High IQ May "Mask" the Diagnosis of ADHD by Compensating for Deficits in Executive Functions in Treatment-Naïve Adults With ADHD.
To evaluate and compare the performance of adults with ADHD with high and standard IQ in executive functions (EF) tasks. We investigated the neuropsychological performance of 51 adults with ADHD, compared with 33 healthy controls (HC) while performing a wide battery of neuropsychological tests that measure executive functioning. Adults with clinical diagnosis of ADHD were divided into two groups according to their IQ level (IQ ≥ 110-ADHD group with more elevated IQ, and IQ < 110-ADHD group with standard IQ). The ADHD group with standard IQ presented a worse executive functioning compared with the HC group in the following measures: Stroop 2 ( p = .000) and 3 ( p = .000), Trail Making Test (TMT) B ( p = .005), Wisconsin Card-Sorting Test (WCST)-perseverative errors ( p = .022) and failures to maintain set ( p = .020), Continuous Performance Test (CPT)-omission errors ( p = .005) and commission errors ( p = .000), and Frontal Assessment Battery (FAB)-conceptualization ( p = .016). The ADHD group with more elevated IQ presented only impairments in the CPT-commission errors ( p = .019) when compared with the control group. Adults with ADHD and more elevated IQ show less evidence of executive functioning deficits compared with those with ADHD and standard IQ, suggesting that a higher degree of intellectual efficiency may compensate deficits in executive functions, leading to problems in establishing a precise clinical diagnosis.


The addition of 0.2 mg subarachnoid morphine to hyperbaric bupivacaine for cesarean delivery: a prospective study of 856 cases.
In an effort to determine the incidence of respiratory depression and other side effects of subarachnoid morphine, we conducted the following prospective study in a large number (856) of young female patients undergoing cesarean delivery in one hospital. During the period from July 1987 to January 1989, patients receiving subarachnoid hyperbaric bupivacaine combined with 0.2 mg preservative-free morphine were included. They were continuously monitored for 24 hours using a pulse oximeter. For 24 hours, the vital signs, including respiratory rate every hour, and the side effects, including pruritus, nausea, and vomiting, were recorded. The need for analgesia and the total dose of opioids during the first 24 hours were documented. Our results showed that respiratory depression (SaO2 less than or equal to 85% and/or respiratory rate ten breaths per minute or less) occurred in eight patients, all of whom were markedly obese. Fifty-eight percent of the patients did not require analgesics for 24 hours. In those requiring an added opioid, the dose was (9.1 +/- 0.5 mg morphine, mean +/- SEM). Eighty-five percent of the patients were satisfied with the postoperative analgesia. Six percent were dissatisfied due to the side effects, i.e., pruritus, nausea and/or vomiting. Nine percent were dissatisfied with the pulse oximeter because it caused false alarms and limited their mobility.


Cost effectiveness of magnetic resonance imaging in the neurosciences.
To measure, in a service setting, the effect of magnetic resonance imaging on diagnosis, diagnostic certainty, and patient management in the neurosciences; to measure the cost per patient scanned; to estimate the marginal cost of imaging and compare this with its diagnostic impact; to measure changes in patients' quality of life; and to record the diagnostic pathway leading to magnetic resonance imaging. Controlled observational study using questionnaires on diagnosis and patient management before and after imaging. Detailed costing study. Quality of life questionnaires at the time of imaging and six months later. Diagnostic pathways extracted from medical records for a representative sample. Regional superconducting 1.5 T magnetic resonance service. 782 consecutive neuroscience patients referred by consultants for magnetic resonance imaging during June 1988-9; diagnostic pathways recorded for 158 cases. Costs of magnetic resonance imaging and preliminary investigations; changes in planned management and resulting savings; changes in principal diagnosis and diagnostic certainty; changes in patients' quality of life. Average cost of magnetic resonance imaging was estimated at 206.20/patient pounds (throughput 2250 patients/year, 1989-90 prices including contrast and upgrading). Before magnetic resonance imaging diagnostic procedures cost 164.40/patient pounds (including inpatient stays). Management changed after imaging in 208 (27%) cases; saving an estimated 80.90/patient pounds. Confidence in planned management increased in a further 226 (29%) referrals. Consultants' principal diagnosis changed in 159 of 782 (20%) referrals; marginal cost per diagnostic change was 626 pounds. Confidence in diagnosis increased in 236 (30%) referrals. No improvement in patients' quality of life at six month assessment. Any improvement in diagnosis with magnetic resonance imaging is achieved at a higher cost. Techniques for monitoring the cost effectiveness of this technology need to be developed.


Inguinal bubo: problems in diagnosis.
Two of the four patients with tropical venereal diseases underwent incision and drainage of the inguinal bubo resulting in discharging sinus before they were referred to the Skin Clinic. Clinical diagnosis was made in all four but could not be confirmed. With appropriate therapy resolution was achieved without complications. The difficulties in arriving at and establishing the diagnosis are discussed.


Add-on melatonin improves sleep behavior in children with epilepsy: randomized, double-blind, placebo-controlled trial.
This double-blind, randomized, placebo-controlled study in epileptic children, aged 3 to 12 years, evaluated the effect of add-on melatonin on the sleep behavior of these children on sodium valproate monotherapy using a parental questionnaire. Of the 31 patients, 16 randomly received add-on melatonin, whereas 15 received add-on placebo. The questionnaire showed good internal consistency in our patient population (Cronbach's alpha = .83). The percentage decrease in the median total sleep score was 24.4 (range 0.0-34.9) in the valproate + melatonin group compared with 14.0 (range -2.2-18.8) in the valproate + placebo group, the difference being statistically significant (P < .05). The median percentage decrease in the parasomnias score was 60 (range 0.0-70.8) in the valproate + melatonin group compared with 36.4 (range 0.0-63.2) in the valproate + placebo group, the difference being statistically significant (P < .05). There was no significant difference between the percentage decrease in the daytime drowsiness scores and sleep fragmentation scores. Parent-child interaction subscale scores were not significantly different between age groups. The age at onset of seizures and the type of seizures did not correlate significantly to the total sleep scores. Given that sleep problems are known to complicate epilepsy, add-on melatonin, which has a wide safety window, can be of promise in the pharmacotherapy of pediatric epilepsy.


Insights Into Comparative Analyses and Phylogenomic Implications of Acer (Sapindaceae) Inferred From Complete Chloroplast Genomes.
Acer L. (Sapindaceae) is one of the most diverse and widespread plant genera in the Northern Hemisphere. It comprises 124-156 recognized species, with approximately half being native to Asia. Owing to its numerous morphological features and hybridization, this genus is taxonomically and phylogenetically ranked as one of the most challenging plant taxa. Here, we report the complete chloroplast genome sequences of five Acer species and compare them with those of 43 published Acer species. The chloroplast genomes were 149,103-158,458 bp in length. We conducted a sliding window analysis to find three relatively highly variable regions (psbN-rps14, rpl32-trnL, and ycf1) with a high potential for developing practical genetic markers. A total of 76-103 SSR loci were identified in 48 Acer species. The positive selection analysis of Acer species chloroplast genes showed that two genes (psaI and psbK) were positively selected, implying that light level is a selection pressure for Acer species. Using Bayes empirical Bayes methods, we also identified that 20 cp gene sites have undergone positive selection, which might result from adaptation to specific ecological niches. In phylogenetic analysis, we have reconfirmed that Acer pictum subsp. mono and A. truncatum as sister species. Our results strongly support the sister relationships between sections Platanoidea and Macrantha and between sections Trifoliata and Pentaphylla. Moreover, series Glabra and Arguta are proposed to promote to the section level. The chloroplast genomic resources provided in this study assist taxonomic and phylogenomic resolution within Acer and the Sapindaceae family.


Arteriovenous malformation of the hand: a case study.
Arteriovenous malformations (AVMs) are complex congenital vascular anomalies resulting from faulty embryonic development of arterial and venous structures. The present discussion will specifically address AVMs of the extremities. Complications of these lesions can include tissue damage, functional impairment and amputation. The article reviews current diagnostic procedures and treatment options. A case study is presented with a discussion of nursing care focusing on pain, anxiety, and alteration in peripheral tissue perfusion.


Mechanisms of resistance to imipenem and ampicillin in Enterococcus faecalis.
We found ampicillin- and imipenem-resistant isolates of vanA-possessing Enterococcus faecalis with MICs of 8 to 16 microg/ml and 4 to 32 microg/ml, respectively. There have been few reports about penicillin- and imipenem-resistant E. faecalis. Two mechanisms of beta-lactam resistance in E. faecalis, the production of beta-lactamase and the overproduction of penicillin-binding proteins (PBPs), have been reported. The resistant isolates in the current study did not produce any beta-lactamases and analysis of the PBPs showed no overproduction. However, the affinities of PBP4 for beta-lactams in the resistant strains were lower than those of susceptible strains but the affinities of other PBPs for beta-lactams did not change. Accordingly, whole pbp4 fragments from these resistant isolates were sequenced. Two amino acid substitutions at positions 520 and 605 were observed in the highly resistant strains compared to the susceptible ones, Pro520Ser and Tyr605His, and a single Tyr605His amino acid substitution was found in the low-resistance strains. These two point mutations exist in the region between the active-site-defining motifs SDN and KTG of the penicillin-binding domain, the main target of beta-lactams. A strong correlation was seen between these substitutions and decreasing affinities of PBP4 to beta-lactams. In E. faecalis, resistance due to mutations in PBPs has not been reported, though it has in Enterococcus faecium. Our results suggest that development of high-level resistance to penicillins and imipenem depends on point mutations of PBP4 at positions 520 and 605.


Purification and properties of hemagglutinin from culture supernatant of Bacteroides gingivalis.
The hemagglutinating factor (hemagglutinin) of Bacteroides gingivalis was prepared from the supernatant of a 5-day diffusate broth culture by ammonium sulfate precipitation and column chromatography with a hydrophobic column of Phenyl-Sepharose CL-4B, DEAE-Sephadex A-50, and Sephadex G-100 gel filtration. The hemagglutinating activity of the preparation was 53.3 times higher than that of ammonium sulfate precipitate. In electron microphotographs, hemagglutinin appears to have a vesicle or tubelike structure. The hemagglutinating activity of intact cells was completely destroyed by heating at 100 degrees C for 10 min, but the activity of extracted hemagglutinin was heat stable. The activity of hemagglutinin was inhibited by L-arginine and L-lysine and partially inhibited by phospholipase D, but it was not affected by proteolytic enzymes, neuraminidase, hyaluronidase, lipase, phospholipase A and C, or sugars. The B. gingivalis hemagglutinin appeared to be comprised mainly of a 40,000-molecular-weight material. The Fab fragment of immunoglobulin G prepared from rabbit antiserum to whole cells of B. gingivalis and monoclonal antibody against the hemagglutinin bound to the cell surface and inhibited the hemagglutinating activity of both the cells and the purified hemagglutinin.


[Environmental and biological monitoring of exposure to polycyclic aromatic hydrocarbons in workers of an electric steel foundry].
To assess and classify exposure to Polycyclic Aromatic Hydrocarbons (PAHs) in some specific working areas of a steel foundry operating with a continuous casting process and evaluate biomonitoring data in different job tasks. Exposure to dusts and six PAHs classified as carcinogenic by EU directives was studied in a cohort of 35 male foundry workers (aged 41.1 +/- 6.9 years), who were examined both prior to and at the end of the work-shift (06:00 a.m.-02:00 p.m.) in two different periods. The urinary excretion of 1-hydroxypyrene (1-OH-P) was measured as a biomarker of exposure to pyrene. PAHs concentrations ranged from 461.8 to 935.6 ng/m3 near the continuous casting area, whereas lower values were measured near the ladle furnace. End of shift 1-OH-P values were higher in 11 non-smoking workers involved in continuous casting process as compared to those employed in mantenance and furnace areas (median of the second determination: 5.70 microg/g creatinine--range: 1.24-21.24 vs 1.17 microg/g creatinine--range: 0.23-4.49; p< 0.001). 1-OH-P excretion was significantly correlated with both the sum of six carcinogenic PAHs and pyrene airborne concentrations. In two biomonitoring sessions, 9.1% and 34.3% of the workers respectively showed end-of-shift 1-OH-P values exceeding the occupational exposure limit (OEL) (4.4 microg/g creatinine or 2.3 micromol/mol(-1) creatinine) recommended for coke-oven workers. 1-OH-P is a useful biomarker in assessing PAH exposure and is associated with job category at a Steelplant. Due to exposure variability, to assess risk associated with PAHs exposure, biological monitoring should be carried out periodically.


Increased human cytomegalovirus (HCMV) DNA load in peripheral blood leukocytes after lung transplantation correlates with HCMV pneumonitis.
Human cytomegalovirus (HCMV) reactivation and disease remain relatively common in lung transplant recipients (LTR) despite the use of ganciclovir prophylaxis protocols for all HCMV at-risk patients. The specific aims of this study were to (1) describe the HCMV DNA viral load in the peripheral blood leukocytes (PBL) of a cohort of LTR during the first 6 months after lung transplantation; (2) prospectively determine whether HCMV DNA viral load predicts episodes of HCMV pneumonitis in LTR; and (3) study the effect of ganciclovir on HCMV viral load. Competitive polymerase chain reaction using an internal standard and fluorometric detection were used to quantitate HCMV DNA in the PBL of a cohort of 26 LTR monthly for the first 6 months after transplantation (145 samples). All patients were treated with standard triple immunosuppression, and ganciclovir prophylaxis was given to all at-risk LTR (donor or recipient HCMV seropositive) for at least 8 weeks after transplantation. Thirteen episodes of histopathologically proven HCMV pneumonitis in nine subjects occurred during follow-up with a wide intra- and intersubject variation in the HCMV DNA PBL levels. HCMV detection had a sensitivity of 92% and specificity of 76% for HCMV pneumonitis (negative likelihood ratio, 9.5), whereas greater than 10-fold increases in HCMV DNA load had a specificity of 93% and sensitivity of 67% (positive likelihood ratio, 11). HCMV DNA detection had an adjusted odds ratio for HCMV pneumonitis of 107 (95% confidence interval, 14-821; P<0.005). In those with detectable HCMV DNA in PBL (n=44), HCMV DNA levels were 4.4 (95% confidence interval, 1.2-16.8) times higher in those with HCMV pneumonitis than in those without HCMV pneumonitis. Although ganciclovir treatment was very effective in treating HCMV pneumonitis and suppressing HCMV DNA levels, thrice weekly ganciclovir prophylaxis only partially controlled HCMV DNA levels and did not eliminate HCMV pneumonitis risk as three patients developed HCMV pneumonitis while on this regimen. HCMV DNA detection, absolute levels, and relative change from baseline in the PBL of LTR correlate with HCMV pneumonitis episodes and may be a useful intermediate outcome measure of the efficacy of ganciclovir prophylaxis and treatment strategies.


Supervised versus unsupervised primaquine radical cure for the treatment of falciparum and vivax malaria in Papua, Indonesia: a cluster-randomised, controlled, open-label superiority trial.
There is a high risk of Plasmodium vivax recurrence in patients treated for Plasmodium falciparum malaria in co-endemic areas. Primaquine radical cure has the potential to reduce P vivax recurrences in patients presenting with P falciparum as well as P vivax malaria but is undermined by poor adherence to the currently recommended 14-day regimen. We aimed to assess the efficacy and safety of supervised versus unsupervised primaquine radical cure in patients presenting with uncomplicated malaria. We did a cluster-randomised, controlled, open-label superiority trial in Papua, Indonesia. 21 clusters of village health posts, matched by annual parasite index, were randomly assigned (1:1) to treat patients (age >12 months and body weight >5 kg) presenting with confirmed uncomplicated P falciparum or P vivax malaria with oral dihydroartemisinin-piperaquine plus either a supervised or unsupervised 14-day course of oral primaquine (0·5 mg/kg per day). Patients in the supervised group were supervised taking their primaquine dose on alternate days. Patients were followed-up for 6 months and those who presented again with malaria were retreated with the same drug regimen. Masking was not possible due to the nature of the study. The primary outcome was the incidence risk of P vivax malaria over 6 months, assessed in the modified intention-to-treat population (all patients who were assigned to a treatment group, excluding patients who were lost to follow-up after their first visit). This trial is now complete, and is registered with ClinicalTrials.gov, NCT02787070. Between Sept 14, 2016, and July 31, 2018, 436 patients were screened for eligibility and 419 were enrolled; 223 (53%) patients in 11 clusters were assigned to supervised primaquine treatment and 196 (47%) in ten clusters to unsupervised primaquine treatment. 161 (72%) of 223 patients in the supervised group and 151 (77%) of 196 in the unsupervised group completed 6 months of follow-up. At 6 months, the incidence risk of P vivax recurrence in the supervised group was 29·7% (95% CI 16·4-49·9) versus 55·8% (32·3-81·8) in the unsupervised group (hazard ratio 0·23 [95% CI 0·07-0·76]; p=0·016). The incidence rate for P vivax recurrence was 539 (95% CI 390-747) infections per 1000 person-years in the supervised group versus 859 (673-1096) in the unsupervised group (incidence rate ratio 0·63 [95% CI 0·42-0·94]; p=0·025). The corresponding rates in the 224 patients who presented with P falciparum malaria were 346 (95% CI 213-563) and 660 (446-977; incidence rate ratio 0·52 [95% CI 0·28-0·98]; p=0·043). Seven serious adverse events were reported (three in the supervised group, four in the unsupervised group), none of which were deemed treatment-related, and there were no deaths. In this area of moderate malaria transmission, supervision of primaquine radical cure treatment reduced the risk of P vivax recurrence. This finding was apparent for patients presenting with either P falciparum or P vivax malaria. Further studies are warranted to investigate the safety and efficacy of radical cure for patients presenting with uncomplicated falciparum malaria in other co-endemic areas. The Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Foreign Affairs and Trade of the Australian Government. For the Indonesian translation of the abstract see Supplementary Materials section.


Effect of acute administration of malathion by oral and dermal routes on serum histamine levels.
Previous studies have shown that acute, oral administration of malathion increased the generation of a humoral immune response, stimulated macrophage function and caused mast cell degranulation and histamine release. In this study, the effect of acute administration of various doses of malathion via oral and dermal routes to mice and rats on serum levels of histamine was evaluated. Oral administration of malathion to mice led to an increase in the level of serum histamine 4 and 8 h after administration. At 4 h after administration, the peak in serum histamine levels was observed at a dose of 10 mg/kg malathion. At 8 h, a maximal effect was observed at a dose of 700 mg/kg and the response was more prolonged than at lower doses. At 12 and 24 h after administration, the level of histamine in the serum of treated mice was comparable to controls. A similar pattern was observed in rats. However, the time point at which histamine levels returned to control was 8 rather than 12 h. After application of malathion to the skin of mice or rats in dimethyl sulphoxide (DMSO), the level of histamine in the blood was also increased. As before, the peak increase was observed at 4 h after administration and the level had returned to control levels within 8 h (slight increase at 8 h in rats) after application. However, after dermal application the maximal levels of histamine in the serum were noted at the highest doses of malathion. The no effect levels for histamine in the blood after malathion administration to these two species by these two routes are as follows: (1) Mice, oral in corn oil, 0.1 mg/kg; (2) Rats, oral in corn oil, 0.1 mg/kg; (3) Mice, dermal in DMSO, 2 mg/kg; (4) Rats, dermal in DMSO--not determined (2 mg/kg low effect level).


Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors.
Appropriate localization and migration of T cells is a prerequisite for antitumor immune surveillance. Studies using fixed tumor samples from human patients have shown that T cells accumulate more efficiently in the stroma than in tumor islets, but the mechanisms by which this occurs are unknown. By combining immunostaining and real-time imaging in viable slices of human lung tumors, we revealed that the density and the orientation of the stromal extracellular matrix likely play key roles in controlling the migration of T cells. Active T cell motility, dependent on chemokines but not on β1 or β2 integrins, was observed in loose fibronectin and collagen regions, whereas T cells migrated poorly in dense matrix areas. Aligned fibers in perivascular regions and around tumor epithelial cell regions dictated the migratory trajectory of T cells and restricted them from entering tumor islets. Consistently, matrix reduction with collagenase increased the ability of T cells to contact cancer cells. Thus, the stromal extracellular matrix influences antitumor immunity by controlling the positioning and migration of T cells. Understanding the mechanisms by which this collagen network is generated has the potential to aid in the development of new therapeutics.


Exploring the Genetic Architecture of Spontaneous Coronary Artery Dissection Using Whole-Genome Sequencing.
Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndrome that predominantly affects women. Its pathophysiology remains unclear but connective tissue disorders (CTD) and other vasculopathies have been observed in many SCAD patients. A genetic component for SCAD is increasingly appreciated, although few genes have been robustly implicated. We sought to clarify the genetic cause of SCAD using targeted and genome-wide methods in a cohort of sporadic cases to identify both common and rare disease-associated variants. A cohort of 91 unrelated sporadic SCAD cases was investigated for rare, deleterious variants in genes associated with either SCAD or CTD, while new candidate genes were sought using rare variant collapsing analysis and identification of novel loss-of-function variants in genes intolerant to such variation. Finally, 2 SCAD polygenic risk scores were applied to assess the contribution of common variants. We identified 10 cases with at least one rare, likely disease-causing variant in CTD-associated genes, although only one had a CTD phenotype. No genes were significantly associated with SCAD from genome-wide collapsing analysis, however, enrichment for TGF (transforming growth factor)-β signaling pathway genes was found with analysis of 24 genes harboring novel loss-of-function variants. Both polygenic risk scores demonstrated that sporadic SCAD cases have a significantly elevated genetic SCAD risk compared with controls. SCAD shares some genetic overlap with CTD, even in the absence of any major CTD phenotype. Consistent with a complex genetic architecture, SCAD patients also have a higher burden of common variants than controls.


The Intriguing Connections between von Willebrand Factor, ADAMTS13 and Cancer.
von Willebrand factor (VWF) is a complex and large protein that is cleaved by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13), and together they serve important roles in normal hemostasis. Malignancy can result in both a deficiency or excess of VWF, leading to aberrant hemostasis with either increased bleeding or thrombotic complications, as respectively seen with acquired von Willebrand syndrome and cancer-associated venous thromboembolism. There is emerging evidence to suggest VWF also plays a role in inflammation, angiogenesis and tumor biology, and it is likely that VWF promotes tumor metastasis. High VWF levels have been documented in a number of malignancies and in some cases correlate with more advanced disease and poor prognosis. Tumor cells can induce endothelial cells to release VWF and certain tumor cells have the capacity for de novo expression of VWF, leading to a proinflammatory microenvironment that is likely conducive to tumor progression, metastasis and micro-thrombosis. VWF can facilitate tumor cell adhesion to endothelial cells and aids with the recruitment of platelets into the tumor microenvironment, where tumor/platelet aggregates are able to form and facilitate hematogenous spread of cancer. As ADAMTS13 moderates VWF level and activity, it too is potentially involved in the pathophysiology of these events. VWF and ADAMTS13 have been explored as tumor biomarkers for the detection and prognostication of certain malignancies; however, the results are underdeveloped and so currently not utilized for clinical use. Further studies addressing the basic science mechanisms and real word epidemiology are required to better appreciate the intriguing connections between VWF, ADAMTS13 and malignancy. A better understanding of the role VWF and ADAMTS13 play in the promotion and inhibition of cancer and its metastasis will help direct further translational studies to aid with the development of novel cancer prognostic tools and treatment modalities.


Age-related variability in network engagement during music listening.
Listening to music is an enjoyable behaviour that engages multiple networks of brain regions. As such, the act of music listening may offer a way to interrogate network activity, and to examine the reconfigurations of brain networks that have been observed in healthy aging. The present study is an exploratory examination of brain network dynamics during music listening in healthy older and younger adults. Network measures were extracted and analyzed together with behavioural data using a combination of hidden Markov modelling and partial least squares. We found age- and preference-related differences in fMRI data collected during music listening in healthy younger and older adults. Both age groups showed higher occupancy (the proportion of time a network was active) in a temporal-mesolimbic network while listening to self-selected music. Activity in this network was strongly positively correlated with liking and familiarity ratings in younger adults, but less so in older adults. Additionally, older adults showed a higher degree of correlation between liking and familiarity ratings consistent with past behavioural work on age-related dedifferentiation. We conclude that, while older adults do show network and behaviour patterns consistent with dedifferentiation, activity in the temporal-mesolimbic network is relatively robust to dedifferentiation. These findings may help explain how music listening remains meaningful and rewarding in old age.


Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia.
Notch regulates cell-cell contact-dependent signaling and is activated by hypoxia, a microenvironmental condition that promotes cellular invasion during both normal physiology and disease. The mechanisms by which hypoxia and Notch regulate cellular invasion are not fully elucidated. In this paper, we show that, in cancer cells, hypoxia increased the levels and activity of the ADAM12 metalloprotease in a Notch signaling-dependent manner, leading to increased ectodomain shedding of the epidermal growth factor (EGF) receptor (EGFR) ligand heparin-binding EGF-like growth factor. Released HB-EGF induced the formation of invadopodia, cellular structures that aid cancer cell invasion. Thus, we describe a signaling pathway that couples cell contact-dependent signaling with the paracrine activation of the EGFR, indicating cross talk between the Notch and EGFR pathways in promoting cancer cell invasion. This signaling pathway might regulate the coordinated acquisition of invasiveness by neighboring cells and mediate the communication between normoxic and hypoxic areas of tumors to facilitate cancer cell invasion.


Cholesterol moieties as building blocks for assembling nanoparticles to achieve effective oral delivery of insulin.
Although nanoparticles (NPs) have emerged as a promising strategy to improve oral absorption of insulin, most of them still have minimal oral bioavailability due to the harsh gastrointestinal (GI) environment and epithelial barriers. A novel platform of oral insulin delivery is herein proposed based on amphiphilic cholesterol-phosphate conjugate (CHP). The CHP was synthesized with a cholesterol moiety as a hydrophobic block and a phosphate group as a hydrophilic block. The structural characteristics of CHP made cholesteryl moieties to point outward to form a shell coated on the surface of NPs, and phosphate groups toward inside as the core via the water-in-oil (W/O) emulsion method. The additional Ca2+ could chelate to phosphate groups in the core to bind adjacent phosphate groups and further increased the stability of NPs (CP-Ca NPs). Phospholipid and glycocholate were modified on the surface of CP-Ca NPs to form hydrophilic corona coated CP-Ca NPs (Hc@CP-Ca NPs) and didn't change the structure of CP-Ca NPs. The NPs exhibited high encapsulation efficiency (>95%) and had high stability in the GI tract by reducing insulin release and protecting insulin from enzymatic degradation. Compared to free insulin, Hc@CP-Ca NPs demonstrated 31-fold higher cellular uptake in Caco-2 cells for 1 h incubation. Furthermore, the transepithelial transport efficiency of Hc@CP-Ca NPs was 12-fold higher than that of free insulin. Moreover, CP-Ca NPs and Hc@CP-Ca NPs generated a rapid-onset and long-lasting hypoglycemic effect following gavage in type 1 diabetic mellitus (T1DM) rats. The pharmacological activity and the relative bioavailability were increased to 13.5% and 12.2%, respectively. Thus, these results indicated that CHP assembled NPs may provide a promising potential for oral insulin delivery by protection and absorption promotion.


Nonstigmatizing and Precise Terminology to Describe Processes and Outcomes in Addiction Medicine.
Scholarly journals and professional organizations in addiction medicine have recently discussed the importance of adopting nonstigmatizing and precise terminology. The present commentary expands that ongoing discussion to terms related to treatment processes and outcomes. Four implicit assumptions of stigmatizing and imprecise terms related to treatment processes and outcomes are overviewed, and research evidence against these assumptions is presented. The commentary ends with recommendations for the use of positive behavioral indicators of processes and outcomes and, more importantly, accompanying them with nonevaluative, objective descriptors of patients' behaviors.


Hormonal induction and regulation of lactose synthetase in mouse mammary gland.
The augmentation of lactose synthetase activity during late pregnancy and lactation was measured by using both a tissue-culture assay and a cell-free assay. The results indicated at least a 100-fold augmentation in specific activity between late pregnancy and lactation. The cell-free assay indicated that the activities of both subunits of this enzyme had increased to 20-30% of the value during lactation by the last day of pregnancy. The tissue-culture assay, however, showed activities only 3-4% of the maximum at the time of parturition. This suggests that not all the enzyme present in the tissue before lactation commenced was active. Since at all stages of pregnancy and lactation the B subunit, alpha-lactalbumin (which is also a milk protein), was rate-limiting, it is suggested that the rate of lactose synthesis may be linked to the rate of milk-protein synthesis. Both subunits of lactose synthetase could be induced in tissue culture by the hormones insulin+hydrocortisone+prolactin. Of the three hormones, prolactin appeared to be the ;trigger' that induced the synthesis of these proteins if the tissue had been stimulated previously by insulin+hydrocortisone.


Risk-decreasing factors in the angiographic examination of intracranial haemorrhage.
The neuroradiological examination in patients with clinical symptoms of intracranial bleeding is indicated in a high percentage of cases, especially since large series of CT examinations have proven that in many cases the false clinical diagnosis of cerebrovascular accident is made with patients actually bleeding out of arterial lesions. In a large number of cases angiography will be necessary in addition to CT examination. Naturally the complications which may occur with these angiographic procedures should be avoided as much as possible. Measures to minimalize the haemodynamic effect of catheterization or puncture and the following contrast injection in the brachiocephalic vessels are discussed. The application of metrizamide as a contrast medium with these angiographic analyses is explained.


Regional isolated perfusion of extremities for melanoma: a 20-year experience with drugs other than L-phenylalanine mustard.
Recurrent melanoma of the extremities can lead to bulky symptomatic lesions that become difficult management problems. Treatment of these tumors with isolated limb perfusion with high dose chemotherapy may offer palliation in a number of patients. Unfortunately, the most commonly used drug, L-phenylalanine mustard, has been known to have significant associated tissue toxicity. Therefore, during the years 1976-1995, we perfused 67 limbs in 60 patients with various other drugs: 36 with dimethyltriazeno imidazole carboxamide, 6 with cisplatin, 20 with carboplatin, and 5 with thiotepa). Perfusion was performed for 16 upper extremities and 51 lower extremities using the pump oxygenator for 1 hour. Among the 60 patients, 17 were treated prophylactically for high-risk melanoma, whereas 43 were treated for local and in-transit recurrences. The technique of perfusion successfully isolated the limbs from the systemic circulation: the median leaks over time were 0.5-1.6 percent for the upper extremities, and 0.2-7.5 percent for the lower extremities. Among the 43 patients treated with therapeutic isolated limb perfusion, 11 patients (26 percent) are alive with no evidence of disease for a median of 58 months (range: 8 months to 17 years 9 months), and another 5 patients (12 percent) are alive with recurrence for a median of 45 months (range: 27 months to 10 years 7 months). Four patients required two perfusions, and two patients required three perfusions (one patient has no evidence of disease 6 years after her third perfusion for recurring in-transit disease). There were 19 complications noted after 14 of the 67 perfusions (21%): postoperative edema, 5; seroma, 4; wound separation/infection, 9; and nonfatal pulmonary embolus, 1. In our experience, aggressive treatment in selected patients with regional isolated perfusion of limbs for melanoma has provided meaningful palliation and salvage of the limbs with adequate disease-free control, and occasional survival benefit. This regional treatment modality is associated with meaningful control and with few serious complications, especially when compared with studies using L-phenylalanine mustard. This series illustrates the safety of controlling limb recurrence with this technique, even with repeat perfusions in the same patient.


Modulation of the gut microbiota by nutrients with prebiotic and probiotic properties.
Experimental data in animals, but also observational studies in humans, suggest that the composition of the gut microbiota differs in obese vs. lean individuals, in patients with vs. without diabetes, or in patients presenting other diseases associated with obesity or nutritional disbalance, such as non-alcoholic fatty liver disease (NAFLD) or cardiovascular diseases. In this review, we describe how changes in the composition and/or activity of the gut microbiota by administration of nutrients with probiotic or prebiotic properties can modulate host gene expression and metabolism and thereby positively influence host adipose tissue development and related metabolic disorders.


Discrimination of fearful and angry emotional voices in sleeping human neonates: a study of the mismatch brain responses.
Appropriate processing of human voices with different threat-related emotions is of evolutionarily adaptive value for the survival of individuals. Nevertheless, it is still not clear whether the sensitivity to threat-related information is present at birth. Using an odd-ball paradigm, the current study investigated the neural correlates underlying automatic processing of emotional voices of fear and anger in sleeping neonates. Event-related potential data showed that the fronto-central scalp distribution of the neonatal brain could discriminate fearful voices from angry voices; the mismatch response (MMR) was larger in response to the deviant stimuli of anger, compared with the standard stimuli of fear. Furthermore, this fear-anger MMR discrimination was observed only when neonates were in active sleep state. Although the neonates' sensitivity to threat-related voices is not likely associated with a conceptual understanding of fearful and angry emotions, this special discrimination in early life may provide a foundation for later emotion and social cognition development.


Prevalence of New Zealand children and adolescents achieving current physical activity and television watching recommendations.
Aims were to investigate sex, ethnicity, and age differences in achieving daily step count and television (TV) watching recommendations in schoolchildren. Participants were 615 children (n = 325) and adolescents (n = 290) aged 5 to 16 years. Activity was assessed over 5 days using pedometers; TV time was collected via parental proxy-report and self-report. Ethnic, sex, and age differences in step counts, TV time, and odds of meeting TV and step count recommendations were examined for weekdays, weekend days, and overall using generalized estimation equation modeling. Overall, girls were more active than boys (P < .001). Adolescents were more active than children (P = .044), watched more TV (P = .005), and were less likely to meet TV watching recommendations (P = .004). Non-European children watched significantly more TV (P = .008), and were significantly less likely to meet TV recommendations than non-European children (P = .001). Participants watched more TV and accumulated less steps on weekend days than weekdays. Multifaceted interventions focusing on both increasing activity and decreasing TV time are needed, especially on weekends. Children and girls may benefit more from activity interventions, while ethnic-specific interventions focusing on TV habits may be most efficacious for adolescents.


Achieving the Goals of Healthy China 2030 Depends on Increasing Smoking Cessation in China: Comparative Findings from the ITC Project in China, Japan, and the Republic of Korea.
Tobacco smoking is the number one preventable cause of disease and death in China as it is globally. Indeed, the toll of smoking in China is much greater than its status as the world's most populous country. There is a persistent and continuing need for China to implement the measures specified in the global tobacco control treaty, the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC), which China ratified in 2005. The theme for the 2021 WHO World No Tobacco Day focuses on the need to support smoking cessation. This article presents findings from the International Tobacco Control (ITC) Policy Evaluation Project cohort surveys in China, in comparison to ITC cohort surveys in two neighboring countries: Japan and the Republic of Korea. These findings demonstrate that smokers in China very much want to quit, but these intentions are not being translated into quit attempts, relative to smokers in Japan and the Republic of Korea. Additionally, about 80% of Chinese smokers want the Chinese government to do more to control smoking. These findings reaffirm the need for China to implement strong, evidence-based measures to reduce smoking. The objective of Healthy China 2030 to reduce deaths from non-communicable diseases by 30% can be achieved by reducing smoking prevalence from its current 26.6% to 20%, and this reduction can be achieved through strong implementation of FCTC measures.


Bioinformatic identification and characterization of human endothelial cell-restricted genes.
In this study, we used a systematic bioinformatics analysis approach to elucidate genes that exhibit an endothelial cell (EC) restricted expression pattern, and began to define their regulation, tissue distribution, and potential biological role. Using a high throughput microarray platform, a primary set of 1,191 transcripts that are enriched in different primary ECs compared to non-ECs was identified (LCB >3, FDR <2%). Further refinement of this initial subset of transcripts, using published data, yielded 152 transcripts (representing 109 genes) with different degrees of EC-specificity. Several interesting patterns emerged among these genes: some were expressed in all ECs and several were restricted to microvascular ECs. Pathway analysis and gene ontology demonstrated that several of the identified genes are known to be involved in vasculature development, angiogenesis, and endothelial function (P < 0.01). These genes are enriched in cardiovascular diseases, hemorrhage and ischemia gene sets (P < 0.001). Most of the identified genes are ubiquitously expressed in many different tissues. Analysis of the proximal promoter revealed the enrichment of conserved binding sites for 26 different transcription factors and analysis of the untranslated regions suggests that a subset of the EC-restricted genes are targets of 15 microRNAs. While many of the identified genes are known for their regulatory role in ECs, we have also identified several novel EC-restricted genes, the function of which have yet to be fully defined. The study provides an initial catalogue of EC-restricted genes most of which are ubiquitously expressed in different endothelial cells.


Evaluation of surveillance protocols for detecting porcine reproductive and respiratory syndrome virus infection in boar studs by simulation modeling.
Because porcine reproductive and respiratory syndrome virus (PRRSV) can be transmitted through semen, PRRSV-free boar studs need to be routinely monitored to rapidly detect any potential PRRSV introduction. However, current protocols for monitoring PRRSV in boar studs are diverse, sometimes very costly, and their effectiveness has not been quantified. The objective of this study was to evaluate the ability of different monitoring protocols to detect PRRSV introduction into a negative boar stud by using a simulation modeling approach. A stochastic transmission model was constructed to simulate the spread of PRRSV in a typical negative boar stud in the USA (herd size of 200 boars, 60% annual replacement) and the performance of monitoring protocols by using different sample sizes (10, 30, and 60 samples), sampling frequency (3 times a week, weekly, and biweekly), and diagnostic procedures (PCR on semen, PCR on serum, ELISA on serum, and both PCR and ELISA on serum). The monitoring protocols were evaluated in terms of the time from PRRSV introduction into the boar stud to PRRSV detection. Protocols that used PCR on serum detected the PRRSV introduction earlier than protocols that used PCR on semen, and these were earlier than those that used ELISA on serum. The most intensive protocol evaluated (testing 60 boars 3 times a week by PCR on serum) would need 13 days to detect 95% of the PRRSV introductions. These results support field observations, suggesting that an intensive monitoring protocol needs to be in place in a boar stud to quickly detect a PRRSV introduction.


[General practitioners' participation in out-of-hours work].
Out-of-hours work is often perceived as burdensome and there is an inherent increased risk of making mistakes. The aim of the study was to examine Regular General Practitioners' (RGPs') experiences with and attitudes to out-of-hours work. A questionnaire was sent to all RGPs in Norway. Participation in out-of-hours work was analysed against characteristics of the physician, list, and municipality. 2,913 RGPs responded (78%). 50% participated fully, 15% partly, and 35% did not participate in out-of-hours work. 28% were formally exempted, and 13% had a regular locum. Women and elderly RGPs participated less, as did RGPs in large and central municipalities. Out-of-hours cooperatives covering several municipalities reduced the amount of work, but did not increase the RGPs' participation rate. List characteristics had little influence on the participation rate. 60% of the RGPs tried to give away most of their duties, 16% wanted more out-of-hours work than their regular duties and 16% of those below 55 years who were still doing out-of-hours work wanted to continue after 55 years. RGPs in small and remote municipalities considered out-of-hours work more challenging, but less remunerating, and more often wanted to move from the municipality. Many RGPs do not participate in out-of-hours work. As Norwegian RGPs constitute an aging cohort, this may become an increasing problem.


Bioselective membrane electrode probes.
The use of intact bacterial cells or tissue slices of plant and animal origin as immobilized biocatalysts has extended the possible range of potentiometric bioselective membrane electrodes beyond that of conventional enzyme electrodes. The use of such materials as biocatalysts offers advantages in situations where isolated enzymes are not available or where multistep reaction paths are required. The resulting bioselective electrodes also offer exceptional ease of preparation, time stability, and low cost.


Developing a comprehensive breast center.
In 1985 the University of Michigan Medical Center established a multidisciplinary breast care center (BCC) to provide comprehensive diagnosis and treatment for patients with benign and malignant breast disease. Ninety-eight per cent of the first 500 new patients were women and 2 per cent were men. One-hundred thirty-one women (26.7%) and no men had breast cancer. Of the remaining 359 women, 75.3 per cent had some element of fibrocystic disease. Patients who had breast cancer were evaluated during their initial visit to the BCC by a nurse, general surgeon, radiation therapist, and oncologist. Ninety-five per cent of all patients were given a definitive treatment plan or a second opinion at the conclusion of their one visit to the center. Patient and physician satisfaction with the center concept has been high. The center emphasizes patient education and choice between mastectomy and breast-sparing procedures and radiation therapy for the control of primary cancers. Adjuvant chemotherapy or hormonal therapy is given to all nodal-positive patients. Establishment of multidisciplinary centers, such as the BCC, requires the commitment of all physician specialty groups, nursing and hospital administration. High quality patient care can be provided in such centers in a more efficient and coordinated manner than in the non-center setting. The center can serve as a source of increased patient referrals and research opportunities.


Patterns of content, contextual, and working memory impairments in schizophrenia and nonamnesic alcoholism.
This study used tests of content memory (item recognition of words and abstract designs), context memory (order recognition of verbal and nonverbal items), and working memory (recognition at a short retention interval) to examine patterns of performance in 27 schizophrenic patients, 52 chronic alcoholic patients, and 66 healthy control participants. When performance was age- and IQ-adjusted the schizophrenia group was significantly impaired in item and order recognition of verbal and nonverbal material; the alcoholic group was impaired only in order recognition for both material types. Item- and order-recognition deficits in the schizophrenia group were greatest at the shortest retention intervals, a pattern previously observed in patients with Parkinson's disease, suggesting a prominence of a working memory deficit in schizophrenia.


The diagnosis of bacteriuria during pregnancy.
Three diagnostic tests, Nitur, Urobact, and Uricult, were evaluated in the detection of bacteriuria in 865 pregnant women. As reference method agar culture was performed. Heavy growth (greater than 10(5) CFU/ml) of urinary tract bacteria was considered a true positive result and demonstrated in 58 (6.7%) of the women, 14 of whom had gram-negative rods. The sensitivity of the nitrite test was extremely low (0.13). The test gave negative results in eight of 17 specimens yielding heavy growth of Escherichia coli or Proteus mirabilis. Although the Urobact test was highly sensitive as regards gram-negative infection, it had an unacceptably low (0.27) predictive value in positive tests. The sensitivity of the Uricult test was low (0.35) in this study. The predictive value (0.50) of a positive test result may be acceptable, since just over half of the false positive results were explainable by moderate growth of urinary tract pathogens (10(4)-10(5) CFU/ml). It is argued that semi-quantitative urine culture may be preferable to the rapid diagnostic methods studied for the screening of bacteriuria in pregnant women.


Preliminary retrospective investigation of FDG-PET/CT timing in follow-up of ablated lung tumor.
The aim of this study was to clarify the most appropriate follow-up initiation time point for positron emission tomography (PET)/computed tomography (CT) following radio frequency ablation (RFA) of lung tumors, and the cutoff values of maximum standard uptake value (SUV(max)) to evaluate local tumor progression. We enrolled 15 patients (8 men, median age 62 years) with 60 tumors, who were treated with RFA of lung tumors and underwent fluorodeoxyglucose (FDG)-PET/CT following RFA. Local tumor progression was assessed by periodic chest CT images prior to and following intravenous administration of a contrast medium. The SUV(max) of three periods, namely, 0-3 months, 3-6 months, and 6-9 months after RFA, was evaluated. The appropriate time point for follow-up initiation and the cutoff value of SUV(max) were determined using receiver-operating characteristic (ROC) analysis. The median follow-up period was 357 days. Of 60 tumors, 10 showed local progression. The area under the ROC curve (Az) for the 6-9 months (P = 0.044) was the largest and almost equal to that of the 3-6 months (P = 0.024). Az for the 0-3 months was the smallest and statistically insignificant (P = 0.705). The cutoff value of 1.5 of SUV(max) at 3-9 months after RFA showed 77.8% sensitivity and 85.7-90.5% specificity. The appropriate follow-up initiation time point is at least 3 months following RFA. Thus, SUV(max) is a useful and reliable predictive indicator.


Species differences in lipid peroxide levels in lung tissue and investigation of their determining factors.
Marked species differences in thiobarbituric acid reactant value (TBA value) in normal lung tissue of five species of animals were found. The order of the values was mouse greater than hamster greater than rat greater than guinea pig greater than rabbit, and the value for mice was 3.6 times higher than that for rabbit. The vitamin E (VE) and nonprotein sulfhydryls (NPSH) contents in lungs varied widely among the five animal species. Species differences were also observed on polyunsaturated fatty acid composition in lung phospholipids. The peroxidizability index (PI), which shows the relative rate of peroxidation reaction, was calculated from the composition ratio and the reactivity of each polyunsaturated fatty acid, and the PI was found to be significantly correlated to the TBA value in lungs (r = 0.853, p less than 0.001). The PI value was normalized by the contents of VE and/or NPSH. Finally, the log-value of PI, normalized by the log values of the reciprocals of VE and NPSH, log(PI/VE X NPSH), showed the highest correlation coefficient (r = 0.907, p less than 0.001). Normalization by the activities of antioxidative protective enzymes in lungs did not show any significant correlation against TBA value. These results suggest that TBA value as an index of lipid peroxides in the lungs of animals may be regulated mainly by the contents of VE and NPSH, the composition ratio and the reactivity of each polyunsaturated fatty acid in lung phospholipid fraction.


Language selection in bilinguals: a spatio-temporal analysis of electric brain activity.
Language selection refers to the cognitive mechanism that allows bilinguals to communicate in one language or the other and to switch between languages depending on the listener. Previous studies suggested that various brain areas might be involved in this process. However, the question remains whether language selection is achieved through a language-specific mechanism or through a general cognitive control process. To address this question, we compared event-related potentials (ERPs) induced by language selection and task selection processes during image naming. ERPs were collected from bilingual subjects while tested in two different contexts: a monolingual task selection context (TSc) where a post-stimulus cue instructed subjects either to name the image or generate a corresponding verb in their first language (L1), and a bilingual language selection context (LSc) where the cue indicated to name the image either in the first or the second language. By comparing the ERPs induced by the same L1 naming as a function of context, we assumed that if the selection processes varied across contexts, then electric brain responses should differ rapidly after the cue presentation. Our analysis indicated that the first ERP differences accounting for the diverging processes involved appeared between approximately 220 and 300 ms after the cue. The estimation by source localisation of brain regions accounting for these differences pointed to an increased activation during LSc in the left middle frontal-precentral gyri, supramarginal and angular gyri. Our results suggest that language selection is achieved through a neural network involving areas implicated in both general cognitive processes and language processing.


Patient-related keloid scar assessment and outcome measures.
Keloid scars cause pain, itching, functional limitation, and disfigurement, leading to psychological distress. Progress in treatment regimens is hindered by the lack of a universally accepted outcome measure. The Patient and Observer Scar Assessment Scale is a tool for the assessment of scars, incorporating an assessment by both clinician and patient. This study evaluates its application to keloids and compares it to the widely used Vancouver Scar Scale, which is considered the standard mode of assessment for scars. Three observers using the two scales assessed 34 patients with 41 keloid scars independently. Patients evaluated their own scars simultaneously using the patient component of the Patient and Observer Scar Assessment Scale. Internal consistency, interobserver reliability, and convergent validity were examined. Both components of the Patient and Observer Scar Assessment Scale had high internal consistency (0.82 and 0.86 for patient and observer components, respectively); those rates were higher than the rate for the Vancouver Scar Scale (0.65). Interobserver reliability was "substantial" for the Vancouver Scar Scale (0.65) and "almost perfect" for the observer component of the Patient and Observer Scar Assessment Scale (0.85). Convergent validity was very strong (0.83, p < 0.01), although the patient component did not correlate well with either of the observer scales. Patients rated their scars worse than the observer average for 83 percent of the scars, and were influenced by color, stiffness, thickness, and irregularity (p < 0.05). The findings support the use of the Patient and Observer Scar Assessment Scale as a reliable and valid method of assessing keloid scars in a clinical context. Diagnostic, II.


Metastasis associated lung adenocarcinoma transcript 1 is up-regulated in placenta previa increta/percreta and strongly associated with trophoblast-like cell invasion in vitro.
Placenta previa increta/percreta (I/P) is a severe form of invasive placentation associated with massive peripartum hemorrhage, which often requires Cesarean hysterectomy. The pathogenesis of invasive placentation is multidimensional, involving decidual deficiency, endomyometrial damage and excessively deep trophoblast invasion into the uterus. In this study, annealing control primer-polymerase chain reaction (ACP-PCR) was used to identify differentially expressed genes, which may impair placentation resulting in placenta previa I/P. Placental tissues from I/P and non-increta/percreta (non-I/P) sites were concomitantly collected from patients undergoing Cesarean hysterectomy. After ACP-PCR experiments (three patients), the differentially expressed bands, consistently showing up- or down-regulated trends between each of the I/P and non-I/P tissue pairs, were cloned and sequenced. Human non-protein coding metastasis associated lung adenocarcinoma transcript 1 (MALAT-1) gene was identified. Real-time quantitative PCR (10 patients) confirmed significant overexpression of MALAT-1 in I/P samples (P = 0.005). To investigate the role of MALAT-1 gene in the regulation of trophoblast cell invasion, targeting of MALAT-1 mRNA expression with short interfering RNA (siRNA) in trophoblast-like BeWo, JAR and JEG-3 choriocarcinoma cells was performed. The invasion ability of these cells was significantly suppressed after siRNA silencing (P < 0.001), and this was not correlated with abnormal MMP-2 and MMP-9 enzyme activities. Our results suggest that MALAT-1 expression in placenta previa I/P is increased and its down-regulation inhibits trophoblast-like cell invasion in vitro. MALAT-1 might be involved in regulating trophoblast invasion during the development of advanced invasive placentation.


A new antibacterial silver(I) complex incorporating 2,5-dimethylpyrazine and the anti-inflammatory diclofenac.
AgI-containing coordination complexes have attracted attention because of their photoluminescence properties and antimicrobial activities and, in principle, these properties depend on the nature of the structural topologies. A novel two-dimensional silver(I) complex with the anti-inflammatory diclofenac molecule, namely bis{μ-2-[2-(2,6-dichloroanilino)phenyl]acetato-κ3O,O':O}bis(μ-2,5-dimethylpyrazine-κ2N:N')silver(I), [Ag2(C14H10Cl2NO2)2(C6H8N2)]n, (I), has been synthesized and characterized by single-crystal X-ray diffraction, revealing that the AgI ions are chelated by the carboxylate groups of the anionic 2-[2-(2,6-dichloroanilino)phenyl]acetate (dicl) ligand in a μ3-η1:η2 coordination mode. Each dicl ligand links three AgI atoms to generate a one-dimensional infinite chain. Adjacent chains are connected through 2,5-dimethylpyrazine (dmpyz) ligands to form a two-dimensional layer structure parallel to the crystallographic bc plane. The layers are further connected by C-H...π interactions to generate a three-dimensional supramolecular structure. Additionally, the most striking feature is that the structure contains an intramolecular C-H ...Ag anagostic interaction. Furthermore, the title complex has been tested for its in vitro antibacterial activity and is determined to be highly effective on the studied microorganisms.


Patient education leaflet for hypertension: a controlled study.
THIS STUDY ATTEMPTS TO ANSWER THE QUESTION: is a leaflet, designed according to criteria of likely effectiveness, actually more effective in practice than a standard patient education leaflet? A new leaflet was designed, its content determined by the responses of a sample of New Zealand general practitioners. Four matched groups of hypertensive patients were used to compare gain from an old leaflet (group 1), a new leaflet (group 2), a tape-slide programme plus a new leaflet (group 3); group 4 were controls. Group 3 showed the only significant educational gain.


Continence for women: evaluation of AWHONN's third research utilization project.
OBJECTIVE: To develop an evidence-based protocol for initial evaluation and treatment of urinary incontinence and to design procedures that would facilitate the protocol's implementation into clinical practice. DESIGN: Descriptive report of the Association of Women's Health, Obstetric and Neonatal Nurses (AWHONN) Continence for Women Project. SETTING: Twenty-one public, private, and other women's health sites. Participants: Women in ambulatory care settings (N = 1474) provided demographic statistics. METHODS: The protocol was developed, sites were selected, site coordinator training was provided, data collection was facilitated by project-specific teleforms, and the overall process was evaluated by the science team. MAIN OUTCOME MEASURES: Site representation, patient representation, site coordinator feedback on the training program, and site coordinator experience during project implementation. RESULTS: The process yielded a representative mix of site and patient diversity appropriate for testing of the protocol. Site coordinators felt well-prepared to implement the protocol and experienced increased professional satisfaction because of therapeutic benefits achieved for patients and positive collaboration with physicians. CONCLUSIONS: The Continence for Women Project demonstrated the potential for developing and testing evidence-based protocols for clinical practice when the resources of an organization such as AWHONN and the research community are combined.


Ability of a beta-casein phosphopeptide to modulate the precipitation of calcium phosphate by forming amorphous dicalcium phosphate nanoclusters.
The ability of casein in the form of colloidal-sized casein micelles to modulate the phase separation of calcium phosphate during milk secretion is adapted to produce nanometre-sized particles of calcium phosphate stabilized by a casein phosphopeptide (nanoclusters). The nanoclusters were prepared from an undersaturated solution of salts and the peptide by raising the pH homogeneously from about 5.5 to 6.7 with urea plus urease. Chemical analysis and IR spectroscopy showed that they comprise an amorphous dicalcium phosophate bound to the phosphopeptide. Multinuclear NMR spectroscopy of the cluster solutions showed that the small ions and free peptide in the solution were in a state of dynamic exchange with the nanoclusters. The peptide is linked to the calcium phosphate through its sequence of phosphorylated residues, but, in a proportion of adsorbed conformational states, the termini retain the conformational freedom of the unbound peptide. The ability of casein to form nanoclusters in milk suggests a more general mechanism for avoiding pathological calcification and regulating calcium flow in tissues and biological fluids exposed to or containing high concentrations of calcium.


Ultrasound evaluation of the scapholunate ligament and scapholunate joint space in patients with wrist complaints in a rheumatologic setting.
The aims of the study were to perform an ultrasound assessment of the dorsal portion of the scapholunate interosseous ligament and scapholunate joint space in patients with wrist complaints in a rheumatologic setting, to describe ultrasound abnormalities about scapholunate interosseous ligament region, and to correlate them with clinical data, presence of dorsal ganglion cysts and diagnoses of rheumatic diseases. Seventy-four consecutive patients with wrist pain and/or swelling were evaluated by routine power Doppler ultrasound. Forty normal wrists were studied to confirm the normality values of the scapholunate joint. The mean width of the normal scapholunate joint was 2.49 mm (±0.49 SD), with a coefficient of variation on repeated measurements of 3.662%. The best predictors of scapholunate interosseous ligament degeneration were: older age (p <0.0001), male gender (p = 0.0049), and radiocarpal effusion (p = 0.0156). The presence of osteophytosis and calcifications of the scapholunate joint were higher (p <0.001) in rheumatic patients. Scapholunate calcifications showed a sensitivity of 98.2% and a specificity of 61.1% for calcium pyrophosphate deposition disease. Dorsal ganglion cysts were more frequent in younger subjects (p <0.0012) without rheumatic conditions (p <0.0001) or midcarpal synovitis (p <0.0001). Larger cysts often exhibited power Doppler signal (p <0.0001). The best predictors of scapholunate dissociation were: male gender (p = 0.0002), presence of midcarpal synovitis (p <0.0137), and higher grade of scapholunate interosseous ligament degeneration (p <0.0001). Scapholunate widening was greater (p = 0.0419) in calcium pyrophosphate deposition disease or rheumatoid arthritis than in other rheumatic conditions. Ultrasound findings of scapholunate interosseous ligament degeneration and calcification, scapholunate space enlargement, and dorsal ganglion cysts should be considered in ultrasound reporting, since they add useful information about the diagnosis of associated rheumatic conditions.


Effects of a mis-sense DISC1 variant on brain activation in two cohorts at high risk of bipolar disorder or schizophrenia.
Bipolar disorder and schizophrenia share a number of clinical features and genetic risk variants of small effect, suggesting overlapping pathogenic mechanisms. The effect of single genetic risk variants on brain function is likely to differ in people at high familial risk versus controls as these individuals have a higher overall genetic loading and are therefore closer to crossing a threshold of disease liability. Therefore, whilst the effects of genetic risk variants on brain function may be similar across individuals at risk of both disorders, they are hypothesized to differ compared to that seen in control subjects. We sought to examine the effects of the DISC1 Leu(607) Phe polymorphism on brain activation in young healthy individuals at familial risk of bipolar disorder (n = 84), in a group of controls (n = 78), and in a group at familial risk of schizophrenia (n = 47), performing a language task. We assessed whether genotype effects on brain activation differed according to risk status. There was a significant genotype × group interaction in a cluster centered on the left pre/postcentral gyrus, extending to the inferior frontal gyrus. The origin of this genotype × group effect originated from a significant effect of the presumed risk variant (Phe) on brain activation in the control group, which was absent in both high-risk groups. Differential effects of this polymorphism in controls compared to the two familial groups suggests a commonality of effect across individuals at high-risk of the disorders, which is likely to be dependant upon existing genetic background.


A standardised approach towards PROving the efficacy of foods and food constituents for health CLAIMs (PROCLAIM): providing guidance.
Diet is well known to have beneficial health properties that extend beyond traditionally accepted nutritional effects. The approach involved in elucidating these beneficial physiological effects is becoming more important, as reflected by increasing research being undertaken. With growing consumer awareness of foods and food constituents and their relationship to health, the key questions for regulators, scientists and the food industry continue to relate to: (1) how consumers could be protected and have confidence that the health claims on foods are well supported by the evidence; (2) how research on physiological effects of food (constituents) and their health benefits could be stimulated and supported; (3) how research findings could be used in the development of innovative new food products. The objectives of this paper are to provide a set of recommendations on the substantiation of health claims for foods, to develop further guidance on the choice of validated markers (or marker patterns) and what effects are considered to be beneficial to the health of the general public (or specific target groups). Finally, the case for developing a standardised approach for assessing the totality of the available scientific data and weighing the evidence is proposed.


Intrathecal Nalbuphine and Dexmedetomidine as Adjuvants to Bupivacaine versus Plain Bupivacaine for Orthopedic Surgeries under Subarachnoid Block: A Comparative Study.
In long bone surgeries, the severity of pain is more, demanding good intraoperative anesthesia, and prolonged postoperative analgesia. This is achieved in spinal anesthesia with adjuvants to local anesthetics, which act synergistically. The aim of this study was to compare the efficacy of nalbuphine and dexmedetomidine as adjuvants to bupivacaine versus bupivacaine alone in lower limb orthopedic surgeries under the subarachnoid block (SAB). This is a prospective, randomized, double-blind control study conducted on 60 patients belonging to the American Society of Anesthesiologists physical status Classes I and II, undergoing lower limb orthopedic surgeries under SAB. Sixty patients were divided into three groups by computer-generated randomization. Group A received 2.7 mL of 0.5% hyperbaric bupivacaine with 1.5 mg nalbuphine, Group B received 2.7 mL of 0.5% hyperbaric bupivacaine with 10 μg dexmedetomidine, and Group C received 2.7 mL of 0.5% hyperbaric bupivacaine with 0.5 mL of normal saline (total volume made to 3.2 mL in all groups with normal saline). Time of onset of block, duration of sensory, and motor blocks were noted. Changes in hemodynamic parameters, postoperative first rescue analgesia requirement, and side effects were recorded. Data were analyzed using SPSS 22 version software. P < 0.05 was considered statistically significant. There was no significant difference in the onset of sensory or motor blocks in the three groups. However, the time taken for regression of sensory block was longer in Group B that was statistically significant. Intrathecal dexmedetomidine acts as a better adjuvant with bupivacaine in providing quality anesthesia, prolonged sensory and motor block, and good postoperative analgesia with less incidence of adverse effects compared to nalbuphine and bupivacaine alone.


Sesame Extract Promotes Chemopreventive Effect of Hesperidin on Early Phase of Diethylnitrosamine-Initiated Hepatocarcinogenesis in Rats.
The combination of natural products is an alternative approach to achieving chemopreventive potential. Accordingly, citrus hesperidin exhibits numerous biological activities, including anticarcinogenic activities, while the sesamin in sesame exhibits potent anticancer activities and lipid-lowering effects. We investigated the cancer chemopreventive effects of mixed sesame and orange seed extract (MSO) containing hesperidin and sesamin in diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Rats were injected with DEN once a week for 3 weeks to induce hepatocarcinogenesis. Rats were fed with MSO and various compositions that included sesame extract (SE) and hesperidin. The 10-week administration of MSO more effectively inhibited the number and size of hepatic GST-P-positive foci than hesperidin in DEN-initiated rats. MSO and hesperidin decreased the number of PCNA-positive hepatocytes but increased the apoptotic cells in DEN-induced rats. Furthermore, MSO and its constituents suppressed hepatic triglyceride content concurrently along with the expression of fatty acid synthase. Although the 5-week administration of MSO or hesperidin did not alter hepatic, preneoplastic lesion formation in DEN-initiated rats, it alleviated DEN-induced hepatotoxicity. MSO and its applied compositions did not impact upon the cytochrome P450 system. In conclusion, sesame extract promoted the chemopreventive effect of hesperidin on DEN-induced early stage of hepatocarcinogenesis in rats. The inhibitory mechanisms are likely involved with the induction of cell apoptosis, suppression of cell proliferation and modulation of hepatic lipogenesis. This study may provide revelations in the development of alternative treatments against hepatocellular carcinoma.


Characterization of interactions of 4-nitrophenylpropyl-N-alkylamine with ς receptors.
Sigma receptors are small membrane proteins implicated in a number of pathophysiological conditions, including drug addiction, psychosis, and cancer; thus, small molecule inhibitors of sigma receptors have been proposed as potential pharmacotherapeutics for these diseases. We previously discovered that endogenous monochain N-alkyl sphingolipids, including d-erythro-sphingosine, sphinganine, and N,N-dimethylsphingosine, bind to the sigma-1 receptor at physiologically relevant concentrations [Ramachandran, S., et al. (2009) Eur. J. Pharmacol. 609, 19-26]. Here, we investigated several N-alkylamines of varying chain lengths as sigma receptor ligands. Although the K(I) values for N-alkylamines were found to be in the micromolar range, when N-3-phenylpropyl and N-3-(4-nitrophenyl)propyl derivatives of butylamine (1a and 1b, respectively), heptylamine (2a and 2b, respectively), dodecylamine (3a and 3b, respectively), and octadecylamine (4a and 4b, respectively) were evaluated as sigma receptor ligands, we found that these compounds exhibited nanomolar affinities with both sigma-1 and sigma-2 receptors. A screen of high-affinity ligands 2a, 2b, 3a, and 3b against a variety of other receptors and/or transporters confirmed these four compounds to be highly selective mixed sigma-1 and sigma-2 ligands. Additionally, in HEK-293 cells reconstituted with K(v)1.4 potassium channel and the sigma-1 receptor, these derivatives were able to inhibit the outward current from the channel, consistent with sigma receptor modulation. Finally, cytotoxicity assays showed that 2a, 2b, 3a, and 3b were highly potent against a number of cancer cell lines, demonstrating their potential utility as mixed sigma-1 and sigma-2 receptor anticancer agents.


Regulation of binding of phosphofructokinase to myofibrils in the red and white muscle of the barred sand bass, Paralabrax nebulifer (Serranidae).
The binding of phosphofructokinase (PFK) to myofibrils from the white muscle of the fish Paralabrax nebulifer (Girard, 1854) is sensitive to factors known to be allosteric regulators of PFK activity. PFK in Triton-X-100-extracted muscle remains bound to myofibrils at pH 7.0 and is fully solubilized by increasing the pH to 8.0. The curve describing the pH-dependence of PFK binding to myofibrils is similar in its steepness to pH versus activity curves of PFK at low temperature. Nucleotides are also potent modulators, preventing the association of PFK with myofibrils at concentrations between 20 and 60 mumol l-1 of ATP, ADP, MgATP or GTP, listed in order of effectiveness. PFKs in the red and white muscle extracts differ in their pH-dependence of binding to myofibrils, and their kinetic and regulatory properties (response to citrate, pH and fructose-2,6-bisphosphate). Reversible binding of PFK to myofibrils may be important in the control of glycolysis, especially in the highly glycolytic white muscle fibres.


[Augmentation of selective serotonin reuptake inhibitors (SSRI) with atypical antipsychotics in the treatment of depression].
The treatment of severe depression represents a difficult task in the daily psychiatric practice. In certain cases, augmentation therapies in order to improve the efficacy of SSRIs can be useful. Recently, it has become possible to use atypical antipsychotics for SSRI augmentation. This option adds to the existing strategies in the treatment of depression and primary systematic studies show encouraging results. In this review, the possibility of a SSRI augmentation by additionally administering risperidone or olanzapine is critically discussed.


Glaucoma-associated long-term mortality in a rural cohort from India: the Andhra Pradesh Eye Disease Study.
To evaluate glaucoma-associated mortality in a rural cohort in India. The study cohort comprised individuals aged 40 years and above who took part in the Andhra Pradesh Eye Disease Study (APEDS1) during 1996-2000. All participants underwent detailed comprehensive eye examination. Glaucoma was defined using International Society of Geographic and Epidemiologic Ophthalmology criteria. This cohort was followed up after a decade (June 2009 to January 2010; APEDS2). Mortality HR analysis for ocular risk factors was performed using Cox proportional hazards regression after adjusting for sociodemographic, lifestyle and clinical variables. In APEDS1, 2790 individuals aged more than or equal to 40 years were examined. 47.4% were male. Forty-five participants had primary open angle glaucoma (POAG) and 66 had primary angle closure disease (PACD). Ten years later, 1879 (67.3%) were available, 739 (26.5%) had died and 172 (6.2%) had migrated; whereas 22 of the 45 (48.8%) with POAG and 22 of the 66 (33.3%) with PACD had died. In univariate analysis, a higher mortality was associated with POAG (HR 1.9; 95% CI 1.23 to 2.94), pseudoexfoliation (HR 2.79; 95% CI 2.0 to 3.89), myopia (HR 1.78; 95% CI 1.54 to 2.06) and unit increase in cup:disc ratio (HR 4.49; 95% CI 2.64 to 7.64). In multivariable analysis, only cup:disc ratio remained independently associated with mortality (HR 2.5; 95% CI 1.3 to 5.1). The association remained significant when other ocular parameters were included in the model (HR 2.1; 95% CI 1.03 to 4.2). This is the first longitudinal study to assess the association of glaucoma and mortality in a rural longitudinal cohort in India. Increased cup:disc ratio could be a potential marker for ageing and would need further validation.