In vivo Firre and Dxz4 deletion elucidates roles for autosomal gene regulation.
Recent evidence has determined that the conserved X chromosome mega-structures controlled by the Firre and Dxz4 loci are not required for X chromosome inactivation (XCI) in cell lines. Here, we examined the in vivo contribution of these loci by generating mice carrying a single or double deletion of Firre and Dxz4. We found that these mutants are viable, fertile and show no defect in random or imprinted XCI. However, the lack of these elements results in many dysregulated genes on autosomes in an organ-specific manner. By comparing the dysregulated genes between the single and double deletion, we identified superloop, megadomain, and Firre locus-dependent gene sets. The largest transcriptional effect was observed in all strains lacking the Firre locus, indicating that this locus is the main driver for these autosomal expression signatures. Collectively, these findings suggest that these X-linked loci are involved in autosomal gene regulation rather than XCI biology.


Prehospital rounds. Hypertension after having a baby.
Peripartum cardiomyopathy is an infrequent form of congestive heart failure. It occurs in one out of every 3,000-15,000 live births. Since there are approximately four million deliveries in the U.S. each year, 250 to 1,350 women will be affected annually.


An estimate of the proportion of colo-rectal and stomach cancers which might be prevented by certain changes in dietary habits.
The colo-rectum and stomach are the 2 sites for which the role of diet in the etiology of cancer is most heavily implicated. Quantitative estimates as to the proportion of cancer deaths attributable to diet vary considerably. This may be partially due to the application of the concept of population attributable risk which has proved a useful yardstick in estimating the public health impact of completely removing an exposure factor under study. This simple concept may well serve in occupational epidemiology, but with more and more risk factors found on a metric scale, or at least characterized on an ordinal scale, extensions should be considered. In this report, a preventable proportion is defined as the excess risk which would be removed if the population exposure distribution were to change ina favorable direction. A simple way of modelling such changes is proposed. This new measure is illustrated with data from 6 case-control studies on colo-rectal or stomach cancer. The results indicate that the proportion of these cancers which may be prevented assuming arbitrary shifts of a single risk factor towards the next lower risk category if populations were to change their dietary habits is in the order of magnitude of 15% to 20%. This figure is much lower, but not necessarily in contradiction to the figures considered for the proportion of cancers attributable to diet.


Borderline personality and weight divergence in adulthood.
Borderline personality disorder (BPD) is an Axis II dysfunction characterized by extremist thinking (i.e., black/white thinking and thinking in absolutes). In keeping with this cognitive style, and based upon our clinical observations, we wondered whether a possible behavioral marker of extremism, weight divergence (i.e., a large difference between lowest and highest weights in adulthood), might be associated with BPD. Among 95 women psychiatric inpatients, we explored lowest adult weight, current weight, and highest adult weight as well as BPD using two self-report measures for the disorder, the borderline personality disorder scale of the Personality Diagnostic Questionnaire-4 (PDQ-4) and the Self-Harm Inventory (SHI). Results indicated statistically significantly correlations between increasing weight divergence and both BPD measures. Further analyses indicated that this relationship was not explained by overall body size or history of binge eating behavior. Findings suggest that, among psychiatric inpatients, weight divergence in adulthood may be a potential indicator of BPD.


Nuclear Magnetic Resonance-Assisted Prediction of Secondary Structure for RNA: Incorporation of Direction-Dependent Chemical Shift Constraints.
Knowledge of RNA structure is necessary to determine structure-function relationships and to facilitate design of potential therapeutics. RNA secondary structure prediction can be improved by applying constraints from nuclear magnetic resonance (NMR) experiments to a dynamic programming algorithm. Imino proton walks from NOESY spectra reveal double-stranded regions. Chemical shifts of protons in GH1, UH3, and UH5 of GU pairs, UH3, UH5, and AH2 of AU pairs, and GH1 of GC pairs were analyzed to identify constraints for the 5' to 3' directionality of base pairs in helices. The 5' to 3' directionality constraints were incorporated into an NMR-assisted prediction of secondary structure (NAPSS-CS) program. When it was tested on 18 structures, including nine pseudoknots, the sensitivity and positive predictive value were improved relative to those of three unrestrained programs. The prediction accuracy for the pseudoknots improved the most. The program also facilitates assignment of chemical shifts to individual nucleotides, a necessary step for determining three-dimensional structure.


Simultaneous coupling of alpha 2-adrenergic receptors to two G-proteins with opposing effects. Subtype-selective coupling of alpha 2C10, alpha 2C4, and alpha 2C2 adrenergic receptors to Gi and Gs.
Coupling of the three alpha 2-adrenergic receptor (alpha 2AR) subtypes to Gi and Gs was studied in membranes from transfected CHO cells. We observed that in the presence of low concentrations of the alpha 2AR agonist UK-14304, alpha 2C10 mediated inhibition of adenylyl cyclase activity, whereas at high concentrations of agonist, alpha 2C10 mediated stimulation of adenylyl cyclase activity. We considered that this biphasic response was due to the coupling of alpha 2C10 to both Gi and Gs. To isolate functional Gs and Gi coupling, cells were treated with pertussis toxin or cholera toxin in doses sufficient to fully ADP-ribosylate the respective G-proteins. Following treatment with cholera toxin, agonists elicited only alpha 2C10-mediated inhibition (approximately 50%) of adenylyl cyclase while after pertussis toxin treatment, agonists elicited only alpha 2C10-mediated stimulation (approximately 60%) of adenylyl cyclase. Incubation of membranes with antisera directed against the carboxyl-terminal portion of Gs alpha blocked this functional alpha 2AR.Gs coupling to the same extent as that found for beta 2AR.Gs coupling. In addition to functional Gs coupling, we also verified direct, agonist-dependent, physical coupling of alpha 2AR to Gs alpha. In agonist-treated membranes, an agonist-receptor-Gs alpha complex was immunoprecipitated with a specific alpha 2C10 antibody, and the Gs component identified by both western blots using Gs alpha antibody, and cholera toxin mediated ADP-ribosylation. Due to the differences in primary amino acid structure in a number of regions of the alpha 2AR subtypes, we investigated whether G-protein coupling was subtype-selective, using UK-14304 and cells with the same alpha 2AR expression levels (approximately 5 pmol/mg). Coupling to Gi was equivalent for alpha 2C10, alpha 2C4, and alpha 2C2: 53.4 +/- 8.8% versus 54.9 +/- 1.0% versus 47.6 +/- 3.5% inhibition of adenylyl cyclase, respectively. In marked contrast, distinct differences in coupling to Gs were found between the three alpha 2AR subtypes: stimulation of adenylyl cyclase was 57.9 +/- 6.3% versus 30.7 +/- 1.1% versus 21.8 +/- 1.7% for alpha 2C10, alpha 2C4, and alpha 2C2, respectively. Thus, alpha 2AR have the potential to couple physically and functionally to both Gi and Gs; for Gi coupling we found a rank order of alpha 2C10 = alpha 2C4 = alpha 2C2, while for Gs coupling, alpha 2C10 greater than alpha 2C4 greater than alpha 2C2.


Adherence to the MIND diet is inversely associated with odds and severity of anxiety disorders: a case-control study.
The association between the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diet, odds, and severity of anxiety disorders (AD) is still unclear. We aimed to investigate whether adherence to MIND diet is associated with odds and severity of AD. The present case-control study carried out on 85 patients who were group matched by gender with 170 healthy subjects. Data for dietary intake was assessed by using a 147-item validated food frequency questionnaire (FFQ). Anthropometric measures were collected using standard methods. The MIND diet score was calculated using FFQ. We assessed anxiety disorder severity using the Generalized Anxiety Disorder-7 (GAD-7) questionnaire. Multivariate odds ratios (OR) with 95% confidence intervals (CI) were used to investigate the association of MIND diet and anxiety disorder. We observed that higher adherence to MIND diet was associated with the lower GAD-7 score (p < 0.001). Individuals in the top category of MIND diet score were 97% less likely to have AD compared with those in the bottom category (OR: 0.03, 95% CI: 0.01, 0.09). There was significant reverse linear association between MIND diet score and AD (β = -3.63, p < 0.001). In conclusion, we provided some evidence indicating negative association between adherence to MIND diet, odds, and severity of AD. Finally, due to the probable preventive role of diet, it is vital to clarify the association between diet and AD through large-scale prospective cohort studies in the future.


Term pregnancy after three trophoblastic disease events.
A case of successful pregnancy following two hydatidiform moles and a choriocarcinoma, treated with the EMA-CO regime, is reported. This is the first reported successful pregnancy after administration of etoposide.


Preparation and experimental research into retrievable rapamycin- and heparin-coated vena cava filters: a pilot study.
The use of retrievable vena cava filters (RVCFs) was once commonplace, but filter retrieval was often very difficult. Most unsuccessful retrieval was due to intimal hyperplasia of the inferior vena cava and in-filter thrombosis. This pilot study aimed to design a drug-eluting RVCF. The hypothesis was that coated drugs could be released continuously to inhibit vena intimal hyperplasia and thrombosis, and thus improve the retrieval rates of RVCFs. Various concentrations of polycaprolactone (PCL)/chloroform solution were made from a mixture of Rapamycin and Heparin according to the quality of PCL. The drug was coated onto the surface of the filters by a process of dipping. In vitro tests were performed to check stability and in vitro drug release. Animals receiving filter implantation were divided into 4 groups, the experimental intervention group (EI), experimental laparotomy group (EL), control intervention group (CI), and control laparotomy group (CL). Filters were retrieved by laparotomy in the EL and CL groups, and by interventional operation in the EI and CI groups at 10, 20 and 30 days after implantation. Pathological endothelia biopsies were performed with wood grain-eosin (HE) staining and immunohistochemical examination, with the proliferating cell nuclear antigen (PCNA) index, and the results were compared between the experimental and control groups. The weight of thrombus within the filters was also measured by scale and compared. The coating concentration that succeeded in completely covering the surface was 0.2 g/ml. There was better coverage by SEM at this concentration, and the coated drugs had no obvious loss after filter release. The drug release curves showed that the amount of Heparin released was more than 50 % at day 1; Rapamycin released little in the first few days, beginning in earnest at 20 to 30 days. The filters were easy to retrieve at 10 days for both groups, while neither could be retrieved at 30 days. However, at 20 days the filter in the EI group could be retrieved with some difficulty, but the filter in the CI group couldn't be removed at all. The pathological examination and immunohistochemical PCNA examination results showed that the use of drug-eluting filters could effectively inhibit endothelial hyperplasia at 10 and 20 days, but was less effective at 30 days. There was no apparent difference in the total weight of blood clots between the experimental and control groups. We successfully conducted a pilot study into preparing Rapamycin- and Heparin-coated RVCFs. In vitro and in vivo tests further proved the possibility of improving the retrieval rates of RVCFs by effectively inhibiting vein endothelial proliferation, but the anticoagulation and antithrombosis effects of Heparin were unsatisfactory.


Mechanisms of neutrophil extracellular trap in chronic inflammation of endothelium in atherosclerosis.
Cardiovascular diseases are a primary cause of morbidity and mortality around the world. In addition, atherosclerosis (AS)-caused cardiovascular disease is the primary cause of death in human diseases, and almost two billion people suffer from carotid AS worldwide. AS is caused by chronic inflammation of the arterial vessel and is initiated by dysfunction of vascular endothelial cells. Neutrophils protect against pathogen invasion because they function as a component of the innate immune system. However, the contribution of neutrophils to cardiovascular disease has not yet been clarified. Neutrophil extracellular traps (NETs) represent an immune defense mechanism that is different from direct pathogen phagocytosis. NETs are extracellular web-like structures activated by neutrophils, and they play important roles in promoting endothelial inflammation via direct or indirect pathways. NETs consist of DNA, histones, myeloperoxidase, matrix metalloproteinases, proteinase 3, etc. Most of the components of NETs have no direct toxic effect on endothelial cells, such as DNA, but they can damage endothelial cells indirectly. In addition, NETs play a critical role in the process of AS; therefore, it is important to clarify the mechanisms of NETs in AS because NETs are a new potential therapeutic target AS. This review summarizes the possible mechanisms of NETs in AS.


Lung transplantation and concomitant cardiac surgery: Is it justified?
Increasing numbers of lung transplant candidates have cardiac conditions that affect their survival after transplantation. Our objective was to determine if patients who undergo concomitant cardiac surgery (CCS) during the lung transplant procedure have similar outcomes, as a cohort of isolated lung transplant recipients. This was a retrospective, observational, matched-cohort analysis. The records of lung transplant recipients who underwent CCS from August 2000 to August 2013 were reviewed. A cohort of isolated lung transplant recipients, matched on the basis of age, lung allocation score, diagnosis, type of procedure, and era, was identified. The primary endpoint of this trial was 5-year survival. The secondary endpoints were primary graft dysfunction, grade III, at 72 hours, intensive care unit and hospital length of stay, and 5-year major adverse cardiac event rates. A total of 120 patients underwent lung transplantation and CCS. Compared with the isolated lung transplant group, the donor, recipient, and operation characteristics were similar. No difference was found in the survival of the 2 groups for up to 5 years, or in the incidence of primary graft dysfunction Grade III at 72 hours, intensive care unit length of stay, invasive ventilation, hospital length of stay, or incidence of 5-year major adverse cardiac events. Lung transplant recipients undergoing CCS have early and midterm clinical outcomes similar to those of isolated lung transplant recipients. Given that this report is the largest published experience, offering cardiac surgery at the time of lung transplantation, to selected patients, remains justified.


Methacholine and physostigmine airway reactivity in asthmatic and nonasthmatic subjects.
Inhalation challenges using methacholine and physostigmine were performed in 3 human asthmatic and 3 nonallergic normal subjects. Plethysmographic measurements of specific airways conductance (Gaw/Vtg) were used to monitor the response. The dose required to produce a 17% fall in Gaw/Vtg was significantly lower in asthmatic subjects than in normal subjects for both physostigmine (p less than 0.0125) and methacholine (p less than 0.05). Moreover, in all subjects the relative airway sensitivity to methacholine correlated with the relative airway sensitivity to physostigmine. Both methacholine and physostigmine are cholinergic agents. Whereas methacholine acts directly at the end organ cholinergic receptor, physostigmine acts by increasing release and decreasing destruction of endogenous acetycholine at the vagal distal innervation. This suggests that the cholinergic airway hyperreactivity characteristic of asthma is a manifestation of end organ hypersensitivity.


[Diagnostic value of assay of brain natriuretic peptide in patients with sepsis of blood-stasis syndrome].
To explore the diagnostic value of brain natriuretic peptide (BNP) level in patients with sepsis of blood-stasis syndrome. The prospective method of clinical diagnostic test and evaluation principles of diagnostic test were applied. One hundred and seventy-four patients with sepsis were divided into two groups: blood-stasis syndrome group and non blood-stasis syndrome group. The levels of serum BNP in two groups were detected. The level of BNP in sepsis patients was related to blood-stasis syndrome (P<0.01). BNP cut-off level was 150 ng/L, sensitivity was 85.3%, specificity was 81%, the maximum value of Youden index was 0.663, and the area under the receiver operating characteristic curve (ROC) value was (0.886+/-0.025). BNP can be used as an objective index of blood-stasis syndrome diagnosis for sepsis, and BNP with boundary value of 150 ng/L is an optimal biological index.


Persian manual therapy method for chronic low-back pain with lumbar radiculopathy; a randomized controlled trial.
Manual therapy is a non-surgical approach for management of musculoskeletal symptoms. This study investigated safety and efficacy of a Persian manual therapy method (Fateh technique) for management of chronic low-back pain (LBP) and radiculopathy. In this controlled trial, 52 eligible patients with chronic LBP and lumbar radiculopathy were randomly assigned into two intervention groups; one received a 16-min soft tissue manipulation for four weekly sessions and did two daily home active exercises. The other group only did the two daily exercises for four weeks. Roland-Morris disability score, Visual Analogue Scale scores of LBP, radiculopathy and paresthesia, and finger-to-floor test result were assessed at the baseline, and in fourth and eighth weeks of trial. Data of 48 participants was analyzed. Distributions of age, sex, and duration of symptoms in two groups were the same. Fateh technique respectively decreased pain, radiculopathy, paresthesia, and disability, by 4.28 [95% confidence interval: 3.36-5.19], 3.85 [2.67-5.03], 1.32 [0.37-2.27], and 4.58 [3.23-5.93] units, and increased body flexibility by 35.42 [6.91-63.92] millimeters. Compared with home exercise, Fateh technique was associated with greater changes in all outcomes. No adverse event has occurred. Fateh technique is safe and effective for management of LBP and radiculopathy in patients without severe progressive symptoms.


Carbon dot-based superhydrophobic modification of a covalent organic framework for oil-in-water emulsion separation.
A super hydrophobic composite is developed for the first time through the non-covalent self-assembly of a hydrophilic covalent organic framework (COF) and amphoteric CDs to achieve highly selective separation of dispersed micro droplets of oil from an oil/water mixture.


Osteopontin: role in immune regulation and stress responses.
Recent research has led to a better but as yet incomplete understanding of the complex roles osteopontin plays in mammalian physiology. A soluble protein found in all body fluids, it stimulates signal transduction pathways (via integrins and CD44 variants) similar to those stimulated by components of the extracellular matrix. This appears to promote the survival of cells exposed to potentially lethal insults such as ischemia/reperfusion or physical/chemical trauma. OPN is chemotactic for many cell types including macrophages, dendritic cells, and T cells; it enhances B lymphocyte immunoglobulin production and proliferation. In inflammatory situations it stimulates both pro- and anti-inflammatory processes, which on balance can be either beneficial or harmful depending on what other inputs the cell is receiving. OPN influences cell-mediated immunity and has been shown to have Th1-cytokine functions. OPN deficiency is linked to a reduced Th1 immune response in infectious diseases, autoimmunity and delayed type hypersensitivity. OPN's role in the central nervous system and in stress responses has also emerged as an important aspect related to its cytoprotective and immune functions. Evidence suggests that either OPN or anti-OPN monoclonal antibodies (depending on the circumstances) might be clinically useful in modulating OPN function. Manipulation of plasma OPN levels may be useful in the treatment of autoimmune disease, cancer metastasis, osteoporosis and some forms of stress.


Challenges of Genetic Data Sharing in African Studies.
Data sharing is a valuable aspect of science and required by most funding bodies and journals. However, the national regulatory guidelines of many African nations do not explicitly allow for broad genetic data sharing. Given these restrictions, there is a need to reconsider these policies and propose creative solutions.


Identification of the outcome distribution and sensitivity analysis under weak confounder-instrument interaction.
Recently, Wang and Tchetgen Tchetgen (2018) showed that the global average treatment effect is identifiable even in the presence of unmeasured confounders so long as they do not modify the instrument's additive effect on the treatment. We use a simple and direct method to show that this no-interaction assumption allows identification of the entire outcome distribution, which leads to multiply robust estimation procedures for nonlinear functionals like the quantile and Mann-Whitney treatment effects. Similarly, we can bound these causal estimands through the outcome distribution in sensitivity analysis against confounder-instrument interaction.


Diffuse Venous Malformations of the Upper Extremity (Bockenheimer Disease): Diagnosis and Management.
Diffuse venous malformations that involve all tissues in the upper limb and ipsilateral chest wall are known as "phlebectasia of Bockenheimer." The authors describe their experience with management of this uncommon vascular anomaly. The authors' Vascular Anomalies Center registry comprised 18,766 patients over a 40-year period. This review identified 2036 patients with venous malformations of the extremities (10.8 percent), of whom only 80 (0.43 percent) had Bockenheimer disease. The authors retrospectively analyzed patient characteristics, diagnostics, treatments, and complications. The venous malformation was first noted at birth or within the first few years of life with slow and gradual progression. Pain was related to engorgement of the limb. Thromboses and phleboliths were common, but diffuse intravascular coagulopathy occurred in only 12 patients (15 percent). Skeletal involvement was demonstrated as lytic lesions, cortical scalloping, osteopenia, and pathologic fractures. Management included compression garments (100 percent), sclerotherapy (27.5 percent), and resection of symptomatic areas in 35 percent of patients. Adjunctive pharmacologic medication was given in 7.5 percent. Following resection, 17 patients (60 percent) had one or more complications: hematoma, wound dehiscence, flap loss, contracture, and psychosis. There were no deaths. Symptoms improved in all patients with useful functional outcomes. The decision to pursue compression, sclerotherapy, pharmacologic treatment, or resection alone or in combination was made by an interdisciplinary team. Although extensive venous malformations cannot be completely ablated, debulking of symptomatic regions, resection of neuromas, and noninvasive treatments improve the quality of life. Despite the bulk and weight of the arm, forearm, and hand, and the ominous appearance on magnetic resonance imaging, these patients remain functional. Therapeutic, V.


Chemical reactivity, molecular electrostatic potential and in-silico analysis on benzimidazole fungicide benomyl.
We are reporting theoretical concepts and biological activity of benomyl using different techniques. The molecular orbital contributions are studied by using Total Density of States (TDOS) analysis. The chemical reactivity of the molecule have been determined with the help of global reactivity descriptors. Molecular electrostatic potential is calculated by the density functional method and predicts the most reactive part in the molecule. In-silico molecular analysis is conducted for Benomyl compound.


Persistent Microembolic Signals in the Cerebral Circulation on Transcranial Doppler after Intravenous Sulfur Hexafluoride Microbubble Infusion.
Microembolic signals (MES) are detectable by transcranial Doppler monitoring and associated with increased risk of first or recurrent ischemic stroke. MES detection can also illuminate stroke etiology and the effect of prophylactic treatment. MES detection cannot accurately distinguish between stroke-related microemboli and ultrasound contrast agents. These agents contain microbubbles and are frequently used in neuro- and cardiovascular diagnostics. We aimed to assess how long after contrast infusion microbubbles are detectable by transcranial Doppler monitoring. Ten healthy volunteers received an intravenous infusion of stabilized sulfur hexafluoride microbubbles (SonoVue®) for 30 minutes. The infusion was followed by continuous unilateral Doppler monitoring (TCD-X, Atys Medical, Soucieu-en-Jarrest, France) for 3.5 hours. MES persisted for 12 to 77 minutes (median 40.5 minutes), and the frequency tended to decrease gradually until cessation. None of the subjects had detectable MES for more than 77 minutes after ultrasound contrast infusion. MES detection with the intent to detect stroke-related microemboli should wait for at least this long after completed infusion.


Stimulation of de novo synthesis of L-phenylalanine ammonia-lyase in relation to phytoalexin accumulation in Colletotrichum lindemuthianum elicitor-treated cell suspension cultures of french bean (Phaseolus vulgaris).
(1) The regulation of the accumulation of the isoflavonoid-derived phytoalexin phaseollin in cell suspension cultures of Dwarf French Bean (Phaseolus vulgaris/ has been investigated. (2) An elicitor preparation from cell walls of Colletotrichum lindemuthianum, the causal agent of anthracnose disease of French bean, caused a marked accumulation of phaseollin in the cultures. The elicitor induced phaseollin accumulation to a level of 60% that obtained with the artificial elicitor autoclaved ribonuclease A and was maximally active at a concentration (weight basis) of at least 50 times lower than required for maximal response to ribonuclease. (3) Elicitor preparations from cell walls of Phytophthora megasperma var. sojae, a fungal pathogen of soybean, and Botrytis cinerea, the common grey mould, were much less effective than the C. lindemuthianum wall-released elicitor. (4) There was a marked but transient increase in the extractable activity of phenylalanine ammonia-lyase, the enzyme catalysing the first reaction in the biosynthesis of phaseollin from L-phenylalanine, in response to the elicitor from C. lindemuthianum. (5) Comparative density labelling with 2H from 2H2O indicated that the elicitor stimulates de novo synthesis of phenylalanine ammonie findings provide the basis of a scheme for elicitor induction of phytoalexin accumulation.


Summary of anti-malarial prophylactic efficacy of tafenoquine from three placebo-controlled studies of residents of malaria-endemic countries.
Tafenoquine is a long half-life primaquine analog being developed for malaria prophylaxis. The US Army recently performed a unified analysis of efficacy in preparation for a regulatory submission, utilizing legacy data from three placebo-controlled studies conducted in the late 1990s and early 2000s. The subjects were residents of Africa who were naturally exposed to Plasmodium falciparum for 12-26 weeks. The prophylactic efficacy of tafenoquine and mefloquine (included in some studies as a comparator) was calculated using incidence density among subjects who had completed the three-day loading doses of study drug, had at least one maintenance dose and had at least one blood smear assessed during the prophylactic period. The three placebo-controlled studies were analysed separately and then in two pooled analyses: one for tafenoquine versus placebo (three studies) and one for tafenoquine and mefloquine versus placebo (two studies). The pooled protective efficacy (PE) of a tafenoquine regimen with three daily loading doses plus weekly maintenance at 200-mg for 10 weeks or longer (referred to as 200-mg weekly hereafter) relative to placebo in three placebo-controlled studies was 93.1 % [95 % confidence interval (CI) 89.1-95.6 %; total N = 492]. The pooled PEs of regimens of tafenoquine 200-mg weekly and mefloquine 250-mg weekly relative to placebo in two placebo-controlled studies (total N = 519) were 93.5 % (95 % CI 88.6-96.2 %) and 94.5 % (95 % CI 88.7-97.3 %), respectively. Three daily loading plus weekly maintenance doses of 50- and 100-mg, but not 25-mg, exhibited similar PEs. The PEs of tafenoquine regimens of a three-day loading dose at 400-mg with and without follow-up weekly maintenance doses at 400-mg were 93.7 % (95 % CI 85.4-97.3 %) and 81.0 % (95 % CI 66.8-89.1 %), respectively. Tafenoquine provided the same level of prophylactic efficacy as mefloquine in residents of Africa. These data support the prophylactic efficacy of tafenoquine and mefloquine that has already been demonstrated in the intended malaria naive population.


Early and sustained expression of latent and host modulating genes in coordinated transcriptional program of KSHV productive primary infection of human primary endothelial cells.
Coordinated expression of viral genes in primary infection is essential for successful infection of host cells. We examined the expression profiles of Kaposi's sarcoma-associated herpesvirus (KSHV) transcripts in productive primary infection of primary human umbilical vein endothelial cells by whole-genome reverse-transcription real-time quantitative PCR. The latent transcripts were expressed early and sustained at high levels throughout the infection while the lytic transcripts were expressed in the order of immediate early, early, and lytic transcripts, all of which culminated before the production of infectious virions. Significantly, transcripts encoding genes with host modulating functions, including mitogenic and cell cycle-regulatory, immune-modulating, and anti-apoptotic genes, were expressed before those encoding viral structure and replication genes, and sustained at high levels throughout the infection, suggesting KSHV manipulation of host environment to facilitate infection. The KSHV transcriptional program in a primary infection defined in this study should provide a basis for further investigation of virus-cell interactions.


NHS-IL12 and bintrafusp alfa combination therapy enhances antitumor activity in preclinical cancer models.
Combinatorial immunotherapy approaches are emerging as viable cancer therapeutic strategies for improving patient responses and outcomes. This study investigated whether two such immunotherapies, with complementary mechanisms of action, could enhance antitumor activity in murine tumor models. The immunocytokine NHS-IL12, and surrogate NHS-muIL12, are designed to deliver IL-12 and muIL-12, respectively, to the tumor microenvironment (TME) to activate NK cells and CD8+ T cells and increase their cytotoxic functions. Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domains of the TGF-β receptor II to function as a TGF-β "trap" fused to a human IgG1 antibody blocking PD-L1. With this dual-targeting strategy, BA enhances efficacy over that of monotherapies in preclinical studies. In this study, NHS-muIL12 and BA combination therapy enhanced antitumor activity, prolonged survival, and induced tumor-specific antitumor immunity. This combination therapy increased tumor-specific CD8+ T cells and induced immune profiles, consistent with the activation of both adaptive and innate immune systems. In addition, BA reduced lung metastasis in the 4T1 model. Collectively, these findings could support clinical trials designed to investigate NHS-IL12 and BA combination therapy for patients with advanced solid tumors.


Role of ApneaGraph® in the Surgery for Obstructive Sleep Apnoea.
To evaluate the utility of ApneaGraph® AG 200 in diagnosing Obstructive Sleep Apnoea (OSA) as compared to Polysomnography, localization of the site of upper airway obstruction, and the success rate of surgery. A prospective study was conducted including fifteen patients of OSA undergoing surgical treatment. All patients underwent sequential overnight ApneaGraph (AG) and Polysomnogram (PSG) before and after 3 months following surgery. The preoperative and post-operative Apnoea-Hypopnoea Index (AHI) values were compared between AG and PSG. The success of surgery was defined as mean reduction in AHI by ≥ 50% and post-operative AHI < 20. The mean preoperative AHI using PSG was 53.7 and using AG was 44.9 (r = 0.83, p = 0.0001). All patients underwent AG-directed site-specific surgery. The mean postoperative AHI using PSG was 15.3 and using AG was 13.8 (r = 0.67, p = 0.0062). There was significant improvement in AHI post-surgery (p < 0.05, AG & PSG). The surgical success was achieved in 93.3%. The median follow-up was 14 months. ApneaGraph is a reliable alternative to PSG to diagnose OSA with an added advantage to localize the site of obstruction, yielding good surgical outcomes.


Comparative Association Mapping Reveals Conservation of Major Gene Resistance to White Pine Blister Rust in Southwestern White Pine (Pinus strobiformis) and Limber Pine (P. flexilis).
All native North American white pines are highly susceptible to white pine blister rust (WPBR) caused by Cronartium ribicola. Understanding genomic diversity and molecular mechanisms underlying genetic resistance to WPBR remains one of the great challenges in improvement of white pines. To compare major gene resistance (MGR) present in two species, southwestern white pine (Pinus strobiformis) Cr3 and limber pine (P. flexilis) Cr4, we performed association analyses of Cr3-controlled resistant traits using single nucleotide polymorphism (SNP) assays designed with Cr4-linked polymorphic genes. We found that ∼70% of P. flexilis SNPs were transferable to P. strobiformis. Furthermore, several Cr4-linked SNPs were significantly associated with the Cr3-controlled traits in P. strobiformis families. The most significantly associated SNP (M326511_1126R) almost colocalized with Cr4 on the Pinus consensus linkage group 8, suggesting that Cr3 and Cr4 might be the same R locus, or have localizations very close to each other in the syntenic region of the P. strobiformis and P. flexilis genomes. M326511_1126R was identified as a nonsynonymous SNP, causing amino acid change (Val376Ile) in a putative pectin acetylesterase, with coding sequences identical between the two species. Moreover, top Cr3-associated SNPs were further developed as TaqMan genotyping assays, suggesting their usefulness as marker-assisted selection (MAS) tools to distinguish genotypes between quantitative resistance and MGR. This work demonstrates the successful transferability of SNP markers between two closely related white pine species in the hybrid zone, and the possibility for deployment of MAS tools to facilitate long-term WPBR management in P. strobiformis breeding and conservation.


Static analysis of composite beams on variable stiffness elastic foundations by the Homotopy Analysis Method.
New analytical solutions for the static deflection of anisotropic composite beams resting on variable stiffness elastic foundations are obtained by the means of the Homotopy Analysis Method (HAM). The method provides a closed-form series solution for the problem described by a non-homogeneous system of coupled ordinary differential equations with constant coefficients and one variable coefficient reflecting variable stiffness elastic foundation. Analytical solutions are obtained based on two different algorithms, namely conventional HAM and iterative HAM (iHAM). To investigate the computational efficiency and convergence of HAM solutions, the preliminary studies are performed for a composite beam without elastic foundation under the action of transverse uniformly distributed loads considering three different types of stacking sequence which provide different levels and types of anisotropy. It is shown that applying the iterative approach results in better convergence of the solution compared with conventional HAM for the same level of accuracy. Then, analytical solutions are developed for composite beams on elastic foundations. New analytical results based on HAM are presented for the static deflection of composite beams resting on variable stiffness elastic foundations. Results are compared to those reported in the literature and those obtained by the Chebyshev Collocation Method in order to verify the validity and accuracy of the method. Numerical experiments reveal the accuracy and efficiency of the Homotopy Analysis Method in static beam problems.


Scavenging of chlorpromazine cation radical by ascorbic acid or glutathione.
The report presented here demonstrates that scavenging of chlorpromazine cation radical (an absorption maximum = 530 nm) by ascorbic acid or glutathione can be kinetically and stoichiometrically analyzed at pH 1.5 but not at pH 3.0 and 6.0 using a conventional absorption spectrophotometer. The cation radical decays spontaneously about 10 and 200 times faster at pH 3.0 and 6.0, respectively, than at pH 1.5. At pH 1.5, ascorbic acid scavenges the cation radical faster than glutathione does, and the following different scavenging mechanisms are postulated from the above kinetic and stoichiometric analysis. The reaction of the cation radical with ascorbic acid is second order. The ascorbic acid free radical, which decays mainly by dismutation, is generated by the bimolecular reaction. In the case of glutathione, on the other hand, about 70% of the scavenged cation radical disappears through free radical chain reactions that glutathione thiol anion and glutathione free radical probably initiate. The remaining (about 30%) disappears by conjugation with glutathione. It may be due to relative nonreactivity of ascorbic acid free radical that free radical chain reactions, found commonly in radical chemistry, do not occur in the scavenging reaction by ascorbic acid. Based on the above results, the physiological scavenging mechanisms of the cation radical by the two reducing substances are discussed briefly.


[Gastrointestinal parasitic fauna of cats in the cities of Bologna, Florence and Milan].
The results of a parasitological survey carried out on 116 cats found dead in Bologna, Firenze and Milano was reported. The parasites identified were: Toxocara cati (49.1%); Toxascaris leonina (3.4%); Ancylostoma tubaeforme (9.5%); Ollulanus tricuspis (3.4%); Dipylidium caninum (41.4%); Taenia taeniaeformis (11.2%); Mesocestoides lineatus (1.7%); Spirometra sp. (0.9%); Coccidia (12.9%). The autopsies' results were compared with coprological ones in order to assess their reliability.


A functional analysis of gestural behaviors emitted by young children with severe developmental disabilities.
Many children with severe developmental disabilities emit idiosyncratic gestures that may function as verbal operants (Sigafoos et al., 2000). This study examined the effectiveness of a functional analysis methodology to identify the variables responsible for gestures emitted by 2 young children with severe developmental disabilities. Potential verbal operants for each participant were functionally analyzed using a multi-element design. Results indicate that gestures were maintained by access to tangible items or the delivery of information about novel stimuli. This study extends the use of functional analysis to identify conditions under which children with developmental disabilities emit gestural verbal behavior.


Total mercury and methylmercury in rice: Exposure and health implications in Bangladesh.
Rice methylmercury (MeHg) contamination has attracted global attention, especially in countries where rice is considered a staple food. The daily rice intake rate in Bangladesh ranks first in the world; however, no attention has been paid to rice MeHg contamination in Bangladesh. Total Hg (THg) and MeHg concentrations of commercial rice (n = 172) from Bangladesh were first analyzed to accurately evaluate both rice MeHg and inorganic Hg (IHg) exposure in different age-gender groups of Bangladeshis. The corresponding adverse health impacts and associated economic loss were also assessed. The results showed that THg concentration in all samples ranged from 0.42 to 14.4 ng/g, with an average of 2.48 ± 1.41 ng/g, while the MeHg concentration ranged from 0.026 to 7.47 ng/g, with an average of 0.83 ± 0.60 ng/g. The highest average MeHg and IHg were both recorded in rice from Chittagong. The highest mean MeHg and IHg exposures were observed in 2-5 years-old group and were 16.2% of the reference dose (RfD) of 0.1 μg/kg/day for MeHg and 7.09% of the provisional tolerable weekly intake (PTWI) of 0.571 μg/kg/day for IHg. Surprisingly, MeHg exposure of the 2-5 year-old children could be up to 93.7% of the RfD at a high percentile (P99.9). The total intelligence quotient reduction caused by rice MeHg exposure could be 54700 points, and the associated economic loss is approximately 42.5 million USD. To avoid high rice MeHg exposure, it was suggested that diet structure be improved. More attention should be paid to residents with long-term rice MeHg exposure, especially children in the 2-5 year-old group.


Left Ventricular Dyssynchrony by Three-Dimensional Echocardiography: Current Understanding and Potential Future Clinical Applications.
Left ventricular mechanical dyssynchrony is an important prognostic factor for patients with symptomatic systolic heart failure and has emerged as a therapeutic target for cardiac resynchronization therapy (CRT). However, approximately one-third of patients fail to improve after CRT based on current guideline recommendations and electrocardiographic criteria. Two-dimensional echocardiography and tissue Doppler-based techniques have shown variable results in assessment of left ventricular (LV) dyssynchrony and have limited value in clinical practice. Three-dimensional echocardiography (3DE) is an appealing novel imaging modality that has been recently used in quantitative evaluation of global and regional LV function. There is accumulating evidence that 3DE measurement of LV systolic dyssynchrony index may potentially play a role in predicting the short- and long-term response to CRT and further improve patient selection for CRT. New developments in 3DE speckle tracking technique and strain analysis may further improve the accuracy of LV mechanical dyssynchrony assessment in this population. In addition, recent studies suggest that mechanical dyssynchrony is present in patients with LV hypertrophy and diastolic heart failure. Three-dimensional echocardiographic assessment of dyssynchrony may aid in diagnosis and in predicting long-term outcome in these patients. We will summarize current understanding of 3DE techniques and parameters in assessment of LV mechanical dyssynchrony in the population of patients with systolic heart failure, LV hypertrophy, and diastolic heart failure. A number of the novel 3DE techniques described in this review are early in their stage of development, and they will continue to evolve and need further testing in large multicenter studies.


Supramolecular hydrogels based on cellulose for sustained release of therapeutic substances with antimicrobial and wound healing properties.
A multifaceted hydrogel-based formulation was reported. The hydrogel was prepared by crosslinking cellulose and substituted chalcone. Moreover, the formulation was conjugated with carbon nanotubes with the aim of increasing the loading amount of bioactive compounds such as allantoin, dexpanthenol, resveratrol and linezolid. The hydrogel formation was confirmed by swelling tests, FT-IR spectroscopy, thermogravimetric analysis and SEM. The hydrogel showed an improved release rate of therapeutic substances, exhibiting a simultaneous and coordinated release according to the chromatographic studies. The efficacy of drug release was confirmed by wound closure and in vivo wound healing studies that showed promising healing results. The antibacterial assays demonstrated that the sustained release of linezolid tends to be very effective. In conclusion, a multifaceted formulation based on carbon nanotube-containing cellulose-chalcone was developed that can potentially be utilized in treating complex wounds owing to its improved wound healing properties and prevention of potential infections.


Impact of elexacaftor/tezacaftor/ivacaftor on fat-soluble vitamin levels in children with cystic fibrosis.
Children with cystic fibrosis are at risk of fat-soluble vitamin deficiency. CFTR modulators positively effect nutritional status. This study aimed to assess changes in serum vitamins A, D & E after starting ETI therapy to ensure levels were not abnormally high. Retrospective review of annual assessment data over 3½ years, before and after starting ETI in a specialist paediatric CF centre, including vitamin levels. 54 eligible patients were included, aged 5-15 yrs (median age 11.5). Median time to post measurements was 171 days. Median vitamin A was increased (1.38 to 1.63 µmol/L, p<0.001). Three patients (6%) had high vitamin A post-ETI, compared with none at baseline; and 2 (4%) had low levels compared to 4 (8%) at baseline. No changes in vitamins D&E. This study found increased vitamin A, sometimes to high levels. We recommend testing levels within 3 months of starting ETI.


The mode of administration of total parenteral nutrition and nature of lipid content influence the generation of peroxides and aldehydes.
The absence of light protection of neonatal total parenteral nutrition (PN) contributes to the generation of 4-hydroxynonenal and peroxides. 4-Hydroxynonenal is suspected to be involved in PN-related liver complications. To find a practical modality to reduce 4-hydroxynonenal in PN and assess in vivo the impact of PN containing low 4-hydroxynonenal concentration. Six modalities of delivering PN were compared for the in vitro generation of peroxides and 4-hydroxynonenal: 1) MV-AA-L: light-protected (-L) solution containing multivitamin (MV) mixed with amino acids + dextrose (AA); 2) MV-AA+L: MV-AA without photo-protection (+L); 3) MV-LIP+L: MV mixed with lipid emulsion (LIP). LIP was a) Intralipid20%(®) or b) Omegaven(®). Hepatic markers of oxidative stress (glutathione, F(2α)-isoprostanes, GS-HNE) and inflammation (mRNA of TNF-α and IL-1) were measured in newborn guinea pigs infused during 4-days with MV-AA+L compounded with Intralipid20%(®) or Omegaven(®). Hydroperoxides and 4-hydroxynonenal were the lowest in MV-AA-L and the highest in MV-LIP+L. MV-AA+L with Omegaven(®) was associated with the lowest levels of markers of oxidative stress and inflammation. Compared to Intralipid20%(®), Omegaven(®) reduces oxidative stress associated with PN and prevents liver inflammation. These findings offer an alternative strategy to light protection of PN, which in the clinical setting is a cumbersome modality.


Hydronephrosis in rats associated with postnatal exposure to a fatty acid oxidation inhibitor.
Methyl palmoxirate, an inhibitor of long-chain fatty acid oxidation, was administered by gavage (0, 1, 5, or 20 mg/kg/day) to female rats over the last third of gestation and throughout lactation. Weight gain (mid- and high-dosage group) and survivability (high-dosage group) were significantly (p less than or equal to 0.05) reduced in offspring of methyl palmoxirate-treated dams as compared to control offspring. Mid- and high-dosage male offspring found dead after Day 4 of lactation exhibited grossly distended bladders and renal pelves. A dosage-related increased incidence of dilated renal pelves was observed in both sexes at necropsy of 21-day-old mid- and high-dosage group pups. Microscopic examination of the urinary tracts of a number of affected pups revealed renal parenchymal atrophy and urethral obstruction. Drug disposition studies indicated lactating pups were exposed to significant amounts of methyl palmoxirate via mammary secretions. Cross-fostering experimentation suggested that some of the adverse effects observed in offspring were due to lactational, rather than in utero, exposure.


Disparities in vulnerability to complications from COVID-19 arising from disparities in preexisting conditions in the United States.
The COVID-19 pandemic has magnified U.S. health disparities. Though disparities in COVID-19 hospitalization by race-ethnicity are large, disparities by income and education have not been studied. Using an index based on preexisting health conditions and age, we estimate disparities in vulnerability to hospitalization from COVID-19 by income, education, and race-ethnicity for U.S. adults. The index uses estimates of health condition and age effects on hospitalization for respiratory distress prior to the pandemic validated on COVID-19 hospitalizations. We find vulnerability arising from preexisting conditions is nearly three times higher for bottom versus top income quartile adults and 60 % higher for those with a high-school degree relative to a college degree. Though non-Hispanic Blacks are more vulnerable than non-Hispanic Whites at comparable ages, among all adults the groups are equally vulnerable because non-Hispanic Blacks are younger. Hispanics are the least vulnerable. Results suggest that income and education disparities in hospitalization are likely large and should be examined directly to further understand the unequal impact of the pandemic.


A pooled analysis to evaluate results of capsule endoscopy trials.
Capsule endoscopy is a new tool in the evaluation of the small intestine. To speed evaluation and acceptance of this technology, the manufacturer (Given Imaging Ltd, Yoqneam, Israel) funded several trials. The data from these trials were collected at a central repository using a standardized reporting tool. Presentation of this data to the US Food and Drug Administration (FDA) in July 2003 led to the removal of the adjunctive term with regard to indication for capsule endoscopy, recognizing that the method is of independent importance for evaluating the small bowel. The aim of the present study was to combine the data from several capsule trials to help determine the yield and miss rate of capsule endoscopy for different diseases, compared with alternative diagnostic modalities. Capsule studies were identified from a master database of funded studies. Studies were included in the pooled analysis if they reported a prospective comparison with another modality for evaluation of the small intestine. 32 studies with a total of 691 patients were found in the master database, of which 24 studies, representing 530 patients, met inclusion criteria and were entered into the pooled analysis. Prior to study entry, patients had undergone a mean of 6.77 diagnostic procedures, without findings. Of these 24 studies, 14 (involving 310 patients) were categorized as "bleeding" studies, and 10 studies (220 patients) as "nonbleeding small-bowel disorders" studies. The comparison procedure was push enteroscopy in 300 patients (in 45 for nonbleeding disorders), small-bowel series in 140 patients (in 125 for non-bleeding disorders), and colonoscopy with ileoscopy in 90 patients (50 for nonbleeding disorders). Overall analysis per patient showed new findings from capsule endoscopy in 50 % of patients; 17 % had new findings from the comparison method; in 22 % there were similar findings; and in 11 % there were no findings. A total of 1349 instances of disease were identified in the 530 examinations. Capsule endoscopy solely detected 87 % of the disease instances, while the comparison method solely detected 13 %. The yield for push enteroscopy alone was 14.8 %, for small-bowel series it was 9.9 %, and for colonoscopy it was 13.2 %. Capsule endoscopy missed 146 disease instances for a miss rate of 10 %; 989 were missed by the comparison methods for a miss rate of 73 %; and 214 were detected by both methods. Capsule endoscopy is the state of the art method for noninvasive detection of small-bowel disease.


Retinoblastoma (Rb) protein upregulates expression of the Ifi202 gene encoding an interferon-inducible negative regulator of cell growth.
Studies have indicated that ectopic expression of p202, an interferon (IFN)-inducible retinoblastoma (Rb)-binding protein, in cultured cells retards cell proliferation and modulates cell survival. Consistent with a role of p202 in cell cycle regulation, levels of p202 increase in cells arrested in the G0/G1 phase of cell cycle after withdrawal of serum growth factors. However, a role for p202 in cell growth arrest remains to be defined. Moreover, it remains unclear how levels of p202 are upregulated during the cell growth arrest. Here, we report that Rb upregulates expression of Ifi202 gene. We found that basal as well as IFN-induced levels of p202 were significantly higher in wild-type (Rb(+/+)) mouse embryonic fibroblasts (MEFs) than isogenic Rb(-/-) MEFs. Consistent with the regulation of Ifi202 gene by Rb, expression of functional Rb, but not a pocket mutant of it, stimulated the activity of a reporter whose expression was driven by the 5'-regulatory region of Ifi202 gene. Importantly, the stimulation by Rb was dependent, in part, on a JunD/AP-1 DNA-binding site present in the 5'-regulatory region of the Ifi202 gene. Moreover, basal levels of p202 were significantly higher in wild-type (JunD(+/+)) than isogenic JunD(-/-) MEFs. Additionally, we found that increased expression of p202 potentiated the Rb-mediated inhibition of cell growth and mutations in the Rb-binding motif (LxCxE) of p202 significantly reduced cell survival. Together, our observations support the idea that the transcriptional activation of Ifi202 gene by Rb/JunD may be important for the regulation of cell growth and survival.


A verified report of spurious programming: a case study.
A case of unintentional misprogramming is described in which a DDDR pacemaker, programmed to the VVIR mode, reverted to the originally programmed parameters and mode. The misprogramming requires that a particular sequence of steps be followed and has been verified by the manufacturer. This misprogramming may be clinically significant and can be reproduced in an entire family of current pacemakers based on the same software platform.


High-performance liquid chromatographic separation and quantification of alanopine and strombine in crude tissue extracts.
A method for the separation and quantification of the levels of alanopine and strombine in neutralized, perchloric acid extracts of tissues of marine invertebrates is presented. The method is based on high-performance liquid chromatographic (HPLC) separation, postcolumn derivatization using o-phthaldialdehyde and sodium hypochlorite, and subsequent fluorometric detection. Isocratic separation results in the rapid elution of alanopine and strombine, with elution times of 4.7 and 5.4 min, respectively. The sensitivity of this method is in the range 50-250 pmol. However, the fluorometric detection approach provides the capability for even greater sensitivity.


Five-year results of 5-fluorouracil augmented needling revision of failing blebs.
To report the 5-year intraocular pressure (IOP) outcomes of patients requiring a 5-fluorouracil (5-FU) needling revision compared to a matched sample. Forty eyes receiving 5-FU bleb needling revision were matched to 40 patients not needled. IOP was recorded preoperatively and annually to 5 years. The main outcome measure was surgical success: IOP control without medications or surgery. Thirty-two patients with 5-FU needling revision (80.0%) required anti-glaucoma medication postoperatively versus 28 control patients (70%) (P > .05). Thirty-two patients with 5-FU needling revision were complete or qualified successes compared to 36 control patients (P = .34). Eight patients with 5-FU needling revision (20%) had a reoperation versus 4 control patients (10%) (P > .05). 5-FU needling revision can produce long-term IOP control levels similar to those who did not require the procedure. No statistically significant differences between the two groups was seen in either the use of medications or further surgery.


Defining the polyposis/colorectal cancer phenotype associated with the Ashkenazi GREM1 duplication: counselling and management recommendations.
Hereditary mixed polyposis is a genetically heterogeneous, autosomal dominant condition with adenomatous, hyperplastic and juvenile polyps. We conducted a comprehensive clinical evaluation of a large Ashkenazi Jewish family with this phenotype and performed extensive genetic testing. As seen in one previous report, a 40 kb duplication upstream of GREM1 segregated with the polyposis/colon cancer phenotype in this kindred. Our study confirms the association of GREM1 with mixed polyposis and further defines the phenotype seen with this mutation. This gene should be included in the test panel for all Jewish patients with mixed polyposis and may be considered in any Ashkenazi patient with unexplained hereditary colon cancer when mutations in other hereditary colon cancer genes have been ruled out.


R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study.
The role of re-treatment with rituximab in aggressive B-cell lymphomas still needs to be defined. This study evaluated the influence of prior exposure to rituximab on response rates and survival in patients with diffuse large B-cell lymphoma treated with rituximab plus etoposide, cytarabine, cisplatinum and methylprednisolone (R-ESHAP). We retrospectively analyzed 163 patients with relapsed or refractory diffuse large B-cell lymphoma who received R-ESHAP as salvage therapy with a curative purpose. Patients were divided into two groups according to whether rituximab had been administered (n=94, "R+" group) or not (n=69, "R-" group) prior to R-ESHAP. Response rates were significantly higher in the R- group in the univariate but not in the multivariate analysis. In the analysis restricted to the R+ group, we observed very low complete remission and overall response rates in patients with primary refractory disease (8% and 33%, respectively), as compared to those in patients who were in first partial remission (41% and 86%) or who had relapsed disease (50% and 75%) (p<0.01 in both cases). Overall, 60% and 65% of patients in the R+ and R- groups, respectively, underwent stem-cell transplantation after the salvage therapy. With a median follow-up of 29 months (range, 6-84), patients in the R+ group had significantly worse progression-free survival (17% vs. 57% at 3 years, p<0.0001) and overall survival (38% v 67% at 3 years, p=0.0005) than patients in the R- group. Prior exposure to rituximab was also an independent adverse prognostic factor for both progression-free survival (RR: 2.0; 95% CI: 1.2-3.3, p=0.008) and overall survival (RR: 2.2; 95% CI: 1.3-3.9, p=0.004). R-ESHAP was associated with a high response rate in patients who were not refractory to upfront rituximab-based chemotherapy. However, the survival outcome was poor for patients previously exposed to rituximab, as compared to in those who had not previously been treated with rituximab.


Metronomic and metronomic-like therapies in neuroendocrine tumors - Rationale and clinical perspectives.
Metronomic therapy is characterized by the administration of regular low doses of certain drugs with very low toxicity. There have been numerous debates over the empirical approach of this regimen, but fewest side effects are always something to consider in order to improve patients' quality of life. Neuroendocrine tumors (NETs) are rare malignancies relatively slow-growing; therefore their treatment is often chronic, involving several different therapies for tumor growth control. Knowing that these tumors are highly vascularized, the anti-angiogenic aspect is highly regarded as something to be targeted in all patients harboring NETs. Additionally the metronomic schedule has proved to be effective on an immunological level, rendering this approach as a multi-targeted therapy. Rationalizing that advanced NETs are in many cases a chronic disease, with which patients can live for as long as possible, a systemic therapy with regular low doses and a very low toxicity is in many cases a judicious manner of pursuing stabilization. Metronomic schedule is usually correlated with chemotherapy in oncology, but other therapies, such as radiotherapy and biotherapy can be delivered in a metronomic like manner. This review describes clinical trials and case series involving metronomic therapies alone or in combination in patients with advanced NETs. Nowadays level of evidence about metronomic therapy in NETs is quite low, therefore future prospective clinical studies are needed to validate the metronomic approach in specific clinical settings.


Cysteamine and prostaglandin F2 beta stimulate rat gastric mucin release.
Gastric mucin glycoproteins form an adherent gel over the surface epithelium that is thought to protect the stomach against chemical and physical damage. The purpose of this study was to measure the release of mucin glycoproteins from rat stomach after treatment with cysteamine and prostaglandin F2 beta, two structurally unrelated drugs that have been shown to protect the stomach against the noxious effects of alcohol and other damaging agents. Gastric mucin was separated into soluble (washout) and insoluble (adherent) phases before colorimetric quantitation of total mucin, protein-bound hexose, and sialic acid. Cysteamine produced a dose-dependent increase in release of soluble and gel mucin. Prostaglandin F2 beta caused a dose-dependent release of hexose-containing mucin but had no effect on sialic acid-containing glycoproteins. Sepharose 4B chromatography of both the soluble and adherent mucus revealed that greater than 90% was a high molecular weight glycoprotein fraction. N-Ethylmaleimide, a known inhibitor of cytoprotection by cysteamine, had no effect on mucin secretion. Similarly, indomethacin inhibited mucin secretion by cysteamine but did not significantly influence cytoprotection. Thus the secretion of mucin by cytoprotective agents is unlikely by itself to explain the ability of the stomach to resist chemical or physical damage.


Induction of lymphangiogenesis through vascular endothelial growth factor-C/vascular endothelial growth factor receptor 3 axis and its correlation with lymph node metastasis in nasopharyngeal carcinoma.
The contribution of the lymphatic system to tumor metastasis is being increasingly appreciated through studies of human cancers. As the biological behavior of nasopharyngeal carcinoma (NPC) depends on its nodal status, patients with advanced nodal status show a higher tendency toward a poor outcome. Here, we examined the role of lymphangiogenesis on lymphatic spread of NPC. We also evaluated the involvement of vascular endothelial growth factor (VEGF)-C/VEGF receptor 3 (VEGFR3) signaling pathway on lymphangiogenesis in NPC. Furthermore, we tested whether Epstein-Barr virus (EBV)-latent membrane protein (LMP) 1 induces VEGF-C. Forty-one patients with NPC were evaluated for expressions of VEGF-C and its receptor, VEGFR3, and LMP1 proteins and lymphatic vessel counts (LVC) highlighted by anti-podoplanin employing immunohistochemistry. The VEGF-C induction by LMP1 was then tested with Western blotting and enzyme-linked immunosorbent assay in vitro. The LVC and VEGF-C expression were significantly higher in cases with advanced regional lymph node metastasis (N2,3) than those with no or limited lymph node involvement (N0,1) (p=0.0380 and p=0.0109, respectively). In VEGF-C/VEGFR3-positive cases, the LVC were significantly increased compared with VEGF-C/VEGFR3-negative cases (p=0.0007). However, LMP1 expression did not show significant associations with LVC and VEGF-C-expression scores (p=0.1210 and p=0.1324, respectively). Induction of VEGF-C protein by LMP1 was not detected in vitro. These results suggest the involvement of the VEGF-C/VEGFR3 axis in the induction of lymphangiogenesis which results in lymphatic spread of NPC. However, EBV-LMP1 was not associated with the mechanism.


Kidney cancer.
In the USA, the incidence of kidney cancer has increased 43% since 1973. The risk of the disorder is higher in men than in women and increases with age. The von Hippel-Lindau tumour-suppressor gene is inactivated in over 75% of sporadic cases. Metastatic disease is present in 20-30% of patients at diagnosis. Early-stage kidney cancer is treated with a radical nephrectomy, but under certain circumstances a partial nephrectomy may be done. Tumour thrombus into the vena cava or right atrium requires thoracotomy and hypothermic circulatory arrest for successful removal of the tumour, but should not be done if extensive nodal or frank metastatic disease is present. Interleukin-2 is the systemic therapy of choice for metastatic disease at present, with long-term relapse-free survival of 5-8%. Several treatments including anti-angiogenesis drugs, cyclin-dependent kinase inhibitors, and differentiating agents are being actively investigated. Fluorouracil has a 10-15% response rate, and surgical excision of isolated metastases should always be considered. Therapy for metastatic renal cancer remains inadequate, but recent developments in basic and clinical research suggest future improvement.


Molecular origin of the cation selectivity in OmpF porin: single channel conductances vs. free energy calculation.
Ion current through single outer membrane protein F (OmpF) trimers was recorded and compared to molecular dynamics simulation. Unidirectional insertion was revealed from the asymmetry in channel conductance. Single trimer conductance showed particularly high values at low symmetrical salt solution. The conductance values of various alkali metal ion solutions were proportional to the monovalent cation mobility values in the bulk phase, LiCl<NaCl<KCl<RbCl approximately CsCl, but the conductance differences were quantitatively larger than conductivity differences in bulk solutions. Selectivity measurements at low concentration showed that OmpF channels favored permeation of alkali metal ions over chloride and suggested size preference for smaller cations. These results suggest that there are specific interactions between the permeating cation and charged residues lining the channel walls. This hypothesis was supported by computational study which predicted that monovalent cations bind to Asp113 at low concentration. Here, free energy calculations revealed that the affinity of the alkali metal ions to its binding site increased with their atomic radii, Li(+) approximately Na(+)<K(+) approximately Rb(+) approximately Cs(+). A detailed inspection of both experimental and computational results suggested that stronger binding at the central constriction of the channel increases the translocation rate of cations under applied voltage by increasing their local concentration relative to the bulk solution.


Iron content and bioavailability in rice.
Iron deficiency is probably the most widespread micronutrient deficiency in humans. Since rice is the main staple food for more than half of the global population, improving the iron content and bioavailability in rice is a perspective and an effective way to alleviate or even solve this problem. The present paper evaluates the iron content in different cereal foods (black rice, rice, red rice, sticky rice and millet) and different rice seeds as well as in the milling products, and the iron bioavailability of different forms. The data show that the iron content in black rice is higher than in the other rice types, and in rice chaff and husk the content is still fairly high. However, the iron content in rice and fine rice, which are the people's main staple food, is fairly low. As to the bioavailability of iron, it is fairly low in vegetable foods, almost at the level of 10%. Several methods have been applied to improve iron content and bioavailability in rice seed. Apart from breeding and genetic engineering, biochemical and physical approaches have frequently been used as prospective methods to regulate iron content and bioavailability in rice grains.


Use of procedure specific preoperative warm-up during surgical priming improves operative outcomes: A systematic review.
Preoperative warm-up in preparation for surgery is a technique used in recognition of similarities between surgeons and performance based professionals. The aim of this review was to evaluate the use of simulation-based preoperative warm-up on surgical performance in the operating room and its impact on both clinical and patient outcomes. A systematic review of the literature was carried out in accordance with PRISMA guidelines between August-September 2021. In total 15 studies were retrieved. Seven studies across general surgery, urology, and vascular surgery used a procedure specific warm-up, with significant improvement in operative performance, rate of errors, radiological and patient-based outcomes. Variables including level of experience and specialty appeared to have no impact on the merits of preoperative warm-up demonstrated. While heterogeneity in the benefit of generic warm-up procedures was noted, procedure specific warm-up methods consistently resulted in significantly better operative outcomes.


Subphrenic abscess simulating metastatic carcinoma.
Subphrenic abscess is reported in two patients, one previously operated on for pancreatic carcinoma and the other for clear cell carcinoma of the left kidney. The subphrenic abscess presented with cachexia and low grade fever six months and one year after surgery. Metastatic carcinoma was erroneously diagnosed in both patients. Despite massive antibiotic treatment, both patients succumbed to sepsis. Because of the inherent diagnostic challenge, delineation of a subphrenic abscess in cancer patients without clear-cut evidence of a metastatic spread is crucial.


Fetal risk in delivery with the Shute parallel forceps: analysis of 1,503 forceps deliveries.
A total of 1,503 vaginal deliveries with the Shute parallel forceps during a 10 year period are analyzed as to the risk of instrumental damage. In this series, 35 infants died intrapartum or neonatally. Eliminating all deaths from unrelated causes, three remain in which the forceps could possibly have been implicated. Investigation of these, however, revealed in each case the presence of other concomitant and potentially lethal factors, none of which could be completely ruled out as the primary cause of fetal death. Each of the three cases is discussed in detail. We conclude from our series that the Shute forceps is useful in the delivery of premature infants, but should be employed for this maneuver only by very experienced operators. In these cases, midforceps should be performed only for critical indications. The risk of damage with parallel forceps deliveries from the pelvic floor is minimal if decision for operation is based on cardiotocographic criteria, and under favorable degrees of oxygenation. In the delivery of the immature infants, the parallel forceps can, in fact, hardly be superseded by any other instrument because of its unique controlled protection of the fragile fetal head from even the pressures of the birth canal. Delivery with the Shute forceps can be performed effectively under pudendal block or local infiltration anesthesia.


Revisiting the bilingual lexical deficit: The impact of age of acquisition.
Whereas the cognitive advantages brought about by bilingualism have recently been called into question, the so-called 'lexical deficit' in bilinguals is still largely taken for granted. Here, we argue that, in analogy with cognitive advantages, the lexical deficit does not apply across the board of bilinguals, but varies as a function of acquisition trajectory. To test this, we implement a novel methodological design, where the variables of bilingualism and first/second language status have been fully crossed in four different groups. While the results confirm effects of bilingualism on lexical proficiency and processing, they show more robust effects of age of acquisition. We conclude that the traditional view of the linguistic costs of bilingualism need to give way to a new understanding of lexical development in which age of acquisition is seen as a major determinant.


An evaluation of McCoy balloon laryngoscopy in patients with moderate-to-major endotracheal intubation difficulty.
We hypothesized that combined McCoy-balloon laryngoscopy may facilitate airway management relative to McCoy or balloon laryngoscopy. In 10 anesthetized/paralyzed patients with prior intubation difficulty scale scores of >5, McCoy-balloon laryngoscopy versus conventional/balloon/McCoy laryngoscopies resulted in greater laryngeal aperture exposure (2.3 +/- 0.6 versus 0.6 +/- 0.2/1.4 +/- 0.4/1.5 +/- 0.6 cm2, respectively), lower intubation difficulty scale score (0.00 (0.00-0.00) versus 6.00 (6.00-8.25)/1.50(0.00-4.00)/2.00(0.75-5.00), respectively, median [interquartile range]), and 9%-74% shorter time to intubation confirmation (P < 0.05-0.001 for all). Balloon and McCoy laryngoscopies improved laryngoscopic/intubating conditions relative to conventional laryngoscopy. In patients with moderate-to-major conventional airway management difficulty, McCoy-balloon laryngoscopy further improves laryngoscopic/intubating conditions. This study shows that, in patients with moderate-to-major conventional airway management difficulty, combined McCoy-balloon laryngoscopy results in improved laryngoscopic/intubating conditions when compared with the conventional, McCoy, and balloon laryngoscopic techniques. McCoy-balloon laryngoscopy combines the merits of McCoy and balloon laryngoscopy and can be recommended for patients with moderate-to-major intubation difficulty.


Epidemiology and clinical characteristics of parainfluenza virus 3 outbreak in a Haemato-oncology unit.
We describe molecular investigations of a large hospital outbreak of parainfluenza virus type 3 (PIV3), in which 32 patients became infected. We outline infection control measures that successfully limited further spread of PIV3 in a Haemato-oncology unit. Clinical retrospective review of infected haemato-oncology patients was undertaken. PIV3 haemagglutinin sequences from each case (n = 32) and local epidemiologically unlinked controls (n = 53) were compared to identify potential linkage. PIV3-infected patients presented with upper (n = 18) and lower (n = 11) respiratory tract infections, 3 showed pyrexia only and one was asymptomatic. All symptomatic patients received antibiotics; bacterial co-infection was confirmed in eleven patients. PIV3 infections were associated with lower mortality than documented previously; three of the PIV3-infected patients died (3/32; 9%). All deaths were associated with relapsed malignancies, and PIV3 was not believed to be the primary cause of death in any of these patients. Sequences from 27 cases clustered closely together, consistent with nosocomial infections from PIV3 circulating within the ward. Factors favouring transmission were high patient turnaround between the day treatment unit and in-patient ward, and limited isolation facilities for immunocompromised and infected patients, especially within the day treatment unit. New infections reduced to baseline levels three days after enhanced infection control interventions were introduced. Molecular epidemiological analysis provided evidence for nosocomial transmission of PIV3 infection that facilitated effective implementation of infection control measures. These were instrumental in restricting further spread of the virus among high-risk patients.


Fate of presynaptic afferents to Purkinje cells in the adult nervous mutant mouse: a model to study presynaptic stabilization.
The hemispheric cerebellar cortex from 174- to 420-day-old nervous mice has been studied with Golgi, Cajal-reduced silver and electron microscopic techniques. In all mice, the existence of a continuous process of Purkinje cell death, indicated by the presence of few of these neurons in early stages of degeneration, has been established. The morphology of such degenerating cells, as well as the removal of the necrotic debris and the consecutive isolation of presynaptic fibers by glia are described. In the molecular layer, and in spite of the important Purkinje cell loss, numerous varicosities belonging to parallel fibers persist. They can be either synapsing on interneurons or concentrated in small clusters of 2-10 boutons covered by astrocytic processes. The synaptic investment of stellate and basket cells, as well as the length and the branching pattern of their dendritic fields are not significantly changed, besides the increase in afferent terminals deprived of their postsynaptic targets. Basket formations, as numerous as in control cerebellum, are forming a discontinuous row at the superficial third of the granular layer. Over 90% of these baskets are devoid of Purkinje cells, however, their ultrastructural features mimic those of the same terminals in control mice, with the exception that few of them can either establish heterologous synapses with granule cell dendrites, or develop gap junctions between them. The significance of the persistence of normal looking presynaptic elements long time after deprivation of their postsynaptic targets is discussed in relation to the role that function can play in the stabilization of synaptic contacts.


Free flap reconstruction of plantar weight-bearing heel defects: Long-term functional and patient-reported outcomes.
Non-healing plantar weight-bearing heel ulcers are a challenging problem to treat. Free tissue transfer (FTT) reconstruction of the heel is an opportunity for limb salvage to preserve gait and ambulation. The aim of this study is to describe surgical and functional outcomes in patients who underwent FTT to treat chronic heel ulcers. A retrospective review of patients who underwent FTT for plantar heel ulcers from 2011 to 2021 was conducted. Patient demographics, comorbidities, perioperative data, postoperative complications, and long-term outcomes were recorded. Primary outcomes included flap success, complications, postoperative ambulation, patient-reported outcome measures and limb salvage, with patients stratified into limb salvage or eventual amputation groups. Forty-four patients underwent 45 heel reconstructions. Average age and BMI were 57.3 years and 30.1 kg/m2 , respectively. Thirty-eight patients (86.4%) had calcaneal osteomyelitis, 35 patients (79.5%) had diabetes, and 18 patients (40.9%) had peripheral vascular disease (PVD). Immediate microsurgical success rate was 95.6%. At mean follow-up of 19.6 ± 20.9 months, overall limb salvage rate was 73.3% (n = 33). Preoperative albumin levels were higher in limb salvage group compared to the amputation group (3.0 vs. 2.4 g/dl, p = .018). Prior stroke history and hypoalbuminemia were significantly higher in the amputation group compared to limb salvage group (p = .012 and p = .018, respectively). Risk for eventual amputation was associated with PVD (OR 4.0, p = .053), hypoalbuminemia (OR 4.9, p = .020), and postoperative infection (OR 6.3, p = .013). Of the 12 amputations that occurred, the most common indication for amputation was infection (n = 8, 66.7%), which most often occurred at the original wound location (62.5%). At most recent follow-up, 90.7% of patients (n = 39) were ambulatory. FTT is an effective alternative to amputation in patients with chronic heel ulcers. Proper patient selection, preoperative optimization, and postoperative care are imperative to the success of this limb salvage procedure.


Frequency of asymptomatic genital herpes in pregnant women at term.
A group of 579 asymptomatic women from Jackson Memorial Hospital, Miami, Florida, and 207 from Kaiser Foundation Hospital in Honolulu, Hawaii, admitted in labor at 37 to 40 weeks of gestation had vaginal cultures for herpes simplex virus (HSV). No cultures were positive and no neonates developed HSV infection. Seven patients gave a history of previous HSV infection in the group from Florida and three from the group in Hawaii. Herpes appears to be a low incidence risk factor in both the populations studied.


Hb I: A α-globin chain variant causing unexpected HbA1c results.
HbA1c is the standard bio-marker for glycemic control in patients with diabetes. Here, we report a α-globin chain variant and evaluate its effect on HbA1c measurements. A 21-year-old female was suspected of harboring a hemoglobin variant following HbA1c measurement during a routine examination using Variant II Turbo 2.0 (Bio-Rad). An oral glucose tolerance test was performed using an AU5800 clinical chemistry system (Beckman Coulter). HbA1c was reanalyzed using D10 (Bio-Rad), Capillarys 2 Flex Piercing (Sebia), and Premier Hb9210 (Trinity Biotech). Hemoglobin analysis was performed using high-performance liquid chromatography (HPLC) on the Bio-Rad Variant II (β-thalassemia short program) and capillary electrophoresis (CE, Capillarys 2 Flex Piercing, Hb program). Sanger sequencing of α and β genes was also conducted. HbA1c was initially measured at 24.2% using Variant II Turbo 2.0. For the oral glucose tolerance test, fasting glucose, 1-hour, and 2-hour levels were recorded as 4.25, 7.89, and 5.34 mmol/L, respectively. Subsequently, HbA1c values determined by D10, Capillarys 2 Flex Piercing (HbA1c program), and Premier Hb9210 were 4.5% (26 mmol/mol), no HbA1c value, and 4.8 (29 mmol/mol), respectively. Hemoglobin analyzed using CE and HPLC revealed an abnormal hemoglobin. Sanger sequencing identified a transversion mutation of the α2 gene [CD16(AAG>GAG), Lys>Glu, HBA2: c.49 A>G], corresponding to a Hb I variant. An unusually high HbA1c or discordance between blood sugar and HbA1c values should alert about the possibilities of hemoglobin variants.


Skilled readers begin processing sub-phonemic features by 80 ms during visual word recognition: evidence from ERPs.
Two masked priming experiments investigated the time-course of the activation of sub-phonemic information during visual word recognition. EEG was recorded as participants read targets with voiced and unvoiced final consonants (e.g., fad and fat), preceded by nonword primes that were incongruent or congruent in voicing and vowel duration (e.g., fap or faz). Experiment 1 used a long duration mask (100 ms) between prime and target, whereas Experiment 2 used a short mask (22 ms). Phonological feature congruency began modulating the amplitude of brain potentials by 80 ms; the feature incongruent condition evoked greater negativity than the feature congruent condition in both experiments. The early onset of the congruency effect indicates that skilled readers initially activate sub-phonemic feature information during word identification. Congruency effects also appeared in the middle and late periods of word recognition, suggesting that readers use phonological representations in multiple aspects of visual word recognition.


Kinetic studies on oxidized and partially reduced cytochrome c oxidase.
1. Kinetic studies have been performed with beef-heart cytochrome c oxidase, with the enzyme either in its oxidized, resting state or pretreated anaerobically with different amounts of reduced cytochrome c. The techniques used for the study have been stopped-flow spectrophotometry and electron paramagnetic resonance (EPR) spectroscopy. 2. The results show that the one-electron equivalent-reduced enzyme rapidly oxidizes one further equivalent of aerobically or anaerobically added ferrocytochrome c, with a rate constant of 5 . 10(6) M-1 . s-1. 3. When an excess of ferrocytochrome c in the presence of oxygen is added to the one-electron-reduced enzyme, the same turnover rate is obtained as in experiments with the resting enzyme. 4. The one-electron equivalent-enzyme reacts with CO with a rate constant of 4 . 10(4) M-1 . s-1 to yield approx. 35% of the CO compound as compared with the reaction between the fully reduced enzyme and CO. 5. It is shown that on reduction the enzyme is converted into an active form, but it is concluded that the enzyme does not have to be fully reduced before it is catalytically active.


A sensitive flow cytometry-based cytotoxic T-lymphocyte assay through detection of cleaved caspase 3 in target cells.
We describe a highly sensitive flow cytometry-based CTL assay using the cleavage of caspase 3 in target cells as a readout. The assay involved labeling of cells with a cell tracker dye and staining permeabilized cells with an antibody recognizing cleaved caspase 3. The assay proved to be robust and reliable in measuring antigen-specific CTL activity in a number of human and murine systems, including MLR, human peptide-specific T-cell responses induced in vitro, and CTL responses following immunization of mice with viral and peptide vaccines. The assay was found to yield comparable results as 51Cr-release, but with markedly higher sensitivity. When compared to detection of antigen-specific T cells via HLA tetramer/pentamer-based methods of T-cell staining in HIV gag peptide-specific human T cell lines the caspase 3 cleavage readout assay exhibited a comparable level of sensitivity with detection of CTL function at antigen-specific T-cell frequencies of 1:15,000 or lower. A similar level of sensitivity was obtained when murine CTL assays were performed with MLR in which effector cells were highly diluted with naïve syngeneic spleen cells. Our results indicate that the caspase 3 cleavage assay may be a powerful tool to measure antigen-specific CTL responses in human vaccine trials and in pre-clinical animal models of CTL function at both high and low effector cell frequencies.


SCGICAR: Spatial concatenation based group ICA with reference for fMRI data analysis.
With the rapid development of big data, the functional magnetic resonance imaging (fMRI) data analysis of multi-subject is becoming more and more important. As a kind of blind source separation technique, group independent component analysis (GICA) has been widely applied for the multi-subject fMRI data analysis. However, spatial concatenated GICA is rarely used compared with temporal concatenated GICA due to its disadvantages. In this paper, in order to overcome these issues and to consider that the ability of GICA for fMRI data analysis can be improved by adding a priori information, we propose a novel spatial concatenation based GICA with reference (SCGICAR) method to take advantage of the priori information extracted from the group subjects, and then the multi-objective optimization strategy is used to implement this method. Finally, the post-processing means of principal component analysis and anti-reconstruction are used to obtain group spatial component and individual temporal component in the group, respectively. The experimental results show that the proposed SCGICAR method has a better performance on both single-subject and multi-subject fMRI data analysis compared with classical methods. It not only can detect more accurate spatial and temporal component for each subject of the group, but also can obtain a better group component on both temporal and spatial domains. These results demonstrate that the proposed SCGICAR method has its own advantages in comparison with classical methods, and it can better reflect the commonness of subjects in the group.


Acromioclavicular joint injuries in overhead athletes: a concise review of injury mechanisms, treatment options, and outcomes.
To review the relevant literature surrounding acromioclavicular (AC) joint injuries particularly pertaining to overhead athletes. The AC joint is a unique anatomic and biomechanical portion of the shoulder that can be problematic for athletes, particularly throwers, when injured. Treatment of these injuries remains a topic in evolution. Low-grade injuries (Rockwood types I & II) are typically treated non-operatively while high-grade injuries (types IV, V, and VI) are considered unstable and often require operative intervention. Type III AC separations remain the most controversial and challenging as no clear treatment algorithm has been established. A wide variety of surgical techniques exist. Unfortunately, relatively little literature exists with regard to overhead athletes specifically. Treatment of AC joint injuries remains challenging, at times, particularly for overhead athletes. Operative indications and techniques are still evolving, and more research is needed specifically surrounding overhead athletes.


Layer-by-layer assembled PEI-based vector with the upconversion luminescence marker for gene delivery.
The upconversion luminescence (UCL) marker based on upconversion nanoparticles (UCNPs) shows unique advantages over traditional fluorescence markers, such as enhanced tissue penetration, better photostability, and less autofluorescence. Herein, we constructed a new UCL gene-delivery nonviral vector via layer-by-layer self-assembly of poly(ethylene imine) (PEI) with UCNPs. To reduce the cytotoxicity of PEI, citric acid (CA) was introduced for aqueous modification, and PEI assembly was introduced on the UCNP surface. Our data show that the nonviral vector for UCL gene-delivery demonstrates excellent photostability, low toxicity, and good stability under physiological or serum conditions and can strongly bind to DNA. Moreover, this UCL PEI-based vector could serve as a promising fluorescent gene-delivery carrier for theranostic applications.


The physical organic chemistry of glycopyranosyl transfer reactions in solution and enzyme-catalyzed.
Our understanding of the mechanisms of glycopyranosyl transfer that occur in solution, both for the chemical synthesis of complex structures and that for the cleavage of glycosidic bonds has allowed us to design biologically active molecules. Recent efforts on the reactivity of glycopyranosides, which are critical entities in all biological systems, coupled with the advent of modern spectroscopic instrumentation have allowed physical organic chemists to broaden our knowledge of glycosyl transfer reaction transition states, both in solution and for enzyme-catalyzed processes, and of critical high energy intermediates. This review details recent physical organic, kinetic and structural studies that have led to elucidation of several different mechanism for the transfer of glycopyranosyl moieties from various substrates to acceptors, such as water or a sugar hydroxyl group.


The significance of belief and expectancy within the spiritual healing encounter.
Historically, traditional cultures recognized the importance of belief and expectancy within the healing encounter and created complex rituals and ceremonies designed to elicit or foster the expectancy and participation of both the healer and patient, as well as the community as a whole. This holistic approach to health care was a fundamental component in the spiritual healing rituals of virtually all traditional native cultures. The focus of the current study was to assess the impact of healer and patient expectations on mental and physical health parameters following a spiritual healing session. A pre-post methodological design which incorporated extensive psychophysiological health outcome measures along with independent medical diagnoses was utilized. The study was conducted in a northern California suburb of Marin County utilizing an American-born spiritual healer trained in the Philippines. The results indicated that there was a statistically significant difference between the pre-treatment and post-treatment scores for all fourteen dependent variables examined. The data also demonstrated a significant difference between the high versus low expectancy subjects for both patient and healer groups, as well as a significant relationship between high expectancy in patients and healer and the effectiveness of the spiritual healing encounter. The results of the study therefore suggest that high healer and patient expectancy may be important elements which can serve as both predictors as well as facilitators of the healing process. The degree of bonding or communication between the healer and patient was postulated as an important factor in this regard. Due to the fact that a majority of the conditions reported (75%) were organic disorders that would not commonly disappear within the 3 week time frame of the study, the significant results obtained suggest that spiritual healing in combination with traditional allopathic medicine may have the potential to be an effective treatment protocol for severe or long-term disorders. An important contributing feature of this study was that an independent means of assessing the patients' self-reports, i.e. an allopathic medical examination, was included in the experiment. There was a significant correlation between the patient's expectation level and their assessment of improvement, as well as a significant relationship between the patient's assessment of their condition and the objective evaluations provided by independent medical examinations.


Inhibition of the type 1 fimbriae-mediated adhesion of Escherichia coli to erythrocytes by multiantennary alpha-mannosyl clusters: the effect of multivalency.
Alpha-mannosyl glycoclusters and glycodendrimers were tested as multivalent inhibitors of the type 1 (mannose-specific) fimbriae of a recombinant E. coli HB101 strain. Inhibition of haemagglutination of guinea pig erythrocytes was determined on microtiter plates. The effect of multivalency is pronounced for up to three mannosyl residues in the molecule, whereas larger derivatives do not have an appreciable effect on binding to the fimbrial carbohydrate binding domain. The best glycoclusters tested reach the binding potency of the known potent inhibitor pNPMan (3). The results support the idea of a monovalent recognition site at the adhesive protein FimH, which might best accommodate molecules with the size of a trisaccharide or those which expose up to three alpha-mannosyl residues, such as the glycocluster 8. The results obtained with the thiourea-bridged alpha-mannosyl clusters, possessing defined sugar valencies, facilitate the development of high affinity inhibitors of the fimbrial lectin on type 1 fimbriae.


The Safety and Efficacy of Endovascular Treatment for Patients With ASPECTS<6 in Anterior Circulation Stroke: A Meta-Analysis and Subgroup Analysis by Imaging Techniques.
Endovascular treatment (EVT) is merely recommended as class of recommendation IIb for patients with ASPECTS <6 according to the American Heart Association guideline 2019. In addition, the best determined imaging technique for EVT in patient with ASPECTS<6 remains unknown. The objective of this study was to define the safety and efficacy of EVT for patients with ASPECTS<6 and investigate the superiority between MRI and CT for patient selection. A systematic search of PubMed, EMBASE, The Cochrane Library and other additional sources was performed for studies published with no publication period. Our study was conducted corresponding to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRIMA) guidelines. The analysis was performed using the Comprehensive Meta-Analysis (CMA) 2.0. Five studies reporting data from 844 participants were included in our analysis according to the inclusion criteria. Consequently, EVT was associated with statistically significant higher functional independence compared with MT (OR 5.401, 95% CI 3.227-9.041). Whereas EVT was found to be related to lower mortality compared with MT based on eligible data (OR 0.461, 95% CI 0.329-0.647). No significant difference was identified in sICH between EVT and MT (OR 1.075, 95% CI 0.452-2.558). According to the results of our study, we suggested that EVT is a preferred therapy in ACS patients with ASPECTS<6 in consideration of efficacy and safety. Furthermore, MRI did not show superiority over CT as no statistical difference was detected in all subgroups.


A unifying concept for the role of matrix vesicles and lysosomes in the formal pathogenesis of diseases of connective tissues and blood vessels.
The cells of the connective tissues contain lysosomes with enzymes capable of degrading intercellular substances (collagen, elastin, proteoglycans) and release their enzymes in membrane-bound or in free form into their intercellular substance. In this way extracellularly located lysosomes (= matrix lysosomes) can be detected by morphological and enzymatic means as well as by their metal concentrating property. This function of such matrix-lysosomes is in connection with the two step-degradation of the connective tissue and is thought to be the main part for the fibrocytic fibrolysis, chondrocytic chondrolysis, osteocytic osteolysis and myocytic mediolyses in the vessel wall. The cells of the mesenchymal tissues thus control the turnover and transformation of their own ground substance. Inflammatory and immunologic processes are suggested to be superimposed on this lysosomal action. If the lysosomal enzyme system in the connective tissues and the vessel wall gets out of control, the consequences can be dangerous as e.g. in case of relapsing polychondritis and arterial aneurysms. In this enzyme system proteolytic activators as well as proteolytic decomposable inhibitors are present. The corresponding proteolytic processes are of lysosomal nature and are subordinated to other regulatory mechanisms.