constructed a recombinant IL-39 plasmid and established scleroderma and lupus-like cGVHD models. Quantitative PCR and enzyme-linked immunosorbent assay (ELISA) were used to detect IL-39 expression in mice and patients post transplantation, respectively. Hydrodynamic gene transfer (HGT) was performed to achieve IL-39 overexpression in vivo. Multiparameter flow cytometry, western blotting, and assays in vitro were performed to investigate the effect of IL-39 on cGVHD. The relative expression of IL-23p19 and EBi3 was significantly increased in the intestine of cGVHD mice on day 40 post allo-HSCT, and IL-39 levels were significantly elevated in the serum of patients following allo-HSCT. Overexpression of IL-39 significantly aggravated the severity of cGVHD. Increased IL-39 levels promoted T-cell activation and germinal center responses, and may exacerbate thymic damage. Consistently, blocking IL-39 markedly ameliorated immune dysregulation in the cGVHD mice. Furthermore, we found that IL-39 was produced by B cells, CD11b+ cells, and CD8+T cells after activation. Stimulation of IL-39 led to upregulation of the IL-39 receptor on CD4+T cells and further caused activation of the STAT1/STAT3 pathway, through which IL-39 may exert its pro-inflammatory effects. Our study reveals a critical role for IL-39 in cGVHD pathogenesis and indicates that IL-39 may serve as a potential therapeutic target for cGVHD prevention.


Gamma radiation for in-stent restenosis: effect of lesion length on angiographic and clinical outcomes.
The relation between lesion length and effectiveness of gamma radiation treatment (gamma-RT) has not been well described. We evaluated the acute and long-term outcome according to baseline lesion length in 130 patients treated with (192)Ir in the Washington Radiation for In-Stent Restenosis Trial; 44 (35.5%) had baseline short in-stent restenosis (ISR) lesions (length < 15 mm) and 80 (64.5%) long ISR lesions (length > or = 15 mm). At 6-month follow-up after gamma-RT, the short ISR group had larger lumen dimensions and lower late loss than the long ISR group. Restenosis rate was significantly higher in patients with long ISR for both the placebo (74% vs. 39%; P = 0.01) and the gamma-RT arm (31% vs. 5.3%; P = 0.04). gamma-RT significantly improved the angiographic outcome in the short-lesion groups but had the more pronounced effect on the reduction of clinical events after treatment of long ISR group. Lesion length remains a powerful predictor of recurrent ISR and clinical events after treatment of ISR even with gamma-RT.


Urinary excretion of liver-type fatty acid-binding protein as a marker of progressive kidney function deterioration in patients with chronic glomerulonephritis.
To evaluate the value of basal urinary L-FABP (uL-FABP) excretion as a prognostic indicator of the progression of kidney function impairment in patients with chronic glomerulonephritis (CGN). One hundred twenty-three patients with newly diagnosed, biopsy-proven primary CGN were included. In all patients, and in 28 healthy subjects, uL-FABP was measured using an ELISA. Risk factors of the progression of kidney function were evaluated. The patients were in follow-up for at least 5 years. uL-FABP in the patients with CGN (76.58±17.3 μg/g.cr) was greater than in the healthy subjects. A significant positive correlation between uL-FABP and proteinuria (R=0.501, P<0.01), serum creatinine (R=0.601, P<0.01) were found. Kaplan-Meier analysis revealed that uL-FABP >76.58 μg/g.cr predicts progression of renal function. The cut off values for L-FABP at 119.8 μg/g.cr was found to be more sensitive, area under the curve (AUC) was 0.95. Urinary L-FABP may be a useful clinical biomarker for monitoring chronic glomerular disease. Urinary L-FABP can help predict the progression of chronic glomerular disease.


Uncovering the regulation effect of modified clay on toxin production in Alexandrium pacificum: From physiological insights.
As a common dinoflagellate, Alexandrium pacificum can produce paralytic shellfish toxins (PSTs). It can be removed from water by Polyaluminium chloride modified clay (PAC-MC), but it is unclear whether PAC-MC can prevent PSTs content and toxicity from increasing and whether PAC-MC can stimulate PSTs biosynthesis by A. pacificum. Effect of PAC-MC on PSTs and the physiological mechanism were analysed here. The results showed total PSTs content and toxicity decreased respectively by 34.10 % and 48.59 % in 0.2 g/L PAC-MC group at 12 days compared with control group. And the restriction of total PSTs by PAC-MC was mainly achieved via inhibition of algal cell proliferation, by affecting A. pacificum physiological processes and changing phycosphere microbial community. Meanwhile, single-cell PSTs toxicity did not increase significantly throughout the experiment. Moreover, A. pacificum treated with PAC-MC tended to synthesize sulfated PSTs such as C1&2. Mechanistic analysis showed that PAC-MC induced upregulation of sulfotransferase sxtN (related to PSTs sulfation), and functional prediction of bacterial community also showed significant enrichment of "sulfur relay system" after PAC-MC treatment, which might also promote PSTs sulfation. The results will provide theoretical guidance for the application of PAC-MC to field control of toxic Alexandrium blooms.


Novel mesh suture may resist bone cutting seen with wire-based sternal closures.
Sternal dehiscence is frequently associated with wire-based closures cutting through fragile bone, allowing sternal motion, separation, and infection. We investigated whether bone cutting could be limited by using a newly available mesh suture with improved force distribution. Five sternal models were closed using 8 interrupted single sternal wires, double sternal wires, braided poly(ethylene terephthalate) sutures, single-wrapped mesh sutures, or double-wrapped mesh sutures. To simulate chest-wall forces, closed sternal models were pulled apart using 1020 N of axial force applied incrementally. Double sternal wire and double-wrapped mesh suture were further compared by closing 3 new models with each material and subjecting these models to cyclic loading cycles, simulating breathing and coughing. Image analysis of needle hole size measured "bone cutting" by each closure material and sternal distraction as a function of force. All models exhibited maximal separation at the xiphoid. During axial loading, needle hole size increased 7.2% in the double-wrapped mesh suture model and 9.2% in the double-wire model. Single-wrapped mesh suture, single wires, and braided poly(ethylene terephthalate) extended needle hole size by 6.7%, 47.0%, and 168.3% of original size, respectively. The double-wire model resisted sternal distraction best, separating 0.285 cm at the xiphoid. During cyclic loading, mesh suture exhibited significantly less bone cutting (P = .02) than double wire, with comparable levels of sternal separation (P = .07). Mesh suture may resist bone cutting seen in sternal wire closure in bone models with comparable distraction to currently used sternal closure methods.


Need to prevent and control high-normal and high blood pressure, particularly so-called "mild" hypertension: epidemiological and clinical data.
The need to prevent and control high blood pressure (HBP), including so-called "mild" hypertension [diastolic blood pressure (DBP) 90-104 mm Hg in adults age 30+] stems from the extensive data on the increased risks due to these common blood pressure (BP) levels, including risk of catastrophic cardiovascular events (coronary, cerebrovascular, etc.), both nonfatal and fatal. Prospective population data from the national cooperative Pooling Project and the Chicago Heart Association Detection Project in Industry illustrate the extensively documented facts. They also show that only a small minority of middle-aged and older Americans have optimal low-normal BP levels, i.e., DBP less than 80 mm Hg (SBP less than 120). Thus, the problem of BP above optimal level for health over a long life span is a population-wide problem. The data also show that the great majority of excess catastrophic events attributable to elevated BP occur among people with DBP 90-104 and 80-89 mm Hg, levels very common in the population. Most people with such BP levels also have one or more other major risk factors (e.g., hypercholesterolemia, cigarette use, ECG abnormalities) and thus are at markedly increased risk, both relative and absolute. In addition to these excess risks for major illness, disability, and death, people with BP above optimal levels are more highly prone to other events, clinical and subclinical, that have adverse effects on long-term prognosis, including development of target organ damage and severe hypertension. These data lead to the following inferences about medical care and public health strategy: (a) A key task is, by safe nutritional-hygienic means, to shift the entire population distribution of BP downward, for both primary and secondary prevention of HBP. Such means include prevention and control of obesity, high sodium and alcohol intake, and sedentary habit, from early childhood on. (b) People with DBP 80-89 mm Hg need to be identified promptly, with institution of nutritional-hygienic measures to prevent development of frank hypertension and to correct other risk factors. (c) People with DBP 90-104 and higher need to be identified promptly, with institution of measures to normalize BP and control other major risk factors, by nutritional-hygienic means alone whenever possible or in combination with drug treatment for HBP when necessary to prevent organ system damage, serious illness, disability, and premature death.(ABSTRACT TRUNCATED AT 400 WORDS)


Laminin A chain synthetic peptide which supports neurite outgrowth.
Neurons from peripheral and central nervous tissue as well as from established cell lines respond to low concentrations of laminin with rapid extension of axon-like processes. Two sites on laminin have been identified which stimulate neurite outgrowth, the major site residing at the end of the long arm of laminin. Recently laminin has been cloned and sequenced allowing for synthetic peptides to be prepared and tested for biological activity. We report here that antisera against synthetic peptides corresponding to A and to B1 chain sequences at the end of the long arm can partially inhibit laminin-mediated neurite outgrowth. Further, we show that a 19 amino acid synthetic peptide (CSRARKQAASIKVAVSADR) from the long arm of the laminin A chain is capable of stimulating neuronal-like process formation to almost the same extent as laminin and competes with laminin for stimulation of neurite outgrowth.


Multifractal description of the maternal surface of the placenta.
Recently, multifractal analysis based on generalized concepts of fractals has been applied to biological tissues composed of complex structures. Using digitized images of the maternal surface of 278 placentas, multifractal parameters were measured with a fractal analysis software. The values of alpha(min), alpha(0), alpha(max) and the degree of multifractality given by the alpha(max) - alpha(min) difference calculated from 278 placentas were 1.840 +/- 0.068, 2.089 +/- 0.034, 2.856 +/- 0.128 and 1.017 +/- 0.136, respectively. A significant decrease of alpha(min) and as a consequence a significant increase in the degree of multifractality were observed according to gestational age. The alpha(0) value of the placenta complicated by pregnancy-induced hypertension (PIH) was significantly higher than that without PIH. The alpha(min) and alpha(0) values of the placenta having intrauterine growth restriction (IUGR) were significantly higher than those without IUGR. On the other hand, the presence of chorioamnionitis did not change multifractal properties of the maternal surface of the placenta. The multifractal parameters may be objective indices of the heterogeneity or complexity of the macroscopic morphology of the maternal surface of the placenta. Multifractal analysis holds a promise for quantitatively evaluating physiological and pathological development of the placenta.


Rapid determination of free prolyl dipeptides and 4-hydroxyproline in urine using flow-gated capillary electrophoresis.
Unhydrolyzed prolyl hydroxyproline (Pro-Hyp) and total 4-hydroxyproline (Hyp) in urine have been suggested as disease biomarkers for bone turnover and osteoporosis. Here, a rapid method was developed to accurately and selectively determine free prolyl compounds in unhydrolyzed urine samples. Urine samples were treated with o-phthalaldehyde to block primary amines followed by selective fluorogenic derivatization of secondary amines using 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) at room temperature. The derivatized mixture was then directly analyzed and quantitated on a flow-gated capillary electrophoresis system. Six prolyl compounds: Pro-Hyp, Pro-Pro, Pro-Gly, Pro-Leu, Hyp, and Pro in unhydrolyzed urine samples were separated in 30 s, which was > 60-fold faster than the reported HPLC method, using the separation buffer (pH 9.2) composed of tetraborate, cholate, and deoxycholate at 40 mM each. The limits of detection were ~ 20 nM for the dipeptides and ~ 60 nM for Hyp and Pro. The levels of these prolyl compounds in fresh urine samples were determined by using the one-point standard addition method with nipecotic acid as the internal standard. The present protocol was significantly simplified compared with reported techniques, which could improve accuracy and analytical speed. This method is potentially useful in the determination of prolyl dipeptides and Hyp in biological fluids. Graphical abstract Rapid quantitative analysis of prolyl dipeptides in urine using flow-gated capillary electrophoresis coupled with laser-induced fluorescence detection.


Utility of Clinical and Laboratory Decision Rules in Identifying Bacterial Meningitis Among Children with Suspicion of Central Nervous System Infections in a Malaria-Endemic Area, Mbarara, Uganda.
Several decision rules combining clinical and biological parameters have been proposed to distinguish bacterial from aseptic meningitis, but have not been evaluated in Africa. In children hospitalized with suspected central nervous system infections in Uganda, we found that the Bacterial Meningitis Score and Meningitest showed lower performance than in European children, and that a decision rule designed specifically using parameters associated with bacterial meningitis also showed inadequate diagnostic performance for clinical use.


Presepsin Values Predict Septic Acute Kidney Injury, Acute Respiratory Distress Syndrome, Disseminated Intravascular Coagulation, and Shock.
Sepsis remains a major cause of mortality in critically ill patients. This study aimed to determine whether presepsin is a predictor of septic acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), and shock. A total of 83 adult patients diagnosed with sepsis were prospectively examined. Presepsin values were measured immediately after intensive care unit (ICU) admission and on Days 2, 3, and 5 after ICU admission. Glasgow Prognostic Score (GPS), neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, Prognostic Index, and Prognostic Nutritional Index were also examined at baseline. For category classification, total scores were calculated (hereafter, "inflammation-presepsin scores [iPS]") as follows: a score of 1 was assigned if the presepsin value and inflammation-based prognostic scores at baseline were above cutoffs determined by receiver operating characteristic (ROC) curve analysis for 28-day mortality; a score of 0 was assigned if they were below the cutoffs (total score range, 0-2 points). Presepsin values, inflammation-based prognostic scores, and iPS were compared between patients with septic AKI, ARDS, DIC, or shock and those without these disorders. ROC curve analyses identified the following variables as predictors: presepsin on Days 1 and 2 for septic AKI; presepsin on Days 1 to 3; and iPS-GPS for septic ARDS; and presepsin on Day 2 and Δpresepsin (Day 2-Day 1) for septic DIC. Multivariate analysis revealed presepsin on Day 2 to be a predictor of septic DIC. Presepsin is a predictor of septic AKI, ARDS, and DIC. Combining presepsin values with GPS improved the specificity for predicting septic ARDS relative to using baseline presepsin values alone.


Tumors of the scapula: A retrospective analysis identifying predictors of malignancy.
Osseous tumors of the shoulder girdle occur most frequently in the proximal humerus, scapula and clavicle. Prior studies have determined that tumors occurring in the scapula have a higher risk of malignancy, but few have looked exclusively at tumors of this site to describe incidence, clinical features and potential predictors of malignancy. As imaging technologies for diagnosis have improved, it is important to re-evaluate if patterns of incidence have changed and if new imaging findings could potentially be predictors of malignancy. This retrospective analysis identified 173 patients from a pediatric and an adult hospital between 1990 and 2015. All patients with tumors of the scapula either of bony origin or with bony invasion were included. Diagnosis, tumor location, and patient demographics were collected. Bivariate and logistic regression analyses were performed to identify potential predictors of malignancy. Chondrosarcoma and osteochondroma were the most common malignant and benign tumors, respectively. Benign tumors were more prevalent in the pediatric population. Tumors occurred most frequently in the body of the scapula. Risk for malignancy increased with age (OR 1.09, 95% CI 1.05-1.12), tumors invading multiple sites (OR 10.85, 95% CI 2.37-49.72) and tumors that were lucent (OR 7.02, 95% CI 1.14-43.21) or had a mixed radiographic appearance (OR 11.47, 95% CI 1.36-99.65). Including neoplasia in the differential diagnosis for shoulder complaints is important because the scapula is a site of increased risk of malignancy. Patterns of incidence and prevalence have not changed in the last years with the use of more advance techniques of imaging studies. Older age, lucent or mixed imaging, and tumors that span multiple sites of the scapula were found to be predictors of malignancy. Additional cross-sectional anatomy studies may be warranted for further evaluation in patients presenting with these characteristics given the higher concern for malignant disease. Level IV, Prognostic Study.


Central depressant effects and toxicity of propofol in chicks.
Propofol is an ultra-short acting anesthetic agent. The information on the pharmacological and toxicological effects of propofol in the chicken is rather limited. This study examines the toxicity and pharmaco-behavioral effects of propofol given intraperitoneally in 7-10 day-old chicks. The median effective doses of propofol for the induction of sedation, analgesia to electric stimulation and sleep in the chicks were 1.82, 2.21 and 5.71 mg/kg, respectively. The 24-h median lethal dose of propofol in chicks was 57.22 mg/kg. The therapeutic indices of propofol for sedation, analgesia and sleep were 31.4, 25.9 and 10, respectively. Propofol at 0.5 and 1 mg/kg reduced the locomotor activity and increased the duration of tonic immobility in chicks. Propofol at 2 and 4 mg/kg caused analgesia to electric stimulation as well as analgesia and anti-inflammatory responses against formalin test in chicks. Propofol at 5, 10 and 20 mg/kg induced sleep in chicks for 8.4 to 25 min. Physostigmine shortened the sleep duration of propofol. Data suggest that propofol induces anti-inflammatory action and central nervous system depression in chicks resulting in sedation, analgesia and anesthesia with wide safety margin. These effects could form the basis of further pharmacological and toxicological studies on propofol in the young chick model, and the drug could be safely applied clinically in the chicken.


Preventative effect of ketamine on post-surgical hyperalgesia induced at a body part remote from the surgical site.
It is known that pain hypersensitivity can be induced at a body part remote from a surgical site (tertiary hyperalgesia), leading to patient discomfort. Nevertheless, no reported study to date has investigated methods to attenuate such tertiary hyperalgesia. Ketamine is known to modulate hyperalgesia induced by central sensitization. Thus, we investigated whether intraoperative administration of ketamine could decrease post-surgical tertiary hyperalgesia in patients undergoing a laparoscopic hysterectomy. In total 46 patients were studied. Ketamine (1 mg/kg IV and 0.5 mg/kg/h or the same volume of 0.9% saline) was administered during surgery in the ketamine and control groups, respectively. The mechanical pain threshold was measured on the patients' dominant palm before and 24 hours after the surgery to evaluate hyperalgesia. The change in mechanical pain threshold over time (preoperative and postoperative) differed between the groups, with a lower postoperative threshold in the control group (118.6±170.5 vs. 419.2±233; P=0.015). The postoperative visual analogue scale score at rest was lower in the ketamine group (22±16 vs. 13±9; P=0.02). Visual analogue scale scores during deep breathing, consumption of analgesia and antiemetics, and the incidence of dizziness did not differ significantly between the groups (P>0.05). These results suggest that the intraoperative administration of ketamine may decrease post-surgical hyperalgesia developing at a region remote from the surgical site.


Medicinal herbs for the treatment of anxiety: A systematic review and network meta-analysis.
Anxiety disorder is a common psychiatric illness. Medicinal herbs have become a field of interest in the treatment of anxiety. This study aimed to evaluate and compare the efficacy and acceptability of all possible medicinal herbs for the treatment of anxiety. A Bayesian network meta-analysis was conducted for adults with diagnosed or subthreshold anxiety in randomized controlled trials identified in PubMed, EMBASE, the Cochrane Library, and Web of Science, searched between Jan 1, 1987, and Dec 31, 2021. The outcomes included efficacy (measured by endpoint Hamilton Anxiety Scale [HAMA] Scores) and acceptability (discontinuation by ineffectiveness, worsening of the symptoms, or adverse events). A total of 29 trials were reviewed, comparing 12 medicinal herbs. Silexan (mean difference [MD]: -3.84, 95% credible interval [CrI]: -6.31 to -1.34) displayed a significant effect on anxiety, and possibly benefitted the treatment of depression (standard mean difference [SMD]: -0.37, 95% confidence interval [CI]: -0.53 to -0.20) and insomnia (SMD: -0.48, 95% CI: -0.76 to -0.21). Kava was found to be an effective anxiolytic (MD: -2.46, 95% CrI: -4.47 to -0.32) but possibly ineffective in patients with generalized anxiety disorder (MD: -0.17, 95% CrI: -2.55 to -1.97). Ginkgo biloba (MD: -4.63, 95% CrI: -9.01 to -0.23) and Withania somnifera (MD: -4.90, 95% CrI: -9.70 to -0.17) were efficacious, as measured by HAMA scores but the trials were limited by their small sample sizes. Galphimia glauca (MD: -1.23, 95% CrI: -4.68 to 2.23) and Manasamitravn Vataka (MD: -1.35, 95% CrI: -7.39 to 4.68) exhibited the same anxiolytic effect as standard treatments, but both were absent from trials that were rated low risk, highlighting that confidence in their ability to provide an anxiolytic effect requires additional study. Conversely, although Passionflower (MD: -4.20, 95% CrI: -8.82 to 0.16) and Saffron (MD: -2.71, 95% CrI: -6.06 to 0.57) did not reduce HAMA scores significantly in the summary network, both were worthy of further study because of support from separate networks. There was insufficient evidence to confirm the effectiveness of Valerian (MD: 0.95, 95% CrI: -6.57 to 8.42) in standard-controlled estimation or the ineffectiveness of Chamomile (MD: 0.54, 95% CrI: -5.13 to 6.25) compared with a placebo for anxiety. Gamisoyo-san (MD: -0.98, 95% CrI: -6.48 to 4.54) and L-theanine (MD: -0.49, 95% CrI: -6.54 to 5.57) did not outperform a placebo for the treatment of anxiety in terms of statistical certainty. All medicinal herbs were well-tolerated and exhibited a good safety profile compared with control groups. When all herbs were compared, there was no statistical evidence to suggest any comparison significantly reduced HAMA scores except Ginkgo biloba vs Kava (MD: -4.41, 95% CrI: -8.32 to -0.35), although Ginkgo biloba was ranked as worst due to its poor tolerability. Medicinal herbs may be promising for the treatment of anxiety. However, these results should be considered preliminary because of the unconvincing sample sizes, together with the potential effectiveness of placebos.


Reactive oxygen species and human inflammatory periodontal diseases.
Reactive oxygen species (ROS) have emerged as important signaling molecules in the regulation of various cellular processes. They can be generated by the mitochondrial electron transport chain in mitochondria and activation of polymorphonuclear leukocytes (PMN) during inflammatory conditions. Excessive generation of ROS may result in attack of and damage to most intracellular and extracellular components in a living organism. Moreover, ROS can directly induce and/or regulate apoptotic and necrotic cell death. Periodontal pathologies are inflammatory and degenerative diseases. Several forms of periodontal diseases are associated with activated PMN. Damage of tissues in inflammatory periodontal pathologies can be mediated by ROS resulting from the physiological activity of PMN during the phagocytosis of periodontopathic bacteria.


[Psychoeducation and cognitive remediation, which place in rehabilitation?].
Rehabilitation techniques aim to reduce the functional impact of severe psychological disorders. The recent development of techniques aimed at the manifestations of the pathology, such as psychoeducation and cognitive remediation, raise questions about how they differ from standard therapies. Beyond their functional purpose, the consideration of the individual's current or future action potential, seems to constitute one of the key aspects.


Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson's disease.
Parkinson's disease (PD) is mediated, in part, by intraneuronal accumulation of α-synuclein aggregates andsubsequent death of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc). Microglial hyperactivation of the NOD-like receptor protein 3 (NLRP3) inflammasome has been well-documented in various neurodegenerative diseases, including PD. We show here that loss of parkin activity in mouse and human DA neurons results in spontaneous neuronal NLRP3 inflammasome assembly, leading to DA neuron death. Parkin normally inhibits inflammasome priming by ubiquitinating and targeting NLRP3 for proteasomal degradation. Loss of parkin activity also contributes to the assembly of an active NLRP3 inflammasome complex via mitochondrial-derived reactive oxygen species (mitoROS) generation through the accumulation of another parkin ubiquitination substrate, ZNF746/PARIS. Inhibition of neuronal NLRP3 inflammasome assembly prevents degeneration of DA neurons in familial and sporadic PD models. Strategies aimed at limiting neuronal NLRP3 inflammasome activation hold promise as a disease-modifying therapy for PD.


Differential reduction of the inter-chain disulfide bonds of rat immunoglobulin E: relation to biological activity.
Monoclonal rat IgE was reduced over a range of dithiothreitol (DTT) concns. The number of disulfide bonds reduced and their location in the IgE molecule were studied. One millimolar DTT was found to split the two inter-heavy-chain disulfide bonds of the C epsilon 2 domain while increasing DTT concn to 10 mM split the two inter-heavy-light-chain disulfide bridges. Therefore, the sensitivities to reduction of disulfide bonds in rat IgE were found to be the opposite of those in human IgE. In addition, the results indicated the absence, in rat IgE, of the intra-epsilon-chain labile disulfide bond of the C epsilon 1 domain, which is reduced by 2 mM DTT in human IgE. Circular dichroism studies showed significant modifications, mainly of tertiary structure, for rat IgE reduced with 10 mM DTT, but not for IgE reduced with 1 mM DTT. The ability to block passive sensitization with reaginic antibody was not modified when IgE was reduced with 1 mM DTT (which split the two inter-heavy-chain disulfide bonds), but was lost when inter-heavy-light-chain bridges were reduced with 10 mM DTT. In addition, a non-covalent epsilon-chain dimer was found to have the same blocking activity as native IgE (or IgE reduced with 1 mM DTT). Therefore, the results suggest that reduction of most or all the inter-chain disulfide bonds, in rat as in human IgE, induces changes in quaternary structure, more especially in the relationship between the Fab and Fc parts of the molecule, leading to steric blockade, by Fab, of the binding sites for mast cells present on Fc.


A fatal clomipramine intoxication case of a chronic alcoholic patient: application of postmortem hair analysis method of clomipramine and ethyl glucuronide using LC/APCI/MS.
Toxicological investigations of postmortem specimens of a 26-year-old man were performed with the use of LC/APCI/MS. They revealed in the blood of the deceased clomipramine (9.49 microg/g) and its main metabolite norclomipramine (1.10 microg/g) at concentrations explaining the fatal outcome. The presence of these xenobiotics in a 12-cm-long strand of hair (clomipramine, 7.60 ng/mg in I segment; 4.19 ng/mg in II segment; 1.86 ng/mg in III segment; norclomipramine, 5.71 ng/mg in I segment; 9.71 ng/mg in II segment; 4.13 ng/mg in III segment) confirmed the fact obtained from the medical history that the deceased had been receiving clomipramine as an antidepressant for 1 year prior to his death. The analysis demonstrated ethanol in autopsy blood (2.5mg/ml) and urine (3.2mg/ml); ethyl glucuronide as a marker of chronic alcohol abuse was detected in the deceased's hair (0.44 ng/mg in I segment; 0.07 ng/mg in II segment; n.d. in III segment). These findings may suggest the contribution of alcohol in the mechanism of drug-ethanol interaction, which in consequence might have affected the biotransformation of clomipramine in the final period of his life and evoked the ultimate toxic effect.


Compatibility Study of Danggui Buxue Tang on Chemical Ingredients, Angiogenesis and Endothelial Function.
Danggui Buxue Tang (DBT) is a classic Chinese herbal formula which consists of Astragali mongholici Radix and Angelica sinensis Radix (ASR). For chemical ingredients, HPLC were performed. Results showed compared with single herbs, DBT decoction could promote the dissolution of ingredients such as ferulic acid and calycosin. Furthermore, when ratio of AMR to ASR was 5 to 1, synthetic score was the best. For angiogenesis, normal and injured zebrafish model were applied. Results showed DBT and its ingredients had angiogenesis effects on Sub Intestinal vessels (SIVs) of normal zebrafish. Meanwhile, DBT and its single herbs could also recover Inter-Segmental Vessels (ISVs) injured by VRI. Angiogenesis effects of DBT on ISVs were better than single herbs. AMR extract, Total Saponins of AMR, Polysaccharide of ASR, ferulic acid, calycosin and calycosin-7-glucoside could be effective ingredients for angiogenisis. For endothelium functions, Lysoph-Osphatidyl choline was used to damage rat endothelial function of thoracic aorta. The results showed DBT and its single herbs could improve endothelial dysfunctions in dose-dependence. Both ferulic acid and calycosin-7-glucoside could also improve endothelium dysfunction in dose dependence. Therefore, compatibility of DBT was reasonable. Compared with single herbs, DBT could promote dissolution of effective ingredients, enhance angiogenesis and relieve endothelial dysfunction.


Interleukin-8 dysregulation is implicated in brain dysmaturation following preterm birth.
Preterm birth is associated with dysconnectivity of structural brain networks, impaired cognition and psychiatric disease. Systemic inflammation contributes to cerebral dysconnectivity, but the immune mediators driving this association are poorly understood. We analysed information from placenta, umbilical cord and neonatal blood, and brain MRI to determine which immune mediators link perinatal systemic inflammation with dysconnectivity of structural brain networks. Participants were 102 preterm infants (mean gestational age 29+1 weeks, range 23+3-32+0). Placental histopathology identified reaction patterns indicative of histologic chorioamnionitis (HCA), and a customized immunoassay of 24 inflammation-associated proteins selected to reflect the neonatal innate and adaptive immune response was performed from umbilical cord (n = 55) and postnatal day 5 blood samples (n = 71). Brain MRI scans were acquired at term-equivalent age (41+0 weeks [range 38+0-44+4 weeks]) and alterations in white matter connectivity were inferred from mean diffusivity and neurite density index across the white matter skeleton. HCA was associated with elevated concentrations of C5a, C9, CRP, IL-1β, IL-6, IL-8 and MCP-1 in cord blood, and IL-8 concentration predicted HCA with an area under the receiver operator curve of 0.917 (95% CI 0.841 - 0.993, p < 0.001). Fourteen analytes explained 66% of the variance in the postnatal profile (BDNF, C3, C5a, C9, CRP, IL-1β, IL-6, IL-8, IL-18, MCP-1, MIP-1β, MMP-9, RANTES and TNF-α). Of these, IL-8 was associated with altered neurite density index across the white matter skeleton after adjustment for gestational age at birth and at scan (β = 0.221, p = 0.037). These findings suggest that IL-8 dysregulation has a role in linking perinatal systemic inflammation and atypical white matter development in preterm infants.


Quadriceps function after TKA--an in vitro study in a knee kinematic simulator.
The purpose of this in vitro study was to investigate the amount of quadriceps force required to extend the knee during an isokinetic extension cycle before and after total knee arthroplasty. The magnitude of the extension torque used in simulating a constant moment extension exercise was derived from tests made using a dynamometer on patients who had received a total knee arthroplasty. Quadriceps force needed to extend the knee was measured. Human knee specimens (n=8, mean age=65 SD 7 years, all male) were tested in a kinematic knee simulating machine untreated and after implantation of two different knee prosthesis. During simulation, a hydraulic cylinder applied sufficient force to the quadriceps tendon to produce an extension moment of 31 Nm about the knee. The quadriceps forces needed to extend the knee during the physiologic simulation reached levels as high as 1238.9 N (SD 46.6). After implantation the Interax-prosthesis, quadriceps force increased up to 13.9% (P=0.003), in conjunction with resurfacing of the patella 11.9% (P=0.01). With the LCS-prosthesis implanted, quadriceps force showed a somewhat smaller increase of up to 6.6% (P=0.007). The following study helps to clarify postoperative problems related to the extensor mechanisms of the knee after implantation of total knee arthroplasty.


Synthesis and evaluation of some masked phosphate esters of the anti-herpesvirus drug 882C (netivudine) as potential antiviral agents.
A number of symmetric and asymmetric 5'-phosphate esters of the potent anti-varicella-zoster virus (VZV) agent 1-(beta-D-arabinofuranosyl)-5-prop-1-ynyluracil (882C; netivudine) were prepared as potential lipophilic, membrane-soluble prodrugs of the bio-active phosphate forms. The compounds were prepared by the base-catalysed coupling of various phosphorochloridates with the free nucleoside analogue. Compounds were fully characterized by a range of spectroscopic and analytical methods and were studied for their inhibition of several viruses in tissue culture. All of the phosphate esters were inactive against human cytomegalovirus, herpes simplex virus type 2, VZV, human immunodeficiency virus type 1 and influenza A virus (EC50 > 100 microM) except the 5'-(4-nitrophenyl phenyl) phosphate, which inhibited influenza A virus. The relative rate of esterase-mediated hydrolysis of one of the lead target structures was measured in order to rationalize the poor antiviral action, and data were collected on possible metabolites in support of this analysis. Cell-specific esterases are implicated as key determinants of the antiviral potency of prodrugs of this type.


A multicenter prospective study of 3,110 consecutive cases of elective epinephrine use in the fingers and hand: the Dalhousie Project clinical phase.
To examine prospectively the incidence of digital infarction and phentolamine rescue in a large series of patients in whom local anesthesia with adrenaline was injected electively into the hand and fingers. There continues to be a commonly held belief that epinephrine injection is contraindicated in the finger despite a lack of valid evidence to support this concept in the literature. From 2002 to 2004 there were 9 hand surgeons in 6 cities who prospectively recorded each consecutive case of elective hand and finger epinephrine injection. They recorded each instance of skin or tissue loss and the number of times phentolamine reversal of adrenaline vasoconstriction was required. There were 3,110 consecutive cases of elective injection of low-dose epinephrine (1:100,000 or less) in the hand and fingers and none produced any instance of digital tissue loss. Phentolamine was not required to reverse the vasoconstriction in any patients. The true incidence of finger infarction in elective low-dose epinephrine injection into the hand and finger is likely to be remote, particularly with the possible rescue with phentolamine.


The ontogenetic evolution of acidic phosphoprotein phosphatase activity in the lymphatic tissue and the liver of the rat.
We have shown that an acidic phosphoprotein phosphatase (APP-ase) has a different pattern of postnatal maturation in the spleen, thymus and liver of rats and mice. The APP-ase activity increases during the first eight months of postnatal life in the spleen of rats (when it attains an 8--10 times higher value than at birth) and up to the sixth month of life in the spleen of mice. It increases considerably during the first two weeks of postnatal life in the thymus of rats and mice; in the liver of rats it reaches maximum activity before birth, but continues to increase up to the sixth month of postnatal life in the liver of mice. The results show also that the APP-ase from the spleen, thymus and liver of rats is equally active in dephosphorylating ATP and phenyl phosphate during the whole life span of rats, but not in relation to beta-glycerol phosphate. After analyzing its substrate specificity, its pH dependence in relation to different substrates, its kinetic properties, as well as its behaviour towards ascorbic acid and different inhibitors (sodium tungstate and sodium molybdate, L-tartrate, L-phenylalanine and L-cysteine) we have come to the conclusion that the rat spleen APP-ase is different from "nonspecific" acid and alkaline phosphatases and very similar to the EC 126.96.36.199 acid phosphoprotein phosphatase.


Natural history of pathologically confirmed pulmonary subsolid nodules with deep learning-assisted nodule segmentation.
To explore the natural history of pulmonary subsolid nodules (SSNs) with different pathological types by deep learning-assisted nodule segmentation. Between June 2012 and June 2019, 95 resected SSNs with preoperative long-term follow-up were enrolled in this retrospective study. SSN detection and segmentation were performed on preoperative follow-up CTs using the deep learning-based Dr. Wise system. SSNs were categorized into invasive adenocarcinoma (IAC, n = 47) and non-IAC (n = 48) groups; according to the interval change during the preoperative follow-up, SSNs were divided into growth (n = 68), nongrowth (n = 22), and new emergence (n = 5) groups. We analyzed the cumulative percentages and pattern of SSN growth and identified significant factors for IAC diagnosis and SSN growth. The mean preoperative follow-up was 42.1 ± 17.0 months. More SSNs showed growth or new emergence in the IAC than in the non-IAC group (89.4% vs. 64.6%, p = 0.009). Volume doubling time was non-significantly shorter for IACs than for non-IACs (1436.0 ± 1188.2 vs. 2087.5 ± 1799.7 days, p = 0.077). Median mass doubling time was significantly shorter for IACs than for non-IACs (821.7 vs. 1944.1 days, p = 0.001). Lobulated sign (p = 0.002) and SSN mass (p = 0.004) were significant factors for differentiating IACs. IACs showed significantly higher cumulative growth percentages than non-IACs in the first 70 months of follow-up. The growth pattern of SSNs may conform to the exponential model. The initial volume (p = 0.042) was a predictor for SSN growth. IACs appearing as SSNs showed an indolent course. The mean growth rate was larger for IACs than for non-IACs. SSNs with larger initial volume are more likely to grow. • Invasive adenocarcinomas (IACs) appearing as subsolid nodules (SSNs), with a mean volume doubling time (VDT) of 1436.0 ± 1188.2 days and median mass doubling time (MDT) of 821.7 days, showed an indolent course. • The VDT was shorter for IACs than for non-IACs (1436.0 ± 1188.2 vs. 2087.5 ± 1799.7 days), but the difference was not significant (p = 0.077). The median MDT was significantly shorter for IACs than for non-IACs (821.7 vs. 1944.1 days, p = 0.001). • SSNs with lobulated sign and larger mass (> 390.5 mg) may very likely be IACs. SSNs with larger initial volume are more likely to grow.


Scoring protein sequence alignments using deep learning.
A high-quality sequence alignment (SA) is the most important input feature for accurate protein structure prediction. For a protein sequence, there are many methods to generate a SA. However, when given a choice of more than one SA for a protein sequence, there are no methods to predict which SA may lead to more accurate models without actually building the models. In this work, we describe a method to predict the quality of a protein's SA. We created our own dataset by generating a variety of SAs for a set of 1351 representative proteins and investigated various deep learning architectures to predict the local distance difference test (lDDT) scores of distance maps predicted with SAs as the input. These lDDT scores serve as indicators of the quality of the SAs.Using two independent test datasets consisting of CASP13 and CASP14 targets, we show that our method is effective for scoring and ranking SAs when a pool of SAs is available for a protein sequence. With an example, we further discuss that SA selection using our method can lead to improved structure prediction. Code and the data underlying this article are available at https://github.com/ba-lab/Alignment-Score/. Supplementary data are available at Bioinformatics online.


Should ACE2 be given a chance in COVID-19 therapeutics: A semi-systematic review of strategies enhancing ACE2.
The severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) has resulted in almost 28 million cases of COVID-19 (Corona virus disease-2019) and more than 900000 deaths worldwide since December 2019. In the absence of effective antiviral therapy and vaccine, treatment of COVID-19 is largely symptomatic. By making use of its spike (S) protein, the virus binds to its primary human cell receptor, angiotensin converting enzyme 2 (ACE2) which is present in the pulmonary epithelial cells as well as other organs. SARS-CoV-2 may cause a downregulation of ACE2. ACE2 plays a protective role in the pulmonary system through its Mas-receptor and alamandine-MrgD-TGR7 pathways. Loss of this protective effect could be a major component of COVID-19 pathogenesis. An attractive strategy in SARS-CoV-2 therapeutics would be to augment ACE2 either directly by supplementation or indirectly through drugs which increase its levels or stimulate its downstream players. In this semi-systematic review, we have analysed the pathophysiological interplay between ACE and ACE2 in the cardiopulmonary system, the modulation of these two proteins by SARS-CoV-2, and potential therapeutic avenues targeting ACE-Ang II and ACE2-Ang (1-7) axes, that can be utilized against COVID-19 disease progression.


Disruption of centrifugal inhibition to olfactory bulb granule cells impairs olfactory discrimination.
Granule cells (GCs) are the most abundant inhibitory neuronal type in the olfactory bulb and play a critical role in olfactory processing. GCs regulate the activity of principal neurons, the mitral cells, through dendrodendritic synapses, shaping the olfactory bulb output to other brain regions. GC excitability is regulated precisely by intrinsic and extrinsic inputs, and this regulation is fundamental for odor discrimination. Here, we used channelrhodopsin to stimulate GABAergic axons from the basal forebrain selectively and show that this stimulation generates reliable inhibitory responses in GCs. Furthermore, selective in vivo inhibition of GABAergic neurons in the basal forebrain by targeted expression of designer receptors exclusively activated by designer drugs produced a reversible impairment in the discrimination of structurally similar odors, indicating an important role of these inhibitory afferents in olfactory processing.


Solubilization, isolation, and immunochemical characterization of the major outer membrane protein from Rhodopseudomonas sphaeroides.
Solubilization of the major outer membrane protein of Rhodopseudomonas sphaeroides, and subsequent isolation, has been achieved by both non-detergent- and detergent-based methods. The protein was differentially solubilized from other outer membrane proteins in 5 M guanidine thiocyanate which was exchanged by dialysis for 7 M urea. The urea-soluble protein was purified to homogeneity by a combination of DEAE-Sephadex chromatography and preparative electrophoretic techniques. Similar to the peptidoglycan-associated proteins of other Gram-negative bacteria, the protein was also purified by differential temperature extraction of the outer membrane in the presence of sodium dodecyl sulfate (SDS) followed by preparative SDS-polyacrylamide gel electrophoresis. Immunochemical analysis of the proteins isolated by the two techniques established the immunochemical identity and homogeneity of each preparation. Immunoblots of SDS-polyacrylamide gels revealed that antibody directed against the major outer membrane protein reacted with the three high molecular weight aggregates present in the outer membrane which we have previously shown to be composed of the major outer membrane protein and three nonidentical small molecular weight proteins.


[Role of nonspecific factors in the therapeutic action of general hyperthermia in oncologic diseases].
A study was made of the indices of hemodynamics, the immune status and thiol-disulfide system of the blood of cancer patients subjected to artificial total hyperthermia-hyperglycemia. The authors revealed the phase nature of the body response to total hyperthermia resulting in stimulation of the body adaptation mechanisms with a tendency to the normalization of disturbed homeostatic parameters. The effect of total hyperthermia in cancer therapy depended not only on the factor of selective temperature damage of tumor cells but also on the competence of the system of nonspecific body resistance.


Chiral modes and directional lasing at exceptional points.
Controlling the emission and the flow of light in micro- and nanostructures is crucial for on-chip information processing. Here we show how to impose a strong chirality and a switchable direction of light propagation in an optical system by steering it to an exceptional point (EP)-a degeneracy universally occurring in all open physical systems when two eigenvalues and the corresponding eigenstates coalesce. In our experiments with a fiber-coupled whispering-gallery-mode (WGM) resonator, we dynamically control the chirality of resonator modes and the emission direction of a WGM microlaser in the vicinity of an EP: Away from the EPs, the resonator modes are nonchiral and laser emission is bidirectional. As the system approaches an EP, the modes become chiral and allow unidirectional emission such that by transiting from one EP to another one the direction of emission can be completely reversed. Our results exemplify a very counterintuitive feature of non-Hermitian physics that paves the way to chiral photonics on a chip.


Obesity Management in Primary Care During and Beyond the COVID-19 Pandemic.
With 6.1 million United States cases as of early September 2020, the coronavirus disease 2019 (COVID-19) pandemic is presenting unprecedented challenges to primary care. As a complex multifactorial chronic disease, obesity is a significant risk for severe COVID-19 complications associated with high morbidity and mortality. Sustainable lifestyle changes and weight loss can be effective to address obesity and its complications. With COVID-19 expected to persist for the foreseeable future, treatment and prevention of obesity is more imperative than ever. This report summarizes how obesity management and lifestyle counseling can be incorporated and applied in primary care during and beyond the COVID-19 pandemic.


Organ procurement in children--surgical, anaesthetic and logistic aspects.
To cover the need in paediatric organ transplantation, every potential donor should be considered as a multi-organ donor. Successful transplantation may be performed with kidneys retrieved from very young infants, even anencephalic neonates if the en-bloc technique using both kidneys is used. Regarding the liver, paediatric donors can be accepted from one month of age while livers harvested from older children and even young adults can be transplanted into small children after ex-vivo reduction of the size of the graft. Multi-organ procurement from the same donor provides valuable organs if the anaesthetic management of the donor is appropriate. Active transplant programs needs international cooperation which is made possible by the organ exchange organizations.


Pioneer studies on HCl and silylation treatments of chrysotile.
In the light of some recent studies on organosilicon derivatives of HCl-leached chrysotile, pioneer works not cited in this area are chronologically and briefly commented on, emphasizing the infrared spectroscopy (FTIR-PAS) characterization of such chrysotile products. The latter have opened a far-reaching potential for the development of, e.g., highly stable hydrophobic or organophilic materials, including fibrous sheet polymers.


Effect of different methods of maintenance on the pathogenicity and infectivity of Babesia bigemina for the vector Boophilus microplus.
Observations were made on the effects of five different methods of laboratory maintenance on the infectivity and virulence of Babesia bigemina for the tick Boophilus microplus. The original isolate was highly infective and virulent, causing premature death of engorged female ticks and reduced egg production. Maintenance of the strain by syringe passage in unsplenectomised calves at six to 10 week intervals reduced both its infectivity and virulence for ticks. When slow passages were preceded by a series of rapid passages in splenectomised calves, the changes to the strain were less pronounced. The other three procedures, rapid syringe passage in splenectomised calves and tick passage in either splenectomised or intact calves, had no statistically significant effect on the characteristics measured.


Risk and risk estimation of placental abruption.
Several variables related to increased risk of placental abruption are also risk factors for venous thromboembolism. Prior second trimester-, third trimester, and repeated fetal loss are reported to be associated to thrombophilias. However, it is yet not known if they are also related to placental abruption. A retrospective case-control study of 161 women with placental abruption and 2371 unselected gravidae without placental abruption. The medical files were scrutinized and the selected variables were investigated in relation to the development of placental abruption. As compared to controls, previous second trimester-, third trimester-, repeated fetal loss, and prior placental abruption were related to a 3-, 13-, 3-, and a 25-fold increased risk of placental abruption, respectively. Several other factors were associated with a roughly three-fold increased risk such as: preeclampsia, IUGR, high maternal age (>35), family history of venous thromboembolism, smoking, and multiple birth. A risk score was created and as compared with those with no risk factors present, the risk of placental abruption was increasing from 2.5-fold for those with risk score=1, to almost 100-fold for risk score 4 or above. Easily obtainable information might be used to classify the risk of placental abruption.


Cost-related immunosuppressive medication nonadherence among kidney transplant recipients.
Immunosuppressive medications are essential in preventing kidney transplant rejection. Continuous insurance coverage for outpatient immunosuppressive medications remains a major issue. The objective of this study was to establish the prevalence and consequences of cost-related immunosuppressive medication nonadherence. A descriptive survey of all U.S. kidney transplant programs (n = 254) was conducted. The response rate for the survey exceeded 99%. The main outcome measures included the following: transplant recipient concerns related to medication costs, ability to pay for medications, medication nonadherence and its consequences, and failure of transplant centers to place patients on the transplant waiting list. Continuous insurance coverage for outpatient immunosuppressive drugs is a problem having potentially grave consequences for the majority of kidney transplant recipients. More than 70% of kidney transplant programs report that their patients have an extremely or very serious problem paying for their medications. About 47% of the programs indicate that more than 40% of their patients are having difficulty paying for their immunosuppressive medications. In turn, 68% of the programs report deaths and graft losses attributable to cost-related immunosuppressive medication nonadherence. Some of the problems identified here are more significant for adult than pediatric patients. The prevalence and consequences of cost-related immunosuppressive medication nonadherence among kidney transplant recipients have now been documented. The results presented here should serve as the necessary impetus for the development of health care policies supporting Medicare coverage of immunosuppressive medications for the life of the transplanted kidney.


Blurred world view: A study on the relationship between television viewing and the perception of the justice system.
Previous studies suggest that distorted representations of reality on television can lead to distorted perceptions of reality among viewers. In this study, 322 individuals in Austria reported their weekly television consumption and whether they believe that there is active practice of capital punishment in Austria, which has been abolished since 1968. The more television participants watched, the more likely they mistakenly believed that there is, or recently was, capital punishment in Austria, even when controlling for participants' age and education. It seems that television has the potential to influence viewers' perception and knowledge of core aspects of society.


Route-dependent effects of cadmium/cadmium and magnesium acute treatment on parameters of oxidative stress in rat liver.
The study was designed to evaluate and compare the effects of single oral (or) and intraperitoneal (i.p.) cadmium (Cd) administration on parameters of oxidative stress in liver of rats. Furthermore, investigation on protective effects of magnesium (Mg) or and i.p. pretreatment on the same parameters was performed. Wistar rats were administrated oral dose of Cd (30 mg Cd/kg b.w.)/Cd+Mg (30 mg Cd/kg b.w., 50 mg Mg/kg b.w.) or i.p. dose of Cd (1.5 mg Cd/kg b.w.)/Cd+Mg (1.5 mg Cd/kg b.w., 3 mg Mg/kg b.w.) and sacrificed after 24 h. In liver homogenates superoxide anion, malondialdehyde, non-protein sulfhydryl groups, total sulfhydryl groups content, and superoxide dismutase activity were determined. Cadmium intoxication caused the increase of superoxide anion and malondialdehyde levels and had negative effect on investigated parameters of antioxidant defense system, except on total sulfhydryl groups. The negative effect was more emphasized after i.p. Cd administration. Oral Mg pretreatment induced more pronounced positive effect than Mg given intraperitoneally that can be attributed, at least partly, to Cd and Mg interactions on the level of GIT. On the basis of the obtained results it can be concluded that both Cd and Cd+Mg effects on parameters of oxidative stress in rats liver are route-dependent.


High-performance liquid chromatography method for the separation of isomers of 9 beta-methylcarbacyclin (ciprostene) and the analysis of pharmaceutical samples.
An high-performance liquid chromatography method was developed that separates (5Z)-9 beta-methyl-6 alpha-carbaprostaglandin I2 (9 beta-methylcarbacyclin; ciprostene) from several closely related isomers: (i) a double bond isomer at C-5, (ii) an epimer at C-15, and (iii) combinations of i and ii. The method uses a Zorbax ODS column with a mobile phase consisting of acetonitrile-buffer pH 2.5 at a ratio of 45:55 for determination of purity and 40:60 for optimum separation of isomers. Detection is measurement of absorbance at 200 nm. Peak heights are measured relative to butylparaben which is used as an internal standard. The method is linear, free from interferences from degradation of ciprostene and has a relative standard deviation of 0.5-1% for solutions at 60 micrograms/ml. This assay has been applied to bulk powders and solutions of the drug. Stressed chemical stability studies have shown that the C-15 allylic secondary alcohol group undergoes epimerization under acidic conditions in solution and oxidation in the solid and solution state under thermal stress or in the presence of oxidants.


Uncovering RNAi mechanisms in plants: biochemistry enters the foray.
In plants, the RNA interference (RNAi) machinery responds to a variety of triggers including viral infection, transgenes, repeated elements and transposons. All of these triggers lead to silencing outcomes ranging from mRNA degradation to translational repression to chromatin remodeling. Thus, plants offer us a potentially unique opportunity to understand the full range of RNAi effector mechanisms. In this review, we discuss the recent developments in our understanding of plant RNAi mechanisms from a biochemical perspective.


Fertile pea plants regenerate from protoplasts when calluses have not undergone endoreduplication.
Large numbers of viable protoplasts were isolated and cultured from five pea genotypes. Calluses obtained (percent final plating efficiency (% FPE)=0.65-2.82% of initially plated protoplasts) exhibited great differences in proliferation and regeneration competence between and within genotypes. Flow cytometric analyses showed the occurrence of endoreduplication processes correlated with such differences, and could serve as a tool for the early prediction of plant regeneration competence from protoplasts. Fertile plants were produced only from calluses with a normal DNA level.


Polyanionic Polydentate Europium Complexes as Ultrabright One- or Two-photon Bioprobes.
A family of europium (III) complexes based on a polydentate ligand functionalized by charge-transfer antennae presents remarkable one- and two-photon photophysical proper-ties in water or buffer. A detailed analysis of their emission properties suggests that the wrapping of the ligand around the central rare-earth ion results in an overall Cs symmetry in agreement with the theoretical simulation and that about 65-70 % of the emission intensity is concentrated in the hypersensitive 5 D0 →7 F2 transition at 615 nm. Their brightness is excellent, in the range of the best lanthanide bioprobes making them very attractive for bio-imaging experiments.


Preoperative evaluation of the high-risk patient.
The benefits of surgery are usually clear and easy to define. The risk to which a particular patient is subjected during a specific operation, however, is a multifactorial and complex question related to preoperative condition, the complexity of the surgery proposed, and the skill and experience of the surgeon. We have concentrated our discussion only on preoperative evaluation of the patient's condition. By our system of evaluation of preoperative cardiac, pulmonary, carotid artery, nutritional, and general medical status some estimation of the risk of postoperative complication can be formulated. In some of our discussion we reported studies of other investigators, in which the likelihood of postoperative complications was expressed in percentages. An approach derived by study of groups of patients may or may not apply to a particular patient. Although such an approach may not be entirely accurate, it can assist in the estimation of the chance of serious postoperative complications. Obviously the most ideal situation would be to define precisely the risks and benefits of each operative procedure we recommend to a patient. Because this is not possible, we should state the benefits and estimate the risks of surgery preoperatively. We should also delay operation until the patient's preoperative condition is optimal, thereby decreasing the risks of complications. With a systematic preoperative evaluation these goals can be approximated. A critical part of the benefit-to-risk equation is the surgeon's judgment of whether the patient is a good operative risk. This opinion should not be ignored and should be part of any system of preoperative evaluation of risk of postoperative complications.


Pathways of iron acquisition and utilization in Leishmania.
Iron is essential for many metabolic pathways, but is toxic in excess. Recent identification of the ferric iron reductase LFR1, the ferrous iron transporter LIT1, and the heme transporter LHR1 greatly advanced our understanding of how Leishmania parasites acquire iron and regulate its uptake. LFR1 and LIT1 have close orthologs in plants, and are required for Leishmania virulence. Consistent with the lack of heme biosynthesis in trypanosomatids, LHR1 and LABCG5, a protein involved in heme salvage from hemoglobin, seem essential for Leishmania survival. LFR1, LIT1 and LHR1 are upregulated under low iron availability, in agreement with the need to prevent excessive iron uptake. Future studies should clarify how Leishmania interacts with the iron homeostasis machinery of its host cell, the macrophage.


Importance of glucose-6-phosphate dehydrogenase (G6PDH) for vanillin tolerance in Saccharomyces cerevisiae.
Vanillin is derived from lignocellulosic biomass and, as one of the major biomass conversion inhibitors, inhibits yeast growth and fermentation. Vanillin was recently shown to induce the mitochondrial fragmentation and formation of mRNP granules such as processing bodies and stress granules in Saccharomyces cerevisiae. Furfural, another major biomass conversion inhibitor, also induces oxidative stress and is reduced in an NAD(P)H-dependent manner to its less toxic alcohol derivative. Therefore, the pentose phosphate pathway (PPP), through which most NADPH is generated, plays a role in tolerance to furfural. Although vanillin also induces oxidative stress and is reduced to vanillyl alcohol in a NADPH-dependent manner, the relationship between vanillin and PPP has not yet been investigated. In the present study, we examined the importance of glucose-6-phosphate dehydrogenase (G6PDH), which catalyzes the rate-limiting NADPH-producing step in PPP, for yeast tolerance to vanillin. The growth of the null mutant of G6PDH gene (zwf1Δ) was delayed in the presence of vanillin, and vanillin was efficiently reduced in the culture of wild-type cells but not in the culture of zwf1Δ cells. Furthermore, zwf1Δ cells easily induced the activation of Yap1, an oxidative stress responsive transcription factor, mitochondrial fragmentation, and P-body formation with the vanillin treatment, which indicated that zwf1Δ cells were more susceptible to vanillin than wild type cells. These findings suggest the importance of G6PDH and PPP in the response of yeast to vanillin.


MicroRNA-211-5p attenuates spinal cord injury via targeting of activating transcription factor 6.
The recovery of spinal cord injury (SCI) involves multiple factors, of which miRNAs take an important part. In this study, we evaluated the function of microRNA-211-5p (miR-211-5p) on SCI in a rat model. SCI model was established using modified Allen's weight-drop method and Basso-Bcattie-Bresnahan score was applied to assess the locomotor function. MiR-211-5p agomir was utilized to increase miR-211-5p expression and endoplasmic reticulum (ER) stress inhibitor, 4-PBA (4-phenylbutyric acid), was utilized to suppress ER stress. Neuron apoptosis and the expressions of miR-211-5p, activating transcription factor 6 (ATF6), apoptosis-related proteins, pro-inflammatory cytokines and endoplasmic reticulum stress-related proteins were detected. Dual luciferase reporter gene assay was performed to verify the binding between miR-211-5p and ATF6. The results showed that miR-211-5p directly targeted ATF6. MiR-211-5p was down-regulated and ATF6 was up-regulated in SCI rats. Both interferences with miR-211-5p agomir and 4-PBA effectively attenuated neuron apoptosis and reversed the expressions of apoptosis, inflammation and endoplasmic reticulum stress-related molecules post SCI in rats. These findings demonstrated that miR-211-5p could effectively alleviate SCI-induced neuron apoptosis and inflammation via directly targeting ATF-6 and regulating ER stress.


The overshoot and phenotypic equilibrium in characterizing cancer dynamics of reversible phenotypic plasticity.
The paradigm of phenotypic plasticity indicates reversible relations of different cancer cell phenotypes, which extends the cellular hierarchy proposed by the classical cancer stem cell (CSC) theory. Since it is still questionable if the phenotypic plasticity is a crucial improvement to the hierarchical model or just a minor extension to it, it is worthwhile to explore the dynamic behavior characterizing the reversible phenotypic plasticity. In this study we compare the hierarchical model and the reversible model in predicting the cell-state dynamics observed in biological experiments. Our results show that the hierarchical model shows significant disadvantages over the reversible model in describing both long-term stability (phenotypic equilibrium) and short-term transient dynamics (overshoot) in cancer cell populations. In a very specific case in which the total growth of population due to each cell type is identical, the hierarchical model predicts neither phenotypic equilibrium nor overshoot, whereas the reversible model succeeds in predicting both of them. Even though the performance of the hierarchical model can be improved by relaxing the specific assumption, its prediction to the phenotypic equilibrium strongly depends on a precondition that may be unrealistic in biological experiments. Moreover, it still does not show as rich dynamics as the reversible model in capturing the overshoots of both CSCs and non-CSCs. By comparison, it is more likely for the reversible model to correctly predict the stability of the phenotypic mixture and various types of overshoot behavior.


Physiotherapy in the management of disorders of the temporomandibular joint--perceived effectiveness and access to services: a national United Kingdom survey.
Up to a quarter of the general population has experienced temporomandibular joint disorder (TMD) at some point in time. Physiotherapy has been used in the management of TMD for many years, but evidence supporting its clinical effectiveness is limited. We investigated the perceived effectiveness of physiotherapy for patients with TMD among consultants in oral and maxillofacial surgery (OMFS) and the accessibility of these services in the United Kingdom (UK). Information was gathered from a postal or electronic questionnaire sent to the 356 OMFS consultants listed on the British Association of Oral and Maxillofacial Surgeons' website. A total of 208 responded (58%) and 72% considered physiotherapy to be effective. Amongst these respondents, jaw exercises (79%), ultrasound (52%), manual therapy (48%), acupuncture (41%) and laser therapy (15%) were considered to be effective. Twenty-eight percent of respondents did not consider physiotherapy to be effective. Reasons for this included lack of knowledge or expertise of the physiotherapist (41%) and lack of awareness of the benefits of physiotherapy (28%). In relation to access to physiotherapy services, 10% of respondents had a designated physiotherapist for patients with TMD, 89% could refer directly to physiotherapy and 7% worked in an environment that provided training for physiotherapists. Patients were prescribed jaw exercises by 69% of respondents. Despite limited evidence to support its effectiveness, approximately three-quarters of OMFS consultants in the UK regard physiotherapy to be beneficial in the management of TMD.


Plausible molecular and crystal structures of chitosan/HI type II salt.
Chitosan/HI type II salt prepared from crab tendon was investigated by X-ray fiber diffraction. Two polymer chains and 16 iodide ions (I(-)) crystallized in a tetragonal unit cell with lattice parameters of a = b = 10.68(3), c (fiber axis) = 40.77(13) A, and a space group P4(1). Chitosan forms a fourfold helix with a 40.77 A fiber period having a disaccharide as the helical asymmetric unit. One of the O-3... O-5 intramolecular hydrogen bonds at the glycosidic linkage is weakened by interacting with iodide ions, which seems to cause the polymer to take the 4/1-helical symmetry rather than the extended 2/1-helix. The plausible orientations of two O-6 atoms in the helical asymmetric unit were found to be gt and gg. Two chains are running through at the corner and the center of the unit cell along the c-axis. They are linked by hydrogen bonds between N-21 and O-61 atoms. Two out of four independent iodide ions are packed between the corner chains while the other two are packed between the corner and center chains when viewing through the ab-plane. The crystal structure of the salt is stabilized by hydrogen bonds between these iodide ions and N-21, N-22, O-32, O-61, O-62 of the polymer chains.


Association between uric acid and carotid atherosclerosis in elderly persons.
Several cohort studies have shown a link between serum uric acid (SUA) and subsequent cardiovascular disease. However, such an association did not remain significant after adjusting for concomitant risk factors for atherosclerosis in some studies. Thus, the role of SUA as an independent risk factor remains controversial. We therefore investigated the association between SUA and sclerotic lesions of common carotid atherosclerosis. We evaluated sclerotic lesions of the common carotid arterial intima-media thickness (IMT) by ultrasonography in 398 men aged 74+/-8 (range, 60-97) years and 521 women aged 75+/-8 (range, 60-104) years. To investigate the relation between SUA and various factors, all subjects were divided into three groups based on the tertile of SUA. Stepwise multiple linear regression analysis using IMT as an objective variable, adjusted by various risk factors as explanatory variables showed that SUA [B, 0.0099; 95% confidence interval (CI), 0.0022-0.0175] was a significant independent contributing factor along with known risk factors such as age, sex, smoking status, systolic blood pressure, diastolic blood pressure, antihypertensive drug use, HDL-cholesterol, and LDL-cholesterol. Multiple logistic regression analysis for carotid IMT as a tertile of SUA and dependent variables showed that the adjusted odds ratio was 1.25 (95% CI, 0.87-1.78) for those in the middle tertile (4.2-5.5 mg/dl), and 1.66 (95% CI, 1.16-2.39) for those in the highest tertile (5.6-14.1 mg/dl) compared to that for subjects in the lowest tertile of SUA levels (0.51-4.1 mg/dl). We suggest that SUA is a risk factor or marker for ultrasonographically determined IMT.


New potential calcium channel modulators: design and synthesis of compounds containing two pyridine, pyrimidine, pyridone, quinoline and acridine units under microwave irradiation.
The synthesis of bifunctional pyridine, pyrimidine, pyridone, quinoline and acridine derivatives was investigated using dialdehyde as a precursor. A rapid and efficient method was developed for the synthesis of a range of bifunctional monocyclic, bicyclic and tricyclic products related to 1,4-DHPs with the aim of finding new classes of biologically active compounds.


Is the Pattern Changing? Atrial Fibrillation and Screening with Holter Electrocardiograms among Ischemic Stroke Patients in Greenland from 2016 to 2021.
A standardized examination regime for ischemic stroke (IS) patients was implemented in Greenland in 2010. Prevalence of atrial fibrillation (AF) of 32% was found among discharged IS patients from 2011 to 2012, and our study aims to estimate the use of Holter ECGs for AF diagnostics and the current prevalence of AF among IS patients in Greenland. Patients discharged from Queen Ingrid's Hospital in Nuuk between 2016 and 2021 with an ICD-10 diagnosis of IS or stroke without specification were included. Data on Holter recordings, age, gender, medical treatment with rivaroxaban or warfarin, and ICD-10 and ICPC codes for AF were extracted for each patient. The overall incidence of IS from 2016 to 2021 was 133/100,000 and unchanged since 2012. Sixty-eight of the study's IS patients (14.5%) had AF, and 46% of IS patients with Holter data accessible had a recording according to international recommendations. Our results indicate that fewer IS patients in Greenland have AF than previously. However, the insufficient use of Holter as a diagnostic tool may explain part of the drop, as well as improved preventive treatment with rivaroxaban among AF patients in Greenland. Regardless, IS remains common, and a focus on diagnostics and preventable risk factors should be maintained.


Simultaneous determination of triptolide, tripterifordin, celastrol and nine sesquiterpene alkaloids in Tripterygium preparations using high-performance liquid chromatography-triple quadrupole mass spectrometry.
Tripterygium wilfordii tablet (TWT) and Tripterygium hypoglaucum tablet (THT), the preparations of the two Tripterygium herbs, are well known for the treatment of rheumatoid arthritis and other related inflammatory diseases clinically. In the present study, a high performance liquid chromatography (HPLC) coupled with electrospray ionization (ESI) tandem triple quadrupole mass spectrometry (QQQ/MS) method was developed for simultaneous quantification of 12 chemical components in Tripterygium preparations. The fragmentation patterns of analytes using ESI and collision-induced dissociation (CID) techniques were reported. This assay method was validated with respect to linearity (r(2)>0.9991), precision, repeatability, and accuracy (recovery rate between 97.2 and 104.2%). The proposed method was successfully applied for simultaneous quantification of the 12 compounds in Tripterygium preparations from the different manufactures. In addition, to evaluate the quality of Tripterygium preparations, partial least square discrimination analysis (PLS-DA) was performed to differentiate the contents of 12 compounds. In conclusion, the established HPLC/QQQ/MS method was proven to be useful and efficient for quality control of Tripterygium preparations.


Inhibitors of hepatitis C virus NS3.4A protease 2. Warhead SAR and optimization.
The alpha-ketoamide warhead (e.g., 15) was found to be a practical replacement for aliphatic aldehydes in a series of HCV NS3.4A protease inhibitors. Structure-activity relationships and prime side optimization are discussed.


A non-metal catalysed oxidation of primary azides to nitriles at ambient temperature.
A novel non-metal catalyzed oxidation of organic azides to nitriles under solvent-free conditions is presented employing catalytic amounts of KI, and DABCO in aq. TBHP at room temperature. This non-metal catalyzed oxidation of azides provides good selectivity as double and triple bonds were not oxidized under the present reaction conditions.


Report of Lutzomyia longipalpis (Lutz & Neiva, 1912) (Diptera: Psychodidae: Phlebotominae) in a cutaneous-leishmaniasis-endemic area of Panama.
Lutzomyia longipalpis is the primary vector of the parasite responsible for visceral leishmaniasis in the Americas. In the present study, Lu. longipalpis was found in a domiciliary area in Limón, a district in Capira, a region in which cutaneous leishmaniasis is endemic in Panama. Previously, this species has been found in a humid forest in this same region. Finding Lu. longipalpis in domiciliary areas indicates that this species may be adapting to new habitats and that it may play a role in the transmission of leishmaniasis in Panama.


Fine root biomass under light gap openings in an Amazon rain forest.
Belowground processes in light gap openings are poorly understood, particularly in tropical forests. Fine roots in three zones of light gap openings and adjacent intact forest were regularly measured in buried bags and surface litter envelopes for 2 years. Fine root biomass does not vary significantly within gaps for either buried bags or for surface litter envelopes. When entire gaps are compared without regard for within gap zones, root growth into both surface litter and buried bags is significantly different between gaps, with highest rates of fine root biomass accumulation in the smallest gap. These results suggest that the aboveground within-gap zones do not result in a congruent pattern of below-ground zonation. Gap size, decomposition of the fallen tree, and pre-gap fine root growth rates should be considered to determine fine root growth patterns following the formation of light gap openings.


Comparison of standard- and nano-flow liquid chromatography platforms for MRM-based quantitation of putative plasma biomarker proteins.
The analytical performance of a standard-flow ultra-high-performance liquid chromatography (UHPLC) and a nano-flow high-performance liquid chromatography (HPLC) system, interfaced to the same state-of-the-art triple-quadrupole mass spectrometer, were compared for the multiple reaction monitoring (MRM)-mass spectrometry (MS)-based quantitation of a panel of 48 high-to-moderate-abundance cardiovascular disease-related plasma proteins. After optimization of the MRM transitions for sensitivity and testing for chemical interference, the optimum sensitivity, loading capacity, gradient, and retention-time reproducibilities were determined. We previously demonstrated the increased robustness of the standard-flow platform, but we expected that the standard-flow platform would have an overall lower sensitivity. This study was designed to determine if this decreased sensitivity could be compensated for by increased sample loading. Significantly fewer interferences with the MRM transitions were found for the standard-flow platform than for the nano-flow platform (2 out of 103 transitions compared with 42 out of 103 transitions, respectively), which demonstrates the importance of interference-testing when nano-flow systems are used. Using only interference-free transitions, 36 replicate LC/MRM-MS analyses resulted in equal signal reproducibilities between the two platforms (9.3 % coefficient of variation (CV) for 88 peptide targets), with superior retention-time precision for the standard-flow platform (0.13 vs. 6.1 % CV). Surprisingly, for 41 of the 81 proteotypic peptides in the final assay, the standard-flow platform was more sensitive while for 9 of 81 the nano-flow platform was more sensitive. For these 81 peptides, there was a good correlation between the two sets of results (R(2) = 0.98, slope = 0.97). Overall, the standard-flow platform had superior performance metrics for most peptides, and is a good choice if sufficient sample is available.


Use of Topical Glycolic Acid Plus a Lovastatin-Cholesterol Combination Cream for the Treatment of Autosomal Recessive Congenital Ichthyoses.
Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders caused by defects in signaling pathways involved in epidermal proliferation and differentiation, leading to a wide range of skin manifestations. Therapeutic options are limited and often unsatisfactory. Topical cholesterol and statin as a combined formulation has proven successful in the treatment of patients with CHILD syndrome (congenital hemidysplasia ichthyosis and limb defects). To assess change in disease severity score after a 3-month therapeutic regimen consisting of a glycolic acid, 10% to 20%, cream and a combination cream of lovastatin, 2%, with cholesterol, 2%, in the treatment of ARCI. This case series of 15 patients with ARCI was conducted at the American University of Beirut, a referral center in the Middle East region for genodermatoses, between May 2017 and January 2018. No age groups were excluded; all patients were from the Middle East area; and all were initially not responsive to treatment with hydrating creams in combination with urea creams, 30% to 40%, or glycolic acid, 10% to 20%. Excluded were patients who had been taking systemic retinoids within 3 months before the start of the study. A 3-month therapeutic regimen of glycolic acid, 10% to 20%, cream and a combination of lovastatin, 2%, with cholesterol, 2%, cream. Percentage change in disease severity scores following 2 and 3 months of study treatment. Of the 15 patients included in the study, 10 were male (mean age, 11.2 years; age range, 2-38 years). The average percentage reduction in the disease severity score was 33.7% at 2 months (from 60.8 to 40.2) and 57.5% at 3 months (from 60.8 to 21.9). Adverse effects were mild and consisted mainly of irritation and burning. These findings suggest a benefit from a treatment regimen consisting of glycolic acid, 10% to 20%, and a combination of lovastatin, 2%, with cholesterol, 2%, in the treatment of ARCI. This combination of creams might also prove to be beneficial in other types of ichthyoses and other dermatological diseases with a defective skin barrier.


The level of S-glutathionylated protein is a predictor for metastasis in colorectal cancer and correlated with those of Nrf2/Keap1 pathway.
The Nrf2 (nuclear factor erythroid 2-like 2; NFE2L2)/Keap1 (Kelch-like ECH-associated protein 1) pathway and the TXN (thioredoxin)/GSH (glutathione) system interact mutually and regulate cellular redox with impacts on cancer metastasis and S-glutathionylation of protein, which is an indicator of cell distress. This study investigates the levels of proteins in the Nrf2/Keap1 pathway and the TXN/GSH system and SGP (S-glutathionylated protein) in CRC (colorectal cancer) with or without metastasis. The protein levels of Nrf2, Keap1, Bach1 (BTB domain and CNC homolog 1), TXN, TXNRD1 (thioredoxin reductase 1), GSR (glutathione reductase) and SGP with molecular weight 31-172 kDa in the normal and tumour tissues of 64 CRC subjects were determined by Western blot. The protein levels and their T/N (tumour/normal tissue) ratios of the Nrf2/Keap1 pathway, the TXN/GSH system and SGP were correlated to different extents in the tissues of CRC subjects with or without lymph node/distant metastasis. The T/N ratios of SGP (odd ratio: 0.19; 95% CI: 0.04-0.74) and lympho-vascular invasion (4.2; 1.39-13.73) were significant predictors for metastasis. SGPs have protein levels correlated with those of the Nrf2/Keap1 pathway and their T/N ratios are a negative predictor for metastasis in CRC.


Resin-composite cytotoxicity varies with shade and irradiance.
The study was aimed at investigating the cytotoxicity of different composites as a function of composite shade and the light curing unit (LCU) employed. Non-polymerized and polymerized samples of the composites Grandio(®) (VOCO, Cuxhaven), Solitaire(®) (Heraeus Kulzer, Hanau) and Filtek Z 250(®) (3M/Espe, Seefeld) in two markedly differing shades (A2, C2) were prepared. Polymerization was performed with two LCUs: Heliolux II (Ivoclar/Vivadent, Ellwangen) and Swiss Master Light (EMS, Nyon, Switzerland). To obtain composite extracts, the samples were immersed in cell culture medium (DMEM--Dulbecco's Modified Eagle Medium), which was replaced daily up to the 7th day of the experiment, and then on the 14th, 21st and 28th day. After incubation of human gingival fibroblasts (HGF) with the extracts obtained, cytotoxicity was determined using the MTT test. With the non-polymerized samples, essentially no influence of the composite shades investigated on HGF viability was detected, with the exception of the Solitaire material, where a higher cytotoxicity of the shade C2 in the non-polymerized state was found at the end of the observation period. After polymerization of the different composites, the cytotoxic reaction observed for the extracts of shade C2 was stronger than that observed for A2. After polymerization with the Heliolux II (HLX) LCU, the extracts of composites Grandio and Solitaire C2 were significantly more toxic than those of the A2 shade (p<0.01). Polymerization with the Swiss Master Light (SML) reduces this cytotoxic effect. The extracts of the Grandio composite showed the least cytotoxic effect throughout the observation period, irrespective of the LCU used. For the extracts of the Z250 specimens, the cytotoxicity observed was generally higher. The results show that the shade of the composite has an influence on its cytotoxicity and that this cytotoxicity is also influenced by the light curing unit used. It was observed that composites of the darker shade (C2) had a higher cytotoxicity, which varied with the LCU employed.


Characteristics of HIV-infected mothers associated with increased risk of poor mother-infant interactions and infant outcomes.
The current study aimed to investigate the relationship between individual and familial characteristics of HIV-infected mothers and their psychological health as it relates to parenting as well as their parenting beliefs/abilities. A descriptive correlational design was used. Seventeen HIV-infected mothers and their infants were recruited from a university clinic in Alabama. Assessments were gathered at the infant's pediatric clinic appointments (approximately 6 weeks after delivery) and included a demographic questionnaire, the Beck Depression Inventory-II, the Maternal Confidence Questionnaire, the Parenting Stress Index-Short Form, and the Questionnaire About Physical Contact. Dysfunctional parent-child interactions significantly correlated with maternal confidence, parent stress, and overall feeling about physical contact. Difficult child temperament correlated with overall and current feelings of physical contact and parent stress. Significant correlations were found between parent distress, parent stress, and maternal depression. Beyond the need to assist HIV-infected mothers with stress and depression, an intervention is needed to facilitate optimal parent-child interactions and improve both child psychosocial and cognitive outcomes.


Ethanol prevents stress-induced increase in cortical DOPAC: reversal by RO 15-4513.
Electric foot-shock increased DOPAC and decreased DA levels by about 70 and 20% respectively in the medial prefrontal cortex in rats. Pretreatment with diazepam (5 mg/kg IP) or ethanol (1.2 g/kg orally) prevented these stress-induced changes. The protective effect of diazepam and ethanol was eliminated by RO 15-4513 (5 mg/kg IP) a partial inverse benzodiazepine agonist.


Distal myasthenia gravis frequency and clinical course in a large prospective series.
In Myasthenia gravis (MG) proximal limb, ocular and/or bulbar muscles are most commonly affected, whereas distal extremity muscles are typically spared. The aim of the current study was to assess the frequency of primarily distal MG in the Tyrol and to describe its clinical peculiarities. Over the past 20 years 84 patients with MG have undergone follow-up at the Department of Neurology of Innsbruck University. Types of presentation, clinical course and treatment response were followed over a period of 20 years (1980-2000). Six of 84 MG patients showed a predominance of muscle weakness and fatigability in distal limb muscles (two at presentation, four over the later course of the illness). There was no difference between distal MG and MG with a more typical distribution of muscle weakness regarding age, gender and response to therapy. The case series indicates that predominantly distal presentations of otherwise typical MG are more frequent than generally assumed and should be considered in the differential diagnosis of diseases with distal limb weakness.


The 30 kDa abnormal protein in avian dystrophic muscle is indistinguishable from carbonic anhydrase III by physicochemical, immunological, and enzymological criteria.
In the accompanying paper, we described the existence, molecular characterization, and ontogeny of a 30 kDa abnormal protein in chicken dystrophic muscles. In this study, we have purified chicken carbonic anhydrase III and the 30 kDa protein and directly compared them. In terms of its enzymological features, the 30 kDa protein is a typical carbonic anhydrase III. Like carbonic anhydrases, it contains one mole zinc per mole of protein. The protein selectively cross-reacted with a chicken carbonic anhydrase III antibody. Antibody to the 30 kDa protein cross-reacted with chicken skeletal muscle carbonic anhydrase III. Moreover, the distribution of the abnormal protein is exactly identical to that of carbonic anhydrase III; however, there is a possibility that the 30 kDa protein is a variant of carbonic anhydrase III. Slight differences were found in antigenicities and in the apparent molecular weights of the two proteins. We have compared the two proteins by 125I-labeled two-dimensional peptide mapping. Tryptic maps have shown that the two proteins are highly homologous. Combined, these results strongly indicate that the 30 kDa protein and carbonic anhydrase III are similar, if not identical.


The treatment of port wine stains with the carbon dioxide laser.
The carbon dioxide (CO2) laser was used to treat 51 patients with port wine stains (PWS). Twenty-nine patients were adults who had failed to respond to argon or continuous wave dye laser therapy and 22 patients were children with pink PWS. Follow-up assessment of 40 patients 12 months after treatment revealed an excellent or good result in 74% of adults and 53% of children. The results in adult 'therapeutic failures' was encouraging and CO2 laser therapy can be advised for this group. Two children had a poor result, one with a hypertrophic scar, and treatment in this age group with the CO2 laser should be considered with caution.


Nonisotopic assays for reporter gene activity.
This unit describes two nonisotopic systems for reporter gene activity in cells transfected with the firefly luciferase.


Cell-specific actions of HIV-Tat and morphine on opioid receptor expression in glia.
HIV-1 patients who abuse opiate-based drugs, including heroin and morphine, are at a higher risk of developing HIV dementia. The effects of opiates are mediated predominantly through opioid receptors, which are expressed on glial cells. As HIV-1 infection in the CNS is restricted to glial cells, experiments were designed to measure the cell-specific effects of HIV Tat and morphine exposure on opioid receptor expression in both astrocytes and microglia. Specifically, the cell-type-specific pattern of mu opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR) localization (surface vs. intracellular) and expression of opioid receptor mRNA were determined after exposure to morphine in the presence and the absence of Tat in primary cultured microglia and astrocytes. Data show that morphine treatment caused significantly decreased cell surface expression of opioid receptors in microglia but not in astrocytes. However, morphine treatment in the presence of Tat significantly increased intracellular expression of opioid receptors and prevented morphine-induced cell surface opioid receptor down-regulation in microglia. These findings document that cell surface opioid receptor expression is divergently regulated by morphine in microglia compared with in astrocytes, and further suggest that HIV-Tat could exacerbate opioid receptor signaling in microglia by increasing receptor expression and/or altering ligand-induced trafficking of opioid receptors.