A nomogram for predicting the risk of preeclampsia in women with intrahepatic cholestasis of pregnancy based on prenatal monitoring time: a multicenter retrospective cohort study.
Intrahepatic cholestasis of pregnancy (ICP) is a special liver disease during pregnancy, characterized by abnormal bile acid metabolism. However, there is no consensus on how to group women with ICP based on the time of diagnosis worldwide. This study aimed to adopt a new grouping model of women with ICP, and the time from diagnosis to delivery was defined as the monitoring period. This retrospective real-world data study was conducted across multiple centers and included 3172 women with ICP. The study first evaluated the significant difference in medication and nonmedication during different monitoring times. The least absolute shrinkage and selection operator (LASSO) model was then used to screen nine risk factors based on the predictors. The model's discrimination, clinical usefulness, and calibration were assessed using the area under the receiver operating characteristic (ROC) curve, decision curve, and calibration analysis. The incidence of preeclampsia risk in ICP patients without drug intervention increased with the extension of the monitoring period. However, the risk of preeclampsia decreased in ICP patients treated with ursodeoxycholic acid. A predictive nomogram and risk score model was developed based on nine risk factors. The area under the ROC curve of the nomogram was 0.765 [95% confidence interval (CI): 0.724-0.807] and 0.812 (95% CI: 0.736-0.889) for the validation cohort. This study found that a longer ICP monitoring period could lead to adverse pregnancy outcomes in the absence of drug intervention, especially preeclampsia. A predictive nomogram and risk score model was developed to better manage ICP patients, maintain pregnancy to term delivery, and minimize the risk of severe adverse maternal and fetal outcomes.


The relative value of nursing work: a study in progress.
The nursing shortage is likely to continue and, without intervention, may worsen. While retention and recruitment are constantly discussed among nursing leaders, the shortages, particularly in specialty areas, continue. Nurses have frequently stated that they are not valued for their knowledge. Yet many nurses have university degrees, post graduate degrees, specialty certificates and specialty credentials. Nurses seek recognition for what they know and what they do. To date, however, there is no objective method that is used to assess the value of nurses and their work. The study of relative value may provide a method for recognizing nurses' work. The concept of relative value deals with logical operators and facilitates assigning value to a nurse's overall knowledge base and capacity to perform nursing work. Currently, nursing shortages are concentrated in specialty areas. Nurses who work in specialized areas need specialized knowledge in a narrow field of nursing. Specialty nurses are not interchangeable with specialists in other areas or with generalists. A study is in progress to calculate the relative value of nursing work in 15 specialties. The goal is to assess relative value from the point of view of the knowledge base in the specialties and between specialties. In this paper, the research team reports on the background of the study, the study's parameters and its progress to date. Outcomes will include devising a way to recognize nurses' work, developing policies related to retention and recruitment and finding a long-term solution for dealing with the nursing shortage in specialty areas.


Robust image deblurring with an inaccurate blur kernel.
Most existing nonblind image deblurring methods assume that the blur kernel is free of error. However, it is often unavoidable in practice that the input blur kernel is erroneous to some extent. Sometimes, the error could be severe, e.g., for images degraded by nonuniform motion blurring. When an inaccurate blur kernel is used as the input, significant distortions will appear in the image recovered by existing methods. In this paper, we present a novel convex minimization model that explicitly takes account of error in the blur kernel. The resulting minimization problem can be efficiently solved by the so-called accelerated proximal gradient method. In addition, a new boundary extension scheme is incorporated in the proposed model to further improve the results. The experiments on both synthesized and real images showed the efficiency and robustness of our algorithm to both the image noise and the model error in the blur kernel.


The efficacy and safety of conventional transcatheter arterial chemoembolization combined with PD-1 inhibitor and anti-angiogenesis tyrosine kinase inhibitor treatment for patients with unresectable hepatocellular carcinoma: a real-world comparative study.
We sought to evaluate the efficacy and safety of conventional transcatheter arterial chemoembolization (cTACE) sequentially combined with systemic treatment by programmed cell death protein 1 (PD-1) inhibitor and anti-angiogenesis tyrosine kinase inhibitor (Anti-angiogenesis TKI) in patients with unresectable hepatocellular carcinoma (HCC). One hundred and forty-seven advanced HCC patients who received PD-1 inhibitors and TKIs as first-line systemic treatment between August 2019 and April 2021 were collected retrospectively. Fifty-four patients were finally included and divided into cTACE and no-cTACE groups, according to whether cTACE treatment was performed within 8 weeks before systemic treatment. The tumor objective response ratio (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were compared between the groups. Significant factors affecting PFS and OS were determined by Cox regression. Thirty-one patients received cTACE followed by systemic treatment and 23 patients received systemic treatment only. The ORRs of the cTACE group were 48.4% (after two cycles of systemic treatment) and 51.6% (after four cycles of systemic treatment), while those of the no-cTACE group were only 17.4% and 21.7%. cTACE patients also had a longer median PFS (11.70 vs. 4.00 months, P = 0.031) and median OS (19.80 vs. 11.6 months, P = 0.006) than no-cTACE patients. Regression analyses indicated that cTACE therapy and Eastern Cooperative Oncology Group performance status were independent risk factors for PFS and OS. AEs by type were similar between the cTACE and no-cTACE groups, except for liver function injury, which was more common among cTACE patients. Fourteen patients suffered with grade 1-2 of rash in 21 patients with objective response, while only 10 patients suffered with rash in 33 patients without objective response, the adjusted hazard ratio (HR) was 4.382 (1.297-14.803). The combination of cTACE and PD-1 inhibitors and anti-angiogenesis TKIs as therapy significantly improved markers of treatment efficacy, including ORR, PFS, and OS, in unresectable HCC patients, while no more serious AEs recorded in this population compared to those receiving systemic treatment alone. Skin rash might be a predict factor to the efficacy of PD-1 inhibitors and TKI treatment.


Osmotic stress and pore nucleation in charged biological nanoshells and capsids.
A model system is proposed to investigate the chemical equilibrium and mechanical stability of biological spherical-like nanoshells in contact with an aqueous solution with added dissociated electrolyte of a given concentration. The ionic chemical equilibrium across the permeable shell is investigated in the framework of an accurate Density Functional Theory (DFT) that incorporates electrostatic and hardcore correlations beyond the traditional mean-field (e.g., Poisson-Boltzmann) limit. The accuracy of the theory is tested by a direct comparison with Monte Carlo (MC) simulations. A simple analytical expression is then deduced which clearly highlights the entropic, electrostatic, and self-energy contributions to the osmotic stress over the shell in terms of the calculated ionic profiles. By invoking a continuum mean-field elastic approach to account for the shell surface stress upon osmotic stretching, the mechanical equilibrium properties of the shell under a wide variety of ionic strengths and surface charges are investigated. The model is further coupled to a continuum mechanical approach similar in structure to a Classical Nucleation Theory (CNT) to address the question of mechanical stability of the shells against a pore nucleation. This allows us to construct a phase diagram which delimits the mechanical stability of capsids for different ionic strengths and shell surface charges.


Comparison of visual inspection with acetic acid and cervical cytology to detect high-grade cervical neoplasia among HIV-infected women in India.
Human immunodeficiency virus (HIV)-infected women in India and other developing country settings are living longer on antiretroviral therapy, yet their risk for human papillomavirus (HPV)-induced cervical cancer remains unabated because of lack of cost-effective and accurate secondary prevention methods. Visual inspection after application of dilute acetic acid on the cervix (VIA) has not been adequately studied against the current standard: conventional cervical cytology (Pap smears) among HIV-infected women. We evaluated 303 nonpregnant HIV-infected women in Pune, India, by simultaneous and independent screening with VIA and cervical cytology with disease ascertainment by colposcopy and histopathology. At the cervical intraepithelial neoplasia (CIN2+) disease threshold, the sensitivity, specificity and positive and negative predictive value estimates of VIA were 80, 82.6, 47.6 and 95.4% respectively, compared to 60.5, 59.6, 22.4 and 88.7% for the atypical squamous cells of undetermined significance or severe (ASCUS+) cutoff on cytology, 60.5, 64.6, 24.8 and 89.4% for the low-grade squamous intraepithelial cells or severe (LSIL+) cutoff on cytology and 20.9, 96.0, 50.0 and 86.3% for high-grade squamous intraepithelial lesion or severe (HSIL+) cutoff on cytology. A similar pattern of results was found for women with the presence of carcinogenic HPV-positive CIN2+ disease, as well as for women with CD4+ cell counts <200 and <350 μL(-1) . Overall, VIA performed better than cytology in this study with biologically rigorous endpoints and without verification bias, suggesting that VIA is a practical and useful alternative or adjunctive screening test for HIV-infected women. Implementing VIA-based screening within HIV/acquired immunodeficiency syndrome care programs may provide an easy and practical means of complementing the highly anticipated low-cost HPV-based rapid screening tests in the near future, thereby contributing to improve program effectiveness of screening.


Effect of Alcohol Intake on Inflammatory Status and Prognosis in Cancer Patients.
To explore the effect of alcohol on the inflammatory status and prognosis of patients with malignancy. The clinical data of patients with malignant tumor who were admitted to the First Hospital of Jilin University from November 2011 to December 2018 were collected including basic clinical information, anthropometric indicators, body composition analysis, and serological indicators. Univariate and multivariate Cox proportional hazards models were performed to find predictors of survival. A nomogram was generated to indicate the interrelationships between the variables in the prediction model and the extent to which alcohol consumption affects prognosis. The C-index and calibration curves were used to verify the predictive accuracy of the scoring system. A total of 2929 cancer patients were included in this study, of which 552 (18.8%) patients had alcohol consumption habits and 2377 (81.2%) patients had no alcohol history. Patients in the Alcohol group had significantly shorter overall survival (OS) than the Non-Alcohol group, and further sub-analysis indicated alcohol consumption was significantly associated with prognosis of advanced breast cancer (HR = 4.617, 95% CI 1.361-15.664, p=0.014), and early stage hepatocellular carcinoma (HCC) without viral hepatitis (HR = 8.933, 95% CI 1.444-55.275, p = 0.019). Multivariate Cox regression models also demonstrated that daily alcohol intake was a risk factor of survival benefits (HR = 1.256, 95% CI 1.016-1.554, p = 0.036). Finally, a nomogram was constructed and the c-index of this scoring system is 0.751. The 3- and 5-year calibration curves of the model show a high agreement between the predicted probability and the actual observed survival rate. Alcohol intake was demonstrated associates with patient outcomes. A human component-prognosis scoring system was established to predict the survival benefits of cancer patients.


Age-related decline in perception of prosodic affect.
Perception of affect in speech is an important aspect of language, often conveying more about the intent of the speaker than semantic content. Impairment of perception of affect is seen in patients with right-hemisphere lesions. Nevertheless, little attention is paid to perception of emotional prosody in clinical neuropsychology. We present data concerning a revised version of the Emotional Perception Test (EPT-R), which indicates that older participants are significantly worse in prosodic perception than IQ-matched younger participants. The apparent age-related differences in perception of prosody are similar in magnitude to those seen on memory tests.


Comparison of metabolic and mitogenic response in vitro of the rapid-acting insulin lispro product SAR342434, and US- and EU-approved Humalog®.
SAR342434 is a biosimilar of insulin lispro (Humalog® U-100). Batches of SAR342434 were compared with Humalog® batches of either EU or US origin in a panel of in vitro biological assays that included insulin binding to insulin receptor (IR) isoforms A (IR-A) and B (IR-B) and IR-A/IR-B autophosphorylation. A surface plasmon resonance biosensor-based assay was developed to characterize the kinetics of insulin binding to solubilized full-length IR-A or IR-B. Insulin-dependent metabolic activity assays included inhibition of lipolysis in in vitro differentiated human adipocytes, glucose uptake in L6-myocytes, and repression of glucose-6-phosphatase gene expression in human hepatocytes. Mitogenic activity assays included insulin binding to insulin-like growth factor-1 receptor (IGF1R), IGF1R autophosphorylation, and cell proliferation in MCF-7 cells. Weighted geometric means and their respective 95% confidence intervals (CI) were calculated for all 50% inhibitory or effective concentration values and kinetic binding constants for IR-A and IR-B. Statistical evaluation of the data demonstrated that the 90% CIs of the ratio of geometric means between SAR342434 and Humalog® EU or Humalog® US were within the predefined acceptance limits for each assay. Insulin lispro as SAR342434 solution demonstrated similarity to both US- and EU-approved Humalog® based on a side-by-side biological similarity assessment.


Accurate molecular classification of human cancers based on gene expression using a simple classifier with a pathological tree-based framework.
Recent studies suggest accurate prediction of tissue of origin for human cancers can be achieved by applying sophisticated statistical learning procedures to gene expression data obtained from DNA microarrays. We have pursued the hypothesis that a more straightforward and equally accurate strategy for classifying human tumors is to use a simple algorithm that considers gene expression levels within a tree-based framework that encodes limited information about pathology and tissue ontogeny. By considering gene expression data within this framework, we found only a small number of genes were required to achieve a relatively high accuracy level in tumor classification. Using as few as 45 genes we were able to classify 157 of 190 human malignant tumors correctly, which is comparable to previous results obtained with sophisticated classifiers using thousands of genes. Our simple classifier accurately predicted the origin of metastatic tumors even when the classifier was trained using only primary tumors, and the classifier produced accurate predictions when trained and tested on expression data from different labs, and from different microarray platforms. Our findings suggest that accurate and robust cancer diagnosis from gene expression profiles can be achieved by mimicking the classification strategies routinely used by surgical pathologists.


Initial single-centre Canadian experience with 18F-fluoromethylcholine positron emission tomography-computed tomography (18F-FCH PET/CT) for biochemical recurrence in prostate cancer patients initially treated with curative intent.
We sought to determine predictive factors (patient and prostate-specific antigen [PSA] characteristics) for 18F-fluoromethylcholine positron emission tomography-computed tomography (18F-FCH PET/CT) positivity in the context of biochemical recurrence after local treatment of prostate cancer (PCa) with curative intent. This is a retrospective study including 60 18F-FCH PET/CT scans of patients with biochemical recurrence after initial radical prostatectomy (RP), external beam radiation therapy (EBRT), or focal high-intensity focused ultrasound (HIFU) with curative intent. The results were compared to findings on magnetic resonance imaging (MRI), computed tomography (CT), bone scan (BS), and histological analysis when available. Univariate analysis was performed to correlate results with patient characteristics. Thirty-eight (63.3%) scans were positive, 17 (28.3%) negative, and 5 (8.3%) equivocal. Of the positive scans, 16 demonstrated local recurrence, 12 regional/distant lymph nodes, five bone metastasis, and five local and distant recurrences. Among the 22 PET/CTs showing metastasis, conventional imaging was performed in 16 patients (72.7%). Of these, it demonstrated the lesion(s) found on PET/CT in eight patients (50.0%), was negative in seven (43.8%), and equivocal in one (6.3%). The trigger PSA (p=0.04), prostate-specific antigen velocity (PSAV) (p=0.03), and prostate-specific antigen doubling time (PSADT) (p=0.046) were significantly different when comparing positive and negative scans. Patients with positive scans were more likely to have received EBRT initially (odds ratio [OR] 11.0, 95% confidence interval [CI] 2.2-55.3). A trigger PSA of 2.6 ng/mL had a sensitivity of 84% and specificity of 65% for a positive scan. PET/CT changed the clinical management plan in 17 patients (28.3%). 18F-FCH PET/CT demonstrates a high detection rate for local and distant recurrences after localized PCa treatment. A trigger PSA above 2.6 ng/mL seems optimal for appropriate patient selection.


CT and MR imaging findings and their implications in the follow-up of patients with intracranial aneurysms treated with endosaccular occlusion with onyx.
Our purpose was to describe the CT and MR features of intracranial aneurysms occluded with the liquid polymer Onyx. At two centers, 35 aneurysms in 33 patients and 11 in nine patients were treated with the polymer. In 17 patients, adjunctive stents were placed at the aneurysm neck. All but three aneurysms originated from the internal carotid artery (ICA). Eighteen were giant; 15, large; and 13, small. Patients underwent pre- and postprocedural CT and/or MR imaging; MR angiograms (MRAs) were available in 22. In 35 patients (38 aneurysms), 3-month and/or 1-year follow-up angiograms were obtained for correlation with sectional images. Except in two small aneurysms, polymer filling created beam hardening artifacts on CT scans. In 10 aneurysms, the polymer did not fill the aneurysm sac entirely; five showed recanalization at follow-up. On MR images (all sequences), the polymer appeared hypointense, probably because of its tantalum content; it did not create artifacts. MRAs falsely suggested reduced or absent ICA flow in 11 of 22 patients, nine of whom with stents. In the rest, MRA provided results comparable to those of selective angiography. In 12 patients, postprocedural imaging revealed new lesions. Onyx appears hypointense on MR images, with no artifact, and it does not interfere with MRA except in patients with stents. MR imaging may reveal new parenchymal lesions, even in asymptomatic patients. In the immediate control and follow-up of polymer-treated aneurysms, MR imaging and MRA may be preferred. CT may show the degree of filling in the aneurysmal sac, but Onyx creates artifacts that hinder CT evaluation.


Isolation of porcine secretory immunoglobulin A by affinity chromatography and determination of its component chains.
Porcine secretory immunoglobulin A (SIgA) was isolated in a single step from porcine milk whey by affinity chromatography, using antiporcine alpha-chain specific antibody linked to CNBr-activated agarose. The isolated SIgA contained no other proteins detectable by immunodiffusion of immunoelectrophoresis. After reduction and alkylation with dithiothreitol and iodoacetamide, the SIgA was chromatographed on gel equilibrated with 6.0 M urea and 1.0 M propionic acid. Polyacrylamide gel electrohoresis of the fractions eluted revealed the presence of light chain, alpha-chain secretory component, and J-chain.


The value of routine biochemical tests in discriminating between malignant and benign pancreatic tumours.
The probability that routine hematological laboratory tests of liver and pancreatic function can discriminate between malignant and benign pancreatic tumours, incidentally detected during operation, was investigated. The records of 53 patients with a verified diagnosis of pancreatic carcinoma and 19 patients with chronic pancreatitis were reviewed with regard to preoperative total bilirubin, direct reacting bilirubin, alkaline phosphatase, glutamyltranspeptidase, aminotransferases, lactic dehydrogenase and amylase. Multivariate and discriminant analysis were performed to calculate the predictive value for cancer, using SYSTAT statistical package in a Macintosh II computer. Total and direct reacting bilirubin and glutamyltranspeptidase were significantly higher in patients with pancreatic carcinoma. However, only considerably increased levels of direct reating bilirubin were predictive of pancreatic carcinoma.


Nanoscale Chemical Imaging of an Individual Catalyst Particle with Soft X-ray Ptychography.
Understanding Fe deposition in fluid catalytic cracking (FCC) catalysis is critical for the mitigation of catalyst degradation. Here we employ soft X-ray ptychography to determine at the nanoscale the distribution and chemical state of Fe in an aged FCC catalyst particle. We show that both particle swelling due to colloidal Fe deposition and Fe penetration into the matrix as a result of precracking of large organic molecules occur. The application of ptychography allowed us to provide direct visual evidence for these two distinct Fe-based deactivation mechanisms, which have so far been proposed only on the basis of indirect evidence.


Electrically switchable structural colors based on liquid-crystal-overlaid aluminum anisotropic nanoaperture arrays.
Actively tunable or reconfigurable structural colors are highly promising in future development for high resolution imaging and displaying applications. To this end, we demonstrate switchable structural colors covering the entire visible range by integrating aluminum nanoaperture arrays with nematic liquid crystals. The geometrically anisotropic design of the nanoapertures provides strong polarization-dependent coloration. By overlaying a nematic liquid crystal layer, we further demonstrate switchable ability of the structural colors by either changing the polarization of the incident light or applying an external voltage. The switchable structural colors have a fast response time of 28 ms at a driving voltage of 6.5 V. Furthermore, colorful patterns are demonstrated by coding the colors with various dimensions of nanoaperture arrays with dual switching modes. Our proposed technique in this work provides a dual-mode switchable structural colors, which is highly promising for polarimetric displays, imaging sensors, and visual cryptography.


[Ultrastructural organization and distribution of synapses of different size of the neurosecretory cells of the carp preoptic nucleus].
With electron microscope two types of synaptic buttons (SB) are found on the nuerosecretory cells (NSC) in the nucleus preopticus of the mature carp. SB type I contain dense core vesicles and synaptic vesicles, whereas SB type II have only the latter. SB type II is considered to be functionally more active. The density of SB on the NSC body surface varied inversely proportionally to the NSC size, being in average 1.7+/-0.2 on the section of one small NSC in the ventral part of the nucleus preopticus, and 1.0+/-0.1 on the section of a large one in the dorsal part (P less than 0.05). In large NSC type II SB are found more frequent than in small NSC, the synaptic apparatus of NSC in the dorsal part of the nucleus preopticus is in a more active stage, than of NSP in the ventral part. The structural organization of the complex SB-NSC of large cells is more complicated compared to that of small cells. The large cells are supposed to be more differentiated and functionally more active. The synapses of NSC of the nucleus preopticus of the carp are supposed to belong usually to axons of monaminergic neurons.


18β-glycyrrhetinic acid inhibits periodontitis via glucocorticoid-independent nuclear factor-κB inactivation in interleukin-10-deficient mice.
18β-Glycyrrhetinic acid (GA) is a natural anti-inflammatory compound derived from licorice root extract (Glycyrrhiza glabra). The effect of GA on experimental periodontitis and its mechanism of action were determined in the present study. Periodontitis was induced by oral infection with Porphyromonas gingivalis W83 in interleukin-10-deficient mice. The effect of GA, which was delivered by subcutaneous injections in either prophylactic or therapeutic regimens, on alveolar bone loss and gingival gene expressions was determined on day 42 after initial infection. The effect of GA on lipopolysaccharide (LPS)-stimulated macrophages, T cell proliferation and osteoclastogenesis was also examined in vitro. 18β-Glycyrrhetinic acid administered either prophylactically or therapeutically resulted in a dramatic reduction of infection-induced bone loss in interleukin-10-deficient mice, which are highly disease susceptible. Although GA has been reported to exert its anti-inflammatory activity via downregulation of 11β-hydroxysteroid dehydrogenase-2 (HSD2), which converts active glucocorticoids to their inactive forms, GA did not reduce HSD2 gene expression in gingival tissue. Rather, in glucocorticoid-free conditions, GA potently inhibited LPS-stimulated proinflammatory cytokine production and RANKL-stimulated osteoclastogenesis, both of which are dependent on nuclear factor-κB. Furthermore, GA suppressed LPS- and RANKL-stimulated phosphorylation of nuclear factor-κB p105 in vitro. These findings indicate that GA inhibits periodontitis by inactivation of nuclear factor-κB in an interleukin-10- and glucocorticoid-independent fashion.


[Sugar substitute products impact on oral fluid biochemical properties].
Sugar substitute products impact on oral fluid protein and carbohydrate content, as well as oxidative balance were studied in 60 medical school students in compare with conventional sugar. Sugar intake proved to cause cariesogenic carbohydrate metabolism disorders in oral fluid, intensification of lipoperoxidation and decrease in antioxidation activity. Sugar substitute products help to prevent dental decay.


Determinants of rodent longevity in the chaperone-protein degradation network.
Proteostasis is an integral component of healthy aging, ensuring maintenance of protein structural and functional integrity with concomitant impact upon health span and longevity. In most metazoans, increasing age is accompanied by a decline in protein quality control resulting in the accrual of damaged, self-aggregating cytotoxic proteins. A notable exception to this trend is observed in the longest-lived rodent, the naked mole-rat (NMR, Heterocephalus glaber) which maintains proteostasis and proteasome-mediated degradation and autophagy during aging. We hypothesized that high levels of the proteolytic degradation may enable better maintenance of proteostasis during aging contributing to enhanced species maximum lifespan potential (MLSP). We test this by examining proteasome activity, proteasome-related HSPs, the heat-shock factor 1 (HSF1) transcription factor, and several markers of autophagy in the liver and quadriceps muscles of eight rodent species with divergent MLSP. All subterranean-dwelling species had higher levels of proteasome activity and autophagy, possibly linked to having to dig in soils rich in heavy metals and where underground atmospheres have reduced oxygen availability. Even after correcting for phylogenetic relatedness, a significant (p < 0.02) positive correlation between MLSP, HSP25, HSF1, proteasome activity, and autophagy-related protein 12 (ATG12) was observed, suggesting that the proteolytic degradation machinery and maintenance of protein quality play a pivotal role in species longevity among rodents.


The effect of Kawasaki disease on cognition and behavior.
To determine whether there are associated long-term deficits in the cognitive, academic, or behavioral outcomes of children with a previous episode of Kawasaki disease. Cohort analytic study. A tertiary care pediatric hospital in Ottawa, Ontario. Thirty-two patients with a past diagnosis of Kawasaki disease. Siblings of the patients with Kawasaki disease were eligible to be controls. A blinded psychometrist (Y.K.) assessed cognition by the appropriate Wechsler Intelligence scale, academic achievement by the Wechsler Individual Achievement Test, and behavior by the Achenbach Child Behavior Checklist. No differences were found in cognitive or academic measures and the mean scores corresponded closely to national norms. Parents rated their children who had Kawasaki disease as having significantly more internalizing (P<.03) and attentional (P<.02) behavior problems than controls; the risk of a clinically significant behavioral score was 3.3 times greater (P<.03; 95% confidence interval, 1.1-9.9) than for sibling controls. While no effect on cognitive development or academic performance was demonstrated, these results provide preliminary indication of a post-Kawasaki disease deficit in internalizing and attentional behavior.


[Increase of serum procalcitonin levels during a neuroleptic malignant syndrome].
When fever occurs in a patient treated with a neuroleptic, the diagnosis of a neuroleptic malignant syndrome is difficult to differentiate to that of an infectious event. Among inflammation biomarkers of inflammation, serum procalcitonin levels increase both quickly and specifically during a bacterial infection. We report the first case of a neuroleptic malignant syndrome associated with a significant increase of serum procalcitonin levels, without concomitant septic syndrome. The neuroleptic malignant syndrome might be a non-infectious clinical situation associated with an increased serum procalcitonin concentration.


PTEN Down-Regulation Promotes β-Oxidation to Fuel Hypertrophic Liver Growth After Hepatectomy in Mice.
In regenerating liver, hepatocytes accumulate lipids before the major wave of parenchymal growth. This transient, regeneration-associated steatosis (TRAS) is required for liver recovery, but its purpose is unclear. The tumor suppressor phosphatase and tensin homolog (PTEN) is a key inhibitor of the protein kinase B/mammalian target of rapamycin axis that regulates growth and metabolic adaptations after hepatectomy. In quiescent liver, PTEN causes pathological steatosis when lost, whereas its role in regenerating liver remains unknown. Here, we show that PTEN down-regulation promotes liver growth in a TRAS-dependent way. In wild-type mice, PTEN reduction occurred after TRAS formation, persisted during its disappearance, and correlated with up-regulated β-oxidation at the expense of lipogenesis. Pharmacological modulation revealed an association of PTEN with TRAS turnover and hypertrophic liver growth. In liver-specific Pten-/- mice shortly after induction of knockout, hypertrophic regeneration was accelerated and led to hepatomegaly. The resulting surplus liver mass was functional, as demonstrated by raised survival in a lethal model of resection-induced liver failure. Indirect calorimetry revealed lipid oxidation as the primary energy source early after hepatectomy. The shift from glucose to lipid usage was pronounced in Pten-/- mice and correlated with the disappearance of TRAS. Partial inhibition of β-oxidation led to persisting TRAS in Pten-/- mice and abrogated hypertrophic liver growth. PTEN down-regulation may promote β-oxidation through β-catenin, whereas hypertrophy was dependent on mammalian target of rapamycin complex 1. PTEN down-regulation after hepatectomy promotes the burning of TRAS-derived lipids to fuel hypertrophic liver regeneration. Therefore, the anabolic function of PTEN deficiency in resting liver is transformed into catabolic activities upon tissue loss. These findings portray PTEN as a node coordinating liver growth with its energy demands and emphasize the need of lipids for regeneration. (Hepatology 2017;66:908-921).


Clinical outcomes in cancer patients with COVID-19 in Sweden.
The results of studies on the relationship between cancer and COVID-19 have been conflicting and therefore further studies are needed. We aimed to examine the incidence of COVID-19 among patients at one of the largest oncology departments in Sweden, and to evaluate and identify risk factors for poor outcomes, hospital care and death, associated with COVID-19 among cancer patients. This retrospective study included cancer patients at a single center who tested positive for SARS-CoV-2 by PCR either in hospital, primary health care center or commercial laboratory between 1 March and 14 August 2020. Clinical and demographic data were collected from the medical records. Logistic regression analysis was used to identify variables that associated the primary outcomes of need for hospital care and death within 30 days of positive test. Of 10,774 patients from the Department of Oncology at Sahlgrenska University Hospital, 135 tested positive for SARS-CoV-2 (1.3%). Twenty-eight patients were excluded from further the data collection since they did not meet the inclusion criteria. Altogether, 107 cancer patients were included and the case fatality rate (CFR) was 12% (13) within 30 days of confirmed SARS-CoV-2 infection by PCR. Increasing years of age (OR 1.10; CI 95% 1.03-1.18), palliative treatment intent (OR 15.7; CI 95% 1.8-135.8), and transition to end-of-life care (OR 52.0; CI 95% 3.7-735.6) were associated with increased odds of death within 30 days. Male sex was associated with needing hospital care (OR 3.7; CI 95% 1.50-9.1). As in the general population, male sex was found to be at greater risk of needing hospital care for COVID-19, with terminal cancer disease, and older age increasing the odds of fatality. Compared to the general population, slightly more cancer patients had COVID-19. The CFR was within the lower range of others reported in cancer patients.


Senescence in Primary Rat Astrocytes Induces Loss of the Mitochondrial Membrane Potential and Alters Mitochondrial Dynamics in Cortical Neurons.
The decline in brain function during aging is one of the most critical health problems nowadays. Although senescent astrocytes have been found in old-age brains and neurodegenerative diseases, their impact on the function of other cerebral cell types is unknown. The aim of this study was to evaluate the effect of senescent astrocytes on the mitochondrial function of a neuron. In order to evaluate neuronal susceptibility to a long and constant senescence-associated secretory phenotype (SASP) exposure, we developed a model by using cellular cocultures in transwell plates. Rat primary cortical astrocytes were seeded in transwell inserts and induced to premature senescence with hydrogen peroxide [stress-induced premature senescence (SIPS)]. Independently, primary rat cortical neurons were seeded at the bottom of transwells. After neuronal 6 days in vitro (DIV), the inserts with SIPS-astrocytes were placed in the chamber and cocultured with neurons for 6 more days. The neuronal viability, the redox state [reduced glutathione/oxidized glutathione (GSH/GSSG)], the mitochondrial morphology, and the proteins and membrane potential were determined. Our results showed that the neuronal mitochondria functionality was altered after being cocultured with senescent astrocytes. In vivo, we found that old animals had diminished mitochondrial oxidative phosphorylation (OXPHOS) proteins, redox state, and senescence markers as compared to young rats, suggesting effects of the senescent astrocytes similar to the ones we observed in vitro. Overall, these results indicate that the microenvironment generated by senescent astrocytes can affect neuronal mitochondria and physiology.


Measurement of low-field faraday rotation and ellipticity.
A convenient measurement technique for Faraday rotation is extended to include the effect of ellipticity. The measurement theory is presented, and a procedure for determining the correction for the rotation measurement is explained. Also, a simple test to determine whether ellipticity is an important factor and the means for deducing ellipticity when the rotation is known are described. A graphical representation of the effect of ellipticity on the measurement as a function of minor-to-major axes ratio is included.


Toward a Behavior Theory-Informed and User-Centered Mobile App for Parents to Prevent Infant Falls: Development and Usability Study.
Falls account for approximately 50% of infant injury hospitalizations, and caretaker behavior is central to preventing infant falls. Behavior theory-informed interventions for injury prevention have been suggested, but to date, few have been reported. The potential of using smartphones for injury prevention intervention delivery is also underexploited. This study aims to develop a behavior theory- and evidence-based as well as user-centered digital intervention as a mobile app for parents to prevent infant falls following agile development practices. Infant falls while feeding was selected as the fall mechanism to demonstrate the approach being taken to develop this intervention. In phase 1, the Behaviour Change Wheel was used as a theoretical framework supported by a literature review to define intervention components that were then implemented as a mobile app. In phase 2, after the person-based approach, user testing through think-aloud interviews and comprehension assessments were used to refine the content and implementation of the intervention. The target behaviors identified in phase 1 were adequate rest for the newborn's mother and safe feeding practices defined as prepare, position, and place. From behavioral determinants and the Behaviour Change Wheel, the behavior change functions selected to achieve these target behaviors were psychological capability, social opportunity, and reflective motivation. The selected behavior change techniques aligned with these functions were providing information on health consequences, using a credible source, instruction on performing each behavior, and social support. The defined intervention was implemented in a draft Android app. In phase 2, 4 rounds of user testing were required to achieve the predefined target comprehension level. The results from the think-aloud interviews were used to refine the intervention content and app features. Overall, the results from phase 2 revealed that users found the information provided to be helpful. Features such as self-tracking and inclusion of the social and environmental aspects of falls prevention were liked by the participants. Important feedback for the successful implementation of the digital intervention was also obtained from the user testing. To our knowledge, this is the first study to apply the Behaviour Change Wheel to develop a digital intervention for child injury prevention. This study provides a detailed example of evidence-based development of a behavior theory-informed mobile intervention for injury prevention refined using the person-based approach.


Modeling cytoskeletal traffic: an interplay between passive diffusion and active transport.
We introduce the totally asymmetric simple exclusion process with Langmuir kinetics on a network as a microscopic model for active motor protein transport on the cytoskeleton, immersed in the diffusive cytoplasm. We discuss how the interplay between active transport along a network and infinite diffusion in a bulk reservoir leads to a heterogeneous matter distribution on various scales: we find three regimes for steady state transport, corresponding to the scale of the network, of individual segments, or local to sites. At low exchange rates strong density heterogeneities develop between different segments in the network. In this regime one has to consider the topological complexity of the whole network to describe transport. In contrast, at moderate exchange rates the transport through the network decouples, and the physics is determined by single segments and the local topology. At last, for very high exchange rates the homogeneous Langmuir process dominates the stationary state. We introduce effective rate diagrams for the network to identify these different regimes. Based on this method we develop an intuitive but generic picture of how the stationary state of excluded volume processes on complex networks can be understood in terms of the single-segment phase diagram.


Effect of NO 2 on airborne Venezuelan equine encephalomyelitis virus.
Studies were conducted to determine the effect of nitrogen dioxide (NO(2)) on aerosol survival and biological decay rate of Venezulean equine encephalomyelitis (VEE) virus and spores of Bacillus subtilis var. niger. The NO(2) concentrations used in the experiments were 0.5, 5, and 10 ppm at 24 C and 85% RH. The survival of airborne VEE virus disseminated as particles 1 to 5 mum in diameter was significantly influenced by the presence of 5 ppm of NO(2). At this concentration, the biological decay rate increased threefold and the aerosol recovery and aerosol survival of the VEE virus were significantly lower than at 0.5 ppm or in the absence of NO(2). Airborne spores of B. subtilis were not significantly affected by as much as 10 ppm of NO(2).


Trigger points and pressure pain hypersensitivity in people with postmeniscectomy pain.
The objectives of this study are (1) to assess the presence of myofascial trigger points (TrPs) and widespread pressure hyperalgesia; and (2) to assess the relationship between the presence of active TrPs, pain intensity, and widespread pressure hypersensitivity in individuals with postmeniscectomy pain. Thirty-three patients with postmeniscectomy pain, 46 to 60 years of age, and 33 matched controls participated. TrPs were explored bilaterally within the tensor fasciae latae, rectus femoris, vastus lateralis, vastus medialis, adductor magnus, adductor longus, semitendinosus, biceps femoris, and gastrocnemius muscles in a blinded manner. TrPs were considered active if the referred pain reproduced knee symptoms. Pressure pain thresholds (PPT) were also assessed bilaterally over the vastus medialis, vastus lateralis, patellar tendon, second metacarpal, and tibialis anterior. Pain was collected with a numerical pain rate scale (0 to 10). Patients with postmeniscectomy pain showed a greater (P<0.001) number of active TrPs (mean: 2±1) and a similar number (P=0.611) of latent TrPs (mean: 4±4) than pain-free controls (mean latent TrP: 4±1). A greater number of active TrPs was associated with higher pain intensity (r=0.352; P=0.045). Patients also exhibited reduced PPT over the affected vastus medialis and patellar tendon (P<0.05) and bilaterally over the tibialis anterior muscle (P=0.001). A greater the number of active muscle TrPs was also associated with widespread pressure pain hyperalgesia. The referred pain elicited by active TrPs reproduced knee symptoms in patients with postmeniscectomy pain. Patients also showed localized reduction of PPT. The number of TrPs was associated with the intensity of pain and pressure hyperalgesia. Our findings suggest the presence of peripheral sensitization in patients with postmeniscectomy pain could be associated with the presence of active TrPs.


Alterations in the genome of wheat seedlings grown under drought stress and the effect of gibberellic acid on these alterations.
The changes in the amount of nuclear, chloroplast and mithocondrial nucleic acids of wheat (Triticum aestivum L.) seedlings in relation with drought stress and the effect of gibberellic acid (GA3) on these changes were investigated by spectrophotometric method. It was found that drought stress caused decrease in the amount of nucleic acids. In the seedlings to which GA3 was applied following drought stress, increase in the amount of nuclear nucleic acids (especially in the amount of labile DNA, which is the active portion) was determined. Similar results were observed in the amount of nucleic acids of mitochondria and chloroplasts. All these results show that drought stress caused quantitative changes in the genetic substrate of wheat seedling cells and GA3 application alleviated this effect by activating the synthesis of nucleic acids.


Application of a Two-Dimensional Mapping-Based Visualization Technique: Nutrient-Value-Based Food Grouping.
Worldwide, several food-based dietary guidelines, with diverse food-grouping methods in various countries, have been developed to maintain and promote public health. However, standardized international food-grouping methods are scarce. In this study, we used two-dimensional mapping to classify foods based on their nutrient composition. The Standard Tables of Food Composition in Japan were used for mapping with a novel technique-t-distributed stochastic neighbor embedding-to visualize high-dimensional data. The mapping results showed that most foods formed food group-based clusters in the Standard Tables of Food Composition in Japan. However, the beverages did not form large clusters and demonstrated scattered distribution on the map. Green tea, black tea, and coffee are located within or near the vegetable cluster whereas cocoa is near the pulse cluster. These results were ensured by the k-nearest neighbors. Thus, beverages made from natural materials can be categorized based on their origin. Visualization of food composition could enable an enhanced comprehensive understanding of the nutrients in foods, which could lead to novel aspects of nutrient-value-based food classifications.


Detailed knowledge of cellular expression of G protein-coupled receptors in the human enteric nervous system is essential for understanding their diverse actions.
G protein-coupled receptors (GPCRs) comprise a large and diverse superfamily of transmembrane receptors that mediate the functions of an extraordinarily large number of extracellular ligands. They control many major physiological processes and are involved in diverse pathological processes, including gastrointestinal diseases. G protein-coupled receptors are one of the most targeted classes in pharmaceutical drug research. At present, much of our knowledge concerning the expression, distribution and function of GPCRs in the gut has been gleaned from studies performed in experimental models. Data obtained in the human digestive tract, especially in the enteric nervous system, are sparse and incomplete, although enteric neurons have a key position in almost all physiological and pathophysiological processes in the gut. Knowledge of cellular distribution of GPCRs, of regional differences in GPCR expression, and of altered GPCR expression during pathophysiological conditions in the human gut, will lead to a better understanding of GPCR activity, but will also contribute to the development of new drugs. In the current issue of the Journal, Harrington et al. describe the presence and cellular localization of muscarinic receptors in the human colon. Morphologically, orientated studies on the cellular expression of GPCRs in the human gut have to be encouraged, because these studies will yield data that are of therapeutic relevance.


Histone modifications and expression of light-regulated genes in Arabidopsis are cooperatively influenced by changing light conditions.
Here, we analyzed the effects of light regulation on four selected histone modifications (H3K4me3, H3K9ac, H3K9me2, and H3K27me3) and the relationship of these histone modifications with the expression of representative light-regulated genes. We observed that the histone modifications examined and gene transcription were cooperatively regulated in response to changing light environments. Using H3K9ac as an example, our analysis indicated that histone modification patterns are set up very early and are relatively stable during Arabidopsis (Arabidopsis thaliana) seedling development. Distinct photoreceptor systems are responsible for mediating the effects of different light qualities on histone modifications. Moreover, we found that light regulation of gene-specific histone modifications involved the known photomorphogenesis-related proteolytic system defined by the pleiotropic CONSTITUTIVE PHOTOMORPHOGENIC/DE-ETOLIATED proteins and histone modification enzymes (such as HD1). Furthermore, our data suggest that light-regulated changes in histone modifications might be an intricate part of light-controlled gene transcription. Thus, it is possible that variations in histone modifications are an important physiological component of plant responses to changing light environments.


Aptamer-integrated α-Gal liposomes as bispecific agents to trigger immune response for killing tumor cells.
A novel bispecific α-Gal liposome was constructed by self-assembling AS1411 aptamers into the α-Gal containing liposomes. The α-Gal liposomes were prepared using cell membranes of red blood cells from rabbit, which are composed of cholesterol, phospholipids, and α-Gal glycolipids. AS1411 is a DNA aptamer with high specificity and affinity for nucleolin and could integrate into liposomes by the modification of cholesterol. The bispecific α-Gal liposomes surface-functionalized by α-Gal and AS1411 aptamer could recognize anti-Gal antibodies and nucleolin overexpressed by tumor cells simultaneously, followed by activating the immune system to attack the tumor cells, resulting in the lysis of the tumor cells by antibody dependent cell-mediated cytotoxicity. Under simulated tumor environment, the lysis rate of MCF-7 cells treated by the AS1411 modified α-Gal liposomes drastically increased compared to the liposomes without AS1411 aptamer. This study suggests that the AS1411 modified α-Gal liposomes can recognize nucleolin-overexpressing tumor cells selectively, subsequently improve the effect of the immunotherapy with high specificity. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1176-1183, 2019.


"Did the trial kill the intervention?" experiences from the development, implementation and evaluation of a complex intervention.
The development, implementation and evaluation of any new health intervention is complex. This paper uses experiences from the design, implementation and evaluation of a rehabilitation programme to shed light on, and prompt discussion around, some of the complexities involved in such an undertaking. Semi-structured interviews were conducted with 15 trial participants and five members of staff at the conclusion of a trial evaluating a rehabilitation programme aimed at promoting recovery after stem cell transplantation. This study identified a number of challenges relating to the development and evaluation of complex interventions. The difficulty of providing a standardised intervention that was acceptable to patients was highlighted in the participant interviews. Trial participants and some members of staff found the concept of equipoise and randomisation challenging and there was discord between the psychosocial nature of the intervention and the predominant bio-medical culture in which the research took place. A lack of scientific evidence as to the efficacy of an intervention does not preclude staff and patients holding strong views about the benefits of an intervention. The evaluation of complex interventions should, where possible, facilitate not restrict that complexity. Within the local environment where the trial is conducted, acquiescence from those in positions of authority is insufficient; commitment to the trial is required.


Association Between Triglycerides and Risk of Dementia in Community-Dwelling Older Adults: A Prospective Cohort Study.
It has been suggested that higher triglyceride levels were associated with a lower risk of Alzheimer disease. This study aimed to examine the association of triglycerides with dementia and cognition change in community-dwelling older adults. This prospective longitudinal study used data from the Aspirin in Reducing Events in the Elderly (ASPREE) randomized trial of adults aged 65 years or older without dementia or previous cardiovascular events at enrollment. The main outcome was incident dementia. Other outcomes included changes in composite cognition and domain-specific cognition (global cognition, memory, language and executive function, and psychomotor speed). The association between baseline triglycerides and dementia risk was estimated using Cox proportional hazard models adjusting for relevant risk factors. Linear mixed models were used to investigate cognitive change. The analysis was repeated in a subcohort of participants with available APOE-ε4 genetic data with additional adjustment for APOE-ε4 carrier status and an external cohort (UK Biobank) with similar selection criteria applied. This study included 18,294 ASPREE participants and 68,200 UK Biobank participants (mean age: 75.1 and 66.9 years; female: 56.3% and 52.7%; median [interquartile range] triglyceride: 106 [80-142] mg/dL and 139 [101-193] mg/dL), with dementia recorded in 823 and 2,778 individuals over a median follow-up of 6.4 and 12.5 years, respectively. Higher triglyceride levels were associated with lower dementia risk in the entire ASPREE cohort (hazard ratio [HR] with doubling of triglyceride: 0.82, 95% CI 0.72-0.94). Findings were similar in the subcohort of participants with APOE-ε4 genetic data (n = 13,976) and in the UK Biobank cohort (HR was 0.82 and 0.83, respectively, all p ≤ 0.01). Higher triglycerides were also associated with slower decline in composite cognition and memory over time (p ≤ 0.05). Older adults with higher triglyceride levels within the normal to high-normal range had a lower dementia risk and slower cognitive decline over time compared with individuals with lower triglyceride levels. Higher triglyceride levels may be reflective of better overall health and/or lifestyle behaviors that would protect against dementia development. Future studies are warranted to investigate whether specific components within the total circulating pool of plasma triglycerides may promote better cognitive function, with the hope of informing the development of new preventive strategies.


Occurrence of pleural effusion due to tuberculosis in patients with sarcoidosis.
Sarcoidosis is a systemic granulomatous disease of unknown aetiology. Pleural effusion is very rare in sarcoidosis. In cases with pleural effusion, usually other etiologic factors such as tuberculosis, heart failure, renal failure and malignancy should be considered. We retrospectively reviewed the records of 512 sarcoidosis patients followed up at Ceraphasa Medical Faculty, Internal Medicine-Respiratory Disease Department, Turkey. Only four patients with pleural effusion were documented, in three of them it was due to tuberculosis. The patients were negative for microbiological tests regarding tuberculosis and tuberculin tests as well, when the diagnosis of sarcoidosis was made. With the occurrence of effusion tuberculin tests became positive. Acid-fast bacilli (AFB) was cultured in pleural fluid and biopsy materials. After addition of antituberculosis therapy, pleural effusion regressed in all the three cases. In a sarcoidosis patient with no active disease activity who present with a pleural effusion, if other causes are excluded, it is advisable to start anti-tuberculosis therapy since sarcoid pleural effusion is a rare form of disease occurring at advanced stage of disease. Moreover, corticosteroid therapy renders patients susceptible to tuberculosis. Tuberculin conversion could be a clue to diagnosis in these patients.


Relative eye size in elasmobranchs.
Variation in relative eye size was investigated in a sample of 46 species of elasmobranch, 32 species of sharks and 14 species of batoids (skates and rays). To get a measure of eye size relative to body size, eye axial diameter was scaled with body mass using least-squares linear regression, using both raw species data, where species are treated as independent data points, and phylogenetically independent contrasts. Residual values calculated for each species, using the regression equations describing these scaling relationships, were then used as a measure of relative eye size. Relative and absolute eye size varies considerably in elasmobranchs, although sharks have significantly relatively larger eyes than batoids. The sharks with the relatively largest eyes are oceanic species; either pelagic sharks that move between the epipelagic (0-200 m) and 'upper' mesopelagic (200-600 m) zones, or benthic and benthopelagic species that live in the mesopelagic (200-1,000 m) and, to a lesser extent, bathypelagic (1,000-4,000 m) zones. The elasmobranchs with the relatively smallest eyes tend to be coastal, often benthic, batoids and sharks. Active benthopelagic and pelagic species, which prey on active, mobile prey also have relatively larger eyes than more sluggish, benthic elasmobranchs that feed on more sedentary prey such as benthic invertebrates. A significant positive correlation was found between absolute eye size and relative eye size, but some very large sharks, such as Carcharodon carcharias have absolutely large eyes, but have relatively small eyes in relation to body mass.


A systems approach can ensure high-quality care and low costs.
Risk management programs in hospitals are necessary not only because of some state laws that require them, but also because they can help to cut malpractice costs. In a systems approach to risk management, an effective incident reporting system should be developed, a medical incident review committee should be established, and attempts to involve attending physicians should be made. This approach can encourage a higher level of patient care and can cut costs.


Retinotopy and attention in human occipital, temporal, parietal, and frontal cortex.
Novel mapping stimuli composed of biological motion figures were used to study the extent and layout of multiple retinotopic regions in the entire human brain and to examine the independent manipulation of retinotopic responses by visual stimuli and by attention. A number of areas exhibited retinotopic activations, including full or partial visual field representations in occipital cortex, the precuneus, motion-sensitive temporal cortex (extending into the superior temporal sulcus), the intraparietal sulcus, and the vicinity of the frontal eye fields in frontal cortex. Early visual areas showed mainly stimulus-driven retinotopy; parietal and frontal areas were driven primarily by attention; and lateral temporal regions could be driven by both. We found clear spatial specificity of attentional modulation not just in early visual areas but also in classical attentional control areas in parietal and frontal cortex. Indeed, strong spatiotopic activity in these areas could be evoked by directed attention alone. Conversely, motion-sensitive temporal regions, while exhibiting attentional modulation, also responded significantly when attention was directed away from the retinotopic stimuli.


History of precordial leads in electrocardiography.
Precordial leads were first used by Waller, whose capillary electroscope was too insensitive to detect the electric forces emanating from the human heart unless the electrode was placed over the precordium as near to the heart as possible. When Einthoven developed the elegant, reliable and sensitive string galvanometer, he could record the electric forces of the heart from the hands and feet of the subject without even undressing him. When Einthoven's great galvanometer became available, only the three standard limb leads were used. Thomas Lewis and others experimented with precordial direct leads and made many important discoveries in electrocardiography and cardiology. Wolferth and Wood, in 1932, introduced the first precordial lead in clinical, diagnostic cardiology. The recordings were 'upside-down', i.e. positive deflections were down and negative ones up. They called this the 4th lead (lead IV). The precordial electrode was placed on the chest over the apex of the heart, regardless of where the apex was located. This immediately opened new avenues of study in infarction, ventricular hypertrophy, bundle branch block, and all other cardiac states. Then CL, CR, CF, CB and V leads were introduced. The points considered best for placing the 'exploring' or precordial electrode became an issue, and much confusion prevailed until Wilson and his associates developed the central or isopotential terminal and until the American Heart Association and the Heart Society of Britain and Ireland met in London and published the standards for recording precordial leads in 1938. There followed, for obvious reasons, a slow settling of the confusion until the V1 through V6 precordial leads became standard procedure all over the world, as exists today. Goldberger introduced the augmented unipolar limb leads (aVR, aVL and aVF) which have resulted in the standard 12-lead electrocardiogram of routine use today. No one would consider an electrocardiographic evaluation adequate in a cardiac study at present unless the 12-lead ECG were recorded.


Correlates of delusion-like experiences in a non-psychotic community sample.
Several large population-based studies have reported that otherwise-well individuals endorse items related to delusion-like experiences. The aim of the present study was to examine selected correlates of delusion-like experiences in a sample of non-psychotic individuals. Subjects (n=310) were screened with the Diagnostic Interview for Psychosis in order to exclude psychotic disorders. Delusion-like experiences were assessed with the Peters Delusional Inventory (PDI). Non-parametric statistics were used to assess the relationship between total PDI score and a range of demographic (age, sex, migrant status, paternal age), physical (minor physical anomalies) symptom-related variables (hallucinations, awareness of thought disorder) and family history of mental illness. The median (range) PDI score was 4 (0-26), while one-third of the subjects endorsed seven or more items. The presence of a family history of any psychiatric condition was significantly correlated with a higher PDI score. PDI score was significantly positively correlated with endorsement of hallucinations and awareness of thought disorder. PDI was not significantly associated with sex, family history of schizophrenia, paternal age, migrant status nor scores related to minor physical anomalies. There was a trend level association between younger age and higher PDI score. Delusion-like experiences are relatively common in non-psychotic individuals. The association with a family history of mental disorders provides clues to the mechanisms underlying the profile of delusion-like experience.


Statin therapy in patients with acute coronary syndrome: low-density lipoprotein cholesterol goal attainment and effect of statin potency.
Elevated low-density lipoprotein cholesterol (LDL-C) is associated with an increased risk of coronary artery disease. Current guidelines recommend an LDL-C target of <70 mg/dL (<1.8 mmol/L) for acute coronary syndrome (ACS) patients, and the first-line treatment to lower lipids is statin therapy. Despite current guidelines and the efficacious lipid-lowering agents available, about half of patients at very high risk, including ACS patients, fail to achieve their LDL-C goal. This study assessed LDL-C goal attainment according to use of high and low potency statins in routine practice in Thailand. A retrospective cohort study was performed by retrieving data from medical records and the electronic hospital database for a tertiary care hospital in Thailand between 2009 and 2011. Included were ACS patients treated with statins at baseline and with follow-up of LDL-C levels. Patients were divided into high or low potency statin users, and the proportion reaching the LDL-C goal of <70 mg/dL was determined. A Cox proportional hazard model was applied to determine the relationship between statin potency and LDL-C goal attainment. Propensity score adjustment was used to control for confounding by indication. Of 396 ACS patients (60% males, mean age 64.3±11.6 years), 229 (58%) were treated with high potency statins and 167 (42%) with low potency statins. A quarter reached their target LDL-C goal (25% for patients on high potency statins and 23% on low potency statins). High potency statins were not associated with increased LDL-C goal attainment (adjusted hazards ratio 1.22, 95% confidence interval 0.79-1.88; P=0.363). There was no significant effect of high potency statins on LDL-C goal attainment. Moreover, this study showed low LDL-C goal attainment for patients on either low or high potency statins. The reasons for the low LDL-C goal attainment rate warrants further investigation.


Rapid and nondestructive fraud detection of palm oil adulteration with Sudan dyes using portable NIR spectroscopic techniques.
Non-destructive, simple and fast techniques for identifying authentic palm oil and those adulterated with Sudan dyes using portable NIR spectroscopy would be very beneficial to West Africa countries and the world at large. In this study, a portable NIR spectroscopy coupled with multivariate models were developed for detecting palm oil adulteration. A total of 520 samples of palm oil were used comprising; 40 authentic samples together with 480 adulterated samples containing Sudan dyes (I, II, III, IV of 120 samples each). Multiplicative scatter correction (MSC) preprocessing technique plus Principal component analysis (PCA) was used to extract relevant spectral information which gave visible cluster trends for authentic samples and adulterated ones. The performance of Linear discriminant analysis (LDA) and Support vector machine (SVM) were compared, and SVM showed superiority over LDA. The optimised results by cross-validation revealed that MSC-PCA + SVM gave an identification rate above 95% for both calibration and prediction sets. The overall results show that portable NIR spectroscopy together with MSC-PCA + SVM model could be used successfully to identify authentic palm oils from adulterated ones. This would be useful for quality control officers and consumers to manage and control Sudan dyes adulteration in red palm oil.


Renorenal reflexes: neural components of ipsilateral and contralateral renal responses.
In anesthetized rats, stimulating renal mechanoreceptors (MR) by increasing renal venous pressure (RVP) 22 mmHg increased ipsilateral (ipsi) renal vascular resistance (RVR) from 23.5 to 31.3 mmHg/(ml X min-1 X g-1), ipsi urinary sodium excretion (UNaV) from 0.26 to 0.49 mumol X min-1 X g-1, contralateral (contra) urine flow rate (V) from 3.13 to 4.43 microliter X min-1 X g-1, and UNaV from 0.30 to 0.46 mumol X min-1 X g-1. Ipsi renal denervation (DNX) did not affect the increase in ipsi RVR but reduced the increase in ipsi UNaV. The increases in contra V and UNaV were abolished by either ipsi or contra renal DNX. Increases RVP increased ipsi afferent renal nerve activity (ARNA) 288 counts/10 s and decreased ipsi and contra efferent renal nerve activity (ERNA) 242 and 490 counts/10 s, respectively. Renal pelvic instillation of lidocaine (5 micrograms/ml) did not affect the renal functional or electrophysiological responses to increases RVP but abolished the increase in ipsi ARNA, the decrease in contra ERNA, and the increases in contra V and UNaV produced by increasing ureteral pressure (UP) or retrograde ureteropelvic perfusion with 0.9 M NaCl [chemoreceptor (CR) stimulation]. Chronic T6 spinal cord section abolished the increase in ipsi ARNA, the decrease in contra ERNA, and the increases in contra V and UNaV produced by renal MR (increases RVP, increases UP) and CR stimulation. We conclude increases that RVP results in an ipsi and contra inhibitory renorenal reflex. Differential blockade with pelvic lidocaine suggests that the sensory receptors activated by increases RVP are located in an anatomically different area than those activated by increases UP or retrograde ureteropelvic perfusion with 0.9 M NaCl. An intact spinal cord is required for the normal responsiveness of renal sensory neuroreceptor complexes to specific stimuli in the context of the complete renorenal reflex response.


Allergic Reactions to Pine Nut: A Review.
Pine nut is a nutrient-rich food with a beneficial impact on human health. The many bioactive constituents of pine nut interact synergistically to affect human physiology in a favorable way. However, pine nut can trigger dangerous allergic reactions. Severe anaphylactic reactions to pine nut accounted for most of the 45 cases reported in the scientific literature. Pine nut allergy seems to be characterized by low IgE cross-reactivity with other commonly consumed nuts and a high monosensitization rate. The present review provides updated information on allergic reactions to pine nut, molecular characterization of its allergens, and potential homologies with other nut allergens.


Treatment of recurrent Merkel cell carcinoma: an analysis of 46 cases.
This report describes the course of recurrent Merkel cell carcinoma and defines possible treatment strategies for recurrent disease as seen in a long-term multisite retrospective analysis. Merkel cell carcinoma is a highly aggressive neuroendocrine skin cancer. Surgery and radiation therapy have been demonstrated ability to control this disease; however, recurrence is common. Systemic chemotherapy has, as yet, no presently defined role in primary treatment, and few conclusions can be reached regarding optimal treatment of disease recurrence. Forty-six patients were identified over the last 15 years in a retrospective analysis of patient records from several hospitals in the San Antonio, TX area. Hospital charts as well as outpatient treatment records were reviewed. Almost all patients developing recurrent disease did so within the first 2 years after primary treatment. Patients presenting distant disease had a median survival of 12 months, faring worse than those who display local or nodal disease. For patients with nodal or local recurrence, the mean survival after combination therapy (chemotherapy, radiation +/- surgery) was 36.5 months as compared with 17.5 months for those treated with a single modality (surgery or radiation or chemotherapy). The overall survival rate for the 46 patients with recurrence was 37%. Multimodality therapy has shown the best results for recurrent Merkel cell carcinoma thus far, and should be used if tolerated by the patient. Aggressive salvage surgery for local or nodal recurrence is encouraged, because this disease has a tendency to become more destructive upon recurrence. Adjuvant radiation therapy should also be used, if the patient has not exceeded their dose limitations. Disseminated disease, whether primary or recurrent, warrants further investigation in terms of optimal treatment.


Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis.
Sepsis remains a major medical challenge, for which, apart from improvements in supportive care, treatment has not relevantly changed over the last few decades. Vasodilation and vascular leakage play a pivotal role in the development of septic shock, with vascular leakage being caused by disrupted endothelial integrity. Adrenomedullin (ADM), a free circulating peptide involved in regulation of endothelial barrier function and vascular tone, is implicated in the pathophysiology of sepsis. ADM levels are increased during sepsis, and correlate with extent of vasodilation, as well as with disease severity and mortality. In vitro and preclinical in vivo data show that administration of ADM exerts anti-inflammatory, antimicrobial, and protective effects on endothelial barrier function during sepsis, but other work suggests that it may also decrease blood pressure, which could be detrimental for patients with septic shock. Work has been carried out to negate ADMs putative negative effects, while preserving or even potentiating its beneficial actions. Preclinical studies have demonstrated that the use of antibodies that bind to the N-terminus of ADM results in an overall increase of circulating ADM levels and improves sepsis outcome. Similar beneficial effects were obtained using coadministration of ADM and ADM-binding protein-1. It is hypothesized that the mechanism behind the beneficial effects of ADM binding involves prolongation of its half-life and a shift of ADM from the interstitium to the circulation. This in turn results in increased ADM activity in the blood compartment, where it exerts beneficial endothelial barrier-stabilizing effects, whereas its detrimental vasodilatory effects in the interstitium are reduced. Up till now, in vivo data on ADM-targeted treatments in humans are lacking; however, the first study in septic patients with an N-terminus antibody (Adrecizumab) is currently being conducted.


Genetic and functional analysis of chymotrypsin-like protease (CTRL) in chronic pancreatitis.
Genetic predisposition is crucial in the pathogenesis of early-onset chronic pancreatitis (CP). So far, several genetic alterations have been identified as risk factors, predominantly in genes encoding digestive enzymes. However, many early-onset CP cases have no identified underlying cause. Chymotrypsins are a family of serine proteases that can cleave trypsinogen and lead to its degradation. Because genetic alterations in the chymotrypsins CTRC, CTRB1, and CTRB2 are associated with CP, we genetically and functionally investigated chymotrypsin-like protease (CTRL) as a potential risk factor. We screened 1005 non-alcoholic CP patients and 1594 controls for CTRL variants by exome sequencing. We performed Western blots and activity assays to analyse secretion and proteolytic activity. We measured BiP mRNA expression to investigate the potential impact of identified alterations on endoplasmic reticulum (ER) stress. We identified 13 heterozygous non-synonymous CTRL variants: five exclusively in patients and three only in controls. Functionality was unchanged in 6/13 variants. Four alterations showed normal secretion but reduced (p.G20S, p.G56S, p.G61S) or abolished (p.S208F) activity. Another three variants (p.C201Y, p.G215R and p.C220G) were not secreted and already showed reduced or no activity intracellularly. However, intracellular retention did not lead to ER stress. We identified several CTRL variants, some showing potent effects on protease function and secretion. We observed these effects in variants found in patients and controls, and CTRL loss-of-function variants were not significantly more common in patients than controls. Therefore, CTRL is unlikely to play a relevant role in the development of CP.


Oxidation State Localized Orbitals: A Method for Assigning Oxidation States Using Optimally Fragment-Localized Orbitals and a Fragment Orbital Localization Index.
Oxidation states represent the ionic distribution of charge in a molecule and are significant in tracking redox reactions and understanding chemical bonding. While effective algorithms already exist based on formal Lewis structures as well as using localized orbitals, they exhibit differences in challenging cases where effects such as redox noninnocence are at play. Given a density functional theory (DFT) calculation with chosen total charge and spin multiplicity, this work reports a new approach to obtaining fragment-localized orbitals that is termed oxidation state localized orbitals (OSLO), together with an algorithm for assigning the oxidation state using the OSLOs and an associated fragment orbital localization index (FOLI). Evaluating the FOLI requires fragment populations, and for this purpose a new version of the intrinsic atomic orbital (IAO) scheme is introduced in which the IAOs are evaluated using a reference minimal basis formed from on-the-fly superposition of atomic density (IAO-AutoSAD) calculations in the target basis set and at the target level of theory. The OSLO algorithm is applied to a range of challenging cases including high valent metal oxide complexes, redox noninnocent NO and dithiolate transition metal complexes, a range of carbene-containing TM complexes, and other examples including the potentially inverted ligand field in [Cu(CF3)4]-. Across this range of cases, OSLO produces generally satisfactory results. Furthermore, in borderline cases, the OSLOs and associated FOLI values provide direct evidence of the emergence of covalent interactions between fragments that nicely complements existing approaches.


Enhancement of in vitro growth and resistance to gray mould of Vitis vinifera co-cultured with plant growth-promoting rhizobacteria.
The potential of a plant growth-promoting rhizobacterium, Pseudomonas sp. (strain PsJN), to stimulate the growth and enhancement of the resistance of grapevine (Vitis vinifera L.) transplants to gray mould caused by Botrytis cinerea has been investigated. In vitro inoculation of grapevine plantlets induced a significant plant growth promotion which made them more hardy and vigorous when compared to non-inoculated plantlets. This ability increased upon transplanting. When grown together with B. cinerea, the causal agent of gray mould, significant differences of aggressiveness were observed between the inoculated and non-inoculated plants. The presence of bacteria was accompanied by an induction of plant resistance to the pathogen. The beneficial effect from this plant-microbe association is being postulated.


Diagnosis of pleural tuberculosis by multi-targeted loop-mediated isothermal amplification assay based on SYBR Green I reaction: comparison with GeneXpert® MTB/RIF assay.
Diagnosis of pleural tuberculosis (TB) is tedious owing to its close resemblance with malignant pleural effusion and sparse bacterial load in clinical specimens. There is an immediate need to design a rapid and dependable diagnostic test to prevent unnecessary morbidity/mortality. A multi-targeted loop-mediated isothermal amplification (MT-LAMP) was deliberated using mpt64 and IS6110 to diagnose pleural TB within pleural fluids/biopsies. MT-LAMP products were analyzed by gel-based and visual detection methods, viz. SYBR Green I, SYBR Green I+deoxyuridine triphosphate uracil-N-glycosylase (dUTP-UNG), and dry methyl green reactions. In a pilot study, while assessing pleural TB/non-TB control subjects (n = 40), both SYBR Green I+dUTP-UNG/gel-based MT-LAMP assays exhibited better sensitivity/specificity than SYBR Green I and dry methyl green MT-LAMP. Since it is facile to work with SYBR Green I+dUTP-UNG than gel-based MT-LAMP, we validated the performance of SYBR Green I+dUTP-UNG in a higher number of specimens (n = 97), which revealed somewhat higher sensitivity (85.2 vs. 81.5%) and specificity (97.7 vs. 90.7%) than SYBR Green I MT-LAMP. Furthermore, the sensitivity attained by SYBR Green I+dUTP-UNG MT-LAMP was significantly higher (p < 0.001) than GeneXpert. Our SYBR Green I+dUTP-UNG MT-LAMP is a simple and reliable method to diagnose pleural TB, which may translate into a point-of-care test.


High extracellular glucose impairs cardiac E-C coupling in a glycosylation-dependent manner.
Hyperglycemia is a major manifestation of all forms of diabetes mellitus and is associated with increased risk of cardiovascular disease. It is well established that cardiac excitation-contraction (E-C) coupling is adversely affected in diabetic animals such that ventricular myocyte action potential duration is prolonged and intracellular Ca2+ clearing and mechanical relaxation are slowed. We now report that ventricular myocytes incubated in a culture medium containing high extracellular glucose (25.5 mM) also exhibit these same changes in E-C coupling. These effects are not manifested for approximately 24 h after exposure. Furthermore, in the presence of normal glucose (5.5 mM), relaxation is also prolonged by fructose (20 mM), yet is unaffected by equimolar concentrations of nonmetabolizable sugars such as L-glucose and mannitol, implying that the high glucose effects require glucose entry into the cell and metabolic processing. The prolonged relaxation can also be produced by 5 mM glucosamine (an intermediate of glycosylation) and is blocked by 0.5 microgram/ml tunicamycin (an inhibitor of N-linked glycoprotein synthesis). Culturing myocytes with an inhibitor of glycation (10 mM aminoguanidine) does not prevent the high extracellular glucose concentration effects. Thus our data indicate that high extracellular glucose impairs cellular mechanisms contributing to myocardial relaxation and that this impairment may involve glycosylation of nascent proteins.


Co-expression and co-localization of hub proteins and their partners are encoded in protein sequence.
Spatiotemporal coordination is a critical factor in biological processes. Some hubs in protein-protein interaction networks tend to be co-expressed and co-localized with their partners more strongly than others, a difference which is arguably related to functional differences between the hubs. Based on numerous analyses of yeast hubs, it has been suggested that differences in co-expression and co-localization are reflected in the structural and molecular characteristics of the hubs. We hypothesized that if indeed differences in co-expression and co-localization are encoded in the molecular characteristics of the protein, it may be possible to predict the tendency for co-expression and co-localization of human hubs based on features learned from systematically characterized yeast hubs. Thus, we trained a prediction algorithm on hubs from yeast that were classified as either strongly or weakly co-expressed and co-localized with their partners, and applied the trained model to 800 human hub proteins. We found that the algorithm significantly distinguishes between human hubs that are co-expressed and co-localized with their partners and hubs that are not. The prediction is based on sequence derived features such as "stickiness", i.e. the existence of multiple putative binding sites that enable multiple simultaneous interactions, "plasticity", i.e. the existence of predicted structural disorder which conjecturally allows for multiple consecutive interactions with the same binding site and predicted subcellular localization. These results suggest that spatiotemporal dynamics is encoded, at least in part, in the amino acid sequence of the protein and that this encoding is similar in yeast and in human.


Transcriptome analysis of Catharanthus roseus for gene discovery and expression profiling.
The medicinal plant, Catharanthus roseus, accumulates wide range of terpenoid indole alkaloids, which are well documented therapeutic agents. In this study, deep transcriptome sequencing of C. roseus was carried out to identify the pathways and enzymes (genes) involved in biosynthesis of these compounds. About 343 million reads were generated from different tissues (leaf, flower and root) of C. roseus using Illumina platform. Optimization of de novo assembly involving a two-step process resulted in a total of 59,220 unique transcripts with an average length of 1284 bp. Comprehensive functional annotation and gene ontology (GO) analysis revealed the representation of many genes involved in different biological processes and molecular functions. In total, 65% of C. roseus transcripts showed homology with sequences available in various public repositories, while remaining 35% unigenes may be considered as C. roseus specific. In silico analysis revealed presence of 11,620 genic simple sequence repeats (excluding mono-nucleotide repeats) and 1820 transcription factor encoding genes in C. roseus transcriptome. Expression analysis showed roots and leaves to be actively participating in bisindole alkaloid production with clear indication that enzymes involved in pathway of vindoline and vinblastine biosynthesis are restricted to aerial tissues. Such large-scale transcriptome study provides a rich source for understanding plant-specialized metabolism, and is expected to promote research towards production of plant-derived pharmaceuticals.


Patients' Perceptions of Dental Students' Empathic, Person-Centered Care in a Dental School Clinic in Malaysia.
Empathy has been identified as a crucial foundation in building an effective dentist-patient relationship. The aim of this study was to assess patients' perceptions of dental students' empathic care in the primary oral health care clinic at International Medical University in Kuala Lumpur, Malaysia in May-October 2014. The study also assessed the validity and reliability of the Consultation and Relational Empathy (CARE) Measure in this setting; the association between number of encounters and students' CARE Measure scores; and the association between students' empathy (measured by the Toronto Empathy Questionnaire) and CARE Measure scores. Participants were 283 patients (aged ≥18 years) who were asked to self-complete the ten-item CARE Measure immediately after their clinical encounter with students who provided care under supervision of the teaching staff. The results showed that the CARE Measure demonstrated good internal consistency (Cronbach's α=0.95). A single factor solution emerged, accounting for 69% of the variance. The mean CARE Measure score in the consultations was 43.55±6.14, and 26% of the students achieved the maximum possible score of 50. The mean number of encounters with each student was 2.33±2.78. An increase of one episode was associated with an insignificant average CARE score decrease of 0.05 (-0.28, 0.38), whereas students' empathy was associated with a small increase in average CARE Measure score of 0.63 (0.08, 1.18). These results provide evidence of the measure's ability to support feedback to dental students on their empathy when interacting with patients.


In Vitro Interactions of Antibiotic Combinations of Colistin, Tigecycline, and Doripenem Against Extensively Drug-Resistant and Multidrug-Resistant Acinetobacter baumannii.
Acinetobacter baumannii infections are difficult to treat owing to the emergence of various antibiotic resistant isolates. Because treatment options are limited for multidrug-resistant (MDR) A. baumannii infection, the discovery of new therapies, including combination therapy, is required. We evaluated the synergistic activity of colistin, doripenem, and tigecycline combinations against extensively drug-resistant (XDR) A. baumannii and MDR A. baumannii. Time-kill assays were performed for 41 XDR and 28 MDR clinical isolates of A. baumannii by using colistin, doripenem, and tigecycline combinations. Concentrations representative of clinically achievable levels (colistin 2 μg/mL, doripenem 8 μg/mL) and achievable tissue levels (tigecycline 2 μg/mL) for each antibiotic were used in this study. The colistin-doripenem combination displayed the highest rate of synergy (53.6%) and bactericidal activity (75.4%) in 69 clinical isolates of A. baumannii. Among them, the-doripenem-tigecycline combination showed the lowest rate of synergy (14.5%) and bactericidal activity (24.6%). The doripenem-tigecycline combination showed a higher antagonistic interaction (5.8%) compared with the colistin-tigecycline (1.4%) combination. No antagonism was observed for the colistin-doripenem combination. The colistin-doripenem combination is supported in vitro by the high rate of synergy and bactericidal activity and lack of antagonistic reaction in XDR and MDR A. baumannii. It seems to be necessary to perform synergy tests to determine the appropriate combination therapy considering the antagonistic reaction found in several isolates against the doripenem-tigecycline and colistin-tigecycline combinations. These findings should be further examined in clinical studies.


Providing coaching and cotinine results to preteens to reduce their secondhand smoke exposure: a randomized trial.
Secondhand smoke exposure (SHSe) poses health risks to children living with smokers. Most interventions to protect children from SHSe have coached adult smokers. This trial determined whether coaching and cotinine feedback provided to preteens can reduce their SHSe. Two hundred one predominantly low-income families with a resident smoker and a child aged 8 to 13 years who was exposed to two or more cigarettes per day or had a urine cotinine concentration ≥ 2.0 ng/mL were randomized to control or SHSe reduction coaching groups. During eight in-home sessions over 5 months, coaches presented to the child graphic charts of cotinine assay results as performance feedback and provided differential praise and incentives for cotinine reductions. Generalized estimating equations were used to determine the differential change in SHSe over time by group. For the baseline to posttest period, the coaching group had a greater decrease in both urine cotinine concentration (P = .039) and reported child SHSe in the number of cigarettes exposed per day (child report, P = .003; parent report, P = .078). For posttest to month 12 follow-up, no group or group by time differences were obtained, and both groups returned toward baseline. Coaching preteens can reduce their SHSe, although reductions may not be sustained without ongoing counseling, feedback, and incentives. Unlike interventions that coach adults to reduce child SHSe, programs that increase child avoidance of SHSe have the potential to reduce SHSe in all settings in which the child is exposed, without requiring a change in adult smoking behavior.


Zinc inactivates melastatin transient receptor potential 2 channels via the outer pore.
Zinc ion (Zn(2+)) is an endogenous allosteric modulator that regulates the activity of a wide variety of ion channels in a reversible and concentration-dependent fashion. Here we used patch clamp recording to study the effects of Zn(2+) on the melastatin transient receptor potential 2 (TRPM2) channel. Zn(2+) inhibited the human (h) TRPM2 channel currents, and the steady-state inhibition was largely not reversed upon washout and concentration-independent in the range of 30-1000 μM, suggesting that Zn(2+) induces channel inactivation. Zn(2+) inactivated the channels fully when they conducted inward currents, but only by half when they passed outward currents, indicating profound influence of the permeant ion on Zn(2+) inactivation. Alanine substitution scanning mutagenesis of 20 Zn(2+)-interacting candidate residues in the outer pore region of the hTRPM2 channel showed that mutation of Lys(952) in the extracellular end of the fifth transmembrane segment and Asp(1002) in the large turret strongly attenuated or abolished Zn(2+) inactivation, and mutation of several other residues dramatically changed the inactivation kinetics. The mouse (m) TRPM2 channels were also inactivated by Zn(2+), but the kinetics were remarkably slower. Reciprocal mutation of His(995) in the hTRPM2 channel and the equivalent Gln(992) in the mTRPM2 channel completely swapped the kinetics, but no such opposing effects resulted from exchanging another pair of species-specific residues, Arg(961)/Ser(958). We conclude from these results that Zn(2+) inactivates the TRPM2 channels and that residues in the outer pore are critical determinants of the inactivation.


Potentiated Hsp104 variants suppress toxicity of diverse neurodegenerative disease-linked proteins.
Protein misfolding is implicated in numerous lethal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD). There are no therapies that reverse these protein-misfolding events. We aim to apply Hsp104, a hexameric AAA+ protein from yeast, to target misfolded conformers for reactivation. Hsp104 solubilizes disordered aggregates and amyloid, but has limited activity against human neurodegenerative disease proteins. Thus, we have previously engineered potentiated Hsp104 variants that suppress aggregation, proteotoxicity and restore proper protein localization of ALS and PD proteins in Saccharomyces cerevisiae, and mitigate neurodegeneration in an animal PD model. Here, we establish that potentiated Hsp104 variants possess broad substrate specificity and, in yeast, suppress toxicity and aggregation induced by wild-type TDP-43, FUS and α-synuclein, as well as missense mutant versions of these proteins that cause neurodegenerative disease. Potentiated Hsp104 variants also rescue toxicity and aggregation of TAF15 but not EWSR1, two RNA-binding proteins with a prion-like domain that are connected with the development of ALS and frontotemporal dementia. Thus, potentiated Hsp104 variants are not entirely non-specific. Indeed, they do not unfold just any natively folded protein. Rather, potentiated Hsp104 variants are finely tuned to unfold proteins bearing short unstructured tracts that are not recognized by wild-type Hsp104. Our studies establish the broad utility of potentiated Hsp104 variants.


Rhes influences striatal cAMP/PKA-dependent signaling and synaptic plasticity in a gender-sensitive fashion.
Mechanisms of gender-specific synaptic plasticity in the striatum, a brain region that controls motor, cognitive and psychiatric functions, remain unclear. Here we report that Rhes, a GTPase enriched in medium spiny neurons (MSNs) of striatum, alters the striatal cAMP/PKA signaling cascade in a gender-specific manner. While Rhes knockout (KO) male mice, compared to wild-type (WT) mice, had a significant basal increase of cAMP/PKA signaling pathway, the Rhes KO females exhibited a much stronger response of this pathway, selectively under the conditions of dopamine/adenosine-related drug challenge. Corticostriatal LTP defects are exclusively found in A2AR/D2R-expressing MSNs of KO females, compared to KO males, an effect that is abolished by PKA inhibitors but not by the removal of circulating estrogens. This suggests that the synaptic alterations found in KO females could be triggered by an aberrant A2AR/cAMP/PKA activity, but not due to estrogen-mediated effect. Consistent with increased cAMP signaling, D1R-mediated motor stimulation, haloperidol-induced catalepsy and caffeine-evoked hyper-activity are robustly enhanced in Rhes KO females compared to mutant males. Thus Rhes, a thyroid hormone-target gene, plays a relevant role in gender-specific synaptic and behavioral responses.


Oxidative stress in systemic lupus erythematosus: relationship to Th1 cytokine and disease activity.
Imbalance between oxidative stress and helper T-cell (Th1)-derived cytokines is one possible cause for the pathogenesis of systemic lupus erythematosus (SLE). To evaluate the correlation between oxidative stress and Th1 cytokine level with the disease activity of SLE in the North Indian population, oxidative/anti-oxidant profiles: malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH) and interferon (IFN)-gamma, interleukin (IL)-12 were studied. The estimation of oxidant and anti-oxidant enzymes was done in erythrocyte hemolysate and the levels of IFN-gamma and IL-12 were determined in the culture supernatant of peripheral blood mononuclear cells (PBMC) by a sandwich enzyme-linked immunosorbent assay (ELISA). A significant increase in the level of lipid peroxidation, measured as malondialdehyde (MDA), was found in SLE patients. The activities of anti-oxidant enzymes: SOD, CAT, GPx and anti-oxidant molecule GSH were significantly reduced in SLE patients as compared to controls. Increased levels of IFN-gamma and IL-12 were found in the culture supernatant of PBMC of SLE patients. MDA level was positively correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, IFN-gamma, IL-12 and negatively correlated with GSH in SLE patients. Strong positive correlations of IFN-gamma and MDA with SLEDAI score suggest that lipid peroxidation and pro-inflammatory cytokine, both are involved in the pathogenesis of SLE. Collectively, this study advocates that severity of disease might be enhanced by imbalance between oxidative stress and helper T-cell (Th1)-derived cytokines in SLE.


Generation of a long-acting fusion inhibitor against HIV-1.
AIDS has evolved from a fatal infectious disease to a manageable chronic disease under the treatment of anti-AIDS medications. HIV fusion inhibitors with high activity, low side effects and strong selectivity are promising drugs against HIV. Only one fusion inhibitor is currently approved, thereby highly active long-acting fusion inhibitors need to be developed for long-term AIDS treatment. Here, we synthesised MT-SC22EK (a small HIV fusion inhibitor) derivatives containing 1-2 staples to improve its stability. Antiviral activity studies showed that MT-SC22EK-2 with two staples exhibited potent inhibitory activity against HIV-1 standard strains and Chinese epidemic strains, and at the same time, MT-SC22EK-2 presented strong anti-T20 resistance. Surprisingly, MT-SC22EK-2 possessed excellent protease stability with a half-life of 3665 min. MT-SC22EK-2 is a potential HIV fusion inhibitor considered as a long-acting anti-HIV drug candidate.