An additional dimension to grating perception.
Visual acuity (A) for a two-dimensional multiplicative sinusoidal contrast grid (sinusoidal chessboard) was measured as a function of spatial frequency (omega) of modulation in one of the dimensions. The reduction in acuity as frequency was increased was well described by the equation: A = -2pikomega + c, where k and c are constants. At suprathreshold contrasts, the frequency of modulation appeared to be doubled relative to the underlying modulation frequency. This doubling is not related to the frequency of the harmonic components of the chessboard, but suggests the existence of a perceptual mechanism sensitive to areas of sinusoidal modulation which are seen at twice the frequency of the variation in contrast.


Functionally distinct subpopulations of striatal neurons are differentially regulated by GABAergic and dopaminergic inputs--I. In vivo analysis.
Two subpopulations of striatal neurons, Type I and Type II, are distinguished by their contrasting electrophysiological responses to paired impulse stimulation of cortical afferents. Although both Type I and Type II striatal neurons are excited by the first impulse of any pair of impulses, in response to short interstimulus intervals (10-30 ms) Type I neurons display an increase in probability of spike discharge to the second impulse (facilitation), whereas Type II neurons exhibit a decrease in probability of discharge (inhibition); in response to longer interstimulus intervals (50-250 ms) Type I cells display inhibition, whereas Type II cells show facilitation. The present experiments investigated the possibility that the unique paired impulse responses of Type I and Type II neurons reflect differential regulation by GABAergic and dopaminergic afferents. Extracellular recording techniques were combined with micropressure ejection of specific antagonists for GABAA (bicuculline), GABAB (phaclofen), D1 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-IH-3-benzazepin+ ++-7-ol; SCH23390) or D2 (sulpiride) receptors; the role of dopamine was also examined using the specific neurotoxin, 6-hydroxydopamine. Results showed that bicuculline (250-500 microM) reduced stimulation threshold for spike discharge of both Type I and Type II neurons and completely antagonized the paired impulse inhibition in response to short interstimulus intervals characteristic of Type II neurons. In contrast, phaclofen (2-30 mM) had only a variable influence on spike threshold for Type II cells and no effect on the paired impulse responses of either Type I or Type II neurons. Micropressure ejection of SCH23390 (1 mM) decreased spike thresholds for both cell types and attenuated the inhibition of spike discharge to long interstimulus intervals distinctive of Type I neurons, an effect which was mimicked by dopaminergic denervation. In contrast, sulpiride (1 mM) had little effect on spike thresholds, and no influence on the paired impulse responses of either cell type. These results indicate that the excitability of both Type I and Type II neurons is tonically inhibited by GABAergic and dopaminergic input via stimulation of GABAA and D1 receptors, respectively. Moreover, the bicuculline sensitivity of Type II neurons suggests that GABAergic input to this cell class arises from neurons within a cortically driven feedforward and/or feedback loop, whereas Type I cells receive input from neurons which lie outside of such a loop. In addition, the inhibition to longer interstimulus intervals characteristic of Type I cells is, at least in part, dependent on dopaminergic input through D1 receptor stimulation.


Is the trend of the polarizability per atom for all small 3d transition metal clusters the same? The case of Nin (n< or =5) clusters.
The first theoretical study on static polarizability and polarizability anisotropy of small nickel clusters up to the pentamer is presented. All-electron-type calculations were performed using a finite field approach as implemented in the density functional program deMon2K. A newly developed first-order field-induced basis set for density functional calculations was employed. For the static polarizability per atom of these clusters, a different trend to the one reported in the literature for other transition metal cluster systems of similar size, is observed.


Priming, response learning and repetition suppression.
Prior exposure to a stimulus can facilitate its subsequent identification and classification, a phenomenon called priming. This behavioural facilitation is usually accompanied by a reduction in neural response within specific cortical regions (repetition suppression, RS). Recent research has suggested that both behavioural priming and RS can be largely determined by previously learned stimulus-response associations. According to this view, a direct association forms between the stimulus presented and the response made to it. On a subsequent encounter with the stimulus, this association automatically cues the response, bypassing the various processing stages that were required to select that response during its first presentation. Here we reproduce behavioural evidence for such stimulus-response associations, and show the PFC to be sensitive to such changes. In contrast, RS within ventral temporal regions (such as the fusiform cortex), which are usually associated with perceptual processing, is shown to be robust to response changes. The present study therefore suggests a dissociation between RS within the PFC, which may be sensitive to retrieval of stimulus-response associations, and RS within posterior perceptual regions, which may reflect facilitation of perceptual processing independent of stimulus-response associations.


CO2 Laser for De-epithelialization in Tympanoplasty.
Tympanoplasty repairs tympanic membrane perforations but also covers an umbrella of procedures characterized by surgery of the mastoid bone. Tympanoplasty is widely regarded as a beneficial procedure with an over 90% graft closure success rate and an over 80% return to normal hearing range. Though surgical technique and graft type are important in determining surgical outcomes of the procedure, results are most greatly correlated with location of the perforation. Marginal perforations are associated with the most complications in reconstruction of the tympanic membrane, lack of vascularization and limited membrane area delaying the healing process (4). Lasers have been used in medical procedures dating back to the 1960s. The advantage of infrared lasers such as CO2 are the precision of cutting and the smooth interaction with tissues (5). The CO2 laser is absorbed by the tympanic membrane and does not damage the middle ear while visible lasers penetrate and can damage the ear drum (6). This retrospective study of 150 patients from 2013-2016 assesses and demonstrates the viability of using carbon dioxide laser as an alternative to the traditional method for de-epithelialization of tympanic perforation margins during tympanoplasty. By comparing closure rates and audiogram data, this study reveals parameters of use, benefits and adverse outcomes on healing and hearing restoration with the CO2 laser-assisted method. Perforation closure rate of 91% and hearing improvement in 66% of patients was observed. Fourteen patients did not undergo closure of the tympanic membrane with an overwhelming majority of the 14 having large and marginal perforations.


Future imperfect: the limitations of clinical prediction models and the limits of clinical prediction.
Stepwise regression procedures are often used to identify a small set of variables that serve as important predictors of clinical outcome and to construct prediction models based on those variables. Several theoretical and practical limitations of this process are discussed and highlighted with a variety of examples from published reports. Wider appreciation of these limitations should encourage the development of more relevant models, and thereby improve the quality of clinical prediction.


Occurrence, transmission, and zoonotic potential of chronic wasting disease.
Chronic wasting disease (CWD) is a fatal, transmissible prion disease that affects captive and free-ranging deer, elk, and moose. Although the zoonotic potential of CWD is considered low, identification of multiple CWD strains and the potential for agent evolution upon serial passage hinders a definitive conclusion. Surveillance for CWD in free-ranging populations has documented a continual geographic spread of the disease throughout North America. CWD prions are shed from clinically and preclinically affected hosts, and CWD transmission is mediated at least in part by the environment, perhaps by soil. Much remains unknown, including the sites and mechanisms of prion uptake in the naive host. There are no therapeutics or effective eradication measures for CWD-endemic populations. Continued surveillance and research of CWD and its effects on cervid ecosystems is vital for controlling the long-term consequences of this emerging disease.


Characterization of single heart cell contractility by rapid imaging.
1. A rapid imaging technique with temporal resolution of about 1 ms was employed to describe cell-length changes during the isotonic contraction cycle of adult rat ventricular myocytes at 22 degrees C. 2. Parameters of cell contraction and relaxation were defined and values obtained under control conditions and after treatment with 5 mumol/L verapamil. 3. Over 15 min, verapamil dramatically reduced the maximum shortening attained. This was associated with delay in both excitation-contraction coupling latency and the time at which maximum rate of shortening occurred. However, peak shortening was recorded earlier in the contraction cycle. Total cell-cycle time was abbreviated under the influence of verapamil and maximum rates of shortening and lengthening were depressed in a similar manner. 4. The results highlight the value of improved temporal precision in describing myocyte contractility and validate the use of the parameters defined in the single-cell model for the study of the mechanisms of action of cardiotonic agents.


Variability in life history traits of the aphid, Acyrthosiphon pisum (Harris), from sexual and asexual populations.
Many aphid species have shown remarkable adaptability by invading new habitats and agricultural crops, although they are parthenogenetic and might be expected to show limited genetic variation. To determine if the mode of reproduction limits the level of genetic variation in adaptively important traits, we assess variation in 15 life history traits of the pea aphid, Acyrhosiphon pisum (Harris), for five populations sampled along a north-south transect in central North America, and for three traits for three populations from eastern Australia. The traits are developmental times and rates as affected by temperature, body weights as affected by temperature, fecundity, measures of migratory tendency, and photoperiodic responses. The most southerly population from North America is shown to be obligately parthenogenetic, as are the Australian populations, and the four more northerly North American populations are facultatively parthenogenetic with the number of parthenogenetic generations per year increasing from north to south. The broad-sense heritabilities of life history traits varied from 0.36 to 0.71 for nine quantitive traits based on a comparison of within-and between-lineage variances. Using these traits, 7-13 distinct genotypes (i.e. clones) were identified among each of the 18 lines sampled from the North American populations, but the number did not differ significantly among populations. The level of genetic variation differed from trait to trait. For 4 of 12 quantitative traits, the level of variation in the obligately parthenogenetic population from North America was lowest, but significantly lower than all the sexual populations for only 1 trait. The obligately parthenogenetic population had the highest level of genetic variation for two traits, and had intermediate levels for the others. The most northerly population, which was sexual and had relatively few parthenogenetic generations each year, had the lowest level of variation for 5 of 12 traits and the highest level of variation for 2 traits. There was no decline in variability from north to south correlated with the increase in the annual number of parthenogenetic generations. The Australian populations showed no less variation than the North American populations for two of three traits, although the pea aphid was introduced to Australia only 5 years prior to the study, whereas the aphid has been in North America for at least 100 years. The mode of reproduction has not had a substantial impact on the level of genetic variation in life history traits of the pea aphid, but there are population-specific factors that effect the level of variation in certain traits.


Diuretic agents related to indapamide. III--Synthesis and pharmacological activity of N-(4-chloro-3-sulfamoylbenzamido)-1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydroisoquinolines.
A series of N-(4-chloro-3-sulfamoylbenzamido)-1,2,3,4-tetrahydroquinoline++ + (IV-1) and isoquinoline (IV-2) have been synthesized and their diuretic and antihypertensive activities evaluated. While none of the test compounds was found to be provided with antihypertensive properties, most of them displayed a diuretic activity comparable to (IV-2 a) or higher (IV-1 a,b) (IV-2 c) than those of indapamide and clopamide, taken as reference drugs.


Consistency in women's orientations to food and nutrition in midlife and older age: a 10-year qualitative follow-up.
The objective of this study was to discover and understand women's perceptions of stability and change in their orientations to food and nutrition during a time of physical, social, and psychological transitions. A 10-year follow-up to a 1988 study was conducted. PARTICPANTS/SETTINGS: Seventeen women from a 1988 study in a semirural county in New York participated. They were well-educated, Caucasian mothers, aged 44 to 75 years in 1998. Semistructured, qualitative interviews in 1988 and 1998 were analyzed using grounded theory analysis. The 1998 and 1988 interviews with the same women were compared to understand patterns in orientations to food and nutrition. The life-course perspective was a conceptual guide. Most women in this sample described consistent orientations to food and nutrition at interviews 10 years apart. Even in the face of expected and unexpected changes in healthy, social environment, and roles, 14 of the 17 women perceived that their thoughts, beliefs, and strategies related to food and nutrition had been consistent across 10 years. The few women who perceived that they had changed orientations attributed changes to debilitating disease and transitions in work and family roles. Perceptions of consistency in their orientations to food and nutrition through midlife and older age among these women may be signs of stable trajectories that influence their response to nutrition education and their approach to dietary change.


Effect of cold storage in University of Wisconsin solution on the responses of porcine hepatic arteries to 5-hydroxytryptamine and bradykinin in vitro.
1. Responses to 5-hydroxytryptamine (5-HT), bradykinin and sodium nitroprusside (SNP) were examined in hepatic arteries of the pig 1 h after dissection (fresh) and following 24 h storage in either Ca(2+)-free Krebs solution or the cryopreservative University of Wisconsin (UW) solution. 2. In fresh arteries contracted to approximately 40% of the maximum response to potassium with U46619, a thromboxane A2-mimetic, concentration-response curves to 5-HT (10(-10)-10(-5) M) were biphasic, with relaxation at low concentrations (< 10(-8) M) and contraction at high concentrations. Bradykinin (10(-10)-10(-7) M) produced concentration-dependent relaxation of precontracted fresh arteries with no apparent constrictor response. 3. Following 24 h storage in Ca(2+)-free Krebs solution, relaxation responses to 5-HT and the sensitivity of the arteries to bradykinin were significantly reduced. Storage in UW solution did not affect relaxation responses to either 5-HT or bradykinin. Relaxation responses to SNP (10(-8)-10(-3) M) were unaffected by storage in either solution. 4. Treatment of fresh arteries with NG-nitro-L-arginine (L-NOARG, 10(-4) M) significantly attenuated the relaxation response to 5-HT and displaced the bradykinin concentration-response curve four fold to the right with no affect on its maximum relaxation. 5. From these results it is concluded that endothelial cell function is better preserved during cold storage in UW solution than in Ca(2+)-free Krebs solution.


Response of immune response genes to adjuvants poly [di(sodium carboxylatoethylphenoxy)phosphazene] (PCEP), CpG oligodeoxynucleotide and emulsigen at intradermal injection site in pigs.
Understanding the mechanisms by which adjuvants mediate their effects provide critical information on how innate immunity influences the development of adaptive immunity. Despite being a critical vaccine component, the mechanisms by which adjuvants mediate their effects are not fully understood and this is especially true when they are used in large animals. This lack of understanding limits our ability to design effective vaccines. In the present study, we administered polyphosphazene (PCEP), CpG oligodeoxynucleotides (CpG), emulsigen or saline via an intradermal injection into pigs and assessed the impact on the expression of reported 'adjuvant response genes' over time. CpG induced a strong upregulation of the chemokine CXL10 several 'Interferon Response Genes', as well as TNFα, and IL-10, and a down-regulation of IL-17 genes. Emulsigen upregulated expression of chemokines CCL2 and CCL5, proinflammatory cytokines IL-6 and TNFα, as well as TLR9, and several IFN response genes. PCEP induced the expression of chemokine CCL2 and proinflammatory cytokine IL-6. These results suggest that emulsigen and CpG may promote recruitment of innate immune cells and Th1 type cytokine production but that PCEP may promote a Th-2 type immune response through the induction of IL-6, an inducer of B cell activity and differentiation.


Environmental temperature as a mediator on the association between photoperiod at birth and chronotype.
The association between chronotypes and season of birth (SOB) remains an inconclusive issue due, in some extension, to the lack of investigations of mediation mechanisms. We evaluated the association of photoperiod at birth (PAB) with chronotypes and sleep duration in Brazil (n = 810), and the mediating effect of meteorological factors, sex, age and rs4753426 polymorphism in the melatonin receptor MTNR1B. Longer PAB was associated with a delayed mid-sleep phase with a suppressive effect of maximum environmental temperature. No significant interactions were identified for the other variables. These findings suggest that photoperiod and environmental temperature modulate chronotype development at early stages.


Prime-boost vaccination with plasmid DNA and a chimeric adenovirus type 5 vector with type 35 fiber induces protective immunity against HIV.
Immunization involving a DNA vaccine prime followed by an adenovirus type 5 (Ad5) boost elicited a protective immune response against SHIV challenge in monkeys. However, the hepatocellular tropism of Ad5 limits the safety of this viral vector. This study examines the safety and immunogenicity of a replication-defective chimeric Ad5 vector with the Ad35 fiber (Ad5/35) in BALB/c mice and rhesus monkeys. This novel Ad5/35 vector showed minimal hepatotoxicity after intramuscular administration with the novel Ad5/35 vector. In addition, an Ad5/35 vector expressing HIV Env gp160 protein (Ad5/35-HIV) generated strong HIV-specific immune responses in both animal models. Priming with a DNA vaccine followed by Ad5/35-HIV boosting yielded protection against a gp160-expressing vaccinia virus challenge in BALB/c mice. The Ad5/35-HIV vector was significantly less susceptible to the pre-existing Ad5 immunity than a comparable Ad5 vector. These findings indicate that an Ad5/35 vector-based HIV vaccine may be of considerable value for clinical use.


Adsorption of acid fuchsine dye from wastewater by Mg-ferrite particles.
Adsorption is a widely applied waste water treatment technology, especially for removing micro-pollutants and dyes of industrial effluents. Over the past decade, adsorbing metal oxide micron- and nano-particles have been successfully developed and investigated as adsorbents. In the present research, Mg-ferrite adsorbent particles were synthesized and their properties were fully determined. The pore volume is 0.139 cm3/g. The BET analysis reveals a surface area of 94.4 m2/g. The porosity is of meso- and microporous nature. The adsorbent was used to adsorb acid fuchsine, an important industrial dye. The equilibrium adsorption capacity was 796.4 mg/g, with an adsorption yield of 78.7-82.0%. The adsorption kinetics can be adequately fitted by a pseudo-second-order model. The isotherms of both Langmuir and Freundlich are applicable. The stability, recovery and reuse of the ferrite particles were proven in multi-cycle experiments, and the adsorption activity decreased by less than 3% between the first and fifth cycle. Experimental and fitting results were finally used to design a batch adsorber to remove a given concentration of acid fuchsine from different volumes of wastewater.


Regional cerebral blood flow measured during symptom provocation in obsessive-compulsive disorder using oxygen 15-labeled carbon dioxide and positron emission tomography.
The study was designed to determine the mediating neuroanatomy of obsessive-compulsive disorder (OCD). The short half-life tracer oxygen 15-labeled carbon dioxide was used to allow for repeated positron emission tomographic determinations of regional cerebral blood flow on each of eight patients with OCD during a resting and a provoked (symptomatic) state. Individually tailored provocative stimuli were successful in provoking OCD symptoms, in comparison with paired innocuous stimuli, as measured by self-report on OCD analogue scales (P = .002). Omnibus subtraction images demonstrated a statistically significant increase in relative regional cerebral blood flow during the OCD symptomatic state vs the resting state in right caudate nucleus (P < .006), left anterior cingulate cortex (P < .045), and bilateral orbitofrontal cortex (P < .008); increases in the left thalamus approached but did not reach statistical significance (P = .07). These findings are consistent with results of previous functional neuroimaging studies and contemporary neurocircuitry models of OCD. The data further implicate orbitofrontal cortex, caudate nucleus, and anterior cingulate cortex in the pathophysiology of OCD and in mediating OCD symptoms.


Creation of a novel synthetic amniotic fluid for use in fetal therapy with in vitro testing on human amniotic membranes.
Normal saline or lactated Ringer's solutions are usually infused at the time of fetal interventions; however, the effect of these fluids on the amniotic membranes has never been assessed. Given both the significant differences between the composition of normal saline solution, lactated Ringer's solution, and amniotic fluid and the significant risk of prematurity after fetal interventions, an investigation is warranted. This study aimed to evaluate the effect of current amnioinfusion fluids on the human amnion compared with a novel synthetic amniotic fluid. Amniotic epithelial cells from term placentas were isolated and cultured per protocol. A synthetic amniotic fluid was created with similar electrolyte, pH, albumin, and glucose concentrations to human amniotic fluid, termed "Amnio-well." The cultured human amniotic epithelium was exposed to normal saline solution, lactated Ringer's solution, and Amnio-well. As a control, 1 group of cells remained in culture media. Cells were evaluated for apoptosis and necrosis. A second analysis to examine if cells could be "rescued" was performed, wherein the cells were allowed to remain in the culture media for an additional 48 hours after amnioinfusion. Subsequently, tissue testing with human amniotic membrane explants was evaluated similarly. Immunofluorescent intensity studies were undertaken to evaluate reactive oxygen species-mediated cell damage. Real-time quantitative polymerase chain reaction was used to evaluate gene expression in apoptotic pathways. With simulated amnioinfusion, 44%, 52%, and 89% of amniotic epithelial cells were alive after exposure to normal saline solution, lactated Ringer's solution, and Amnio-well, respectively, compared with 85% in control (P<.001). After amnioinfusion and attempted cell rescue, 21%, 44%, 94%, and 88% of cells were alive after exposure to normal saline solution, lactated Ringer's solution, Amnio-well, and control, respectively (P<.001). In simulated amnioinfusion with full-thickness tissue explants, 68%, 80%, 93%, and 96% of cells were viable in normal saline solution, lactated Ringer's solution, Amnio-well, and control, respectively (P<.001). In culture, reactive oxygen species production was higher in normal saline solution, lactated Ringer's solution, and Amnio-well than in control (4.9-, 6.6-, and 1.8-fold higher, respectively, P<.001); however, this could be mitigated in Amnio-well by adding ulin-A-statin and ascorbic acid. Gene expression data revealed abnormal signaling in the p21 and BCL2/BAX pathways with normal saline solution compared with control (P=.006 and P=.041); changes were not seen with Amnio-well. In vitro, normal saline and lactated Ringer's solutions caused increased amniotic membrane reactive oxygen species and cell death. The use of a novel fluid similar to human amniotic fluid led to the normalization of cellular signaling and less cell death.


Deep Learning Techniques in the Classification of ECG Signals Using R-Peak Detection Based on the PTB-XL Dataset.
Deep Neural Networks (DNNs) are state-of-the-art machine learning algorithms, the application of which in electrocardiographic signals is gaining importance. So far, limited studies or optimizations using DNN can be found using ECG databases. To explore and achieve effective ECG recognition, this paper presents a convolutional neural network to perform the encoding of a single QRS complex with the addition of entropy-based features. This study aims to determine what combination of signal information provides the best result for classification purposes. The analyzed information included the raw ECG signal, entropy-based features computed from raw ECG signals, extracted QRS complexes, and entropy-based features computed from extracted QRS complexes. The tests were based on the classification of 2, 5, and 20 classes of heart diseases. The research was carried out on the data contained in a PTB-XL database. An innovative method of extracting QRS complexes based on the aggregation of results from established algorithms for multi-lead signals using the k-mean method, at the same time, was presented. The obtained results prove that adding entropy-based features and extracted QRS complexes to the raw signal is beneficial. Raw signals with entropy-based features but without extracted QRS complexes performed much worse.


Free cytoplasmic Ca++ at rest and after cholinergic stimulus is increased in cultured muscle cells from Duchenne muscular dystrophy patients.
We used a fluorescent dye, quin 2, to measure intracellular free calcium ([Ca++]i) in cultured skeletal muscle cells and skin fibroblasts from five Duchenne muscular dystrophy (DMD) patients and from five controls. We observed an enhanced [Ca++]i level, at rest and after acetylcholine (ACh) stimulation, in DMD muscle cells, but we did not detect any difference between DMD and normal skin fibroblasts. The abnormally higher [Ca++]i transient induced by ACh suggests that it plays a critical role in muscle degeneration. The skin fibroblast results suggests that there is no generalized membrane defect.


Effects of a mixed-subsistence diet on the growth of Hadza children.
We investigated the preliminary effects of dietary changes on the anthropometric measurements of child and adolescent Hadza foragers. We conducted a cross-sectional study comparing height and weight of participants (aged 0-17 years) at two time points, 2005 (n = 195) and 2017 (n = 52), from two locations: semi-nomadic "bush camps" and sedentary "village camps". World Health Organization (WHO) calculators were used to generate standardized z-scores for weight-for-height (WHZ), weight-for-age (WAZ), height-for-age (HAZ), and BMI-for-age (BMIFAZ). Cross tabulations were constructed for each measurement variable as a function of z-score categories and the variables year, location, and sex. Residency in a village, and associated mixed-subsistence diet, was associated with favorable growth, including greater WAZ (P < .001), HAZ (P < .001), and BMIFAZ (P = .004), but not WHZ (P = .717). Regardless of residency location, participants showed an improved WAZ (P = .021) and HAZ (P < .001) in the 2017 study year. We found no sex differences. These preliminary findings suggest that a mixed-subsistence diet may confer advantages over an exclusive wild food diet, a trend also reported among other transitioning foragers.


Preoperative chemotherapy combined with para-aortic lymph node dissection has clinical value in the treatment of gastric cancer with para-aortic lymph node metastases.
Lymph node metastases often occur in advanced gastric cancer, with some patients presenting with metastases in the para-aortic lymph nodes. There are persistent Controversies about the benefit of para-aortic lymph node dissection (PAND). Our purpose is to probe whether PAND following preoperative chemotherapy had any clinical significance in individuals with PALNs in gastric cancer. To retrospectively analyze the clinical data of 86 gastric cancer patients (40 in the D2 + PAND group and 46 in the D2 group) who attended the abdominal surgery department of Zhejiang Cancer Hospital between September 1, 2008, and July 30, 2018. In the D2 + PAND group (40 cases), the average number of lymph nodes cleared per case was 4.3 in group 16 (16a2, 16b1), and the postoperative pathology confirmed lymph node positivity in 16 cases, with a metastasis rate of 40%. The median overall survival times were 63 and 34 months for the patients in the D2 + PAND group and D2 group, respectively. The 3-year overall survival (OS) compared to the D2 group (D2 + PAND 69.1% vs. D2 50%, P = 0.012) and a statistically significant difference in 3-year disease-free survival (DFS) (D2 + PAND 69.6% vs. D2 38.3%, P = 0.007). Lymph node dissection extent and recurrence of para-aortic lymph nodes were independent prognostic variables for the patients. The recurrence rate was reduced in the D2 + PAND group compared to the D2 group (D2 + PAND 7.5% vs. D2 26.1%, p = 0.023). For patients with gastric cancer whose imaging suggests metastasis in the para-aortic lymph nodes, preoperative chemotherapy combined with PAND is an effective and safe treatment that may benefit patient survival.


Body fat distribution, serum glucose, lipid and insulin response to meals in Alström syndrome.
Alström syndrome is an autosomal recessive condition characterized by obesity, insulin resistance and hypertriglyceridaemia. Responses to fat and carbohydrate ingestion are important in planning dietetic advice and may help to explain the mechanism of metabolic disorder in the syndrome. After a 12-h fast, five Alström subjects received a 3.1 MJ (742 kcal), 75.8% fat breakfast on day 1, and a 3.3 MJ (794 kcal), 77.5% carbohydrate breakfast on day 2. Serum glucose, triglyceride and insulin levels were measured at baseline, and 2 and 3.5 h post-meal. Abdominal computerized tomography in three subjects and magnetic resonance imaging in one demonstrated distribution of abdominal fat. Body fat was distributed subcutaneously, as well as viscerally. There were no changes in serum glucose, insulin or triglycerides after the high fat meal. Triglycerides remained stable after the high carbohydrate meal but glucose and log insulin levels increased [8.4 +/- 4.1 to 13.4 +/- 6.9 mmol L(-1) (P < 0.05) and 2.6 +/- 0.27 to 3.15 +/- 0.42 pmol L(-1) (P < 0.05), respectively]. Dietetic advice in Alström syndrome must include calorie restriction to reduce obesity, which is predominantly subcutaneous. This study has shown that low carbohydrate advice may prove more effective than fat restriction in control of hyperglycaemia and hyperinsulinism. A single high energy meal does not exacerbate hypertriglyceridaemia.


Normal glenoid vault anatomy and validation of a novel glenoid implant shape.
Current glenoid implants are designed to be secured to the articular surface. When the articular surface is compromised, a glenoid component could be implanted if it obtained fixation from the endosteal surface of the glenoid vault. The first step for designing such a glenoid implant is to define the normal three-dimensional anatomy of the glenoid vault. The purpose of this study was to define the variations in glenoid vault shape in a large group of cadaver scapula. Computed tomographic (CT) scans of 61 normal scapulae (mean, 25-34 years) from the Haman-Todd Osteological Collection, with a wide range of sizes, were examined to define the normal glenoid vault anatomy. A custom software program was used to manipulate and measure the scans to determine the morphologic variations among the different glenoid vaults. From these data, we defined a unique glenoid vault shape and empirically developed 5 sizes to represent the study population of the 61 scapulae. A second group of 11 cadaver scapulae were used to validate the shape defined using the other 61. Prototype implants were placed into the real 11 scapulae using standard surgical techniques and then CT-scanned to analyze the shape of the glenoid vault. In the 61 scapulae, 85% of the points defining the endosteal surfaces vary among scapulae by less than 2 mm. For each of the 11 cadaver scapulae, the implant size used in the virtual computer implantation was the same size used for the plastic components placed into the cadaver scapulae. Fifty percent of the measured distances between the outer dimensions of the plastic models was within 2.4 mm of the glenoid endosteal surface. Eighty percent of the surface area of the plastic models was within 3.1 mm of the glenoid endosteal surface. Five percent of the dimensions were less than 1 mm and were considered to be areas of point contact. Before designing implants that can be used in pathologic glenoids, the shape of the normal glenoid vault must first be defined. This study defined a normal glenoid vault shape that can accommodate different sized scapula with 5 sizes. This glenoid shape may be used as a template to design a glenoid implant that obtains fixation within the glenoid vault.


Sex in Plasmodium: a sign of commitment.
The gametocyte, or sexual blood-stage, of the malaria parasite represents the only stage of the parasite that can be transmitted to the mosquito vector following sexual development within the infected bloodmeal. Little is known about the processes leading to this cellular differentiation and specialization. The recent completion of the Plasmodium genome, and subsequent transcriptome and proteome analyses have revealed for the first time a molecular map of the genes that are differentially regulated at the onset of and during gametocytogenesis. In this review, we outline the underlying mechanisms involved in this process, focusing on the transition between the asexual and the sexual blood-stages of the parasite.


Foraging strategies of caterpillars : Leaf damage and possible predator avoidance strategies.
An analysis of the foraging behaviors of several species of palatable and unpalatable lepidopterous larvae indicates that palatable caterpillars partition their time between feeding and behaviors that could be related to escape visually oriented predators. Depending on the species, palatable caterpillars do all or several of the following: 1) restrict themselves to the underside of leaves at all times, 2) restrict foraging to night-time, 3) commute to and from their feeding area on leaves, 4) move from the unfinished leaf to a distant leaf after a feeding bout, thus removing themselves from the evidence of their eating, 5) snip off partially-eaten leaves after feeding on them. The less palatable, or unpalatable, caterpillars do not snip off partially-eaten leaves, feed from leaves leaving tattered edges, and are often exposed resting and feeding on the leaf surfaces in direct sunshine. I conclude that some caterpillar foraging behaviors may have evolved under the selective pressure of visually-oriented predators that use leaf-damage as a cue in their searching behavior.


Intraocular Pressure and Myopia Progression, Axial Length Elongation in Rural Chinese Children.
This study reported the relationship between intraocular pressure (IOP) and myopia progression, which helps to understand more comprehensively whether IOP can be an important reference factor to intervene in the progression of myopia. This study aimed to investigate the association between IOP and myopia progression as well as axial length elongation in rural Chinese children. A total of 598 (598 of 878 [68.1%]) children (6 to 17 years) from the baseline Handan Offspring Myopia Study who completed a 3.5-year follow-up vision examination were included. Ocular examinations at both visits included cycloplegic autorefraction, IOP, and axial length measurements. Children with myopia had the highest baseline IOP of the three refractive groups (14.13 ± 1.31, 13.78 ± 1.71, and 13.59 ± 1.64 mmHg in myopes, emmetropes, and hyperopes, respectively, P = .002). However, IOPs showed no significant difference between eyes with or without newly developed myopia (13.63 ± 1.68 vs. 13.89 ± 1.68, P = .16), with or without faster myopia progression (13.75 ± 1.61 vs. 13.86 ± 1.63, P = .46), or with axial length elongation (13.80 ± 1.61 vs. 13.76 ± 1.64, P = .80). The multivariate regression analysis demonstrated that neither baseline refractive error ( β = -0.082, P = .13) nor baseline axial length ( β = -0.156, P = .08) was associated with baseline IOP. Myopic eyes have slightly higher IOP compared with emmetropic and hyperopic eyes, although it was not clinically significant. However, IOP was not found to be associated with either myopia progression or axial length elongation in this cohort sample of rural Chinese children.


Butein inhibits NF-κB activation and reduces infiltration of inflammatory cells and apoptosis after spinal cord injury in rats.
The IKK/NF-κB signalling pathway plays a predominant role in the regulation of inflammation and apoptosis in spinal cord injury (SCI). We have previously demonstrated that targeting of the IKK/NF-κB pathway improved the recovery of locomotor function by reducing the infiltration of inflammatory cells and apoptosis after SCI in rats. Recently, the neuroprotective effects of butein have been shown via direct inhibition of the IKK/NF-κB pathway in vitro. In this study, we investigated the effects of butein on the IKK/NF-κB pathway in rats after SCI. Our results indicated that butein reduced the expression of NF-κB and activation of its inhibitor I-κBα at 24h after injury. Treatment with butein also resulted in significant inhibition of caspase-3 activation and neutrophil infiltration. Overall, our findings demonstrated the neuroprotective effects of butein in SCI in vivo and its potential mechanism. Our results further indicated that targeting of the IKK/NF-κB pathway may be useful in SCI therapy.


Augmentation of anti-proliferative efficacy of quercetin encapsulated chitosan nanoparticles by induction of cell death via mitochondrial membrane permeabilization in oral cancer.
Quercetin (QCT), an antioxidant plant flavonoid, is known to impart prominent anti-cancer properties. However, its clinical application as a potential drug is hindered owing to its hydrophobicity, extensive metabolism, low absorption, and rapid elimination. The drawbacks of these phytochemical-based therapies can be addressed using nanotechnology-based drug delivery systems. In this study, we sought to develop chitosan nanoparticles (CSNPs) as the drug vehicle for encasing quercetin (QCT-CSNPs) and further investigate its anti-tumor potential against human oral cancer cell line Cal33. Our findings indicate that the average particle diameter of the formulated chitosan nanoparticles was around 100 nm, and they had a spherical structure, as per the TEM and FESEM images. The efficient entrapment of quercetin inside the CSNPs matrix is confirmed by XRD, UV-Vis spectrophotometry, FTIR, and DSC analysis. The in vitro cell cytotoxicity study against Cal33 oral cancer cells revealed that QCT-CSNPs exhibited superior toxicity compared to free QCT post-24-hour treatment. The improved anti-cancer efficacy of QCT-CSNPs was further confirmed by enhanced cellular apoptosis, colony formation inhibition, migration inhibition, and chromatin condensation. Moreover, the mitochondrial dysfunction and enhanced ROS (Reactive oxygen species) production indicated mitochondrial-mediated cell death in QCT-CSNPs treated Cal33 cells. In conclusion, our data suggest that quercetin-encapsulated chitosan nanoparticles may serve as a potential drug candidate against oral cancer.


Balloon dilatation versus CO2 laser surgery in subglottic stenosis, a retrospective analysis of therapeutic approaches.
Subglottic stenosis (SGS) is a narrowing of the airway just below the vocal folds. The cause of SGS and the optimal care for these patients, have remained elusive. Endoscopic surgery of SGS using either balloon or CO2 laser is associated with recurrence. Our aim is to compare surgery free intervals (SFI) between these two methods applied in two different timeframes. The knowledge gained from this project can support decision-making regarding surgical method choice. Participants were retrospectively identified using medical records between 1999 - 2021. We used pre-defined broad inclusion criteria to identify cases using the International Classification of Disease (ICD-10). Primary outcome was surgery free intervals. 141 patients were identified, 63 met the criteria for SGS, and were included in the analysis. Results show no significant difference in SFI, comparing balloon dilatation and CO2 laser. These findings demonstrate no detected difference in treatment intervals (SFI) when comparing these two commonly used surgical alternatives for SGS. The outcome of this report supports surgical freedom of choice based on the surgeon's experience and skill and ushes for further studies on patient experience regarding these two therapeutic approaches.


The MutS C terminus is essential for mismatch repair activity in vivo.
An Escherichia coli K-12 strain was constructed with a chromosomal deletion (mutSdelta800) in the mutS gene that produced the removal of the C-terminal 53 amino acids which are not present in the MutS crystal structure. This strain has a MutS null phenotype for mutation avoidance, anti-recombination, and sensitivity to cytotoxic agents in a dam mutant background.


Polymorphisms of microRNA sequences or binding sites and lung cancer: a meta-analysis and systematic review.
Functional single nucleotide polymorphisms (SNPs) of microRNA (miRNA) sequences or binding sites (miRNA-SNPs) are associated with lung cancer risk and survival. The objective of this study was to systematically review genetic association studies about miRNA-SNPs in lung cancer. Eligible genetic association studies were retrieved from databases of PubMed, EMBASE, China National Knowledge Infrastructure and SinoMed. Two investigators selected related studies and assessed methodological quality independently. Quantitative data synthesis was conducted for common SNPs of miRNA (miRNA-196a2 rs11614913, miRNA146a rs2910164, miRNA149 rs2292832, miRNA-605 rs2043556 and miRNA499 rs3746444). GRADE profiler was used to grade the quality of evidence for each miRNA-SNP. 15 eligible studies and 27 miRNA-SNPs were retrieved and 10 miRNA-SNPs were reported with a significant association with susceptibility to or survival of lung cancer. Methodological quality of eligible studies was adequate with an average score of 8.5. miRNA-196a2 rs11614913 polymorphism was associated with increased lung cancer risk (homozygote comparison, OR = 1.299, 95% CI: 1.096-1.540; dominant model, OR = 1.217, 95% CI: 1.041-1.421) and decreased survival. And according to GRADE profiler, quality of evidence was moderate for MYCL1 rs3134615, while quality of the other significant associations was low. Based on this first systematic review about miRNA-SNPs in lung cancer, quality of evidence was low for most genetic association studies. Polymorphisms of miRNA-196a2 rs11614913 and MYCL1 rs3134615 could be potential biomarkers of lung cancer.


Effects of manipulating tetanic calcium on the curvature of the force-velocity relationship in isolated rat soleus muscles.
In dynamically contracting muscles, increased curvature of the force-velocity relationship contributes to the loss of power during fatigue. It has been proposed that fatigue-induced reduction in [Ca++ ]i causes this increased curvature. However, earlier studies on single fibres have been conducted at low temperatures. Here, we investigated the hypothesis that curvature is increased by reductions in tetanic [Ca++ ]i in isolated skeletal muscle at near-physiological temperatures. Rat soleus muscles were stimulated at 60 Hz in standard Krebs-Ringer buffer, and contraction force and velocity were measured. Tetanic [Ca++ ]i was in some experiments either lowered by addition of 10 μmol/L dantrolene or use of submaximal stimulation (30 Hz) or increased by addition of 2 mmol/L caffeine. Force-velocity curves were constructed by fitting shortening velocity at different loading forces to the Hill equation. Curvature was determined as the ratio a/F0 with increased curvature reflecting decreased a/F0 . Compared to control levels, lowering tetanic [Ca++ ]i with dantrolene or reduced stimulation frequency decreased the curvature slightly as judged from increase in a/F0 of 13 ± 1% (P = < .001) and 20 ± 2% (P = < .001) respectively. In contrast, increasing tetanic [Ca++ ]i with caffeine increased the curvature (a/F0 decreased by 17 ± 1%; P = < .001). Contrary to our hypothesis, interventions that reduced tetanic [Ca++ ]i caused a decrease in curvature, while increasing tetanic [Ca++ ]i increased the curvature. These results reject a simple causal relation between [Ca++ ]i and curvature of the force-velocity relation during fatigue.


Kallikrein-kinin system in hepatic experimental models.
The purpose of this brief review is to describe some characteristics of the kallikrein-kinin system (KKS) in the liver. The liver synthesizes kininogens and prekallikrein and the synthesis of both proteins is increased in rats during the acute phase reaction. It is also the main organ to clear tissue as well as plasma kallikrein from the circulation in normal and pathological conditions. Bradykinin (BK), yielded by the kallikrein-kinin system, is a potent arterial hypotensive peptide, but in the liver it induces a portal hypertensive response. The portal hypertensive action of bradykinin is mediated by B2 receptors located on sinusoidal cells of the periportal region and is followed by its hydrolysis by angiotensin-converting enzyme, which is primarily present in the perivenous (centrolobular) region.


Pharmacokinetics of losartan and its metabolite E-3174 in relation to the CYP2C9 genotype.
Losartan is metabolized by polymorphic CYP2C9 to E-3174. Our aim was to evaluate the pharmacokinetics of losartan and E-3174 in relation to the CYP2C9 genotype. A 50-mg oral dose of losartan was given to 22 Swedish volunteers with different CYP2C9 genotypes. Losartan and E-3174 were analyzed by HPLC in plasma and urine samples collected up to 24 hours after drug intake. Furthermore, losartan and E-3174 were analyzed in 8-hour urine samples collected from 17 Spanish subjects after a single oral dose of 25 mg losartan. The maximum plasma concentration of E-3174 was significantly (P <.05) lower in the CYP2C9*1/*3 (n = 5) and CYP2C9*2/*3 (n = 4) groups compared with the CYP2C9*1/*1 (n = 6) and CYP2C9*1/*2 (n = 3) groups and extremely low in 1 subject with the CYP2C9*3/*3 genotype. The ratio of the total losartan area under the plasma concentration-time curve (AUC) to the total E-3174 AUC (AUC(losartan)/AUC(E-3174)) was higher in the subject with the CYP2C9*3/*3 genotype (30-fold) and also in the CYP2C9*1/*3 and *2/*3 groups (approximately 2- and 3-fold, respectively) compared with the CYP2C9*1/*1 group. The plasma ratios correlated significantly with the 0- to 8-hour urinary losartan/E-3174 ratios. Among the total of 39 subjects, the urinary ratio was significantly higher in subjects with the CYP2C9*1/*3 (n = 10) and *2/*3 (n = 4) genotypes than in those with the CYP2C9*1/*1 genotype (n = 11; P <.01) and approximately 40-fold higher in subjects with the CYP2C9*3/*3 genotype (n = 3). The CYP2C9*3 allele was shown to be associated with decreased formation of E-3174 from losartan. The significant differences between genotypes in plasma and urine losartan/E-3174 ratios and the good correlation between the plasma and urine ratios suggest that the losartan/E-3174 ratio in 0- to 8-hour urine specimens may serve as a phenotyping assay for CYP2C9 activity. Further studies in larger populations will be required to establish this.


Abnormal Thalamic Metabolism in Patients With Lifelong Premature Ejaculation.
Although some recent neuroimaging studies have indicated the abnormal brain structure or function in patients with lifelong premature ejaculation (LPE), whether and how the abnormal thalamic function participates in processing sexual behavioral information are still unclear in patients with LPE. The aim of this study was to assess the changes in the thalamus metabolism and structural integrity in patients with LPE. We performed a multimodal magnetic resonance approach in a 3.0 T system, including proton magnetic resonance spectroscopy (1H-MRS), diffusion tensor imaging, and volumetric analysis to detect the differences in thalamic metabolism and structure between 20 patients with LPE and 15 healthy controls. We analyzed and correlated the clinical symptoms of the subjects with significant 1H-MRS-based features. Peak areas of N-acetylaspartate, choline, creatine (Cr), and glutamate/glutamine (Glu) were calculated with the LCModel software. Diffusion tensor imaging and volumetric analysis of thalami showed no differences between the 2 groups. On the contrary, 1H-MRS study disclosed that both Glu concentrations and Glu/Cr ratio values in the thalami of patients with LPE were remarkably increased when compared with healthy controls (P < .01 for both variables). In addition, both the intravaginal ejaculatory latency time score and Chinese Index of Sexual Function for Premature Ejaculation-5 score were negatively related to increased Glu concentrations and Glu/Cr ratio values. Glutamatergic activity changes of thalamus may be an underlying indicator for evaluating sensory conduction efficiency in patients with LPE. The present study first found the abnormal thalamic metabolism in patients with LPE and contributed to a better understanding of the LPE etiology. Limitations include a cross-sectional study design with small samples and no examination of other brain areas. Our findings show that the increase in glutamatergic activity of thalamus is related to LPE, suggesting that the increased Glu neurotransmission in the thalamus may contribute to the development of premature ejaculation. Xia J-D, Chen F, Zhang Q-J, et al. Abnormal Thalamic Metabolism in Patients With Lifelong Premature Ejaculation. J Sex Med 2021;18:275-283.


Volume restoration in osmotically swollen lymphocytes does not involve changes in free Ca2+ concentration.
An increase in cytoplasmic free [Ca2+], [Ca2+]i, has been suggested as the trigger for the permeability changes that bring about cell volume restoration following exposure to anisotonic media. This idea was directly tested in human peripheral lymphocytes undergoing regulatory volume decrease following a hypotonic dilution of the suspension. [Ca2+]i was measured with the intracellularly trapped fluorescent indicator, quin2, and showed no measureable change on hypotonic swelling or during the subsequent volume decrease. Moreover, even though the incorporated quin2 adds significant Ca-buffering to the cytoplasm, regulatory volume decrease occurred normally in the quin2-loaded cells. It appears that alterations in [Ca2+]i are not involved in these processes of volume regulation. An intracellularly trapped derivative of fluorescein, bis(carboxyethyl)carboxyfluorescein, was used to monitor cytoplasmic pH, which also showed no change during regulatory volume decrease.


RGDX1 X2 motif regulates integrin αvβ5 binding for pluripotent stem cell adhesion.
The arginine-glycine-aspartic acid (RGD) motif is a cell adhesion sequence that binds to integrins. Some RGD-containing peptides promote adhesion of both embryonic stem cells and induced pluripotent stem cells (iPSCs); however, not all such RGD-containing peptides are active. In this study, we elucidated the role of RGD-neighboring sequences on iPSC adhesion using diverse synthetic peptides and recombinant proteins. Our results indicate that iPSC adhesion requires RGDX1 X2 sequences, such as RGDVF and RGDNY, and that the X1 X2 residues are essential for the adhesion via integrin αvβ5 but not αvβ3. iPSCs express integrin αvβ5 but not αvβ3; therefore, iPSC adhesion requires the RGDX1 X2 -containing sequences. The importance of the X1 X2 residues was confirmed with both HeLa and A549 cells, which express integrin αvβ5 but not αvβ3. Analysis of RGD-neighboring sequences provides important insights into ligand-binding specificity of integrins. Identification of integrin αvβ5-binding motifs is potentially useful in drug development, drug delivery, cell culture, and tissue engineering.


Carbon assimilation patterns and growth of the introduced CAM plant Opuntia inermis in Eastern Australia.
The daily course of CO2 and H2O exchange in cladodes of Opuntia inermis was studied at four sites in Eastern Australia. On most occasions cladode water contents were high and nocturnal stomatal opening resulted in substantial uptake of CO2 and synthesis of about 130 μ equiv cm-2 of malic acid during the night. Under water stress nocturnal stomatal opening was confined to the latter part of the night and acid synthesis was reduced to about 40 μ equiv cm-2. Night temperature had little effect on acid synthesis, which responded primarily to rainfall and changed from the stressed condition within 2-3 days in irrigation experiments. On many occasions following summer rainfall stomata opened for 4 h in the late afternoon permitting net CO2 fixation which may contribute about 25% of the total carbon assimilated. This CO2 fixation was insufficient to have a marked impact on the δ13C value of the Opuntia cladodes. CO2 fixation in the light occurred in conjunction with maximum dark CO2 fixation under mesic conditions. Dark CO2 fixation rates were 3 to 5 times greater than those recorded in desert cacti under favorable conditions. Relative growth rates calculated on the basic of CO2 exchange correspond to measured relative growth rates of 0.05 g g-1 dry wt day-1 which prevailed for 60-90 days in summer. The capacity for very active CO2 fixation in the dark and light following summer rainfall and the capacity to persist at low levels of metabolic activity through summer drought are discussed in relation to the success of this introduced species in this habitat.


Efficient and fast targeted production of murine models based on ENU mutagenesis.
Mice with targeted genetic alterations are the most effective tools for deciphering organismal gene function. We generated an ENU-based parallel C3HeB/FeJ sperm and DNA archive characterized by a high probability to identify allelic variants of target genes as well as high efficiencies in allele retrieval and model revitalization. Our archive size of over 17,000 samples contains approximately 340,000 independent alleles (20 functional mutations per individual sample). Based on an estimated number of approximately 30,000 mouse genes, the parallel sperm/DNA archive should permit the identification and recovery of ten or more alleles per average target gene which translates to a calculated 99% success rate in the discovery of five allelic variants for any given average gene. The low rate of unrelated ENU-induced passenger mutations has no practical impact on the analysis of the allele-specific phenotype at the G3 generation because of dilution and free segregation of such unrelated passenger mutations. To date 39 mouse models representing 33 different genes have been recovered from our archive using in vitro fertilization techniques. The generation time for a murine model heterozygous for a mutation in a gene of interest is less than 2 months, i.e., three to four times faster compared with current embryonic stem-cell-based technologies. We conclude that ENU-based targeted mutagenesis is a powerful tool for the fast and high-throughput production of murine gene-specific models for biomedical research.


RNA processing: new mutants that affect endonucleolytic processing of RNA.
A strain of Escherichia coli carrying the rne-3071 mutation that affects the RNA processing enzyme ribonuclease E, was mutagenized, and double mutants deficient in RNA processing were isolated. The isolation was based on the appearance of a particular RNA precursor molecule upon infection of an rne mutant with a specific bacteriophage T4 deletion strain. From one of the double mutants the rne mutation was removed, and the new single mutant, designated rng, was examined. In this mutant the maturation of host RNA as well as of bacteriophage T4 RNA is affected. The effect of the rng mutation on RNA synthesis is unique and can be distinguished from the effects of the other established mutations in RNA processing. The effects of the rng mutation can be recognized in vivo and in vitro.


Illegal behaviors as a consequence of gambling disorder.
Gambling disorder has been associated with illegal behaviors; however, research using validated scales and in-person assessments has been less common. Four hundred and twenty-seven people with gambling disorders taking part in clinical trials completed multiple instruments and select cognitive tasks. Two groups were identified: those with illegal behaviors linked to gambling disorder and those without. Differences between the groups were examined. 43.3% of people with gambling disorders reported gambling-related illegal behaviors. Illegal behaviors were associated with earlier gambling symptom onset, higher levels of depressive symptoms, worse quality of life, and higher non-planning impulsivity. In those with illegal behaviors, the most common activities reported were writing bad checks/paying bills from accounts that no longer had funds (75.1%), and theft (9.6%). People with illegal gambling-related behaviors did not differ from those without, in terms of levels of symptom severity, or likelihood of responding to treatment in the subsequent clinical trials. Illegal behaviors are commonplace in people with gambling disorders and linked to worse quality of life, but people with gambling-related illegal behaviors respond to core treatments to the same extent as people without these behaviors. The findings from this study extend previous research and support the novel notion that rather than more intensive treatment being indicated for gambling disorders linked to illegal activities, it may be prudent to consider illegal behaviors as part of a wider profile of gambling-related harms that merit interventions in their own right.


The urethral pressure profile in pregnancy and after delivery in healthy nulliparous women.
Simultaneous urethrocystometry by means of a dual microtransducer catheter was performed according to a precise, standardized technique serially at 8, 16, 28, and 36 weeks of pregnancy and at 8 weeks post partum in 43 healthy nulliparous women. The urethral pressure profile at rest and the effect of stress (cough) on the urethral pressure profile during pregnancy and after delivery were measured. At each recording session, blood was obtained for determination of 17 beta-estradiol (E2), progesterone (P), and 17-alpha-hydroxyprogesterone (17-OH-PO). The continence parameters functional urethral length and urethral closure pressure, as well as the urethral closure pressure response to stress, did not change systematically during the course of pregnancy. Engagement of the presenting part at 36 weeks did not influence the urethral pressure profile measurements. Alterations in hormone levels during pregnancy were not correlated with the changes in urethral pressure profile measurements. Both urethral pressure and length parameters in all women who underwent vaginal delivery were notably decreased 8 weeks post partum when compared with early pregnancy values and with values obtained in a group of healthy nulliparous women in the follicular phase of the cycle. The decrease in length parameters was not observed in the six women in whom delivery was by cesarean section. The postpartum changes were not significantly correlated with the duration of the second stage of labor or with the presence or absence of an episiotomy. Also, no relationship with infant birth weight was found. Values of the urethral pressure profile parameters below the median value and defective transmission of pressure over the urethra were observed in almost all women who experienced stress incontinence during pregnancy and/or after delivery. These observations suggest that an inherent weakness of the urethral sphincter mechanism plays a key role in the pathogenesis of stress incontinence.


Pain responses to perineuromal injection of normal saline, gallamine, and lidocaine in humans.
Rat neurons have shown an increase of spontaneously active fibers to systemically administered potassium channel blocking agents such as tetraethylammonium chloride (TEA) and gallamine. Neuroma formation and spontaneous activity have been associated with autotomy in rats and pain in humans. To evaluate the chemosensitivity of human neurons to potassium channel blocking agents, 9 subjects with neuroma pain underwent perineuromal injection in a single-blinded fashion of normal saline, gallamine, and lidocaine. Sodium had no effect on control pain levels, while gallamine significantly increased and lidocaine significantly decreased pain from control levels. Three of 4 patients with accompanying phantom limb pain noted an increase in pain after the injection of gallamine. The data suggest that peripheral input plays a modulating but not solitary role in both neuroma and phantom limb pain. Agents which increase potassium channel permeability or decrease sodium influx would be predicted to decreased perceived pain.


Early molecular-level changes in rat bladder wall tissue following spinal cord injury.
Previously, we demonstrated using a rat model of spinal cord injury (SCI) that bladder wall tissue compliance significantly increased within the first 2 weeks following injury. In order to explore the potential molecular-level mechanisms of this event, the present study quantified molecules pertinent to bladder tissue remodeling and changes in mechanical properties. An initial gene array analysis followed by real-time qPCR revealed that the message levels for tropoelastin and lysyl oxidase were as high as 8-fold in SCI rats compared to normal. Furthermore, both the message and protein levels of TGF-beta1 and IGF-1, known stimulators of elastin synthesis, in SCI rat bladders were significantly higher compared to those of normal rats. Taken together, it can be speculated that functional changes of the bladder associated with SCI induce release of select growth factors, which, in turn, stimulate elastogenesis that lead to alteration of biomechanical properties of the wall tissue.


Quantification of methylcitrate in dried urine spots by liquid chromatography tandem mass spectrometry for the diagnosis of propionic and methylmalonic acidemias.
Accumulation of methylcitrate is a biochemical hallmark of inborn errors of propionate metabolism, a group of disorders that include propionic acidemia, methylmalonic aciduria and cobalamin defects. In clinical laboratories, this analyte is measured without quantification by gas chromatography mass spectrometry as part of urine organic acids. Here we describe a simple, sensitive and specific method to quantify methylcitrate in dried urine spots by liquid chromatography tandem mass spectrometry. Methylcitrate is extracted and derivatized with 4-[2-(N,N-dimethylamino)ethylaminosulfonyl]-7-(2-aminoethylamino)-2,1,3-benzoxadiazole in a single step. A derivatization mixture was added to 3.2 mm disc of dried urine spots, incubated at 65 °C for 45 min and 4 μl of the reaction mixture were analyzed. Separation was achieved on C18 column with methylcitrate eluting at 3.8 min. Intraday and interday imprecision (n = 17) were ≤20.9%. The method was applied on dried urine spots from established patients and controls. In controls (n = 135), methylcitrate reference interval of 0.4-3.4 mmol/mol creatinine. In patients, methylcitrate ranged between 8.3 and 591 mmol/mol creatinine. Quantification of methylcitrate provides important diagnostic clues for propionic acidemia, methylmalonic aciduria and cobalamin disorders. The potential utilization of methylcitrate as monitoring biomarker of patients under treatment and whether it correlates with the clinical status has yet to be established.


Does a major change to a COVID-19 vaccine program alter vaccine intention? A qualitative investigation.
On 8th April 2021, the Australian Technical Advisory Group on Immunisation (ATAGI) made the Pfizer-BioNtech (Comirnaty) vaccine the "preferred" vaccine for adults in Australia aged < 50 years due to a risk of thrombosis with thrombocytopenia syndrome (TTS) following AstraZeneca vaccination. We sought to understand whether this impacted COVID-19 vaccine intentions. We undertook qualitative interviews from February - April 2021 before and after the program change with 28 adults in Perth, Western Australia. Using our COVID-19 vaccine intentions model, we assessed changes in participants' COVID-19 vaccine intention before and after the program change. Participants were classified as 1) 'acceptors': no concerns about COVID-19 vaccine safety, efficacy, access and would accept whatever vaccine is offered, 2) 'cautious acceptors': some concerns and would prefer a particular vaccine brand but would accept whatever is offered, 3) 'Wait awhile': for more data, easier access, for another vaccine brand, a greater perceived COVID-19 threat or until mandatory, or 4) 'refuser': no intention to vaccinate due to concerns about safety and/or efficacy. Before the change, 7/18 of those aged < 50 years were 'acceptors,' 10/18 were 'cautious acceptors' and 1/18 was 'wait awhile.' Overall, 14/18 participants had the same COVID-19 vaccine intention after the change; 4/18 became more concerned. For those aged ≥ 50 years and before the change, 5/10 were 'acceptors' and 5/10 were 'cautious acceptors.' After the change, 8/10 still had the same COVID-19 vaccine intention; 2/10 became more cautious. The major concern before the program change was COVID-19 vaccines having different vaccine efficacy; the concern pivoted to safety. The majority of participants were 'cautious acceptors' who intended on being vaccinated; many had this intention before and after the program change. The Australian government, health care providers and media need to better address COVID-19 vaccine concerns to assist those with COVID-19 vaccine intentions receive a vaccine.


Reduced parasympathetic cardiac control in patients with hypertension at rest and under mental stress.
The neurogenic component in the pathogenesis of essential hypertension has predominantly been analyzed with regard to the sympathetic part of the autonomous nervous system; the parasympathetic branch has largely been neglected. We investigated whether 54 normotensive (mean causal blood pressure [cBP]: 125 +/- 6/82 +/- 4 mm Hg), 41 borderline hypertensive (cBP: 134 +/- 8/90 +/- 5 mm Hg), and 34 hypertensive men (cBP: 152 +/- 13/101 +/- 5 mm Hg) without secondary target organ damage differed in parasympathetic cardiac control. Parasympathetic cardiac control was assessed via the amount of fast fluctuations (0.15 to 0.40 Hz; vagus band) and by the amount of respiratory-linked fluctuations (mean respiratory frequency +/- 0.03 Hz) in the power spectra of continuously registered interbeat intervals under the following conditions: mean of three rest phases with 10, 5, and 5 minutes' duration (REST); mean of two modes of a reaction time task with 10 and 5 minutes' duration (RTT); mean of 5 minutes' mental arithmetic plus noise (MA). Analysis of variance (ANOVA) shows that spectral energy in the so-called vagus band reveals the most prominent differences between blood pressure groups under all conditions: REST = normotensive, 2.70 +/- 0.31; borderline hypertensive, 2.55 +/- 0.33; and hypertensive, 2.43 +/- 0.43 (F[2.126] = 6.19; p < 0.01). RTT = normotensive, 2.41 +/- 0.35; borderline hypertensive, 2.19 +/- 0.33; and hypertensive, 2.17 +/- 0.46 (F[2.126] = 6.04; p < 0.01); MA = normotensive, 2.69 +/- 0.34; borderline hypertensive, 2.52 +/- 0.33; and hypertensive, 2.38 +/- 0.46 (F[2.126] = 7.04; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Imaging of seminal vesicles: a pictorial review.
The seminal vesicles are frequently overlooked when reviewing abdominal and pelvic imaging studies, and normal variants and pathologic conditions are often missed or misinterpreted. This is largely due to lack of familiarity with the organ, its anatomic variants, congenital abnormalities and disease conditions. This pictorial review aims to familiarize the reader with the range of normal appearances, congenital anomalies and disease entities that involve the seminal vesicles to avoid overtreatment and misdiagnoses.


Effects of the kinase inhibitor sorafenib on heart, muscle, liver and plasma metabolism in vivo using non-targeted metabolomics analysis.
The human kinome consists of roughly 500 kinases, including 150 that have been proposed as therapeutic targets. Protein kinases regulate an array of signalling pathways that control metabolism, cell cycle progression, cell death, differentiation and survival. It is not surprising, then, that new kinase inhibitors developed to treat cancer, including sorafenib, also exhibit cardiotoxicity. We hypothesized that sorafenib cardiotoxicity is related to its deleterious effects on specific cardiac metabolic pathways given the critical roles of protein kinases in cardiac metabolism. FVB/N mice (10 per group) were challenged with sorafenib or vehicle control daily for 2 weeks. Echocardiographic assessment of the heart identified systolic dysfunction consistent with cardiotoxicity in sorafenib-treated mice compared to vehicle-treated controls. Heart, skeletal muscle, liver and plasma were flash frozen and prepped for non-targeted GC-MS metabolomics analysis. Compared to vehicle-treated controls, sorafenib-treated hearts exhibited significant alterations in 11 metabolites, including markedly altered taurine/hypotaurine metabolism (25-fold enrichment), identified by pathway enrichment analysis. These studies identified alterations in taurine/hypotaurine metabolism in the hearts and skeletal muscles of mice treated with sorafenib. Interventions that rescue or prevent these sorafenib-induced changes, such as taurine supplementation, may be helpful in attenuating sorafenib-induced cardiac injury.


Wnt5a/Ror2 pathway contributes to the regulation of cholesterol homeostasis and inflammatory response in atherosclerosis.
Atherosclerosis (AS) is characterized by lipids metabolism disorder and inflammatory response. Accumulating evidence has demonstrated that Wingless type 5a (Wnt5a) is implicated in cardiovascular diseases through non-canonical Wnt cascades. However, its precise role during the pathogenesis of AS is still unclear. Therefore, the present study aims to investigate the role and the underlying mechanism of Wnt5a/receptor tyrosine kinase-like orphan receptor 2 (Ror2) pathways in the promotion of AS process through affecting lipid accumulation and inflammation. In atherosclerotic clinical samples, Wnt5a levels were measured by using enzyme-linked immunosorbent assay (ELISA) assay. In vivo experiments were conducted by using apolipoprotein E knockout (apoE-/-) mice model. Vascular smooth muscle cells (VSMCs) were applied for in vitro studies. Wnt5a was highly expressed in both of atherosclerotic clinical samples and apoE-/- mice. The knockdown of Wnt5a significantly inhibited cholesterol accumulation and inflammatory response. Additionally, the lipopolysaccharide (LPS)-induced inflammation aggravated the cholesterol accumulation and decreased adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) expression in VSMCs. Depletion of intracellular cholesterol by β-cyclodextrin (β-CD) led to the upregulation of ABCA1 and the inhibition of inflammation. Conversely, the overexpression of Wnt5a inhibited ABCA1 expression, facilitated cholesterol accumulation, impared cholesterol efflux, promoted NF-κB nuclear translocation and the inflammatory cytokines secretion. Moreover, the knockdown of Ror2 increased ABCA1 expression and reduced Wnt5a-induced cholesterol accumulation and inflammatory responses. Furthermore, the knockdown of ABCA1 enhanced cholesterol accumulation and inflammatory response. Therefore, Wnt5a/Ror2 pathway was critical in regulating cholesterol homeostasis and inflammatory response, which might be a promising therapeutic target for AS therapy.


A novel protoapigenone analog RY10-4 induces apoptosis of breast cancer cells by exacerbating mitochondrial Ca2+ influx through mitochondrial calcium uniporter.
RY10-4, a novel protoapigenone analog with a specific nonaromatic B-ring, displayed enhanced cytotoxicity in various tumor cells, especially for breast cancer cells, but the underlying mechanism remains unclear. In the present study, we confirmed the pro-apoptotic effect of RY10-4 on breast cancer cells. Furthermore, mitochondrial calcium uniporter (MCU) was proved to be up-regulated in RY10-4-treated MDA-MB-231 cells, which resulted in the overload of mitochondrial calcium ([Ca2+]m) and subsequently disrupted mitochondrial functions (characterized by mitochondrial reactive oxygen species (mtROS) accumulation, membrane potential (ΔΨm) depolarization and permeability transition pore (mPTP) opening). And finally, the mitochondrial apoptosis was activated by the release of cytochrome C. Interestingly, knockdown of MCU attenuated the overload of [Ca2+]m and blocked the apoptosis of MDA-MB-231 cells induced by RY10-4, which was consistent with the in vivo results. Taken together, this study proved that RY10-4 could induce apoptosis of breast cancer cells by elevating [Ca2+]m through MCU. Our work contributed previously unknown insights into the mechanisms involving in the clinical efficacy of RY10-4 on breast cancer cells, which also advanced calcium homeostasis as a potential target for chemotherapeutic drugs.


Simulated temperature distribution of the proximal forearm.
Temperature changes in the resting proximal human forearm have been studied non-invasively, using computer simulation. A procedure for spatial model generation, based on digitized slice data, has been applied. A mathematical model and a 3-D computer simulation program have been implemented. Heat transfer in the non-homogenous tissue was modeled with a well known bio-heat equation. The heat production by tissue metabolism was modeled using the Q10 rule, while the heat exchange between the blood and tissue was modeled as a function of local temperature and regional blood flow. The stability and accuracy of the method was confirmed by varying the simulation parameters, the initial and boundary values, and the model dimensions, with subsequent analysis of the results. We have explained, by computer simulation, the variations in the Pennes' well-known in vivo measurements of the steady-state temperatures along the transverse axis of the proximal forearm. Suspecting that the anatomical positioning of his measuring probes varied, we have reconstructed their possible positions by searching for the simulated positions that result in the best agreement between simulated and measured temperature fields. Our simulations indicate that the fluctuations of the measured steady-state temperatures should not be smoothed out because they are the natural consequence of a complex interplay between the position of the measuring probes, anatomical position of the main arteries, dimensions of the forearm, blood flow, inhomogeneity of tissues, and environmental temperature.


BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group.
The HD9 trial aims to evaluate whether moderate dose escalation and/or acceleration of standard polychemotherapy is beneficial for advanced-stage Hodgkin's disease (HD). Two variants of a novel bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) scheme (standard and escalated dose) are compared with cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The randomized, three-arm trial recruited patients in stages IIB and IIIA with risk factors and stages IIIB and IV. BEACOPP in baseline dose contains all drug dosages of COPP/ABVD (except vincristine and procarbazine) rearranged in a shorter, 3-week cycle. Escalated BEACOPP uses higher doses of cyclophosphamide, doxorubicin, and etoposide with granulocyte colony-stimulating factor (G-CSF) support. After eight chemotherapy cycles, initial bulky and residual disease is irradiated. The trial is monitored and analyzed by means of a sequential strategy. An interim analysis with 505 assessable patients and a median follow-up of 23 months showed a significant inferiority (according to sequential monitoring strategy) of the COPP/ABVD regimen in progression rate and freedom from treatment failure (FFTF) compared with the pooled results of both BEACOPP variants. The 24-month FFTF rate was 75% for COPP/ABVD and 84% for BEACOPP pooled (P = .034). There was 12% progressive disease with COPP/ABVD and 6% with BEACOPP pooled. Differences in survival were not significant in sequential analysis. The acute toxicity of baseline BEACOPP resembled that of COPP/ABVD; escalated BEACOPP showed increased but manageable hematologic toxicity. Combined with local irradiation, BEACOPP in one or both variants shows superior disease control compared with COPP/ABVD, with acceptable acute toxicity. Further follow-up is required to assess the effect of dosage and the effect on survival and late toxicities.


Bipolar II disorder is associated with thinning of prefrontal and temporal cortices involved in affect regulation.
The neurobiological substrate of bipolar II disorder (BD-II) remains largely unknown. A few previous studies have found evidence for cerebral cortical thinning in mixed samples of BD-II and bipolar I disorder patients; however, no study of cortical thickness or surface area has been limited to BD-II. In the present study, we compared magnetic resonance imaging (MRI)-based indices of cortical thickness and surface area between individuals with BD-II and healthy controls. Thirty-six individuals with a DSM-IV diagnosis of BD-II and 42 controls underwent 3T MRI. Comparisons of thickness and relative surface areal expansion across the cerebral cortical mantle were performed using Freesurfer. Individuals with BD-II showed significant thinning in two prefrontal clusters primarily comprising the left subgenual anterior cingulate cortex, left perigenual ventromedial prefrontal cortex (PFC), bilateral dorsomedial PFC, and bilateral dorsolateral PFC (p < 0.0002 for both clusters, cluster size corrected) and in a left temporal cluster involving the superior, middle, and inferior temporal gyrus (p = 0.006, cluster size corrected). No group differences in cortical surface area were found. No significant effect of medication, mood state, illness duration, or family history of bipolar disorders on cortical thinning was observed. These results indicate that BD-II is associated with thinning of prefrontal and temporal cortices implicated in the expression and regulation of negative and positive affect. Longitudinal studies are needed to clarify whether cortical thinning is a stable trait of BD-II, an illness effect that might progress during the course of the disease, or a combination of the two.


Endothelial nitric oxide synthase (-786T>C) polymorphism and migraine susceptibility: A meta-analysis.
The aim of this study was to evaluate the correlation between endothelial nitric oxide synthase (eNOS) polymorphism (-786T>C) and migraine susceptibility in a meta-analysis. A literature search was performed for case-control studies from inception to July 30, 2018 focusing on eNOS polymorphism (-786T>C) and risk of migraine. From 454 full-text articles, 6 were included in this study. Heterogeneity was assessed with the I index and quality assessment was performed using the Newcastle-Ottawa scale. CC genotype was not related to higher susceptibility of migraine compared with TT+ TC genotypes with significant difference (fixed effects model; OR = 1.27; 95% CI = 0.90-1.80; P = .17; I = 18%). However, subgroup analysis showed CC variant increase the risk for migraine compared with TT+ TC genotypes in Caucasian populations (fixed effects model; OR = 1.62; 95% CI = 1.03-2.56; P = .04; I = 18%), which could not be observed in non-Caucasian populations (fixed effects model; OR = 0.88; 95% CI = 0.51-1.53; P = .66; I = 0%). There was no significant difference for other genotypes and alleles between patients with migraine and healthy controls (all P > .05). This meta-analysis indicated that CC variant increases the risk for migraine compared with TT + TC genotypes in Caucasian populations.


Performance of an automatic translator in translating medical abstracts.
The aim of the present paper was to quantitatively assess the performance of a free online translator in translating medical texts from English into Italian. Effectiveness was evaluated and established by analyzing the number and percent of translation errors with respect to the original medical abstracts. Furthermore, the present study analyzed the total number and the percent of translation errors and their correlation with lexical density, which was assessed using Text analyzer. The mean number of total translation errors was 21. The mean percentage of total translation errors was 15%. The mean lexical density was 66.7%. A direct correlation was found between total translation errors and the lexical density. The findings of the present study indicate a fairly good performance of Google translator in translating words in highly academic writings such as medical abstracts. However, an effective translation is not a matter only of finding a correspondence between words in the source language and the target language, many other aspects are just as important.


Incidence of cardiovascular events and risk markers in a prospective study of children diagnosed with Marfan syndrome.
Little is known about the incidence of cardiovascular events (CVEs) and their associated risk markers in children with Marfan syndrome (MFS). To assess the incidence of CVEs and determine risk markers in a cohort diagnosed with Marfan syndrome during childhood and followed for several years. From a French multicentre nationwide database, 462 patients with MFS diagnosed during childhood were included prospectively. Patients' files were screened for a period of 20 years (1993-2013). CVEs (e.g. death, aortic dissection, cardiac valve or aortic root surgery) were assessed during the prospective follow-up. Median (interquartile range) age at the end of follow-up was 17.2 (11.1-21.3) years. CVEs were reported for 35 participants (7.6%; 95% confidence interval [CI] 5.3-10.4%). First CVEs were prophylactic aortic root surgery (n=29), aortic dissection (n=4; two aged <18 years) and death (n=2). Kaplan-Meier cumulative incidence of CVEs was 5.3% (95% CI 3.3-8.7%) during childhood (aged≤18 years) and 19.4% (95% CI 13.3-27.9%) at 25years of age. The cumulative rate of CVEs was higher in case of Valsalva sinus Z-score increase of≥0.1 per year (P=0.0003), maximal Valsalva sinus diameter growth speed ≥5mm per year (P=0.03), aortic regurgitation≥2 (P=0.0005) and maximal Valsalva sinus Z-score≥3 before 16 years of age (P<0.0001). In a multivariable Cox proportional analysis, the Valsalva sinus Z-score remained significantly related to outcome. Considering aortic root evolution, aortic regurgitation, age at diagnosis and beta-blocker therapy were related to Valsalva sinus Z-score evolution during follow-up. CVEs in children with MFS are mainly related to prophylactic aortic root surgery. Aortic dissections are rarely observed in children. The Valsalva sinus Z-score is a strong indicator of subsequent CVEs in children with MFS. Attention to follow-up and beta-blocker observance may be warranted in high-risk children.


Medical decision-making in membranous nephropathy: how to use limited clinical research evidence in patient management.
Evidence-based medicine (EBM) originally referred to the use of a combination of clinical expertise and research evidence to make medical decisions, while carefully considering the patient's preference. In Japan, however, EBM has been misunderstood as the more abstract pursuit of acquiring research evidence and building medical guidelines. This review aims to summarize the available data regarding therapy for membranous nephropathy (MN), a field in which no consensus has been reached, and to discuss medical decision-making by using a decision tree in several model cases. In clinical practice, we have to consider both the risks and benefits of treatment. These are evaluated by their therapeutic effect (the rate of improvement, no change, or worsening) and by the patients' quality of life (QOL). This process is compatible with the essential concept of EBM.


Health profiles in quality of life: evaluation of diagnostic technologies.
The use of instruments to measure health-related quality of life has become commonplace in medical research, although their use is still unusual in the evaluation of diagnostic technologies. Dr Greenfield has pointed out the potential to abuse as well as use these methods. The cautions that Dr Greenfield has outlined apply to any such research, whether one is evaluating a new drug or a new imaging device. Even though the chain of events from diagnostic technology to patient outcome is longer than for therapeutic interventions, we maintain that quality-of-life instruments are potentially valuable tools for evaluating any of the links in this chain.


Gene switching rate determines response to extrinsic perturbations in the self-activation transcriptional network motif.
Gene switching dynamics is a major source of randomness in genetic networks, also in the case of large concentrations of the transcription factors. In this work, we consider a common network motif - the positive feedback of a transcription factor on its own synthesis - and assess its response to extrinsic noises perturbing gene deactivation in a variety of settings where the network might operate. These settings are representative of distinct cellular types, abundance of transcription factors and ratio between gene switching and protein synthesis rates. By investigating noise-induced transitions among the different network operative states, our results suggest that gene switching rates are key parameters to shape network response to external perturbations, and that such response depends on the particular biological setting, i.e. the characteristic time scales and protein abundance. These results might have implications on our understanding of irreversible transitions for noise-related phenomena such as cellular differentiation. In addition these evidences suggest to adopt the appropriate mathematical model of the network in order to analyze the system consistently to the reference biological setting.


Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-gamma on STAT3 and Smads.
Suppressor of cytokine signaling 1 (SOCS1) is an important negative regulator for cytokines; however, the role of SOCS1 in Th17 differentiation has not been clarified. We generated T cell-specific SOCS1-deficient mice and found that these mice were extremely resistant to a Th17-dependent autoimmune disease model, experimental autoimmune encephalomyelitis. SOCS1-deficient naive CD4(+) T cells were predominantly differentiated into Th1 and poorly into Th17 in vitro. These phenotypes were canceled in IFN-gamma(-/-) background, suggesting that a large amount of IFN-gamma in SOCS1-deficient T cells suppressed Th17 differentiation. IL-6 plus TGF-beta enhanced retinoic acid receptor-related orphan receptor (ROR)-gammat expression and suppressed IFN-gamma production in wild-type T cells, whereas these effects were severely impaired in SOCS1-deficient T cells. These phenotypes can be partly explained by STAT3 suppression by enhanced SOCS3 induction through hyper-STAT1 activation in SOCS1-deficient T cells. In addition, SOCS1-deficient T cells were much less sensitive to TGF-beta. Suppression of Th1 differentiation by TGF-beta was impaired in SOCS1-deficient T cells. TGF-beta-mediated Smad transcriptional activity was severely inhibited in SOCS1-deficient cells in the presence of IFN-gamma. Such impairment of TGF-beta functions were not observed in SOCS3-overexpressed cells, indicating that suppression of Smads was independent of SOCS3. Therefore, SOCS1 is necessary for Th17 differentiation by suppressing antagonistic effect of IFN-gamma on both STAT3 and Smads. Induction of SOCS3 can partly explain IFN-gamma-mediated STAT3 suppression, while other mechanism(s) will be involved in IFN-gamma-mediated Smad suppression. SOCS1-deficient T cells will be very useful to investigate the molecular mechanism for the STAT1-mediated suppression of Th17 development.


Voltage-gated K+ channels play a role in cAMP-stimulated neuritogenesis in mouse neuroblastoma N2A cells.
Neuritogenesis is essential in establishing the neuronal circuitry. An important intracellular signal causing neuritogenesis is cAMP. In this report, we showed that an increase in intracellular cAMP stimulated neuritogenesis in neuroblastoma N2A cells via a PKA-dependent pathway. Two voltage-gated K(+) (Kv) channel blockers, 4-aminopyridine (4-AP) and tetraethylammonium (TEA), inhibited cAMP-stimulated neuritogenesis in N2A cells in a concentration-dependent manner that remarkably matched their ability to inhibit Kv currents in these cells. Consistently, siRNA knock down of Kv1.1, Kv1.4, and Kv2.1 expression reduced Kv currents and inhibited cAMP-stimulated neuritogenesis. Kv1.1, Kv1.4, and Kv2.1 channels were expressed in the cell bodies and neurites as shown by immunohistochemistry. Microfluorimetric imaging of intracellular [K(+)] demonstrated that [K(+)] in neurites was lower than that in the cell body. We also showed that cAMP-stimulated neuritogenesis may not involve voltage-gated Ca(2+) or Na(+) channels. Taken together, the results suggest a role of Kv channels and enhanced K(+) efflux in cAMP/PKA-stimulated neuritogenesis in N2A cells.


Estimating the refractive index of pharmaceutical solids using predictive methods.
Refractive index is a basic physical property of pharmaceutical solids. In this paper, the refractive index values of 424 pharmaceutical solids from the literature were surveyed. It was found that the refractive index values exhibit a normal distribution with an overall mean value of 1.603. The Eisenlohr and Vogel methods developed for organic liquids were employed to estimate the refractive index for pharmaceutical solids. The estimated results were compared with experimentally measured values determined by polarized light microscopy. Both Eisenlohr and Vogel R(D) methods agreed very well with the measured mean refractive index values from the literature with an average absolute percent error of 1.22% and 1.25%, respectively. The evaluation for in-house measurements for Pfizer active pharmaceutical ingredients showed larger differences between the calculated and measured values. The results indicate that the Eisenlohr and Vogel R(D) methods can provide fast and accurate results for predicting the refractive index of pharmaceutical solids.


Impact of atherosclerosis-related gene polymorphisms on mortality and recurrent events after myocardial infarction.
Although previous epidemiologic studies have suggested an association between the onset of myocardial infarction (MI) and some genetic variations, the impact of these variants on recurrent cardiovascular events after MI has not been fully elucidated. We genotyped 87 polymorphisms of 73 atherosclerosis-related genes in consecutive acute MI patients registered in the Osaka Acute Coronary Insufficiency Study and compared the incidence of death and major adverse cardiac events (MACE) among the polymorphisms of each gene. After initial screening in 507 patients, we selected nine polymorphisms for screening in all 1586 patients. Multivariate Cox regression analysis revealed that G allele carriers at the position 252 of the lymphotoxin alpha (LTA) gene were independently associated with an increased risk of death (hazard ratio [HR]: 2.46; 95% CI: 1.24-4.86). In conclusion, a 252G allele of LTA is associated with an increased risk of death after AMI and may be a useful genetic predictor.


Cerebral Venous Thrombosis: A Challenging Neurologic Diagnosis.
Headache is a common emergency department chief complaint. Although most are benign, emergency physicians must rapidly identify and manage the uncommon, sometimes subtle, presentation of headache from a life-threatening cause. Cerebral venous thrombosis imparts significant morbidity and mortality, and can be a challenging diagnosis. It most commonly occurs in those under 50 years of age with thrombosis of the cerebral veins/sinuses. Diagnosis is frequently delayed. The disease can present with 1 or more clinical syndromes, including intracranial hypertension with headaches, focal neurologic deficits, seizures, and encephalopathy. Diagnosis requires imaging. Treatment includes stabilization, management of complications, and anticoagulation.


Cellular effects of PM2.5 from Suzhou, China: relationship to chemical composition and endotoxin content.
Exposure to PM2.5 can cause adverse health outcomes. In this study, we analyzed PM2.5 samples collected from suburban and urban sites, including a traffic tunnel in Suzhou, China, for their physicochemical properties, endotoxin contents, and effects on HepG2 and A549 cells in vitro. The greatest cellular responses, including oxidative stress, cytotoxicity, genotoxicity, inflammatory, and transcriptional activation of stress-responsive genes (i.e., HSPA1A, GADD45α), were observed in cells treated with traffic tunnel PM2.5. Cytokine expression was also measured and closely correlated with endotoxin content, while other toxic effects were largely related to PM2.5-bound metals and polycyclic aromatic hydrocarbons (PAHs). These findings suggested that chemical and biological composition of PM2.5, including adsorbed trace metals, PAHs, and endotoxin, may contribute significantly to their toxicity. In addition to commonly used in vitro toxicity tests, HSPA1A and GADD45α promoter-driven luciferase reporter cells may provide a potential new tool for rapid screening and quantification of PM2.5 toxicity.


Diagnostic value of ultrasound and contrast-enhanced ultrasound in septic acute kidney injury.
This study aimed to explore the clinical value of ultrasonic Doppler examination and contrast-enhanced ultrasound (US) in the circulation of septic acute kidney injury (AKI). Patients with intensive care unit-related infection were divided into AKI group and control groups. The AKI group was divided into three subgroups according to the serum creatinine value: stage 1, stage 2, and stage 3. Relevant parameters and blood flow of the renal artery were measured, and further contrast-enhanced US was performed and time-intensity curve was analyzed. The renal blood flow (RBF) and time-averaged velocity decreased significantly in the AKI group compared with the control group (p = .021 and p = .001). The peak value decreased and time to peak (TTP) prolonged in the AKI group (p < .001). With the aggravation of the disease, the RBF decreased slightly among subgroups (p = 0.124). However, the peak value gradually decreased and the TTP prolonged (all p < .05). The multiple linear regression model showed that only PI, RI, and TTP were independently and linearly correlated with the serum creatinine value. Doppler US and contrast-enhanced US are of great help in the detection of condition changes and prognosis of patients with sepsis-induced AKI.


Radiation induced heart disease in hypertensive rats.
Spontaneously hypertensive Wistar rats were given single doses of X rays to their heart. Irradiation decreased the blood pressure before any myocardial radiation damage was apparent. Male rats, which were more hypertensive than female rats, had a shorter survival time after local heart irradiation than female rats. Antihypertensive treatment with hydralazine did not increase the survival time. It is considered that myocardial hypertrophy is the cause of the increased susceptibility of spontaneously hypertensive rats to local heart irradiation.