[Establishment of a malignant pleural effusion mouse model with Lewis lung carcinoma cell lines expressing enhanced green fluorescent protein].
Malignant pleural effusion (MPE) is a poor prognosis factor in patients with advanced lung cancer. The aim of this study is to establish a mouse model of MPE using Lewis lung carcinoma (LLC) cell lines expressing enhanced green fluorescent protein (EGFP). The mouse model was created by injecting LLC-EGFP cells directly into the pleural cavity of mice that were sacrificed periodically. The dynamic growth and metastasis of tumor cells were screened using in vivo fluorescence imaging. The remaining mice were subjected to transverse computed tomography (CT) imaging periodically to analyze the formation rate of pleural effusion. The survival rate and tumor metastasis were also observed. Pleural fluid was gently aspirated using a 1 mL syringe and its volume was measured. When two or more mice bore pleural effusion at the same time, we calculated the average volume. The correlation of pleural effusion with the integrated optical density (IOD) were analyzed. Four days after the inoculation of LLC-EGFP cells, green fluorescence was observed by opening the chest wall. The tumor formation rate was 100%, and the IOD gradually increased after inoculation. The metastasis sites were mediastinal, and the hilar lymph nodes were contralateral pleural as well as pericardial. The metastasis rates were 87%, 73% and 20%, respectively. The CT scan revealed that the formation rates of pleural effusion on days 7, 14 and 21 were 13%, 46% and 53%, respectively. The average volume of pleural effusion increased obviously on day 10 and peaked on day 16 with a value of 0.5 mL. The mean survival time of nude mice was 28.8 days. The volume of pleural effusion and IOD were significantly correlated (r=0.91, P<0.000,1). A mouse model of lung cancer malignant pleural effusion was successfully established by injecting LLC lines expressing EGFP into the pleural cavity under a microscope. The model can enable dynamic observations of the biological behavior of tumor cells in the pleural cavity. It might be helpful for basic research on advanced lung cancer as well as anti-tumor drug development.


Kinetics simulation of luminol chemiluminescence based on quantitative analysis of photons generated in electrochemical oxidation.
The kinetics of electrogenerated chemiluminescence (ECL) of luminol at a gold electrode in alkaline solution was investigated by measuring the absolute number of photons emitted in an integrating sphere. The ECL efficiency as the ratio of photon to electric charge was 0.0004 in cyclic voltammography and 0.0005 in chronoamperometry. By numerically solving the rate equations based on a diffusion layer model, the observed time profile of the luminescence intensity could be successfully simulated from the oxidation current of luminol in the chronoamperometry. In the simulation, the rate constant for the oxidation of luminol by superoxide radicals in alkaline solution was determined to be 6 × 10(5) M(-1) s(-1). The present methodology and the achievement could be widely applicable to various analytical techniques using chemiluminescence.


Robust nonfitting way to determine mass diffusivity and initial concentration for VOCs in building materials with accuracy estimation.
This paper presents a novel procedure for estimating mass diffusivity and initial concentration for VOCs in building materials. In contrast to methods that fit data to an organic emission model, this new method determines these two parameters by two observations from a chamber test in a nonfitting and sequential way, which defines a well-posed problem and requires no iterative procedure as well as is robust to initial guess and random uncertainties. The most outstanding feature of this method is that multiple estimates of the parameters can be obtained when more than two experimental data are available; thus, these estimates constitute a sample of population of parameter estimates involving experimental errors. The averages of the sample can be regarded the best estimates of the parameters, and, more importantly, variances (standard deviations) and confidence intervals can be readily and naturally estimated making no assumption about the distribution of experimental errors. Two easy and direct ways are suggested for determining confidence limits: one is percentile method, and the other is the normal approximation. This feature highlights the major difference between the new method and common curve-fitting procedures that generally assume random errors being Gaussian distribution.


Influence of gold coating and interplate voltage on the performance of chevron micro-channel plates for temporally and spatially resolved single particle detection.
We present a study of two different sets of Micro-Channel Plates used for time and space resolved single particle detection. We investigate the effects of the gold coating and that of introducing an interplate voltage between the spatially separated plates. We find that the gold coating increases the count rate of the detector and the pulse amplitude as previously reported for non-spatially resolved setups. The interplate voltage also increases count rates. In addition, we find that a non-zero interplate voltage improves the spatial accuracy in determining the arrival position of incoming single particles (by ~20%) while the gold coating has a negative effect (by ~30%).


Importance of adrenergic receptors in prenatally induced cognitive impairment in the domestic chick.
In the domestic chick, mild hypoxia (24h of 14% oxygen) at two stages of embryonic development results in post-hatch memory deficiencies tested using a discriminated bead avoidance task. The nature of the memory loss depends on the gestational age at which the hypoxia occurs. Hypoxia on embryonic day 10 (E10) of a 21 day incubation results in chicks with no short-term memory 10 min after training, whereas hypoxia on day 14 (E14) results in chicks with good labile memory 30 min after training but no consolidation of memory into permanent storage (120 min). Hypoxia at E14 is associated with increased plasma levels of noradrenaline and therefore we suggest that altered catecholamine exposure within the brain contributes to cognitive problems by modifying the responsiveness of brain beta-adrenoceptors. In ovo administration of noradrenaline, or the beta(2)-adrenoceptor agonist formoterol, at E14 had the same effect on memory consolidation as hypoxia. Following hypoxia at E14, memory could be rescued after training by central injection of a beta(3)-adrenoceptor agonist, but not by a beta(2)-adrenoceptor agonist. The differences in the responsiveness of memory processing to beta(2)-adrenoceptor agonists suggests alterations to the receptors or downstream of the receptor activation. However, both types of beta-adrenoceptor agonists rescued memory in E10 treated chicks implying that at this age hypoxia does not affect the receptors. In summary, hypoxia or increased levels of stress hormones during incubation alters beta-adrenoceptor responsiveness; the outcome of the insult depends upon the cellular developmental processes at a given embryonic stage.


A concise total synthesis of DL-histrionicotoxin.
The synthesis of (+/-)-histrionicotoxin has been achieved in just nine steps using a two-directional synthesis strategy. Key reactions include a two-directional cross-metathesis, a tandem oxime formation/Michael addition/1,4-prototopic shift/[3 + 2]-cycloaddition cascade, a selective Z,Z-bisenyne formation, and a one-pot N-O and bischloroacetylene reduction.


Evaluation of a research diagnostic algorithm for DSM-5 neurocognitive disorders in a population-based cohort of older adults.
There is little information on the application and impact of revised criteria for diagnosing dementia and mild cognitive impairment (MCI), now termed major and mild neurocognitive disorders (NCDs) in the DSM-5. We evaluate a psychometric algorithm for diagnosing DSM-5 NCDs in a community-dwelling sample, and characterize the neuropsychological and functional profile of expert-diagnosed DSM-5 NCDs relative to DSM-IV dementia and International Working Group criteria for MCI. A population-based sample of 1644 adults aged 72-78 years was assessed. Algorithmic diagnostic criteria used detailed neuropsychological data, medical history, longitudinal cognitive performance, and informant interview. Those meeting all criteria for at least one diagnosis had data reviewed by a neurologist (expert diagnosis) who achieved consensus with a psychiatrist for complex cases. The algorithm accurately classified DSM-5 major NCD (area under the curve (AUC) = 0.95, 95% confidence interval (CI) 0.92-0.97), DSM-IV dementia (AUC = 0.91, 95% CI 0.85-0.97), DSM-5 mild NCD (AUC = 0.75, 95% CI 0.70-0.80), and MCI (AUC = 0.76, 95% CI 0.72-0.81) when compared to expert diagnosis. Expert diagnosis of dementia using DSM-5 criteria overlapped with 90% of DSM-IV dementia cases, but resulted in a 127% increase in diagnosis relative to DSM-IV. Additional cases had less severe memory, language impairment, and instrumental activities of daily living (IADL) impairments compared to cases meeting DSM-IV criteria for dementia. DSM-5 mild NCD overlapped with 83% of MCI cases and resulted in a 19% increase in diagnosis. These additional cases had a subtly different neurocognitive profile to MCI cases, including poorer social cognition. DSM-5 NCD criteria can be operationalized in a psychometric algorithm in a population setting. Expert diagnosis using DSM-5 NCD criteria captured most cases with DSM-IV dementia and MCI in our sample, but included many additional cases suggesting that DSM-5 criteria are broader in their categorization.


[Thrombocytopenia in the intensive care unit : Diagnosis, differential diagnosis, and treatment].
Thrombocytopenia is a frequent phenomenon in intensive care medicine. A variety of conditions can be responsible for low platelet counts. As platelets are part of the primary hemostatic system, bleeding is the most important complication of thrombocytopenia. Proper workup of the differential diagnosis to identify the cause of thrombocytopenia is essential because the various underlying disorders require different diagnostic and therapeutic management strategies. A low platelet count is a strong predictor of outcome in critically ill patients.This article summarizes the differential diagnosis and diagnostic workup of thrombocytopenia in the critically ill, describes the most important conditions, and gives an overview on therapeutic options and strategies.


Empty sella syndrome: Multiple endocrine disorders.
Empty sella is a pituitary disorder characterized by the herniation of the subarachnoid space within the sella turcica. This is often associated with a variable degree of flattening of the pituitary gland. Empty sella has to be distinguished in primary and secondary forms. Primary empty sella (PES) excludes any history of previous pituitary pathologies such as previous surgical, pharmacologic, or radiotherapy treatment of the sellar region. PES is considered an idiopathic disease and may be associated with idiopathic intracranial hypertension. Secondary empty sella, however, may occur after the treatment of pituitary tumors through neurosurgery or drugs or radiotherapy, after spontaneous necrosis (ischemia or hemorrhage) of chiefly adenomas, after pituitary infectious processes, pituitary autoimmune diseases, or brain trauma. Empty sella, in the majority of cases, is only a neuroradiological finding, without any clinical implication. However, empty sella syndrome is defined in the presence of pituitary hormonal dysfunction (more frequently hypopituitarism) and/or neurological symptoms due to the possible coexisting of idiopathic intracranial hypertension. Empty sella syndrome represents a peculiar clinical entity, characterized by heterogeneity both in clinical manifestations and in hormonal alterations, sometimes reaching severe extremes. For a proper diagnosis, management, and follow-up of empty sella syndrome, a multidisciplinary approach with the integration of endocrine, neurological, and ophthalmological experts is strongly advocated.


Infiltrative lipoma in dogs: 16 cases (1981-1992).
Medical records of 15 dogs with infiltrative lipoma, 1 of which had 2 lesions, were reviewed. Median age of affected dogs was 6.0 years, and median weight was 30.5 kg. The ratio of females to males was 4:1. Eight of the dogs were Labrador Retrievers. In 8 dogs, the lesions had previously been excised. There was not any apparent site predilection. Excision was the only treatment in all 15 dogs, and follow-up information was available for all dogs. Two dogs, each of which had 1 tumor, were euthanatized immediately after surgery, because the tumor could not be completely excised. Of the remaining 14 tumors, 5 (36%) recurred. Median time to recurrence for these 5 tumors was 239 days (range, 96 to 487 days). By means of Kaplan-Meier analysis, the percentage of dogs disease free 1 year after surgery was calculated to be 67%.


Long-term follow-up study on peer-led school-based HIV/AIDS prevention among youths in Shanghai.
The HIV/AIDS epidemic is a major problem around the world and an increasing percentage of new HIV cases is reported to be by sexual transmission. Many studies have been carried out in the field of peer education on HIV/AIDS among young people, however, few studies focused on the long-term effect of this education. To evaluate both the short- and long-term effects of the peer education programme, we conducted a follow-up study to evaluate the related knowledge, attitudes and behaviour intention to HIV/AIDS among senior high-school students in Shanghai, China. We selected 1950 students from 10 senior high schools in Shanghai, from whom 968 students were selected at random for the intervention group and 982 students for the control group. The same questionnaires were carried out before intervention, one month and one year later in both the groups. In the intervention group, the knowledge score of reproductive health, HIV/AIDS and sexually transmitted disease rose from 21.66 to 31.72 one month later (P < 0.001). After one year it was still 30.97, and there was no significant difference between one month and one year (P > 0.05). The behaviour intention to HIV/AIDS prevention, such as condom use during sexual intercourse also changed before and after the intervention. After both the one month and one-year follow-up intervention, we found that more students declared that they would use condoms during sexual intercourse when compared with the control group (P < 0.001). No change was seen in either knowledge or behaviour intention in the control group. These results showed that peer education on HIV/AIDS prevention among high-school students is both effective in promoting knowledge and in changing behaviour intention long term.


Nintedanib in ovarian cancer.
Advanced ovarian cancer remains an unmet clinical need. Angiogenesis is considered a therapeutic target in ovarian cancer, with bevacizumab, a monoclonal antibody against VEGF, being the first drug to show a progression-free survival benefit. Nintedanib is an oral tyrosine kinase inhibitor targeting VEGF receptor 1-3, FGFR 1-3 and PDGFR α and β, which has entered phase III trial development in ovarian cancer. Areas covered: This article reviews the preclinical and clinical efficacy of nintedanib in ovarian cancer, its pharmacokinetic and pharmacodynamics profile, safety issues, together with an overview of clinical trials carried out so far. A literature search was made in PubMed for nintedanib, ovarian cancer, angiogenesis, and on ClinicalTrials.gov site for clinical trials with nintedanib. Expert opinion: An ongoing phase III trial investigating nintedanib combined with first-line chemotherapy in ovarian cancer has shown a statistically significant progression free survival benefit, although there were toxicity issues. The true clinical benefit of nintedanib in ovarian cancer including its optimal treatment setting and dosage still need to be addressed.


Exploiting Carbonyl Groups to Control Intermolecular Rhodium-Catalyzed Alkene and Alkyne Hydroacylation.
Readily available β-carbonyl-substituted aldehydes are shown to be exceptional substrates for Rh-catalyzed intermolecular alkene and alkyne hydroacylation reactions. By using cationic rhodium catalysts incorporating bisphosphine ligands, efficient and selective reactions are achieved for β-amido, β-ester, and β-keto aldehyde substrates, providing a range of synthetically useful 1,3-dicarbonyl products in excellent yields. A correspondingly broad selection of alkenes and alkynes can be employed. For alkyne substrates, the use of a catalyst incorporating the Ampaphos ligand triggers a regioselectivity switch, allowing both linear and branched isomers to be prepared with high selectivity in an efficient manner. Structural data, confirming aldehyde chelation, and a proposed mechanism are provided.


Retraction: Methanol-induced conformation transition of gland fibroin monitored by FTIR spectroscopy and terahertz spectroscopy.
Retraction of 'Methanol-induced conformation transition of gland fibroin monitored by FTIR spectroscopy and terahertz spectroscopy' by Chao Yan et al., Analyst, 2014, 139, 1967-1972.


Inhibitory effects of wild blueberry anthocyanins and other flavonoids on biomarkers of acute and chronic inflammation in vitro.
Wild lowbush blueberries (Vaccinium angustifolium Ait) are a rich source of anthocyanins and other flavonoids with anti-inflammatory activities; however, their individual effects on cellular signaling remain to be elucidated. This study determined the capacity of blueberry bioactives to protect murine RAW 264.7 macrophages from lipopolysaccharide-induced inflammation. Fractionation of the crude extract (CE) into polyphenol-rich (PPR), anthocyanin-rich (ANC), and proanthocyanidin-rich (PAC) fractions and an ethyl acetate fraction (EA) revealed that PPR, ANC, and PAC components most effectively suppressed mRNA biomarkers of acute inflammation (Cox-2, iNOS, and IL-1β). Among major polyphenols found in the wild blueberries, malvidin-3-glucoside was significantly more effective than epicatechin or chlorogenic acid in reducing the expression of pro-inflammatory genes in vitro.


Complicated Post-Partum HELLP Syndrome Causing Acute Renal Failure and a Spontaneous Acute Subdural Hematoma.
HELLP syndrome is characterized by hemolysis, elevated liver enzymes, and thrombocytopenia. It is a devastating illness that typically occurs in the third trimester of gestation. We present a unique case of complicated post-partum HELLP syndrome. The patient was a 34-year-old Caucasian G1PO woman at 40 weeks' gestational age who presented for induction of labor. She underwent successful vaginal delivery. However, postoperatively the patient developed HELLP syndrome complicated by acute renal failure. She was transferred to the intensive care unit, where her renal function continued to decline, ultimately necessitating hemodialysis. She subsequently spontaneously developed an acute subdural hematoma. Most cases of HELLP syndrome occur in the third trimester, whereas fewer manifest post-partum. The pathophysiology of HELLP syndrome is poorly understood. While the defining organ of injury in HELLP syndrome is the liver, both kidney injury and spontaneous subdural hematomas can occur, as seen in this patient. The gold standard therapy for HELLP syndrome is prompt delivery of the fetus. HELLP syndrome continues to be a serious constellation of symptoms that can affect women late in their gestational period. As illustrated in this case report, prompt diagnosis of HELLP syndrome and appropriate management is critical.


Sources of plasma glucose by automated Bayesian analysis of 2H NMR spectra.
Sources of blood glucose can be determined after oral ingestion of (2)H(2)O followed by isolation of plasma glucose and measurement of the relative (2)H enrichments in select positions within the glucose molecule. Typically, (2)H enrichments are obtained by mass spectrometry but (2)H NMR offers an alternative. Here it is demonstrated that the entire analysis may be automated by Bayesian analysis of a (2)H free induction decay signal of monoacetone glucose to obtain a direct readout of the relative contributions of glycogenolysis, glycerol, and phosphoenol pyruvate to plasma glucose production. Furthermore, Markov Chain Monte Carlo (MCMC) simulations of the posterior probability density provide uncertainties in all metabolic parameters from a single patient, thereby allowing comparisons in glucose metabolism from one individual to another. The combined MCMC Bayesian methodology is operationally simple and requires little intervention from the operator.


A Niobium Oxyiodate Sulfate with a Strong Second-Harmonic-Generation Response Built by Rational Multi-Component Design.
A novel niobium oxyiodate sulfate, Nb2 O3 (IO3 )2 (SO4 ), was fabricated by a rational multi-component design under moderate hydrothermal conditions. This multi-component design is inspired by an interesting niobium oxysulfate reaction, which opens a new door for synthetic method to effectively introduce refractory metals such as Nb into crystal structures by hydrothermal synthesis. Nb2 O3 (IO3 )2 (SO4 ) features a cube-like topological structure with a large phase-matching second harmonic generation (SHG) response (6×KDP), a wide transparency window (0.38-8 μm), and a high laser damage threshold (LDT) (20×AgGaS2 ). It has the highest thermostability (stable up to 580 °C under air) among reported non-centrosymmetric (NCS) iodates and sulfates and is stable in water and even concentrated H2 SO4 . Furthermore, Nb2 O3 (IO3 )2 (SO4 ) is a unique nonlinear optical (NLO) material among iodates and sulfates, because its SHG effect is mainly caused by the MO6 units rather than the IO3 or SO4 units, which is demonstrated by density functional theory (DFT) calculations.


Relationship between social determinants of health and processes and outcomes in adults with type 2 diabetes: validation of a conceptual framework.
The aim of this study was to empirically validate a conceptual framework and elucidate the pathways linking social determinants of health to outcomes in individuals with type 2 diabetes. 615 adults were recruited from adult primary care clinics in the southeastern United States. The model was estimated using path analysis to determine if socioeconomic (education, employment, income) and psychosocial (fatalism, self-efficacy, depression, diabetes distress, serious psychological distress, social support, and perceived stress) factors would independently predict glycemic control or be associated with mediator/moderators of self-care, access to care, and processes of care. Covariates were gender, age, race and health literacy. The final model (chi2 (15) = 17.68, p = 0.28; RMSEA = 0.02, CFI = 0.99) showed lower glycemic control was directly associated with less hours worked (r = 0.13, p = 0.002), more fatalistic attitudes (r = -0.09, p = 0.03), more self-efficacy (r = -0.30, p < 0.001), and less diabetes distress (r = 0.12, p = 0.03), with the majority of total effects being direct. Significant paths associated self-care with diabetes distress (r = -0.14, p = 0.01) and perceived stress (r = -0.15, p = .001); access to care with income (r = 0.08, p = 0.03), diabetes distress (r = -0.21, p < 0.001) and social support (r = 0.08, p = 0.03); and processes of care with income (r = -0.11, p = 0.03), social support (r = 0.10, p = 0.04), and perceived stress (r = 0.10, p = 0.04). The paths explained 76% of the variance in the model. Consistent with the conceptual framework, social determinants were associated with glycemic control through a direct association and mediators/moderators of self-care, access to care and processes of care. This study provides the first validation of a conceptual framework for the relationship between socioeconomic and psychological components of social determinants of health and diabetes outcomes.


Impact of Cerebral Microbleeds in Stroke Patients with Atrial Fibrillation.
Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet). We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use. A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (adjusted hazard ratio [aHR] = 2.74, 95% confidence interval = 1.76-4.26) and ischemic stroke (aHR = 1.29, 95% confidence interval = 1.04-1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleed burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2 to 4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥ 11 microbleeds (94 vs 48 per 1,000 patient-years). Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. ANN NEUROL 2023;94:61-74.


Accelerated mRNA decay in conditional mutants of yeast mRNA capping enzyme.
Current models of mRNA decay in yeast posit that 3' deadenylation precedes enzymatic removal of the 5' cap, which then exposes the naked end to 5' exonuclease action. Here, we analyzed gene expression in Saccharomyces cerevisiae cells bearing conditional mutations of Ceg1 (capping enzyme), a 52 kDa protein that transfers GMP from GTP to the 5' end of mRNA to form the GpppN cap structure. Shift of ceg1 mutants to restrictive temperature elicited a rapid decline in the rate of protein synthesis, which correlated with a sharp reduction in the steady-state levels of multiple individual mRNAs. ceg1 mutations prevented the accumulation of SSA1 and SSA4 mRNAs that were newly synthesized at the restrictive temperature. Uncapped poly(A)+ SSA4 mRNA accumulated in cells lacking the 5' exoribonuclease Xrn1. These findings provide genetic evidence for the long-held idea that the cap guanylate is critical for mRNA stability. The deadenylation-decapping-degradation pathway appears to be short-circuited when Ceg1 is inactivated.


Driven evolution of a constitutional dynamic library of molecular helices toward the selective generation of [2 x 2] gridlike arrays under the pressure of metal ion coordination.
Constitutional dynamics, self-assembly, and helical-folding control are brought together in the efficient Sc(OTf)3/microwave-catalyzed transimination of helical oligohydrazone strands, yielding highly diverse dynamic libraries of interconverting constituents through assembly, dissociation, and exchange of components. The transimination-type mechanism of the ScIII-promoted exchange, as well as its regioselectivity, occurring only at the extremities of the helical strands, allow one to perform directional terminal polymerization/depolymerization processes when starting with dissymmetric strands. A particular library is subsequently brought to express quantitatively [2 x 2] gridlike metallosupramolecular arrays in the presence of ZnII ions by component recombination generating the correct ligand from the dynamic set of interconverting strands. This behavior represents a process of driven evolution of a constitutional dynamic chemical system under the pressure (coordination interaction) of an external effector (metal ions).


[A case with late-onset MELAS with hallucination and delusion].
We report a 53-year-old male patient with late onset mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes(MELAS) with hallucination and delusion. The patient manifested various neurological symptoms including perceptive deafness, muscle weakness of limbs with loss of consciousness, sensory abnormalities in hands, feet and a face, abnormal sense of taste, tremor, palsy of upward eye movement and weak deep tendon reflexes prior to the psychotic episode. He was diagnosed as MELAS, because of high serum lactic acid and pyruvic acid, and the point mutation in the mitochondrial DNA 3243. SPECT imaging showed decreased perfusion in occipital cortex and thalamus. These SPECT changes improved after disappearing visual hallucination. Hallucination might be caused by delirium due to stroke-like episode. Dysfunction in the occipital cortex and thalamus might be involved with this perfusion change.


Detection of mutant p53 in clam leukemia cells.
Leukemia in the soft-shell clam, Mya arenaria, is characterized by tumor cells which are detected initially in the hemolymph. This disease is much more common in clams inhabiting polluted waters, suggesting an environmental component to its pathogenesis. In this study, leukemia cells were identified using a murine monoclonal antibody, 1E10, which recognizes a leukemia-specific protein expressed by tumor cells. Mutant p53 protein was detected using a murine monoclonal antibody (PAb 240) which reacts with mutant p53. Using immunofluorescence, the reactivity of clam cells to the 1E10 antibody was evaluated along with mutant p53 protein reactivity. Reverse transcriptase-polymerase chain reactions followed by sequence analyses were utilized to examine clams with hemocytes reacting with the p53 antibody for possible p53 gene mutations. Mutant p53 protein was expressed by tumor cells from five animals with advanced disease (in which greater than 90% of cells reacted with 1E10). A C-->G transversion was detected at the end of exon 6 from two of the five animals that reacted with both the mutant p53 antibody and 1E10. This substitution changes the amino acid of this codon from proline to alanine. Overall, our results suggest that environmentally induced alterations in p53 can contribute to the pathogenesis of leukemia in soft-shell clams inhabiting polluted water and/or sediment.


Sequence divergence in the 3'-untranslated region has an effect on the subfunctionalization of duplicate genes.
Recent studies demonstrated that sequence divergence in both transcriptional regulatory region and coding region contributes to the subfunctionalization of duplicate gene. However, whether sequence divergence in the 3'-untranslated region (3'-UTR) has an impact on the subfunctionalization of duplicate genes remains unclear. Here, we identified two diverging duplicate vsx1 (visual system homeobox-1) loci in goldfish, named vsx1A1 and vsx1A2. Phylogenetic analysis suggests that vsx1A1 and vsx1A2 may arise from a duplication of vsx1 after the separation of goldfish and zebrafish. Sequence comparison revealed that divergence in both transcriptional and translational regulatory regions is higher than divergence in the introns. vsx1A2 expresses during blastula and gastrula stages and in adult retina but silences from segmentation stage to hatching stage, vsx1A1 starts expression from segmentation onward. Comparing to that zebrafish vsx1 expresses in all the developmental stages and in the adult retina, it appears that goldfish vsx1A1 and vsx1A2 are under going to share the functions of ancestral vsx1. The different but overlapping temporal expression patterns of vsx1A1 and vsx1A2 suggest that sequence divergence in the promoter region of duplicate vsx1 is not sufficient for partitioning the functions of ancestral vsx1. By comparing vsx1A1 and vsx1A2 3'-UTR-linked green fluorescent protein gene expression patterns, we demonstrated that the 3'-UTR of vsx1A1 remains but the 3'-UTR of vsx1A2 has lost the capability of mediating bipolar cell specific expression during retina development. These results indicate that sequence divergence in the 3'-UTRs has a clear effect on subfunctionalization of the duplicate genes.


Applying a most probable number method for enumerating planktonic, dissimilatory, ammonium-producing, nitrate-reducing bacteria in oil field waters.
A most probable number (MPN) method was used to enumerate dissimilatory ammonium-producing, nitrate-reducing bacteria (DAP-NRB) in oil field waters and to determine whether they were stimulated by nitrate addition used to control hydrogen sulfide production. An ammonium production medium with 5 carbon and energy sources (acetate, glucose, glycerol, pyruvate, and succinate) and nitrate was used in a 3-tube MPN procedure to enumerate DAP-NRB. These bacteria were detected in 12 of 18 oil field water samples, but they were seldom detected in wellhead samples. Three oil field water samples were amended with nitrate in serum bottles and the numbers of different NRB were determined over a 38-day incubation time. This amendment stimulated increases in the numbers of heterotrophic NRB and autotrophic nitrate-reducing, sulfide-oxidizing bacteria, but DAP-NRB remained a minor portion of these communities. Overall, DAP-NRB were present in many of the oil field waters that were examined but their numbers were low. It appears that DAP-NRB would play a minor role in the consumption of nitrate injected into oil field waters for the control of hydrogen sulfide production.


Regulation of the zinc transporter ZnT-1 by dietary zinc.
The understanding of mechanisms controlling zinc absorption and metabolism at the molecular level has advanced recently. Kinetics of zinc transport have been investigated for many years, but only recently have genes coding for proteins thought to be involved in the transport process been cloned. Four putative zinc transporters, known as ZnT-1 through ZnT-4, have now been described. Among these transporters, only ZnT-1 is ubiquitously expressed. In this report, we examine the pattern of ZnT-1 expression in the intestine and analyze the regulation of ZnT-1 by dietary zinc in both the intestine and liver. Immunofluorescence demonstrated that intestinal ZnT-1 was most abundant at the basolateral surface of enterocytes lining the villi of the duodenum and jejunum. By Western blot analysis, intestinal and liver ZnT-1 protein migrated as a 42- and 36-kDa protein, respectively. Dietary zinc supplementation elevated the level of intestinal ZnT-1 mRNA and protein approximately 50% and 10%, respectively, but had no effect in the liver. In response to an acute oral zinc dose, the level of intestinal ZnT-1 mRNA was up-regulated 8-fold, without a corresponding increase in ZnT-1 protein. Conversely, the acute oral dose did not affect liver ZnT-1 mRNA, but resulted in a 5-fold increase in liver ZnT-1 protein. These results represent studies on the expression of intestinal and hepatic ZnT-1 in an intact animal model. The data suggest that ZnT-1 is at least part of the mechanism by which dietary zinc is absorbed and that, despite the zinc responsiveness of the ZnT-1 gene, additional factors may be regulating the steady-state level of ZnT-1 transporter protein.


Nasal and oral contribution to inhaled and exhaled nitric oxide: a study in tracheotomized patients.
Nitric oxide (NO) is produced at different sites in the human airways and may have several physiological effects. Orally-produced NO seems to contribute to the levels found in exhaled air. Autoinhalation of nasal NO increases oxygenation and reduces pulmonary artery pressure in humans. The aim of this study was to measure the concentration and output of NO during nasal, oral and tracheal controlled exhalation and inhalation. Ten tracheotomized patients and seven healthy subjects were studied. The mean+/-SEM fraction of exhaled NO from the nose, mouth and trachea was 56+/-8, 14+/-4 and 6+/-1 parts per billion (ppb), respectively. During single-breath nasal, oral and tracheal inhalation the fraction of inhaled NO was 64+/-14, 11+/-3 and 4+/-1, respectively. There was a marked flow dependency on nasal NO output in the healthy subjects, which was four-fold greater at the higher flow rates, during inhalation when compared to exhalation. There is a substantial contribution of nasal and oral nitric oxide during both inhalation and exhalation. Nasal nitric oxide output is markedly higher during inhalation, reaching levels similar to those that are found to have clinical effects in the trachea. These findings have implications for the measurement of nitric oxide in exhaled air and the physiological effects of autoinhaled endogenous nitric oxide.


Children's lung function in relation to changes in socioeconomic, nutritional, and household factors over 20 years in Lanzhou.
Lanzhou has experienced rapid urbanization, leading to changes in socioeconomic, nutritional, and household factors. These changes may affect children's lung function. Two cross-sectional studies of school-age children (6-13 years of age) from the urban (Chengguan) (Period 1 in 1996 with n=390; Period 2 in 2017 with n=192) and the suburban (Xigu) (Period 1 n=344; Period 2 n=492) district were conducted. Demographic information, household factors, and nutrition status were obtained via a questionnaire survey. Forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) were measured in each period. Student's t-test analysis of variance was used to assess the differences in FVC and FEV1 between Periods 1 and 2. Generalized linear models were used to analyze the associations between questionnaire derived factors and lung function. Analyses were done separately for girls and boys. Children had significantly lower mean FEV1 and FVC measures in Period 2 than in Period 1. This reduction was greater in children living in the urban area than those living in the suburban area. Obese children had significantly lower lung function but this was only statistically significant in Period 1. Children's lung function (FVC and FEV1) were lower in 2017 than in 1996. Rapid urbanization may have contributed to the decline of lung function. Obesity may be a risk factor for impaired lung function in children living in Lanzhou and possibly elsewhere.


Identification of a new gene controlling plant height in rice using the candidate-gene strategy.
A gene underlying a quantitative trait locus (QTL) controlling plant height on chromosome 1 (QTLph1) in rice ( Oryza sativa L.) was identified using the candidate-gene strategy. First, the function of a targeted gene was analyzed using near isogenic lines (NILs) in which the chromosomal region of a targeted QTL was substituted with that of another line. Second, for physiological information, the candidate gene was selected in the annotation data by the genome sequencing. Physiological analyses of an NIL-expressing QTLph1 (NIL6) suggested that the targeted gene controls plant height by enabling higher amounts of sucrose to be translocated in leaves. The results indicated that the gene for sucrose phosphate synthase (SPS; EC 220.127.116.11), the major limiting enzyme for sucrose synthesis, is a candidate gene for QTLph1 among the annotation results of the region of QTLph1. The higher level of SPS transcripts and the activity of SPS in NIL6 compared to control plants, and the fact that the relative SPS activity per SPS protein content was almost the same between NIL6 and Nipponbare suggested that the higher plant height in NIL6 compared to Nipponbare was due to the high SPS activity in NIL6. In agreement with this hypothesis, transgenic rice plants with a maize SPS gene that had about 3 times the SPS activity of that in Nipponbare (control plants) were significantly taller than Nipponbare from the early growth stage. From these results and the physiological data from NIL6, we concluded that SPS is the targeted gene underlying QTLph1.


Sieboldine A, a novel tetracyclic alkaloid from Lycopodium sieboldii, inhibiting acetylcholinesterase.
[structure: see text] A novel Lycopodium alkaloid with an unprecedented fused-tetracyclic ring system consisting of an aza-cyclononane ring having a N-hydroxy group, a cyclohexanone, a cyclopentanone, and a tetrahydrofuran ring, sieboldine A (1), was isolated from the club moss Lycopodium sieboldii. The structure and relative stereochemistry were elucidated on the basis of 2D NMR data and X-ray analysis. Sieboldine A (1) exhibited a potent inhibitory activity against acetylcholinesterase and modest cytotoxicity.


Systematic reviews. Some examples.
Reviewing the literature is a scientific inquiry that needs a clear design to preclude bias. It is a real enterprise if one aims at completeness of the literature on a certain subject. Going through refereed English language journals is not enough. On line databases are helpful, but mainly as a starting point. This article gives examples of systematic reviews on vitamin C and the common cold, pyridoxine against the premenstrual syndrome, homeopathy, and physiotherapy.


Current Updates on the Role of MicroRNA in the Diagnosis and Treatment of Neurodegenerative Diseases.
MicroRNAs (miRNA) are small noncoding RNAs that play a significant role in the regulation of gene expression. The literature has explored the key involvement of miRNAs in the diagnosis, prognosis, and treatment of various neurodegenerative diseases (NDD), such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). The miRNA regulates various signalling pathways; its dysregulation is involved in the pathogenesis of NDD. The present review is focused on the involvement of miRNAs in the pathogenesis of NDD and their role in the treatment or management of NDD. The literature provides comprehensive and cutting-edge knowledge for students studying neurology, researchers, clinical psychologists, practitioners, pathologists, and drug development agencies to comprehend the role of miRNAs in the NDD's pathogenesis, regulation of various genes/signalling pathways, such as α-synuclein, P53, amyloid-β, high mobility group protein (HMGB1), and IL-1β, NMDA receptor signalling, cholinergic signalling, etc. Method: The issues associated with using anti-miRNA therapy are also summarized in this review. The data for this literature were extracted and summarized using various search engines, such as Google Scholar, Pubmed, Scopus, and NCBI using different terms, such as NDD, PD, AD, HD, nanoformulations of mRNA, and role of miRNA in diagnosis and treatment. The miRNAs control various biological actions, such as neuronal differentiation, synaptic plasticity, cytoprotection, neuroinflammation, oxidative stress, apoptosis and chaperone-mediated autophagy, and neurite growth in the central nervous system and diagnosis. Various miRNAs are involved in the regulation of protein aggregation in PD and modulating β-secretase activity in AD. In HD, mutation in the huntingtin (Htt) protein interferes with Ago1 and Ago2, thus affecting the miRNA biogenesis. Currently, many anti-sense technologies are in the research phase for either inhibiting or promoting the activity of miRNA. This review provides new therapeutic approaches and novel biomarkers for the diagnosis and prognosis of NDDs by using miRNA.


Assessing Symptom Accommodation of Social Anxiety Symptoms Among Chinese Adults: Factor Structure and Psychometric Properties of Family Accommodation Scale Anxiety-Adult Report.
Symptom accommodation is an important interpersonal construct associated with more severe symptoms, lower levels of functioning, and worse treatment outcomes across various mental health conditions, including social anxiety. Research on this phenomenon is surprisingly absent in Chinese culture, where interpersonal relationships are highly emphasized. This may be due to the absence of a valid Chinese symptom accommodation measure for individuals with social anxiety symptoms. The current study aimed to examine the factor structure and psychometric properties of the Family Accommodation Scale Anxiety-Adult Report (FASA-AR) in Chinese adults. Three hundred and seventy-five Chinese undergraduate students with social anxiety symptoms completed a battery of self-report measures assessing symptom accommodation in relation to social anxiety symptoms and related impairments, as well as overall symptoms of anxiety and depression. Confirmatory factor analysis supported a two-factor model of symptom accommodation, with factors named Participation in symptom-related behaviors and Modification of functioning. The multiple indicators multiple causes model indicated the indicators of the FASA-AR, mainly the participation in symptom-related behaviors subscale, were not invariant across gender. Internal consistency for the FASA-AR total score and subscale scores was good. Convergent validity of the FASA-AR was evidenced by significant positive association with ratings of social anxiety symptoms, social anxiety related impairments, and anxiety symptoms. Divergent validity was supported by non-significant relation with depression symptoms. Nearly all participants (94.7%) endorsed being accommodated to some extent in the past month. Symptom accommodation is an important construct and is related to social anxiety symptoms among Chinese adults. The FASA-AR demonstrated a clear two-factor latent structure and possessed good psychometric properties that can validly and reliably assess symptom accommodation of social anxiety among Chinese adults.


Angiotensin-Converting Enzyme Inhibitor Angioedema.
Angioedema from angiotensin-converting enzyme inhibitors (ACEIs) is a potential, emergent, and frightening problem that presents to the emergency department. This article focuses on angioedema caused by using ACEIs. The presentation, pathology, diagnostic testing, treatment, and patient education of angioedema are explored. This article explores using fresh frozen plasma as an initial approach to the treatment of ACEI angioedema.


Tenderness and radiographic progression in rheumatoid arthritis and psoriatic arthritis.
The aim of this study was to assess the predictive value of tenderness in the absence of swelling with consideration of other potential risk factors for subsequent radiographic progression in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Clinical and sonographic (grey scale and power Doppler (PD)) examination of 22 joints of the hand were performed in patients with RA and PsA. The impact of tenderness on progression after 2 years was analysed in non-swollen joints for RA and PsA separately with multilevel mixed logistic regression analysis. We included 1207 joints in 55 patients with RA and 352 joints in 18 patients with PsA. In RA, tenderness was associated with radiographic progression after 2 years (model 2: OR 1.85 (95% CI 1.01 to 3.27), p=0.047), although the association of PD (OR 2.92 (95% CI 1.71 to 5.00), p<0.001) and erosions (OR 4.74 (95% CI 2.44 to 9.23), p<0.001) with subsequent structural damage was stronger. In PsA, we found a positive but not significant association between tenderness and radiographic progression (OR 1.72 (95% CI 0.71 to 4.17), p=0.23). In contrast, similarly to RA, erosions (OR 4.62 (95% CI 1.29 to 16.54), p=0.019) and PD (OR 3.30 (95% CI 1.13 to 9.53), p=0.029) had a marked effect on subsequent structural damage. Our findings imply that tenderness in non-swollen joints in RA is associated with subsequent damage. In both diseases, additional risk factors, such as sonographic signs for synovitis and baseline radiographic damage are associated with radiographic progression.


Localization of alpha-casein gene transcription in sections of epoxy resin-embedded mouse mammary tissues by in situ hybridization.
The objective of our study was to evaluate the suitability of aldehyde-fixed, epoxy resin-embedded tissue for efficient and reproducible detection of casein mRNA in mouse mammary tissue by in situ hybridization. We used mouse alpha-casein-specific, 35S-labeled riboprobes generated from a Gemini-3 vector. Both complementary (anti-sense) and homologous (sense) RNA probes were utilized in our study (specific activity ranged from 5-7 x 10(8) cpm/micrograms). We tested the stability of newly synthesized [3H]-uridine-labeled RNA in tissue sections subjected to epoxy plastic solvents and found that no detectable loss of label occurred during preparation of semi-thin (1-2 micron) plastic sections for situ hybridization. In addition, it was possible to detect alpha-casein mRNA in deplasticized sections of mammary gland tissue taken from normal, pregnant, or lactating mice, pre-neoplastic mammary alveolar hyperplasias, explant cultures, and mammary tumors. A positive hybridization signal was consistently obtained in sections of mammary tissues where the estimated average copy number for total casein mRNA was greater than or equal to 250/cell. In mammary tumors, where the estimated casein mRNA content was much lower (less than 5/cell), our positive hybridization signal occurred in regions of the tumor that, in consecutive sections, stained positive for casein by immunoperoxidase. After formaldehyde-glutaraldehyde fixation, loss of hybridizable RNA from epoxy-embedded tissues and sections appears to be minimal. Image resolution was greatly enhanced over frozen or paraffin sections of mammary tissue. Non-specific binding of the radioactive probes was very low. Protease treatment of the sections was not necessary for detection of hybridizable signal.


[Spectral study of N2O under pulsed DC discharge].
A new equipment of pulsed DC discharge supersonic molecular beam was set up for producing transient species. Thepulsed DC discharge can be used stably under 10 kV. In data collection using software, it can be utilized as gated integrators and averagers. Using this equipment, the processes of N2O discharge were studied. The emission spectra of N2O+ (A2sigma+ - X2IIi) were obtained. From the intensity of vibrational spectra, the vibrational populations of the N2O+ (A2sigma+ ) states were calculated. Compared with other results, A states of N2O+ depart even more from a Boltzmann distribution.


Serum alpha-fetoprotein in rats after ligation of the common bile duct: relation to ductular cell (oval cell) proliferation.
Serum AFP levels were measured by radio-immunoassay in rats at various periods after ligation and section of the common bile duct and after sham-ligation. Transient elevations of serum AFP reaching statistically significant levels occurred at 3 to 10 days, 17 days and 28 days after ligation of the common bile duct but not in sham-operated rats. The peak elevations of serum AFP followed waves of mitosis in both the ductular cells and the hepatocytes as measured by autoradiography. Proliferation of hepatocytes, however, remained minor when compared to ductular cell multiplication. Ultra-structural and histochemical studies of the liver clearly distinguished ductular (oval) cells from hepatocytes and provided no evidence of transition from ductular cells to hepatocytes. Our findings suggest that ductular cell proliferation in the rat induced by ligation of the common bile duct may produce elevations in the serum AFP.


Association between serum asprosin and diabetic peripheral neuropathy in patients with type 2 diabetes mellitus in the community.
This study aimed to investigate the relationship between serum asprosin level and diabetic peripheral neuropathy (DPN) in community patients with type 2 diabetes mellitus (T2DM). A total of 498 patients with T2DM were recruited from Zhuoma Community Health Service Station and Chengbei West Street Community Health Service Center in Changzhi City of Shanxi Province between November 2019 and July 2021. Their height, weight, and body mass index (BMI), as well as fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), triglyceride (TG), and serum asprosin levels, were analyzed. Patients were divided into the DPN group (n = 329) and the non-DPN group (n = 169) according to the presence or absence of DPN. The t-test, Mann-Whitney U test, and χ² test were used to compare the indicators between the two groups. Pearson or Spearman correlation analysis was used to evaluate the correlation between serum asprosin and other clinical data. Multivariate logistic regression analysis was used to analyze the influencing factors of DPN. Compared with the non-DPN group, the DPN group had higher serum asprosin (p < 0.05). The prevalence of DPN gradually increased according to the tertiles of asprosin (56%, 67%, and 75%; p < 0.05). Multivariate logistic regression analysis showed that after adjustment for covariates, patients with asprosin concentrations between 295.4-367.0 pg/ml and concentrations > 367.0 pg/ml had a higher risk of diabetic neuropathy compared than those with asprosin levels < 295.4 pg/ml (p < 0.05). Serum asprosin was found to be positively correlated with DPN, and it resulted as an influencing factor for DPN in patients with T2DM in the community. With the increase of asprosin, the risk of DPN also increased.


Sleep-time variation for ethanol and the hypnotic drugs tribromoethanol, urethane, pentobarbital, and propofol within outbred ICR mice.
To evaluate the phenotypic variation within a commercial outbred mouse stock, we examined sleep-time (or duration of loss of righting reflex) of outbred ICR mice after i.p. injection of ethanol (4.0 g/kg of body weight), urethane (1.3 g), tribromoethanol (250 mg), and pentobarbital (60 mg), and after i.v. injection of propofol (30 mg). We observed high-grade individual differences in sleep-time that ranged from 0 to 179 min, 83.1 +/- 4.3 (mean and SEM of 100 mice) for ethanol; 0 to 169 min, 64.5 +/- 3.1 for pentobarbital; 0 to 160 min, 36.6 +/- 3.6 for urethane; 0 to 120 min, 21.5 +/- 2.2 for tribromoethanol; and 3 to 20.5 min, 7.1 +/- 0.3 for propofol. This extensive phenotypic variance within the outbred stock was as great as the variation reported among inbred strains or selected lines, and the varied susceptibility within the colony was inherited by Jcl:ICR-derived inbred strains IAI, ICT, IPI, and IQI. The range of sleep-time variance for ethanol, pentobarbital, urethane, tribromoethanol, and propofol within four-way cross hybrid Jcl:MCH(ICR) mice was 86.6%, 63.3%, 124%, 61.0%, and 53.1% that of outbred Jcl:ICR mice, respectively. The present study indicates that phenotypic variance within an outbred Jcl:ICR stock was at high risk for susceptibility to the drugs that depress the central nervous system and that Jcl:ICR-derived inbreds may be an excellent source of animal models for studying the anesthesia gene.


Neuronal degeneration and regeneration induced by axotomy in the olfactory epithelium of Xenopus laevis.
The olfactory epithelium (OE) has the remarkable capability to constantly replace olfactory receptor neurons (ORNs) due to the presence of neural stem cells (NSCs). For this reason, the OE provides an excellent model to study neurogenesis and neuronal differentiation. In the present work, we induced neuronal degeneration in the OE of Xenopus laevis larvae by bilateral axotomy of the olfactory nerves. We found that axotomy induces specific- neuronal death through apoptosis between 24 and 48h post-injury. In concordance, there was a progressive decrease of the mature-ORN marker OMP until it was completely absent 72h post-injury. On the other hand, neurogenesis was evident 48h post-injury by an increase in the number of proliferating basal cells as well as NCAM-180- GAP-43+ immature neurons. Mature ORNs were replenished 21 days post-injury and the olfactory function was partially recovered, indicating that new ORNs were integrated into the olfactory bulb glomeruli. Throughout the regenerative process no changes in the expression pattern of the neurotrophin Brain Derivate Neurotrophic Factor were observed. Taken together, this work provides a sequential analysis of the neurodegenerative and subsequent regenerative processes that take place in the OE following axotomy. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1308-1320, 2017.


Risk Factors for Epilepsy: A National Cross-Sectional Study from National Health and Nutrition Examination Survey 2013 to 2018.
The purpose of this study is to investigate the risk factors of epilepsy based on the National Health and Nutrition Examination Survey (NHANES). The data in this study was obtained from the NHANES database between 2013 and 2018. It included 14,290 participants aged between 20 and 80. We defined people with epilepsy (PWE) when they self-reported took at least one treatment medication for seizures or epilepsy. Analysis of risk factors for epilepsy mainly includes Student's t-test, chi-square test, univariate and multivariate logistic regression analysis. People aged 40-59 shared 1.8 times the risk of epilepsy than those who aged 20-39, P=0.034. People who never married had a 2.8-fold higher risk of epilepsy than those who married/living with partner, P<0.001. The risk of epilepsy in subjects with very good/good general health was 0.4 times than that of subjects with fair/poor general health, P<0.001. Moreover, subjects without sleep disorders had a 0.4-fold higher risk of epilepsy than those who had sleep disorders, P=0.042. People who are older, unmarried, and have sleep disorders are at higher risk of epilepsy. In addition, good/good general health condition is associated with a lower risk of epilepsy.


Mitochondrial encephalomyopathy: variable clinical expression within a single kindred.
The clinical manifestations of mitochondrial encephalomyopathy are described in four generations of a single kindred. The age of onset of major neurological disturbance varied from 3-70 years. In some patients, deafness was the only manifestation; in others, recurrent bouts of status epilepticus associated with focal neurological deficits and headache, caused severe disability or death. Examples of all three adult forms of mitochondrial encephalomyopathy: MELAS, MERFF and Kearns Sayre syndrome, were represented within the kindred. Associated features included deafness, short stature, non-insulin-dependent diabetes mellitus, migraine, peptic ulceration and severe constipation. The nt 3243 A-G MELAS mutation was detected in two members of the kindred. This study highlights the diversity of clinical expression of a mitochondrial mutation within a single kindred.


Maternal employment status and isolated orofacial clefts in Hungary.
To study the role of maternal employment status as indicator of socioeconomic status in the origin of isolated orofacial clefts (OFC) and in the use of periconceptional folic acid/multivitamin supplementation. 1,975 cases with OFC (1,374 cases with cleft lip +/- palate and 601 cases with posterior cleft palate), 38,151 population controls without any defects and 20,868 patient controls with other isolated defects were compared in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA), 1980-1996. The proportion of professionals and managerials was lower, while the proportion of unskilled workers, housewives and others was higher in the mothers of cases with OFC compared with the population control group. However, the comparison of OFC and patient control groups did not show any difference in the employment status of mothers. A lower level of folic acid supplementation occurred in the professional and skilled worker mothers of cases with OFC compared with the population control group. This difference was confirmed by the comparison of folic acid used by mothers of cases with OFC compared with patient controls. An infrequent multivitamin use was displayed in the studied groups. The prevalence of OFC at birth shows a slightly lower maternal employment status as indicator of socioeconomic status than in the population control group. The higher level of maternal education does not imply a higher rate of folic acid supplementation in the group of OFC.


The Licensing Factor Cdt1 Links Cell Cycle Progression to the DNA Damage Response.
The maintenance of genome integrity is essential for cellular survival and propagation. It relies upon the accurate and timely replication of the genetic material, as well as the rapid sensing and repairing of damage to DNA. Uncontrolled DNA replication and unresolved DNA lesions contribute to genomic instability and can lead to cancer. Chromatin licensing and DNA replication factor 1 (Cdt1) is essential for loading the minichromosome maintenance 2-7 helicase complex onto chromatin exclusively during the G1 phase of the cell cycle, thus limiting DNA replication to once per cell cycle. Upon DNA damage, Cdt1 rapidly accumulates to sites of damage and is subsequently poly-ubiquitinated by the cullin 4-RING E3 ubiquitin ligase complex, in conjunction with the substrate recognition factor Cdt2 (CRL4Cdt2), and targeted for degradation. We here discuss the cellular functions of Cdt1 and how it may interlink cell cycle regulation and DNA damage response pathways, contributing to genome stability.


Minor salivary glands. Report of an exceptional dimension case.
A parapharingeal mass of exceptional dimension was observed at our Institution. We report our procedure in order to define the origin of the mass, its anatomopathological caracteristics and the procedure of exereses. The mass originating from minor salivary glands, is reported in Literature for its large dimension, which is rare in absolute and for its particular origin.


[Intrauterine Fetal Growth Restriction- Screening Model. Literature Review.]
Placental dysfunction is involved in a spectrum of obs.tetric conditions including preeclampsia, placental abrution and intrauterine fetal growth restriction. Their timely and accurate recognition is often a chalange since diagnostic criteria are dill based on nonspecific signs and symptomes. Fetal growth restriction (FGR) refers to a fetus that has failed to achieve its genetically determined growth potential and affects up to 5-10% of pregnancies. FRR is associated with an increase in perinatal mortality and morbidity. The diagnoslic challenge is in distinguishing SGA pregnancies from FGR pregnancies because the majority of SGA pregnancies are associated with a good prognosis compared to FGR pregnancies. Multifetal gegations have a high incidence of FGR. About 20-30% of dichorionic twins will suffer from FGR, as will 40% of monochorionic twins. Ultrasound is the benchmark for accurate pregnancy dating and diagnosis of FGR. However, there is room for error and FGR is undetected in about 30% of routinely scanned cases and incorrectly detected in 50% of cases. In recent years, the main priority of the leading obstetric clinics in Europe and the USA is drafting a universal screening model for selecting patients at high risk of developing placental dysfunction. Now, this model is part of the standard screening for chromosomal aneuploidies in the firs and second trimester of pregnancy and prolonged screening in the second and third trimester in patients at high risk.


Oxidative stress and air pollution exposure during pregnancy: A molecular assessment.
Chronic air pollution exposure during pregnancy can cause oxidative stress leading to adverse birth outcomes. The aim of this study was to assess and compare oxidative stress response in peripheral lymphocytes isolated from pregnant women from a highly industrialized locale (south Durban (SD); n = 50) and a control with lower air pollutant levels (north Durban (ND); n = 50). Oxidative stress response was measured by quantifying malondialdehyde (MDA) levels and a SuperArray gene panel. Mitochondrial function (adenosine triphosphate (ATP) levels and mitochondrial depolarization), DNA integrity (comet assay and mitochondrial DNA (mtDNA) viability) and DNA repair (OGG1) were assessed. Antioxidant response was assessed by quantification of glutathione (GSH) and SOD2, nuclear factor erythroid 2-related factor 2 (Nrf2) and uncoupling protein 2 (UCP2) protein and messenger RNA (mRNA) expression. Levels of MDA (p = 0.9), mitochondrial depolarization (p = 0.88), ATP (1.89-fold), SOD2 (1.23-fold) and UCP2 (1.58-fold) gene expression were elevated in the SD group with significantly higher UCP2 protein levels (p = 0.05) and longer comet tail length (p = 0.0004). The expression of Nrf2 protein (p = 0.03) and mRNA levels (-1.37-fold), GSH concentration (p < 0.0001), mtDNA amplification (-2.04-fold) and OGG1 mRNA (-2.78-fold) activity were decreased in the SD group. Of the 84 oxidative stress-related genes evaluated, 26 were differentially regulated. Pregnant women exposed to higher air pollutant levels showed increased markers for oxidative stress and compromised DNA integrity and repair.


First record of Pulvinaria urbicola Cockerell (Hemiptera: Coccidae) from India, with a key to the Indian species of Pulvinaria Targioni Tozzetti.
The notoriously destructive and invasive soft scale, Pulvinaria urbicola Cockerell (Hemiptera: Coccidae), is recorded for the first time from India. This scale, with variable morphological appearance and similarities with other known scales of the same genus established in India, is redescribed to facilitate its identification and separation from other similar species. Information on its host range, natural enemies and distribution is provided. Management options in the event of an outbreak are discussed briefly. A key to the species of Pulvinaria Targioni Tozzetti in India is also provided. This new arrival warrants special attention in India as it is a potentially damaging plant pest and has a broad host range across many plant families.


Involvement of GroEL in nif gene regulation and nitrogenase assembly.
Several approaches were used to study the role of GroEL, the prototype chaperonin, in the nitrogen fixation (nif) system. An Escherichia coli groEL mutant transformed with the Klebsiella pneumoniae nif gene cluster accumulated very low to nondetectable levels of nitrogenase components compared with the isogenic wild-type strain or the mutant cotransformed with the wild-type groE operon. In K. pneumoniae, overexpression of the E. coli groE operon markedly accelerated the rate of appearance of the MoFe protein and its constituent polypeptides after the start of derepression. The groEL mutation in E. coli decreased NifA-dependent beta-galactosidase expression from the nifH promoter but did not affect the constitutive expression of nifA from the tet promoter of ntr-controlled expression from the nifLA promoter. The possibility that GroEL is required for the correct folding of NifA was supported by coimmunoprecipitation of NifA with anti-GroEL antibodies. Kinetic analyses of nitrogenase assembly in 35S pulse-chased K. pneumoniae pointed to the existence of high-molecular-weight intermediates in MoFe protein assembly and demonstrated the transient binding of newly synthesized NifH and NifDK to GroEL. Overall, these results indicate that GroEL fulfills both regulatory and structural functions in the nif system.


Peptide substrate specificity and properties of the zinc-endopeptidase activity of botulinum type B neurotoxin.
Clostridium botulinum type B neurotoxin has been shown to be a zinc endopeptidase specific for vesicle-associated membrane protein (VAMP). A synthetic peptide of human/rat VAMP-2 [VAMP-2-(60-94)] is cleaved by the neurotoxin with the same specificity as that demonstrated for the membrane-associated protein (at the Gln76-Phe77 bond) and has been used to study the properties of the endopeptidase activity of the neurotoxin. Cleavage of the VAMP-2 peptide was demonstrated by both botulinum type B neurotoxin (Km = 3.3 x 10(-4) M) and by its purified light subunit (Km = 3.5 x 10(-4) M). The endopeptidase displayed a pH optimum of 7.0-7.5 and was inhibited by greater than 0.2 M NaCl and greater than 0.05 M sodium phosphate. Neurotoxin which had been inactivated by dialysis against EDTA could be re-activated by incubation with various divalent cations, notably Zn2+ and Cu2+. The substrate specificity of botulinum type B neurotoxin was studied using various analogues of VAMP-2 (60-94). The neurotoxin cleaved selectively to the N-terminal side of phenylalanine and tyrosine; no activity was observed with either leucine, valine or alanine in the P'1 position. The properties of the P1 amino acid were less critical; the neurotoxin cleaving the C-terminus of glutamine, asparagine and alanine. A substrate analogue with valine in the P1 position corresponding to the sequence of rat VAMP-1 was not cleaved. The rate of cleavage of a substrate analogue representing the sequence of human VAMP-1, however, was more than twofold that of the VAMP-2 peptide. The properties and substrate specificity of botulinum type B neurotoxin suggest that the toxin represents a novel class of endopeptidase which requires a specific peptide substrate conformation for the expression of proteolytic activity.


An analysis of auditory manifestations in a group of adults with AIDS prior to antiretroviral therapy.
The chief objective of the current study was to investigate the auditory status in a group of adults with AIDS before commencing antiretroviral therapy (ART) in a hospital outpatient clinic in Gauteng, South Africa. A total sample of 150 participants, aged between 20 and 46 years, was assessed following a prospective qualitative research design. All participants underwent case history interviews and medical record reviews, otoscopy and tympanometry, as well as conventional pure tone audiometry testing. Descriptive statistics was used to analyse data obtained. Prevalence, type, degree, configuration, and symmetry of the auditory manifestations; as well as type of onset of hearing loss and the possible causes of the auditory manifestations were analysed. Findings indicated that auditory manifestations in adults with AIDS are varied in nature and are possibly due to a number of causes. Manifestations including hearing loss, tinnitus and vertigo (in varied combinations) were found; with the types of hearing loss being mainly sensorineural in nature. The severity of hearing loss ranged from mild to severe, occurred either unilaterally or bilaterally; with the type of onset being mainly gradual and progressive in nature. The varied causes of hearing loss included HIV infection or AIDS illness as a primary cause, opportunistic infections, and various ototoxic therapies that the patients had undergone. Implications for future research as well as future assessment and management of patients with AIDS are raised.


The effect of socioeconomic status on gross total resection, radiation therapy and overall survival in patients with gliomas.
Socioeconomic status (SES) is associated with survival in many cancers but the effect of socioeconomic status on survival and access to care for patients with gliomas has not been well studied. This study included 50,170 patients from the Surveillance, Epidemiology, and End Results Program at the National Cancer Institute database diagnosed with gliomas of the brain from 2003 to 2012. Patient SES was divided into tertiles and quintiles. Treatment options included radiation, surgery (gross total resection (GTR)/other surgery), and radiation with surgery. Multivariable logistic regression and Cox proportional hazards model were used to analyze data with SAS v9.4. The results were adjusted for age at diagnosis, race, sex, tumor type, and tumor grade. Kaplan-Meier survival curves were constructed according to SES tertiles and quintiles. Patients from a higher SES tertile were significantly more likely to receive surgery, radiation, GTR, and radiation with surgery (OR 1.092, 1.116, 1.103, 1.150 respectively, all p < 0.0001). This correlation was also true when patients were divided into quintiles (OR 1.054, 1.072, 1.062, 1.089 respectively, all p < 0.0001). Furthermore, the lowest SES tertiles (HR 1.258, 1.146) and the lowest SES quintiles (HR 1.301, 1.273, 1.194, 1.119) were associated with significantly shorter survival times (all p for trend <0.0001). Surgery, radiation therapy, surgery with radiation therapy, and GTR were also found to be associated with improved overall survival in glioma patients (HR 0.553, 0.849, 0.666, 0.491 respectively, all p < 0.0001). The findings from this national study suggest an effect of SES on access to treatment, and survival in patients with gliomas.


Incomplete Recovery from the Radiocontrast-Induced Dysregulated Cell Cycle, Adhesion, and Fibrogenesis in Renal Tubular Cells after Radiocontrast (Iohexol) Removal.
Contrast-induced nephropathy (CIN) is one of the most common causes of acute kidney injury (AKI). However, management is still limited, and the cellular response to radiocontrast removal for CIN remains unclear. This study aimed to explore the latent effects of iohexol in cultured renal tubular cells with or without the removal of iohexol by medium replacement. HK2 renal tubular cells were subcultured 24 h before use in CIN experiments. Three treatment groups were established: the control, a radiocontrast (iohexol)-only group at 75 mg I/mL (I-75), and iohexol exposure for 24 h with culture medium replacement (I-75/M). Cell cycle arrest, fibrogenic mediator assays, cell viability, cell function, and cell-cycle-related protein expression were compared between groups. Iohexol induced numerous changes in HK2 renal tubular cells, such as enlarged cell shape, cell cycle arrest, increased apoptosis, and polyploidy. Iohexol inhibited the expression of cyclins, CDKs, ZO-1, and E-cadherin but conversely enhanced the expression of p21 and fibrosis-related genes, including TGF-β1, CTGF, collagen I, collagen III, and HIF-1α within 60 hr after the exposure. Except for the recovery from cell cycle arrest and cell cycle gene expression, notably, the removal of iohexol by medium replacement could not fully recover the renal tubular cells from the formation of polyploid cells, the adhesion or spreading, or the expression of fibrosis-related genes. The present study demonstrates, for the first time, that iohexol exerts latent cytotoxic effects on cultured renal tubular cells after its removal, suggesting that these irreversible cell changes may cause the insufficiency of radiocontrast reduction in CIN, which is worth investigating further.


Age-associated reductions in cerebral blood flow are independent from regional atrophy.
Prior studies have demonstrated decreasing cerebral blood flow (CBF) in normal aging, but the full spatial pattern and potential mechanism of changes in CBF remain to be elucidated. Specifically, existing data have not been entirely consistent regarding the spatial distribution of such changes, potentially a result of neglecting the effect of age-related tissue atrophy in CBF measurements. In this work, we use pulsed arterial-spin labelling to quantify regional CBF in 86 cognitively and physically healthy adults, aged 23 to 88 years. Surface-based analyses were utilized to map regional decline in CBF and cortical thickness with advancing age, and to examine the spatial associations and dissociations between these metrics. Our results demonstrate regionally selective age-related reductions in cortical perfusion, involving the superior-frontal, orbito-frontal, superior-parietal, middle-inferior temporal, insular, precuneus, supramarginal, lateral-occipital and cingulate regions, while subcortical CBF was relatively preserved in aging. Regional effects of age on CBF differed from that of grey-matter atrophy. In addition, the pattern of CBF associations with age displays an interesting similarity with the default-mode network. These findings demonstrate the dissociation between regional CBF and structural alterations specific to normal aging, and augment our understanding of mechanisms of pathology in older adults.


Resistance and conduit arteries following converting enzyme inhibition in hypertension.
Alterations in the structure of resistance and conduit arteries are a characteristic hallmark in hypertension. Studies carried out in hypertensive rats and in humans suggest that angiotensin I-converting enzyme inhibition has an effect on arterial structure of resistance arteries. In hypertensive rats the reduction of the media to lumen ratio is dose-dependent and significantly different from the effects of other antihypertensive agents at doses causing an equal degree of blood pressure reduction. In large conduit arteries, hypertrophy of the vessels is reversed by converting enzyme inhibition both in hypertensive rats (studies on central arteries) and in human (studies on peripheral arteries) hypertension. The reduction of hypertrophy is associated with a decrease in arterial stiffness, partly independent of blood pressure reduction. These findings suggest that regression of structural vascular changes may contribute to both the decrease in the arteriolar resistance and the improvement in the buffering function of large arteries. The decrease in arteriolar resistance and the improvement of large artery compliance may participate in blood pressure reduction and an improvement in pulse pressure amplification produced by converting enzyme inhibition.


Bayesian inference for spatio-temporal stochastic transmission of plant disease in the presence of roguing: A case study to characterise the dispersal of Flavescence dorée.
Estimating the distance at which pathogens disperse from one season to the next is crucial for designing efficient control strategies for invasive plant pathogens and a major milestone in the reduction of pesticide use in agriculture. However, we still lack such estimates for many diseases, especially for insect-vectored pathogens, such as Flavescence dorée (FD). FD is a quarantine disease threatening European vineyards. Its management is based on mandatory insecticide treatments and the removal of infected plants identified during annual surveys. This paper introduces a general statistical framework to model the epidemiological dynamics of FD in a mechanistic manner that can take into account missing hosts in surveyed fields (resulting from infected plant removals). We parameterized the model using Markov chain Monte Carlo (MCMC) and data augmentation from surveillance data gathered in Bordeaux vineyards. The data mainly consist of two snapshot maps of the infectious status of all the plants in three adjacent fields during two consecutive years. We demonstrate that heavy-tailed dispersal kernels best fit the spread of FD and that on average, 50% (resp. 80%) of new infection occurs within 10.5 m (resp. 22.2 m) of the source plant. These values are in agreement with estimates of the flying capacity of Scaphoideus titanus, the leafhopper vector of FD, reported in the literature using mark-capture techniques. Simulations of simple removal scenarios using the fitted model suggest that cryptic infection hampered FD management. Future efforts should explore whether strategies relying on reactive host removal can improve FD management.


Child neglect: injuries of omission.
Child neglect is the most common form of child maltreatment in the United States. Researchers have indicated that child neglect is strongly correlated with poverty, single-parent caretakers, unemployment, and multifaceted family problems. When neglect is present, it is usually pervasive in the lives of all family members, with both parents and children often perceiving themselves to be powerless and viewing attempts at goal achievement to be futile. Treatment for neglectful families requires multidisciplinary efforts to improve family functioning and promote a safe and supportive environment. Nurses have a variety of roles in the assessment of and primary, secondary, and tertiary prevention interventions for child neglect, with child safety and optimal family functioning as the desired outcomes. Early identification and intervention has the potential for reducing or preventing the developmental consequences associated with the deprivations of neglect. The nurse's role as child/family advocate is often the critical determinant of whether "at-risk" families are identified and receive the therapeutic interventions and tangible services they need. Additionally, nurses often have direct responsibilities for monitoring and remediating parenting patterns that have placed the child in hazardous conditions.


Tonantzin, a New Genus of Bess Beetle (Coleoptera, Passalidae) from a Montane Subtropical Forest in Central Mexico, with a Review of the Taxonomic Significance of the Mesofrontal Structure in Proculini.
Mexico has the third highest diversity of passalid beetles in the World. Here we describe Tonantzin new genus, a new monotypic genus, potentially endemic to the mountains of central Mexico. The new genus is diagnosed by a new configuration of characters from the mesofrontal structure (MFS) in addition to other characters. The MFS in Passalidae has been treated either as a composite complex character or a combination of individual characters. Using a broad taxonomic sample within Proculini, we discuss the taxonomic and systematic implications of the MFS for the tribe. We define the MFS type tepetl. Given the importance of the MFS for passalid taxonomy we propose a new delimitation of the structure using boundaries based on internal and external head structures. We argue that the treatment of the MFS as a complex character better captures the nature of this structure but we ultimately find a need to standardize the way in which this structure is described in the taxonomic literature and used in phylogenetic analyses.


Perspectives on oral chronic graft-versus-host disease from immunobiology to morbid diagnoses.
Chronic Graft-versus-Host Disease (cGVHD) is a major long-term complication, associated with morbidity and mortality in patients following allogenic hematopoietic cell transplantation (HCT) for immune hematopoietic disorders. The mouth is one of the most frequently affected organs after HCT (45-83%) and oral cGVHD, which may appear as the first visible sign. Manifestations present with mucosal lichenoid lesions, salivary gland dysfunction and limited oral aperture. Diagnosis of oral cGVHD severity is based on mucosal lesions with symptoms of sensitivity and pain and reduced oral intake. However, diagnostic difficulties arise due to subjective definitions and low specificity to cover the spectrum of oral cGVHD. In recent years there have been significant improvements in our understanding of the underlying oral cGVHD disease mechanisms. Drawing upon the current knowledge on the pathophysiology and biological phases of oral cGVHD, we address oral mucosa lichenoid and Sjogren's Syndrome-like sicca syndromes. We consider the response of alloreactive T-cells and macrophages to recipient tissues to drive the pathophysiological reactions and biological phases of acute inflammation (phase 1), chronic inflammation and dysregulated immunity (phase 2), and subsequent aberrant fibrotic healing (phase 3), which in time may be associated with an increased malignant transformation rate. When formulating treatment strategies, the pathophysiological spectrum of cGVHD is patient dependent and not every patient may progress chronologically through the biological stages. As such there remains a need to address and clarify personalized diagnostics and management to improve treatment descriptions. Within this review, we highlight the current state of the art knowledge on oral cGVHD pathophysiology and biological phases. We address knowledge gaps of oral cGVHD, with a view to facilitate clinical management and improve research quality on lichenoid biology and morbid forms of oral cGVHD.


LH/hCG-receptor is coupled to both adenylate cyclase and protein kinase C signaling pathways in isolated mouse Leydig cells.
The aim of this study was to examine whether or not a protein kinase C-dependent pathway is involved in the desensitization process of the LH/hCG-receptor-linked adenylate cyclase system in isolated mouse Leydig cells. Treatment of these cells with the phorbol ester, 4-β-phorbol 12-myristate 13-acetate (PMA) leads to a translocation (and a putative activation) of protein kinase C from the cytosol to the plasma membrane, as evidenced by the Western blotting procedure using particulate and cytosolic fractions of Percoll-purified mouse Leydig cells. A similar translocation is also observed following the treatment of mouse Leydig cells with hCG. Data obtained show that this effect is time-dependent and is mediated specifically through the LH/hCG-receptor. Furthermore, we show that the treatment of Leydig cells with either PMA or hCG leads to a desensitization of the adenylate cyclase stimulated with hCG, hCG plus GppNHp or AIF (4) (-) . This desensitization was not accompanied by a change in the [(125)I]-hCG binding to membrane receptors. Thus we provide here direct evidence that hCG is capable of activating protein kinase C. In addition, we postulate that PMA as well as hCG-treatment leads to a lesion located at a site distal to the receptor/G-protein interaction but proximal to the adenylate cyclase activation and that the translocation (and activation) of protein kinase C may be a common mechanism involved in this desensitizing effect caused by both PMA and hCG on Leydig cells.


The Plecoptera of Panama. II. Two new species, one new country record, and additional locality records of Anacroneuria (Perlidae) from western Panama.
Two new species of Anacroneuria (A. chiriqui sp. n. and A. ngabe sp. n.) are described from Chiriqui Province, Panama, and compared with related species. One new country record, A. divisa (Navás), is herein recorded and new locality records are presented for several species previously reported from Panama. Three unassociated females, including one species from Bocas del Toro province are described under informal designations. There are now 25 described species of Plecoptera known from Panama.


Behavioral determinants of drug action. The contributions of Peter B. Dews.
Peter B. Dews played a significant role in shaping the distinctive characteristics and defining the underlying principles of the discipline of behavioral pharmacology. His early and sophisticated use of schedules of reinforcement in the 1950s, incorporated from research in the experimental analysis of behavior and integrated into the discipline of pharmacology, provided tremendous insight, inspiration, and impetus to the newly emerging field of behavioral pharmacology. The experimental findings generated by Dews' research, blending the sophisticated use of behavior and pharmacological principles together with the elegant manner of their presentation and far-reaching implications, provided the force and momentum to establish and direct behavioral pharmacology for several decades. This article attempts to capture some of Dews' research that integrated and inspired the blending of sophisticated behavioral work with that of pharmacology.


Amine modification of digested peptide at C-terminal end during protein digestion by protease.
We recently reported that C-terminal polyamine modification occurs when proteins are digested with trypsin in the presence of polyamine [Biochem. Biophys. Res. Commun., 356, 159-162 (2007)]. In the present study, the characteristics of this C-terminal modification in the presence of protease and amine were investigated. When hemoglobin (HB) was digested with trypsin in the presence of N-(2-pyridyl)-1,4-diaminobutane (Py4), formation of the modified peptide was dependent on time and on HB or Py4 concentration. When synthetic peptide was treated with trypsin in the presence of Py4, ca. 0.1% of the peptide was modified with Py4. When HB or cytochrome C was treated with a range of serine proteases in the presence of various amines (Py4, N-(2-pyridyl)-1,3-diaminopropane, tranexamic acid, isonicotinic acid hydrazide and ampicillin), the modified peptide was detected in all cases tested, thus suggesting that amine modification widely accompanies digestion by proteases.


Feasibility study of a proton CT system based on 4D-tracking and residual energy determination via time-of-flight.
Objective.For dose calculations in ion beam therapy, it is vital to accurately determine the relative stopping power (RSP) distribution within the treatment volume. A suitable imaging modality to achieve the required RSP accuracy is proton computed tomography (pCT), which usually uses a tracking system and a separate residual energy (or range) detector to directly measure the RSP distribution. This work investigates the potential of a novel pCT system based on a single detector technology, namely low gain avalanche detectors (LGADs). LGADs are fast 4D-tracking detectors, which can be used to simultaneously measure the particle position and time with precise timing and spatial resolution. In contrast to standard pCT systems, the residual energy is determined via a time-of-flight (TOF) measurement between different 4D-tracking stations.Approach.To show the potential of using 4D-tracking for proton imaging, we studied and optimized the design parameters for a realistic TOF-pCT system using Monte Carlo simulations. We calculated the RSP accuracy and RSP resolution inside the inserts of the CTP404 phantom and compared the results to a simulation of an ideal pCT system.Main results.After introducing a dedicated calibration procedure for the TOF calorimeter, RSP accuracies less than 0.6% could be achieved. We also identified the design parameters with the strongest impact on the RSP resolution and proposed a strategy to further improve the image quality.Significance.This comprehensive study of the most important design aspects for a novel TOF-pCT system could help guide future hardware developments and, once implemented, improve the quality of treatment planning in ion beam therapy.


Evaluation of features for catalytic residue prediction in novel folds.
Structural genomics projects are determining the three-dimensional structure of proteins without full characterization of their function. A critical part of the annotation process involves appropriate knowledge representation and prediction of functionally important residue environments. We have developed a method to extract features from sequence, sequence alignments, three-dimensional structure, and structural environment conservation, and used support vector machines to annotate homologous and nonhomologous residue positions based on a specific training set of residue functions. In order to evaluate this pipeline for automated protein annotation, we applied it to the challenging problem of prediction of catalytic residues in enzymes. We also ranked the features based on their ability to discriminate catalytic from noncatalytic residues. When applying our method to a well-annotated set of protein structures, we found that top-ranked features were a measure of sequence conservation, a measure of structural conservation, a degree of uniqueness of a residue's structural environment, solvent accessibility, and residue hydrophobicity. We also found that features based on structural conservation were complementary to those based on sequence conservation and that they were capable of increasing predictor performance. Using a family nonredundant version of the ASTRAL 40 v1.65 data set, we estimated that the true catalytic residues were correctly predicted in 57.0% of the cases, with a precision of 18.5%. When testing on proteins containing novel folds not used in training, the best features were highly correlated with the training on families, thus validating the approach to nonhomologous catalytic residue prediction in general. We then applied the method to 2781 coordinate files from the structural genomics target pipeline and identified both highly ranked and highly clustered groups of predicted catalytic residues.


Metaphors and myths in pharmaceutical advertising.
It should come as no surprise that the ancient Greek word for drug, pharmakon, meant remedy. But this same word also meant poison as well as magical charm. We speak of heart attacks and of a long road to recovery. These meanings and phrases are reflective of how society conceives of illness and medical therapies. Metaphors and myths of magic, sports and journey are prevalent in medical terminology and they permeate pharmaceutical advertising. This research investigates the conceptual metaphors that are present in advertisements for pharmaceuticals, both those directed to consumers as well as those directed to physicians, for a broad range of drugs and medical conditions. This research employed a content analysis of advertisements appearing in popular consumer magazines as well as in physician journals and an analysis of online consumer drug reviews. The research concludes with a discussion of the similarities and differences among the conceptual metaphors in consumer versus physician ads, across different medical conditions, and the impact of specific metaphors on consumers' understanding of illness and drug therapies.


Characteristics of infants admitted with hypoglycemia to a neonatal unit.
Neonatal hypoglycemia is a common symptom in early infant life. The currently available literature identifies the risk factors but not the degree to which each factor lends itself to the development or severity of an ensuing hypoglycemia. A retrospective electronic chart review of near-term and term infants (>35 weeks' gestation) admitted to a tertiary-level neonatal unit over 16 months was carried out from the initiation of electronic record keeping. Ninety-five infants admitted with hypoglycemia to the unit were identified with complete records available. Fifty-eight percent of the infants were males, and the median gestation was 38 weeks. Twenty-two percent of the infants were premature, whereas 18% were macrosomic. Maternal diabetes was present in 27% infants. Comorbidities were common in this cohort, with approximately two-thirds of infants having multiple morbidities. The majority of which were jaundice and infection, whereas the minor ones were respiratory distress, initial lactic acidosis, feeding issues, and temperature instability. Neonatal hypoglycemia continues to be a significant morbidity in near-term and term infants. The presence of multiple morbidities is common in the setting of hypoglycemia and is the main determinant of the length of stay in the neonatal unit in this study population.


Kinetic, energetic, and mechanical differences between dark-state rhodopsin and opsin.
Rhodopsin, the photoreceptor pigment of the retina, initiates vision upon photon capture by its covalently linked chromophore 11-cis-retinal. In the absence of light, the chromophore serves as an inverse agonist locking the receptor in the inactive dark state. In the absence of chromophore, the apoprotein opsin shows low-level constitutive activity. Toward revealing insight into receptor properties controlled by the chromophore, we applied dynamic single-molecule force spectroscopy to quantify the kinetic, energetic, and mechanical differences between dark-state rhodopsin and opsin in native membranes from the retina of mice. Both rhodopsin and opsin are stabilized by ten structural segments. Compared to dark-state rhodopsin, the structural segments stabilizing opsin showed higher interaction strengths and mechanical rigidities and lower conformational variabilities, lifetimes, and free energies. These changes outline a common mechanism toward activating G-protein-coupled receptors. Additionally, we detected that opsin was more pliable and frequently stabilized alternate structural intermediates.


Global regulation of photosynthesis and respiration by FnrL: the first two targets in the tetrapyrrole pathway.
Fnr is a regulator that controls the expression of a variety of genes in response to oxygen limitation in bacteria. To assess the role of Fnr in photosynthesis in Rubrivivax gelatinosus, a strain carrying a null mutation in fnrL was constructed. It was unable to grow anaerobically in the light, but, intriguingly, it was able to produce photosynthetic complexes under high oxygenation conditions. The mutant lacked all c-type cytochromes normally detectable in microaerobically-grown wild type cells and accumulated coproporphyrin III. These data suggested that the pleiotropic phenotype observed in FNR is primarily due to the control at the level of the HemN oxygen-independent coproporphyrinogen III dehydrogenase. hemN expression in trans partially suppressed the FNR phenotype, as it rescued heme and cytochrome syntheses. Nevertheless, these cells were photosynthetically deficient, and pigment analyses showed that they were blocked at the level of Mg(2+)-protoporphyrin monomethyl ester. Expression of both hemN and bchE in the FNR mutant restored synthesis of Mg(2+)-protochlorophyllide. We, therefore, conclude that FnrL controls respiration by regulating hemN expression and controls photosynthesis by regulating both hemN and bchE expression. A comprehensive picture of the control points of microaerobic respiration and photosynthesis by FnrL is provided, and the prominent role of this factor in activating alternative gene programs after reduction of oxygen tension in facultative aerobes is discussed.


Spontaneous Pancreatic Pseudocyst-Superior Mesenteric Vein Fistula.
Pancreatic pseudocyst formation is a common complication of chronic pancreatitis. Rarely, a fistula develops between the pseudocyst and the portal venous system. We present a case of a 50-year-old man who was found to have a pancreatic pseudocyst-superior mesenteric vein fistula after being evaluated for several months of abdominal pain and weight loss. The patient was treated with endoscopic stenting of the pancreatic duct along with early enteral nutrition and suppressive antibiotics, which resulted in improvement in his condition. This case report highlights clinical presentation and the complexity of treatment of this rare diagnosis.