Filtering and inference for stochastic oscillators with distributed delays.
The time evolution of molecular species involved in biochemical reaction networks often arises from complex stochastic processes involving many species and reaction events. Inference for such systems is profoundly challenged by the relative sparseness of experimental data, as measurements are often limited to a small subset of the participating species measured at discrete time points. The need for model reduction can be realistically achieved for oscillatory dynamics resulting from negative translational and transcriptional feedback loops by the introduction of probabilistic time-delays. Although this approach yields a simplified model, inference is challenging and subject to ongoing research. The linear noise approximation (LNA) has recently been proposed to address such systems in stochastic form and will be exploited here. We develop a novel filtering approach for the LNA in stochastic systems with distributed delays, which allows the parameter values and unobserved states of a stochastic negative feedback model to be inferred from univariate time-series data. The performance of the methods is tested for simulated data. Results are obtained for real data when the model is fitted to imaging data on Cry1, a key gene involved in the mammalian central circadian clock, observed via a luciferase reporter construct in a mouse suprachiasmatic nucleus. Programmes are written in MATLAB and Statistics Toolbox Release 2016 b, The MathWorks, Inc., Natick, Massachusetts, USA. Sample code and Cry1 data are available on GitHub https://github.com/scalderazzo/FLNADD. Supplementary data are available at Bioinformatics online.


Immunogenicity of formaldehyde and binary ethylenimine inactivated infectious bursal disease virus in broiler chicks.
Infectious bursal disease virus (IBDV) was inactivated by two different chemicals--formaldehyde and binary ethylenimine (BEI). Formaldehyde was used at 0.1% and 0.2%, while BEI was used at concentrations of 0.001 and 0.002 mol/L. These four vaccines were tested for their efficiency in generating humoral immune response in different groups of broiler chicks. Both BEI-inactivated vaccines gave relatively higher antibody titers and were almost twice as efficient as formaldehyde-inactivated ones.


Cancer care and survivorship planning: promises and challenges.
Although we have made some progress in understanding long-term effects of some cancer treatments, there is still much more to learn about the impact of our treatments on our patients.


Alternating six-drug combination chemotherapy induction for intermediate and high-grade non-Hodgkin's lymphoma.
31 patients with intermediate and high-grade non-Hodgkin lymphomas were treated by a six-drug alternating regime comprising four cycles of 200 mg/m2 i.v. methotrexate on days 8, 15, 28 and 35, 50 mg/m2 i.v. Adriamycin on day 1, 40 mg/m2 oral prednisolone on days 1-7 and 21-27, 120 mg/m2 i.v. etoposide on days 21-23, 600 mg/m2 i.v. cyclophosphamide on day 21 and 1.4 mg/m2 i.v. vincristine on day 1 (MAPECO). In all, 3 patients had stage I disease, 12 stage II, 6 stage III and 10 stage IV. Of 28 evaluable patients, 19 were complete responders (68%) and 9 were partial responders (32%); at 2 years, the actuarial relapse-free survival of the 19 patients achieving complete remission is 80%, and 5 patients remain in complete remission at 3 years. This is a preliminary report of an effective intensive regime with acceptable toxicity.


Nonspatial conditional learning impaired in patients with unilateral frontal but not unilateral temporal lobe excisions.
The present study examined the effect of unilateral frontal- or temporal-lobe excisions on the acquisition of a conditional task requiring that the subjects respond to each one of six different coloured stimuli by selecting, from a set of six abstract designs, the correct design for each stimulus. Patients with excisions from the left or right frontal cortex were impaired in learning this task, whereas patients with left or right temporal-lobe excisions, with or without radical involvement of the hippocampal region, were not impaired. These findings demonstrate that the major role played by the frontal cortex in the acquisition of conditional responses is a general one and not restricted to situations involving different movements.


Determinants of early sexual initiation among female adolescents in Bangladesh: evidence from a countrywide cross-sectional survey.
Early sexual initiation (ESI), defined as sexual activity that begins before 15 or 18 years of age, is one of the risky sexual behaviours that has been linked to increased likelihood of adverse consequences, such as sexually transmitted diseases, unintended pregnancies and unsafe abortions. However, to date, there are no studies investigating the prevalence and factors influencing ESI among adolescent females (aged 10-19 years) in Bangladesh. Thus, this study aimed to identify the potential determinants of ESI among adolescent females in Bangladesh based on data that are representative of the country. This was a cross-sectional study. Based on the availability of the data, the analysis included a weighted sample of 2051 adolescent females aged 15-19 years from the Bangladesh Demographic and Health Survey 2017/18. Initial selection of predictor variables was based on the bivariate analysis using the Chi-squared test. Univariate and multivariable logistic regression modelling were performed to measure the crude and adjusted effect of the selected predictor variables on ESI using the odds ratio (OR). The elasticity of the effects was calculated by their 95% confidence intervals (CIs). Approximately 22% and 85% of female adolescents experienced ESI before the age of 15 and 18 years, respectively. Findings revealed that illiteracy (adjusted OR [AOR]: 3.61, 95% CI: 1.82-7.18), primary education (AOR: 2.08, 95% CI: 1.60-2.69), working status (AOR: 1.25, 95% CI: 0.98-1.60), living in Chittagong (AOR: 0.46, 95% CI: 0.27-0.79), living in Sylhet (AOR: 0.21, 95% CI: 0.08-0.56), reading newspapers (AOR: 0.63, 95% CI: 0.40-1.01), earlier marriage preference (AOR: 3.30, 95% CI: 2.31-4.71) and later marriage preference (AOR: 4.10, 95% CI: 3.01-5.59) were significantly linked with ESI before the age of 15 years. ESI before the age of 18 years was significantly association with primary education (AOR: 1.47, 95% CI: 1.01-2.13), religion (AOR: 0.55, 95% CI: 0.32-0.94), female household head (AOR: 1.93, 95% CI: 1.17-3.19), living in Rajshahi (AOR: 1.97, 95% CI: 0.95-4.08), being in the 'poorest' wealth category (AOR: 2.43, 95% CI: 1.45-4.07), being in the 'poorer' wealth category (AOR: 1.70, 95% CI: 1.06-2.72), being in the 'middle' wealth category (AOR: 1.76, 95% CI: 1.12-2.77), being in the 'richer' wealth category (AOR: 1.58, 95% CI: 1.02-2.44), earlier marriage preference (AOR: 15.71, 95% CI: 9.09-27.14), later marriage preference (AOR: 12.62, 95% CI: 8.82-18.06) and heard about family planning (AOR: 0.70, 95% CI: 0.47-1.04). In Bangladesh, the prevalence of ESI among female adolescents is a public health concern. Due to the detrimental impact of ESI on the well-being of adolescents, it is crucial that policymakers consider the factors influencing ESI that have been identified in this study when designing health strategies. The findings from this study will help the development of evidence-based effective initiatives by policymakers in collaboration with governmental and non-governmental organisations.


Clinical utility of an electronic poisons information and clinical decision support tool.
The objective of the study was to assess the use of a computer toxicology database/clinical decision aid by clinical practitioners. The study investigated the sources that Emergency Department (ED) personnel use to obtain toxicology information and performed a quality audit of the current database. A questionnaire survey of ED staff was used in departments with access to the New Zealand Poisons Centre Substance Database (NZSD), a toxicology CD ROM computer database. Outcome measures were reported use of alternative data sources when managing clinical toxicology presentations and the qualities of the NZSD. Computer databases are commonly used for the management of clinical toxicology cases and the toxicology computer database/clinical decision aid studied is well accepted and used in Emergency Medicine practice. The users of the NZSD assessed the usability and quality of the information of the database.


Three-phase partitioning as an efficient method for extraction/concentration of immunoreactive excreted-secreted proteins of Corynebacterium pseudotuberculosis.
The three-phase partitioning (TPP) technique was used upstream to isolate/concentrate secreted proteins from Corynebacterium pseudotuberculosis cultured in a complex liquid medium. Several parameters of the TPP technique (15, 30, or 60% ammonium sulfate concentration; 4.0, 5.5, or 7.0 pH; and primary (n) or tertiary (t)-butanol solvent isomer) were varied to determine the optimal recovery of serologically and cellularly immunoreactive extracted proteins. A TPP extraction made with 30% ammonium sulfate and an initial pH of 4.0 gave the best humoral and cellular immunoreactivity of caseous lymphadenitis infected goats. In particular, two immunogenic secreted (16 and 125 kDa) proteins, which had not been found by other extraction methods, were identified.


Study on the chaperone properties of conserved GTPases.
As a large family of hydrolases, GTPases are widespread in cells and play the very important biological function of hydrolyzing GTP into GDP and inorganic phosphate through binding with it. GTPases are involved in cell cycle regulation, protein synthesis, and protein transportation. Chaperones can facilitate the folding or refolding of nascent peptides and denatured proteins to their native states. However, chaperones do not occur in the native structures in which they can perform their normal biological functions. In the current study, the chaperone activity of the conserved GTPases of Escherichia coli is tested by the chemical denaturation and chaperone-assisted renaturation of citrate synthase and α-glucosidase. The effects of ribosomes and nucleotides on the chaperone activity are also examined. Our data indicate that these conserved GTPases have chaperone properties, and may be ancestral protein folding factors that have appeared before dedicated chaperones.


Healthcare professionals experience with motivational interviewing in their encounter with obese pregnant women.
to explore and describe how healthcare professionals in the Southern Region of Denmark experienced motivational interviewing as a communication method when working with pregnant women with obesity. a qualitative, descriptive study based on face-to-face interviews with 11 obstetric healthcare professionals working in a perinatal setting. a thematic descriptive method was applied to semi-structured interviews. The healthcare professional's experiences were recorded verbatim during individual semi-structured qualitative interviews, transcribed, and analysed using a descriptive analysis methodology. motivational interviewing was found to be a useful method when communicating with obese pregnant women. The method made the healthcare professionals more aware of their own communication style both when encountering pregnant women and in their interaction with colleagues. However, most of the healthcare professionals emphasised that time was crucial and they had to be dedicated to the motivational interviewing method. The healthcare professionals further stated that it enabled them to become more professional in their daily work and made some of them feel less 'burned out', 'powerless' and 'stressed' as they felt they had a communication method in handling difficult workloads. healthcare professionals experienced motivational interviewing to be a useful method when working perinatally. The motivational interviewing method permitted heightened awareness of the healthcare professionals communication method with the patients and increased their ability to handle a difficult workload. Overall, lack of time restricted the use of the motivational interviewing method on a daily basis.


Child abuse-related homicides precipitated by caregiver use of harsh physical punishment.
Physical punishment (PP), which may involve the use of physical force, has been linked to negative effects in children and can escalate to abusive or harsh PP, resulting in injury or death. To examine characteristics associated with fatal abuse involving caregiver use of harsh PP. Data were from the National Violent Death Reporting System in 40 states, the District of Columbia, and Puerto Rico for years 2012-2018. Qualitative analysis was used to code textual material into categorial data, and logistic regression was used to examine associations between various characteristics and harsh PP. Approximately 4 % (n = 87) of the 2414 abuse-related homicides were known to have been precipitated by caregiver use of harsh PP. In adjusted models, homicides had greater odds of being harsh PP-related when incidents involved mothers' male companions (versus fathers), victims had a previous nonfatal injury (versus no previous nonfatal injury), and another adult participated in the fatal incident or had awareness of prior abuse/neglect (versus those without this characteristic). Two common precipitators of caregivers' use of harsh PP were: 1) child had a bathroom-related accident/soiled clothes (23.0 %; n = 20), and 2) child disobeyed a directive given by the perpetrator (17.2 %; n = 15). This study highlights characteristics associated with fatal abuse precipitated by caregiver use of harsh PP. Children were physically punished for developmentally normative behaviors. Ensuring caregivers are aware of and use effective parenting practices that focus on use of nonphysical discipline and promote healthy child development, may help decrease harsh PP and physical abuse-related homicides among children.


Dentistry with a difference: volunteering for 'Dental Project Peru'.
As a young dentist looking for new challenges and experiences, Mary Bussell decided to use her skills and training by volunteering for a dental charity working in Peru. Here she gives an account of her 'dental adventure'.


Comparison of LabSOCS and GESPECOR codes used in gamma-ray spectrometry.
Two dedicated software packages -LabSOCS and GESPECOR- for efficiency evaluation in gamma-ray spectrometry, were compared for equivalence. The detection efficiency and the coincidence-summing corrections coefficients were calculated for a specific HPGe detector, for different sample parameters and energies typically encountered in environmental radioactivity measurements. The discrepancy between the results obtained with the two codes were acceptable for most of the applications. Furthermore, the deviations between the values of the standard sources/ reference materials activities from the certificate and the values obtained after Monte Carlo simulation were less than 8% for LabSOCS and 9% for GESPECOR.


Lectin-mediated drug delivery: binding and uptake of BSA-WGA conjugates using the Caco-2 model.
To examine whether the dietary lectin wheat germ agglutinin (WGA) can facilitate binding and uptake of protein drugs due to its cytoadhesive and cytoinvasive properties, conjugates were prepared by covalent coupling of fluorescein-labeled bovine serum albumin (F-BSA) to WGA using divinylsulfone for crosslinking. Increasing the molar ratio of F-BSA/WGA resulted in 2.6-8.7 times higher Caco-2 binding as compared with glycyl-F-BSA. About 75% of F-BSA-WGA were bound specifically to Caco-2 cells according to inhibition studies in presence of the complementary carbohydrate. The Caco-2 association of F-BSA-WGA was temperature-dependent indicating active uptake of membrane bound conjugate, which was confirmed by confocal microscopy. The conjugate accumulated within lysosomal compartments followed by proteolytic degradation of F-BSA-WGA 1-4 h after conjugate loading as observed by equilibrating the intracellular pH with monensin. Finally low molecular weight degradation products of the proteinaceous prodrug appear in the extracellular medium. Contrary to Caco-2 single cells, a minor part of the conjugate is degraded by brush border proteases already 30 min after exposure to Caco-2 monolayers. But most of the conjugate is taken up into differentiated cells and processed as in single cells. Though the enzymic barrier remains to be surmounted, WGA-mediated drug delivery is a promising strategy for peroral delivery of even high molecular weight drugs to overcome the mucosal barrier.


OnabotulinumtoxinA injections for atypical odontalgia: an open-label study on nine patients.
Atypical odontalgia (AO) manifests as continuous pain in the region of one or several teeth, in the absence of signs of dental pathology. Currently, there is insufficient evidence to establish treatment guidelines for AO. The aim of this study was to describe the effectiveness and safety of treatment with OnabotulinumtoxinA (OnabotA) on a series of patients with AO. Nine patients with AO (four males and five females, aged between 31 and 77 years) received injections of OnabotA in the region of pain. The dosage used in each procedure ranged between 10 and 30 U, spread between 4 and 12 injection sites along the gums (n=9), the lips (n=3), and the hard palate (n=1). The median follow-up time was 27 months (interquartile range, IQR 20-40) and the median number of injection sessions per patient was seven (IQR 4.5-9). The assessment variables included the change in the maximal intensity of pain on a 0-10 numerical rating scale (NRS), the response latency, and the duration of the effect. All patients experienced a significant improvement, with ≥50% of reduction in the intensity of the maximal pain. The median of reduction of maximal pain after treatment was six points on the NRS (IQR 5-8.5). The response latency was 2-15 days and the duration of the effect was 2-6 months. No significant adverse reactions were registered. OnabotA may be a safe and effective option for the treatment of AO.


Nuclear Factor E2-Related Factor 2 Mediates Oxidative Stress-Induced Lipid Accumulation in Adipocytes by Increasing Adipogenesis and Decreasing Lipolysis.
Aims: Nuclear factor E2-related factor 2 (Nrf2) is a regulator of cellular oxidative stress and is also involved in lipid metabolism in adipocytes. However, it remains unknown as to whether Nrf2 is the link between oxidative stress and the induction of lipid accumulation in adipocytes. Results: Here, we show that oxidative stress is markedly increased in white adipose tissue from mice with high-fat diet-induced or genetically (ob/ob)-induced obesity and from human subjects with obesity. Notably, in response to oxidative stress, Nrf2 expression and activity were induced, further promoting lipid accumulation in adipocytes and exacerbating the development of obesity. In contrast, Nrf2 ablation alleviated oxidative stress-induced lipid accumulation. Mechanistically, oxidative stress promoted Nrf2 recruitment to the sterol regulatory element binding protein 1 promoter, inducing target gene transcription and subsequent lipogenesis. In addition, Nrf2 mediated oxidative stress-inhibited lipolysis in adipocytes via the protein kinase A pathway. Innovation and Conclusion: Our data provide a novel insight that Nrf2, as a critical signaling node, links oxidative stress to the induction of fat accumulation in adipocytes.


Myofascial pain dysfunction and viola playing.
Two cases are illustrated to demonstrate the importance of occupation, in the form of viola playing, in the aetiology of myofascial pain dysfunction. An understanding of the contribution of tension and playing style, together with physical limitations, is emphasised and, consequently, it is acknowledged that modification may be necessary to the formulation of a treatment plan.


Sonographic appearance of a soft-tissue gossypiboma in the forearm with pathologic correlation.
We describe the sonographic, radiologic, and histopathologic appearances of a soft tissue gossypiboma in the forearm of an 81-year-old woman with a history of a radial fracture treated with an internal fixation surgery.


Population pharmacokinetic and pharmacodynamic modeling of MNRP1685A in cynomolgus monkeys using two-target quasi-steady-state (QSS) model.
MNRP1685A (anti-NRP1) is a fully human IgG1 monoclonal antibody against neuropilin-1 (NRP1), a protein necessary for blood vessel maturation. MNRP1685A binds to free membrane-bound NRP1 (mNRP1) and circulating NRP1 (cNRP1). Total cNRP1 increased in a dose-dependent manner following anti-NRP1 administration in mice, rats, and monkeys. The purpose of this study is to develop a mechanism-based model to simultaneously describe the kinetics of both unbound drug (MNRP1685A) and total cNRP1 in cynomolgus monkeys. Pharmacokinetic (PK) and pharmacodynamic (PD) profiles after single- or multiple-dose administrations were well described by the two-target quasi-steady-state (QSS) model. The estimated nonspecific clearance was 3.26 mL/day/kg and central compartment volume was 38.2 mL/kg. The maximum elimination rate for mNRP1-mediated disposition was 98.8 nM/day. The synthesis rate (3.8 nM/day), degradation rate constant (1.53 day(-1)), and complex elimination rate constant (0.260 day(-1)) for cNRP1 were also derived from the model. QSS constants were 6.94 nM for mNRP1 and 2.8 nM for cNRP1. The results suggest that cNRP1 has minimal effect on MNRP1685A PK while mNRP1 plays a major role in the target-mediated drug disposition. This finding is favorable as the desired pharmacological target is mNRP1, rather than cNRP1. The two-target QSS model provides mechanistic understanding of the nonlinear PK of MNRP1685A. Based on the model prediction, the free drug concentrations to maintain free mNRP1 and cNRP1 below 10% of baseline level are 10 and 20 μg/mL, respectively. This serves as a target concentration for clinical dose selection, assuming cynomolgus monkeys are predictive for humans.


Resveratrol Mitigates Cerebral Ischemic Injury by Altering Levels of Trace Elements, Toxic Metal, Lipid Peroxidation, and Antioxidant Activity.
Cerebral ischemia causes increased oxidative stress due to the overproduction of reactive oxygen species. The polyphenol compound resveratrol exerts neuroprotective effects through its antioxidant and anti-inflammatory abilities. The trace elements magnesium (Mg), zinc (Zn), and selenium (Se) also exert antioxidant properties. This study mainly investigates whether the neuroprotective effect of resveratrol during cerebral ischemia is related to its modulation of the concentrations of trace element and toxic metal lead (Pb). Experimental rats were administered resveratrol (20 mg/kg) once daily for 10 consecutive days. Cerebral ischemia was surgically induced via ligation of the right middle cerebral artery and right common carotid artery for 1 h. Brain cortex tissues were homogenized, and the supernatants were harvested for biochemical analysis. Experimental results showed that rats pretreated with resveratrol before cerebral ischemia had significantly higher trace element concentrations of Mg, Zn, and Se and higher antioxidant activity (superoxide dismutase and catalase) in the brain cortex as compared to untreated cerebral ischemia rats. Conversely, resveratrol pretreatment markedly attenuated lipid peroxidation and concentrations of the toxic metal Pb as compared to untreated cerebral ischemic rats. Altogether, the findings of this study highlight that the mechanism underlying the neuroprotective effect of resveratrol involves modulation of the brain levels of trace elements, toxic metal lead, lipid peroxidation, and antioxidant activity.


Slow recovery of sodium current and 'gating current' from inactivation.
1. Asymmetrical displacement currents ('gating currents') and Na currents have been recorded in intracellularly perfused squid giant axons with the voltage-clamp method. Inactivation of the currents by a long-lasting depolarization to -30 mV and subsequent removal of inactivation have been studied at temperatures of 0-5-3 degrees and 8-9 degrees C. 2. The asymmetrical displacement current, recorded with the divided pulse procedure, was markedly reduced by a 1-5-800 msec depolarization to -30 mV; a 3 min depolarization led to almost complete blockage. 3. Recovery of the asymmetrical displacement current from a 3 min depolarization to -30 mV was slow (20-40% recovery after 50-800 msec at -70 mV and 8-9 degrees C); full recovery from a long-lasting depolarization took several minutes. 4. Recovery of the Na current followed a similar time course (20% recovery after 50-800 msec at -70 mV and 8-9 degrees C); the time constant of full recovery was 2-3-5 min. 5. Slow recovery was also demonstrated by recording the displacement currents associated with single depolarizing pulses. 6. The results are consistent with the idea that the asymmetrical displacement current is related to the function of the Na gates.


Growth hormone-producing pituitary adenoma with crystal-like amyloid immunohistochemically positive for growth hormone.
Growth hormone (GH)-producing pituitary adenoma from a 50-year-old acromegalic female was studied histochemically, immunohistochemically and electron microscopically. The adenoma was characterized by numerous crystal-like amyloid bodies of 5 to 40 micron in diameter. In the periphery of the crystal-like amyloid, bundles of amyloid fibrils were closely associated with deep invaginations of adenoma cells. The adenoma cells had numerous vesicles and vacuoles filled with amyloid fibrils, some of which were continuous with extracellular space. The crystal-like amyloids, as well as the adenoma cells, were immunohistochemically positive for GH. It might be possible that disorder of hydrolysis of "prohormone," from which GH is elaborated, is responsible for the amyloid production, and that amyloid discharge is accompanied with immunoreactive GH.


[Foot-and-mouth disease in buffaloes (Bubalus bubalis, Linnaeus, 1758): search of antiantigen antibodies and isolation of the virus].
The immune response to virus-infection-associated (VIA) antigen was studied in 379 Indian buffalos (Bubalus bubalis). These animals were vaccinated three times a year with commercial acetylethyleneimine (AEI)--inactivated foot-and-mouth disease vaccines under field conditions. Two months after the last vaccination, antibody against virus-infection-associated (VIA) antigen was found in 23 per cent. Foot-and-mouth disease virus -- (FMDV) type C "Waldmann" was isolated from oesophageal/pharyngeal fluid of 7 samples buffalos.


Positron emission tomographic studies of central cholinergic nerve terminals.
The aim of this study was to develop a quantitative method for the study of cholinergic nerve terminals in vivo. An 18F-labeled analogue of vesamicol ([18F]FMV) that binds with high affinity to synaptic vesicles from Torpedo electric organ was synthesized and evaluated in vivo in rats and monkeys by positron emission tomography (PET). In rats, the tracer was rapidly cleared from the blood and highly extracted into the brain, where it was specifically and irreversibly bound. In monkeys, a specific binding of the tracer was observed in brain regions known to contain cholinergic nerve terminals. Preinjection of non-labeled vesamicol prevented the cerebral binding of [18F]FMV to a high affinity site in both species. Our results are a major step towards quantitative human in vivo studies of presynaptic cholinergic functions.


Apicoplast fatty acid biosynthesis as a target for medical intervention in apicomplexan parasites.
New chemotherapies for human and animal apicomplexan infections are needed as a component of future strategies to deal with these diseases. An extensive search for new treatments exploring the unique developmental physiology, metabolism and molecular structures of Apicomplexa is under way. The description of the full complement of about 5,300 Plasmodium falciparum genes and fast growing sequence databases for other Apicomplexa allow reconstruction of metabolic pathways of these parasites and thus accelerate identification and biochemical analysis of potential targets. The apicoplast de novo fatty acid biosynthetic pathway shows great potential as a target for small-molecule inhibitors in a stand-alone or combination chemotherapy. Three enzymatic activities, acetyl-CoA carboxylase, beta-ketoacyl-ACP synthase and enoyl-ACP reductase, respond to inhibitors previously identified for bacteria and plants, and deserve to be explored in depth. In this connection, screening systems have been established to seek more potent and specific antiparasitic compounds that are harmless to the host. To this end the interconnections of fatty acid biosynthesis in Apicomplexa with other metabolic and cellular processes must be investigated.


Electrophysiologic changes induced by external transthoracic countershock.
The purpose of this study was to characterize the electrophysiological effects of suprathreshold transthoracic shocks. Dogs were anesthetized and two consecutive shocks (10 joules/gk) were applied one minute apart. Ventricular extrasystoles were observed in six of the 11 dogs tested, A-V block in three, ventricular tachycardia in three, and asystole in one. Forty eight hours later the hearts were removed. Conventional electrophysiological techniques revealed the following: 1) injured cells had loss of resting potential, triangularization of the action potential and depressed upstrokes; 2) the functional refractory period was shortened, with an increase in time dependence; 3) action potential alternans; 4) discrete areas of marked depression of conduction; 5) re-excitation with premature stimulation and 6) histological evidence of sub-epicardial injury. These studies suggest that the application of suprathreshold shocks may induce electrophysiological changes potentially inducing tachyarrhythmias.


Palatal neoplasms: reconstruction considerations.
Review of the literature and our personal experience with carcinoma of the palate indicates that a significant number of patients may benefit from palatal resection, either as an initial modality, in a planned combined treatment program, or for salvage after radiation therapy. Under any of these circumstances an integral part of the treatment program is rehabilitation of speech and swallowing function through prosthetic repair. Familiarity with the potentials and techniques of prosthetic rehabilitation after palatal resection is an important concern for the head and neck oncologist.


Dynein cleavage and microtubule accumulation in okadaic acid-treated neurons.
Impairment of protein phosphatase 2A (PP2A) activity is implicated in tau hyperphosphorylation and microtubule (MT) instability in Alzheimer's disease (AD). Here, we report that okadaic acid, an effective PP2A inhibitor, suppresses the levels of acetylated and detyrosinated tubulins, but enhances tyrosinated tubulins in rat primary cortical neuron cultures. Immunocytochemistry experiments reveal that MTs accumulate intensely around soma and proximal neurites, implying impairment of MT transport to distal neurites which is mediated by dynein and dynactin. Here, we reveal that they can be cleaved by calpain. Notably, shortening of process length in OA-treated neurons is alleviated when calpain cleavage activity is inhibited. Based on these results, we propose that calpain-mediated dynein cleavage in OA-treated neurons is responsible for the MT transport deficit, and consequently, neurite retraction.


Posterior Circulation Endovascular Thrombectomy for Large Vessels Occlusion in Patients Presenting with NIHSS Score ≤ 10.
Mechanical thrombectomy (MT) is currently the gold standard treatment for ischemic stroke due to large vessel occlusion (LVO). However, the evidence of clinical usefulness of MT in posterior circulation LVO (pc-LVO) is still doubtful compared to the anterior circulation, especially in patients with mild neurological symptoms. The database of 10 high-volume stroke centers in Europe, including a period of three year and a half, was screened for patients with an acute basilar artery occlusion or a single dominant vertebral artery occlusion ("functional" BAO) presenting with a NIHSS ≤10, and with at least 3 months follow-up. A total of 63 patients were included. Multivariate analysis demonstrated that female gender (adjusted OR 0.04; 95% CI 0-0.84; p = 0.04) and combined technique (adj OR 0.001; 95% CI 0-0.81; p = 0.04) were predictors of worse outcome. Higher pc-ASPECTS (adj OR 4.75; 95% CI 1.33-16.94; p = 0.02) and higher Delta NIHSS (adj OR 2.06; 95% CI 1.16-3.65; p = 0.01) were predictors of better outcome. Delta NIHSS was the main predictor of good outcome at 90 days in patients with posterior circulation LVO presenting with NIHSS score ≤ 10.


The morphological substrate for Renal Denervation: Nerve distribution patterns and parasympathetic nerves. A post-mortem histological study.
Renal Denervation as a possible treatment for hypertension has been studied extensively, but knowledge on the distribution of nerves surrounding the renal artery is still incomplete. While sympathetic and sensory nerves have been demonstrated, there is no mention of the presence of parasympathetic nerve fibers. To provide a description of the distribution patterns of the renal nerves in man, and, in addition, provide a detailed representation of the relative contribution of the sympathetic, parasympathetic and afferent divisions of the autonomic nervous system. Renal arteries of human cadavers were each divided into four longitudinal segments and immunohistochemically stained with specific markers for afferent, parasympathetic and sympathetic nerves. Nerve fibers were semi-automatically quantified by computerized image analysis, and expressed as cross-sectional area relative to the distance to the lumen. A total of 3372 nerve segments were identified in 8 arteries of 7 cadavers. Sympathetic, parasympathetic and afferent nerves contributed for 73.5% (95% CI: 65.4-81.5%), 17.9% (10.7-25.1%) and 8.7% (5.0-12.3%) of the total cross-sectional nerve area, respectively. Nerves are closer to the lumen in more distal segments and larger bundles that presumably innervate the kidney lie at 1-3.5mm distance from the lumen. The tissue-penetration depth of the ablation required to destroy 50% of the nerve fibers is 2.37 mm in the proximal segment and 1.78 mm in the most distal segments. Sympathetic, parasympathetic and afferent nerves exist in the vicinity of the renal artery. The results warrant further investigation of the role of the parasympathetic nervous system on renal physiology, and may contribute to refinement of the procedure by focusing the ablation on the most distal segment.


The calcium pump of the liver nuclear membrane is identical to that of endoplasmic reticulum.
The envelope membrane of rat liver nuclei contains a P-type Ca(2+)-transporting pump, revealed by the presence of a Ca(2+)-stimulated phosphoenzyme. The level of the nuclear phosphoenzyme in autoradiographed polyacrylamide gels was decreased by lanthanum, as typically observed in the endoplasmic reticulum Ca2+ pump. It was also decreased by thapsigargin and 2,5-di-(tert-butyl)-1,4-benzohydroquinone, two accepted inhibitors of the endoplasmic reticulum Ca(2+)-ATPase. Comparative proteolysis of the phosphorylated enzyme of liver microsomes (endoplasmic reticulum) and nuclear membranes revealed an identical cleavage pattern. In addition, antibodies raised against the endoplasmic reticulum Ca2+ pump cross-reacted with the pump in the nuclear membranes. The findings show that nuclear membranes contain a Ca(2+)-transporting pump closely related to that of the endoplasmic reticulum, if not identical to it. The pump is likely to be involved in the control of nuclear free calcium.


Internet-delivered assessment and manipulation of anxiety-linked attentional bias: validation of a free-access attentional probe software package.
It recently has been established within the laboratory that the attentional probe methodology not only can sensitively assess the threat attentional bias associated with anxiety vulnerability, but also can be configured to yield training tasks capable of modifying emotional vulnerability by manipulating such attentional selectivity. In order to appraise and exploit the potential practical applications of such procedures, it is desirable that clinical investigators without specialist equipment should become able to deliver such tasks within field settings. The present research program involved development of a fully customizable attentional probe software package, that delivers assessment and training versions of the probe task across the Internet. Two experimental studies served to validate the assessment and training efficacy of resulting probe task variants, completed remotely by GAD sufferers and nonclinical populations using their own computers. We advise fellow researchers how to freely download this software package for use within their own investigations.


Self-efficacy in service-learning community action research: theory, research, and practice.
The purpose of this article is threefold: In the first section, an overview of research and theory on the self-efficacy construct is provided, and the central role of self-efficacy in service-learning community action research is demonstrated. The second section reviews over 10 years of research validating the Community Service Self-Efficacy Scale (CSSES), which measures the individual's confidence in his or her own ability to make clinically (meaningfully) significant contributions to the community through service. Within the context of this review, recent (previously unpublished) validation research is also reviewed. Alternate versions of the CSSES, each of which was developed for a specific purpose, are presented. The third section provides recommendations for further research focused on (a) validating the CSSES and (b) examining self-efficacy as an outcome, moderator, and mediating variable in service-learning community action research.


Endomorphins delay constitutive apoptosis and alter the innate host defense functions of neutrophils.
Recent studies have shown that opioid peptides are released from cells of the immune system during inflammation and stress, and are associated with altered immune responses. Moreover, concentrations of opioid peptides are increased in peripheral blood and at the sites of inflammatory reactions. The aim of this study was to evaluate immunological effects of opioid peptides endomorphins 1 and 2 on constitutive apoptosis, superoxide anion production, hydrogen peroxide production, adhesion, phagocytosis, and chemotaxis of neutrophils. Neutrophils were isolated by peritoneal lavage from rats. Endomorphins 1 and 2 significantly delayed constitutive neutrophil apoptosis. The delay of neutrophil apoptosis was markedly attenuated by LY294002, a phosphoinositide 3-kinase inhibitor. Moreover, endomorphins 1 and 2 activated the phosphoinositide 3-kinase pathway as determined by phosphorylation of BAD. In contrast, endomorphins 1 and 2 blocked the production of superoxide anion and hydrogen peroxide by PMA-stimulated neutrophils. In addition, endomorphins 1 and 2 inhibited neutrophil adhesion to fibronectin. Moreover, endomorphins 1 and 2 potentiated neutrophil chemotaxis toward zymosan-activated serum and IL-8, respectively. However, endomorphins 1 and 2 did not alter phagocytosis of Escherichia coli by neutrophils. These results suggest that endomorphins 1 and 2 may act to delay neutrophil apoptosis and alter the natural immune functions of neutrophils.


Persistent redundant Eustachian valve interfering with Amplatzer PFO occluder placement: anatomico-clinical and technical implications.
A 28-year-old man with patent foramen ovale and a prominent Eustachian valve with a history of transient ischemic attack underwent transcatheter closure using Amplatzer patent foramen ovale occluder. During deployment, some of the prominent valve tissue was entrapped on the delivery cable and a piece of the valve was extracted unintentionally. Anatomico-clinical and technical implications are discussed.


Involvement of complement in psoriasis and atopic dermatitis--measurement of C3a and C5a, C3, C4 and C1 inactivator.
Normal complement components and activation products were determined in the peripheral blood of 35 patients with atopic dermatitis (AD) and 24 patients with psoriasis at a mild to intermediate stage. None of the patients had received systemic or local steroid therapy 6 weeks prior to blood collection. Levels of C3, C4 and C1 inactivator (C1 INA) were determined in serum by radial immunodiffusion, whereas C3a and C5a levels were measured by radioimmunoassay. In comparison to healthy non-atopic controls, the levels of C3, C4 and C1 INA were found to be significantly increased in both diseases. No substantial differences were detected between patients with psoriasis vulgaris and psoriasis guttata, which suggests that the dissimilarities found were not due to preceding or concomitant infections. In AD, there was a tendency towards increased C3a levels, whereas in psoriasis, C3a levels were significantly increased. In both diseases, no measurable amounts of C5a could be detected. The results indicate that, in both AD and psoriasis, the complement participates in the inflammatory process. Elevated levels of C3a suggest that there is a continuous activation of the complement system leading to the generation of inflammatory mediators.


Analysis of the tetanic and post-tetanic components of intradendritic Ca2+ signals in hippocampal CA1 neurons.
The importance of both the activation of second messenger cascades and an increase of the intracellular Ca2+ concentration for the induction of synaptic plasticity in hippocampal CA1 neurons is well established. Using the dye Calcium Green-1, we analysed the Ca2+ increases evoked by different 100-Hz tetanization paradigms commonly used to induce long-term potentiation. We found that the normalized total area of fluorescence intensity changes (F/F0) was correlated with both the strength and the duration of tetanization. Furthermore, the normalized area of fluorescence intensity changes during the time of tetanization (tetanic component) correlated strongly in a linear manner with the tetanization duration. Moreover, the tetanic component strongly determined the area of the post-tetanic Ca2+ signal. Interestingly, the normalized relationship of the post-tetanic Ca2+ signal to the total Ca2+ change decreased with prolonged tetanizations. In contrast, with an increased stimulation strength, a positive correlation of the relationship of the post-tetanic component to the total amount Ca2+ could be obtained. The time constants of the Ca2+ extrusion depend linearly on both the tetanization duration and the amount of the tetanic Ca2+ signal. Our data demonstrate that augmenting the stimulation strength leads to a respective increase of the post-tetanic Ca2+ portion within the total Ca2+ signal, whereas a prolongation of the tetanization duration does not. Thus, no further significant prolongation of the Ca2+ signal occurs during increased durations of tetanization.


Monte Carlo simulation of linac using PRIMO.
Monte Carlo simulation is considered as the most accurate method for dose calculation in radiotherapy. PRIMO is a Monte-Carlo program with a user-friendly graphical interface. A VitalBeam with 6MV and 6MV flattening filter free (FFF), equipped with the 120 Millennium multileaf collimator was simulated by PRIMO. We adjusted initial energy, energy full width at half maximum (FWHM), focal spot FWHM, and beam divergence to match the measurements. The water tank and ion-chamber were used in the measurement. Percentage depth dose (PDD) and off axis ratio (OAR) were evaluated with gamma passing rates (GPRs) implemented in PRIMO. PDDs were matched at different widths of standard square fields. OARs were matched at five depths. Transmission factor and dose leaf gap (DLG) were simulated. DLG was measured by electronic portal imaging device using a sweeping gap method. For the criterion of 2%/2 mm, 1%/2 mm and 1%/1 mm, the GPRs of 6MV PDD were 99.33-100%, 99-100%, and 99-100%, respectively; the GPRs of 6MV FFF PDD were 99.33-100%, 98.99-99.66%, and 97.64-98.99%, respectively; the GPRs of 6MV OAR were 96.4-100%, 90.99-100%, and 85.12-98.62%, respectively; the GPRs of 6MV FFF OAR were 95.15-100%, 89.32-100%, and 87.02-99.74%, respectively. The calculated DLG matched well with the measurement (6MV: 1.36 mm vs. 1.41 mm; 6MV FFF: 1.07 mm vs. 1.03 mm, simulation vs measurement). The transmission factors were similar (6MV: 1.25% vs. 1.32%; 6MV FFF: 0.8% vs. 1.12%, simulation vs measurement). The calculated PDD, OAR, DLG and transmission factor were all in good agreement with measurements. PRIMO is an independent (with respect to analytical dose calculation algorithm) and accurate Monte Carlo tool.


A Method of Direct Quantitation of Lactobacillus spp. in Intestinal Contents Based on Real-Time PCR.
The method of direct quantitation of Lactobacillus spp. and L. acidophilus in intestinal contents based on real-time PCR was developed. It does not require culturing and allows estimating the number of living lactobacilli cells (measured in lg CFU) in absolute quantitative PCR format.


[Effect of the body's requirements for vitamin K on the electrophoretic characteristics of erythrocyte membrane proteins].
Proteins from rat erythrocyte membranes were separated by polyacrylamide gel disc electrophoresis. Up to II fractions were obtained. Number of these fractions, their content and ratios were altered in rats with primary or secondary vitamin K deficiency.


High Prevalence of Metabolic Syndrome in Patients with Lumbar Spinal Stenosis: Association with Diabetes and Elevated Body Mass Index.
Lumbar spinal stenosis (LSS) is a narrowing of the lumbar canal causing lower back pain, gluteal pain, and neurogenic claudication. LSS has been associated with cardiovascular co-morbidities. Metabolic syndrome (MetS), a pro-inflammatory condition involving a cluster of risk factors for cardiovascular disease and diabetes, is increasingly prevalent worldwide. To evaluate the prevalence of MetS in patients with LSS, compared to age- and sex-matched healthy controls, and to explore potential associations between MetS and LSS-related clinical parameters and cardiovascular risk factors. We conducted a cross-sectional study including 64 patients diagnosed as symptomatic LSS (NASS criteria) and 32 controls. MetS was diagnosed using the 2009 Harmonizing criteria adjusted for South Americans. Multivariate logistic regression was used to identify independent risk factors for MetS. The level of statistical significance was set at 5. The prevalence of MetS was significantly higher in the LSS group than in the control group (76.6% vs. 31.3%; P < 0.001). LSS patients displayed greater waist circumference (P = 0.003), blood glucose levels (P = 0.009) and arterial pressure (P < 0.001) than controls. The variables with independent influence on MetS in the logistic regression model were: diabetes (P = 0.008), blood glucose (P = 0.004), and body mass index (P = 0.005). MetS was significantly more prevalent among LSS patients, and diabetes and elevated body mass index were found to be risk factors for MetS in these LSS patients.


In vitro antifungal susceptibilities and amplified fragment length polymorphism genotyping of a worldwide collection of 350 clinical, veterinary, and environmental Cryptococcus gattii isolates.
The in vitro susceptibilities of a worldwide collection of 350 Cryptococcus gattii isolates to seven antifungal drugs, including the new triazole isavuconazole, were tested. With amplified fragment length polymorphism (AFLP) fingerprinting, human, veterinary, and environmental C. gattii isolates were subdivided into seven AFLP genotypes, including the interspecies hybrids AFLP8 and AFLP9. The majority of clinical isolates (n = 215) comprised genotypes AFLP4 (n = 76) and AFLP6 (n = 103). The clinical AFLP6 isolates had significantly higher geometric mean MICs for flucytosine and fluconazole than the clinical AFLP4 isolates. Of the seven antifungal compounds examined in this study, isavuconazole had the lowest MIC(90) (0.125 μg/ml) for all C. gattii isolates, followed by a 1 log(2) dilution step increase (MIC(90), 0.25 μg/ml) for itraconazole, voriconazole, and posaconazole. Amphotericin B had an acceptable MIC(90) of 0.5 μg/ml, but fluconazole and flucytosine had relatively high MIC(90)s of 8 μg/ml.


Gadolinium-promoted cell cycle progression with enhanced S-phase entry via activation of both ERK and PI3K signaling pathways in NIH 3T3 cells.
The aim of this study was to investigate whether Gd is able to exert the proliferation-promoting effect and to explore its possible underlying mechanism. We showed that Gd promoted cell cycle progression with increased S-phase entry in a concentration- and time-dependent manner in NIH 3T3 cells. The effect was further evidenced by the expressions of key proteins in driving cells through the G(1)/S transition point of the cell cycle. In the presence of Gd, the protein levels of cyclins D, E, and A were dramatically increased and demonstrated a characteristically temporal pattern of sequential mitotic events. Additionally, the levels of phosphorylated retinoblastoma protein were also significantly increased at certain time periods. To further elucidate the underlying mechanism, extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling pathways were assessed. Both pathways were activated by Gd. Moreover, the levels of cyclin D and cyclin A were evaluated after the addition of the pharmacological inhibitors at early and late G(1) phases, correspondingly, to reveal the contribution of the two pathways in the Gd-promoted G(1)/S transition. It showed that both pathways were needed for Gd-promoted cell cycle progression. The results presented here provide novel evidence to advance knowledge leading to further understanding of the mechanisms of both cell growth and death caused by Gd and may be helpful for more rational application of Gd-based compounds in the future.


[On ranges of the malaria mosquitoes (Diptera: Culicidae: Anopheles) of the Maculipennis complex on the territory of Russia].
Maps and distribution data are provided for the seven mosquito species of the genus Anopheles, the maculipennis group: Anopheles atroparvus, A. beklemishevi, A. maculipennis, A. messeae, A. malanoon, A. sacharovi and A. subalpinus.


Effect of vincristine on glucose-induced insulin secretion in man.
60 min after the injection of therapeutic doses of vincristine for cancer chemotherapy, there is a reduction of the total (40%) and of the acute phase (43%) areas of insulin secretion inductedby 5-g i.v glucose load, and the constant of gllcose utilization is reduced by 25%. No differences are observed after 3 5-g i.v. glucose loads given at hourly intervals in control subjects.


Latent common genetic components of obesity traits.
Obesity is rapidly becoming a global epidemic. Unlike many complex human diseases, obesity is defined not just by a single trait or phenotype, but jointly by measures of anthropometry and metabolic status. We applied maximum likelihood factor analysis to identify common latent factors underlying observed covariance in multiple obesity-related measures. Both the genetic components and the mode of inheritance of the common factors were evaluated. A total of 1775 participants from 590 families for whom measures on obesity-related traits were available were included in this study. The average age of participants was 37 years, 39% of the participants were obese (body mass index >or= 30.0 kg/m(2)) and 26% were overweight (body mass index 25.0-29.9 kg/m(2)). Two latent common factors jointly accounting for over 99% of the correlations among obesity-related traits were identified. Complex segregation analysis of the age- and sex-adjusted latent factors provide evidence for a Mendelian mode of inheritance of major genetic effect with heritability estimates of 40.4 and 47.5% for the first and second factors, respectively. These findings provide a support for multivariate-based approach for investigating pleiotropic effects on obesity-related traits, which can be applied in both genetic linkage and association mapping.


Aneurysm surgery above the eighth decade.
A series of nine patients over 70 years of age with saccular aneurysms, operated on by direct surgery, is reviewed in order to discuss aneurysm surgery in older patients. The median age of the patients was 74 years, and the median interval from haemorrhage to surgery was 18 days. Operative mortality was 11%, and morbidity was 33%. Because of arteriosclerosis round the aneurysm neck and parent artery, special considerations for surgical treatment on the older patients are required.


Proportionality changes in the first year of life; the influence of weight for gestational age at birth.
Data on 55 small-for-gestational age (SGA), 56 average-for-gestational age (AGA) and 55 large-for-gestational age (LGA) infants whose growth had been monitored regularly from birth to 12 months are presented. SGA head-chest ratios were high at birth; but by 6 months they were very similar to AGA ratios, with values just below unity. Head-length ratios showed a steady decrement; SGA infants having the highest and LGA infants the lowest values at all ages. Chest-length ratios showed little change up to 6 months, with a steady decrease thereafter. Stem-stature ratios showed a similar pattern; and were confined within a narrow margin from 6 months onwards. These changes seem to be target orientated. We suggest the goal is that proportionality which enables the infant to attain the upright stature; and thus to sit, stand and walk at the appropriate time.


Serum vimentin predicts mortality in pediatric severe sepsis: A prospective observational study.
Vascular hyperpermeability by loss of endothelial barrier integrity is a hallmark of sepsis. Vimentin is involved in the regulation of the endothelial function and inflammatory response. However, the serum level of vimentin and its clinical relevance in pediatric severe sepsis (PSS) remain unknown. We conducted a prospective study of PSS cases who were admitted to the pediatric intensive care unit (PICU) from January 2018 to December 2020. A total of 108 patients with PSS with a median age of 19.5 month were enrolled. The hospital mortality rate was 19.44% (21/108). Comparing with healthy controls, serum vimentin levels on PICU admission were significantly higher in patients with PSS (P < 0.001). The area under the ROC curve for vimentin to predict the hospital mortality was 0.712 (95% CI: 0.578-846) with a sensitivity of 71.43% and a specificity of 70.11%. Moreover, hospital mortality was significantly higher in patients with vimentin level over the cutoff value of 24.53 ng/ml than in patients with vimentin level below 24.53 ng/ml (P < 0.001). Serum vimentin level as an indicator of endothelial injury is associated with the prognosis of PSS, and serum vimentin level ≥24.53 ng/ml on PICU admission predicts high risk for hospital mortality in PSS.


Characterization of in vivo-activated T cell clones from peripheral blood of multiple sclerosis patients.
In vivo-activated interleukin-2 responsive T cell clones were generated from peripheral blood (PBL) of multiple sclerosis patients (MS) and normal subjects (N) by limiting dilution analysis. The frequency with which interleukin-2 responsive cells were cloned from PBL was higher in MS than N. CD8 was the predominant phenotype expressed by both MS (85%) and N (89%) clones. Seven clones from four MS patients but none from five N subjects specifically proliferated against myelin basic protein. These studies demonstrate the existence of MBP-reactive T cells in PBL of MS patients.


Circular RNA circ-Foxo3 inhibits esophageal squamous cell cancer progression via the miR-23a/PTEN axis.
Circ-Foxo3 is a circRNA encoded by the human FOXO3 gene and works as a sponge for potential microRNAs (miRNAs) to regulate cancer progression. However, the role of circ-Foxo3 in esophageal squamous cell cancer (ESCC) is not clear. In this study, circ-Foxo3 was lowly expressed in cell lines and ESCC tissues. Meanwhile, overexpression of circ-Foxo3 inhibited cell growth, migration, and invasion, whether in vivo or in vitro. Mechanically, we found a potential miRNA target, miR-23a, which negatively correlated with circ-Foxo3 in ESCC. Then, a luciferase assay confirmed the relationship between the circ-Foxo3 and miRNA. Moreover, circ-Foxo3 upregulation of PTEN occurred through "sponging" miR-23a. Taken together, these results indicated that the circ-Foxo3/miR-23a/PTEN pathway was critical for inhibiting the ESCC progression. This may provide a promising target for treat ESCC.


Effects of two isomers of DDT and their metabolite DDE on CYP1A1 and AhR function in human placental cells.
The aim of this study was to investigate the actions of two isomers of DDT (p,p'-DDT, o,p'-DDT) and DDE (p,p'-DDE, o,p'-DDE) on the human placenta. We studied the effects of DDT and its metabolite DDE on CYP1A1 activity and on CYP1A1 and aryl hydrocarbon receptor (AhR) protein expression in placental cells. We used explants from third-trimester human placental tissue and JEG-3 cells, which are first-trimester human placenta cells. The main finding of this study was that the activity of CYP1A1 in the human placenta, measured in terms of ethoxyresorufin-O-deethylase (EROD) activity, was suppressed by treatment of 1, 10, and 100 ng/ml p,p'-DDT, o,p'-DDT, p,p'-DDE and o,p'-DDE. Immunoblot analyses indicated that both isomers of DDT and DDE inhibited the expression of CYP1A1 most effectively at 48 h and/or 72 h after the treatment. Because CYP1A1 activity is mediated by AhR, we evaluated the expression of AhR in placental tissue exposed to DDT and DDE for 1 h to 72 h. Our data showed that DDT and DDE gradually decreased the level of AhR protein, starting at 3 h or 24 h after the start of the experiment. Our results strongly support the involvement of the AhR/CYP1A1 signaling pathway in the mechanism of action of DDT and DDE in the human placenta.


Abnormalities of protooncogenes in non-small cell lung cancer. Correlations with tumor type and clinical characteristics.
Twenty-seven primary non-small cell (NSC) lung cancers were analyzed for alterations of protooncogenes by DNA hybridization techniques. Abnormalities were found in 56% of tumors including ten of 16 adenocarcinomas, three of nine squamous cell cancers and two of two larger cell cancers. Five protooncogenes were found to be commonly altered in tumors at frequencies between 12% and 60%. These were c-myc, c-myb, c-ras-Ha, c-erbB-1 and c-erb-B-2. Alterations in c-erbB-1 and c-erbB-2 correlated with histologic type of tumor and were more common in advanced cancers. Allelic deletions of c-ras-Ha or c-myb were frequently observed in primary tumors which recurred or progressed after surgery (five of six). Analysis of protooncogenes may provide insights into the pathogenesis of lung cancer and may aid in predicting clinical behavior.


The correlation between multidomain enzymes and multiple activation mechanisms--the case of phospholipase Cβ and its membrane interactions.
Phospholipase Cβ2 (PLCβ2) is a large, multidomain enzyme that catalyzes the hydrolysis of the signaling lipid phosphoinositol 4,5 bisphosphate (PIP2) to promote mitogenic and proliferative changes in the cell. PLCβ2 is activated by Gα and Gβγ subunits of heterotrimeric G proteins, as well as small G proteins and specific peptides. Activation depends on the nature of the membrane surface. Recent crystal structures suggest one model of activation involving the movement of a small autoinhibitory loop upon membrane binding of the enzyme. Additionally, solution studies indicate multiple levels of activation that involve changes in the membrane orientation as well as interdomain movement. Here, we review the wealth of biochemical studies of PLCβ2-G protein activation and propose a comprehensive model that accounts for both the crystallographic and solution results.


The addition of citrate stimulates the production of acetoin and diacetyl by a citrate-positive Lactobacillus crustorum strain during wheat sourdough fermentation.
In traditional sourdough fermentation recipes of artisan bakeries, often extra ingredients are added to the flour-water mixture. This may accentuate the aroma and taste of the baked products produced from such sourdoughs. This is made possible, for instance, by stimulating certain microbial activities during fermentation. This study examined the effects of the addition of citrate (a food-grade organic acid present in milk and lemons) on wheat sourdough fermentation in the presence of a citrate-positive, homofermentative, lactic acid bacterial starter culture strain, namely Lactobacillus crustorum LMG 23699. Both liquid and firm wheat sourdoughs were produced. The starter culture strain was able to steer all wheat sourdough fermentations performed, as it always prevailed due to its competitiveness, as shown through culture-dependent microbiological plating and culture-independent bacterial community profiling. Moreover, it possessed all enzyme-encoding genes (as unraveled through genome mining) necessary to convert citrate into desirable compounds such as lactic acid, acetic acid, succinate, acetoin, diacetyl, and 2,3-butanediol. Indeed, citrate addition to the wheat flour-water mixture had an impact on the sourdough fermentation dynamics and thus on the aroma profile of the liquid and firm sourdoughs produced and breads made thereof. A higher final pH, higher total titratable acidity values, and low yeast counts were found in wheat sourdoughs produced with citrate. In particular, the starter culture strain added converted the supplemented citrate into more l-lactic acid as well as acetoin and diacetyl (buttery aroma compounds), which was independent of the dough yield. The buttery aroma compounds were also accentuated in the concomitant breads produced. Further, organic acid production was stimulated in the sourdoughs, whereas increased pyrazine concentrations occurred in the breads. Consequently, citrate supplementation to wheat sourdoughs could be of interest to produce baked goods with enhanced buttery aroma compounds and notes.


Ligand-induced disorder-to-order transitions characterized by structural proteomics and molecular dynamics simulations.
For disordered proteins, ligand binding can be a critical event that changes their structural dynamics. The ability to characterize such changes would facilitate the development of drugs designed to stabilize disordered proteins, whose mis-folding is important for a number of pathologies, including neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. In this study, we used hydrogen/deuterium exchange, differential crosslinking, differential surface modification, and molecular dynamics (MD) simulations to characterize the structural changes in disordered proteins that result from ligand binding. We show here that both an ATP-independent protein chaperone, Spy L32P, and the FK506 binding domain of a prolyl isomerase, FKBP-25 F145A/I223P, are disordered, yet exhibit structures that are distinct from chemically denatured unfolded states in solution, and that they undergo transitions to a more structured state upon ligand binding. These systems may serve as models for the characterization of ligand-induced disorder-to-order transitions in proteins using structural proteomics approaches. SIGNIFICANCE: In this study, we used hydrogen/deuterium exchange, differential crosslinking, differential surface modification, and molecular-dynamics simulations to characterize the structural changes in disordered proteins that result from ligand binding. The protein-ligand systems studied here (the ATP-independent protein chaperone, Spy L32P, and the FK506 binding domain of a prolyl isomerase, FKBP-25 F145A/I223P) may serve as models for understanding ligand-induced disorder-to-order transitions in proteins. Additionally, the structural proteomic techniques demonstrated here are shown to be effective tools for the characterization of disorder-to-order transitions and can be used to facilitate study of other systems in which this class of structural transition can be used for modulating major pathological features of disease, such as the abnormal protein aggregation that occurs with Parkinson's disease and Alzheimer's disease.


Evolution and diversity of the crystallins. Nucleotide sequence of a beta-crystallin mRNA from the mouse lens.
We have determined the nucleotide sequence of a cloned beta-crystallin cDNA (pM beta Cr1) derived from the 5- to 10-day-old mouse lens and compared its deduced amino acid sequence with the amino acid sequences of the principal beta-crystallin polypeptide (beta Bp) (Driessen, H. P. C., Herbrink, P., Bloemendal, H., and de Jong, W. W. (1980) Exp. Eye Res. 31, 213-216) and a gamma-crystallin polypeptide (gamma II) (Croft, L. R. (1972) Biochem. J. 128, 961-970) of the bovine lens. A previous comparison indicated that bovine beta Bp and gamma II contain internally homologous sequences of amino acids and are evolutionarily related, suggesting an intragenic duplication of a common ancestral gene (Driessen, H. P. C., Herbrink, P., Bleomendal, H., and de Jong, W. W. (1980) Exp. Eye Res. 31, 213-216). When the amino acids were aligned, we calculated a 43% homology between the murine and bovine beta-crystallin polypeptides and a 22% homology between the murine beta-crystallin and bovine gamma-crystallin polypeptides. As for bovine beta Bp and gamma II, there is a striking homology between the amino and carboxyl halves of the murine beta-crystallin polypeptide. The internally homologous amino acids have been preferentially conserved among the three crystallin chains, a fact consistent with the possibility that these lens proteins arose from a common precursor gene that internally duplicated.


Crosslinking and carbohydrate studies on the hydroxylated glycopeptides which accumulate in alveoli and lamellar bodies.
These data suggest that the alveolar lining layer and lamellar body membranes contain the same saline-insoluble proteins, two of which are unusual in that they contain hydroxyproline and large amounts of glycine. Neither the function nor the origin of these glycopeptides has been established, and we are currently evaluating methods of stimulating their production in animals for further study.


Comparison of different methods of measuring angle of progression in prediction of labor outcome.
First, to compare the manual sagittal and parasagittal and automated parasagittal methods of measuring the angle of progression (AoP) by transperineal ultrasound during labor, and, second, to develop models for the prediction of time to delivery and need for Cesarean section (CS) for failure to progress (FTP) in a population of patients undergoing induction of labor. This was a prospective observational study of transperineal ultrasound in a cohort of 512 women with a singleton pregnancy undergoing induction of labor. A random selection of 50 stored images was assessed for inter- and intraobserver reliability of AoP measurements using the manual sagittal and parasagittal and automated parasagittal methods. In cases of vaginal delivery, univariate linear, multiple linear and quantile regression analyses were performed to predict time to delivery. Univariate and multivariate binomial logistic regression analyses were performed to predict CS for FTP in the first stage of labor. The intraclass correlation coefficient (ICC) for the manual parasagittal method for a single observer was 0.97 (95% CI, 0.95-0.98) and for two observers it was 0.96 (95% CI, 0.93-0.98), indicating good reliability. The ICC for the sagittal method for a single observer was 0.93 (95% CI, 0.88-0.96) and for two observers it was 0.74 (95% CI, 0.58-0.84), indicating moderate reliability for a single observer and poor reliability between two observers. Bland-Altman analysis demonstrated narrower limits of agreement for the manual parasagittal approach than for the sagittal approach for both a single and two observers. The automated parasagittal method failed to capture an image in 19% of cases. The mean difference in AoP measurements between the sagittal and manual parasagittal methods was 11°. In pregnancies resulting in vaginal delivery, 54% of the variation in time to delivery was explained in a model combining parity, epidural and syntocinon use during labor and the sonographic findings of fetal head position and AoP. In the prediction of CS for FTP in the first stage of labor, a model which combined maternal factors with the sonographic measurements of AoP and estimated fetal weight was superior to one utilizing maternal factors alone (area under the receiver-operating-characteristics curve, 0.80 vs 0.76). First, the method of measuring AoP with the greatest reliability is the manual parasagittal technique and future research should focus on this technique. Second, over half of the variation in time to vaginal delivery can be explained by a model that combines maternal factors, pregnancy characteristics and ultrasound findings. Third, the ability of AoP to provide clinically useful prediction of CS for FTP in the first stage of labor is limited. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.


The effect of prostaglandin E2 infusion in the fetal lamb on fetal plasma ACTH, prolactin and cortisol concentrations.
PGE2 (2 micrograms/min) has been infused for 1h into the fetal jugular vein of 8 chronically catheterized fetuses on 13 occasions from 112 to 138 days gestation. Infusion of ethanol vehicle alone was conducted in fetuses from 111-139 days gestation. PGE2 administration produced a significant increase in fetal plasma cortisol after 30 min. No significant change was observed in fetal plasma prolactin concentration. Fetal plasma ACTH concentration was significantly elevated above resting concentration after 30 min. of PGE2 infusion. Metabolic clearance rate of PGE2 was 860 ml/min or 350 ml/kg/min. Intrauterine pressure was not changes during the infusion at any gestational age.


[Electrical activity of the cortex and subcortical structures during the development of hypoxia due to blood loss].
Previous experiments on dogs showed that in several cases, along with the development of hypoxia, polymorphous delta-waves changed into synchronous oscillations, also of delta range, the so-called standard slow complexes (SSC). The new experimental data showed discharges of neuronal pool during SSC to be present in the caudate nucleus, lateral and medial thalamus, hypothalamus, hypocampus, n. amygdale, and mesencephalic reticular formation. The most frequent neuronal pulse activity was connected with the second half of the SSC negative phase (P is less than 0.01). Discharge flashes of the neuronal pool during the SSC indicated that SSC reflected the physiological processes occurring in these structures.


Lung cell membrane-coated nanoparticles capable of enhanced internalization and translocation in pulmonary epithelial cells.
Cell membrane-coated nanoparticles (CMCNP), which involve coating a core nanoparticle (NP) with cell membranes, have been gaining attention due to their ability to mimic the properties of the cells, allowing for enhanced delivery and efficacy of therapeutics. Two CMCNP systems comprised of an acetalated dextran-based NP core loaded with curcumin (CUR) coated with cell membranes derived from pulmonary epithelial cells were developed. The NP were approximately 200 nm and their surface charges varied based on their coating, where CMCNP systems exhibited negative surface charge like natural cell membranes. The NP were smooth, spherical, and homogeneous with distinct coatings on their cores. Minimal in vitro toxicity was observed for the NP and controlled release of CUR was observed. The CMCNP internalized into and translocated across an in vitro pulmonary epithelial monolayer significantly more than the control NP. Blocking endocytosis pathways reduced the transcytosis of NP, indicating a relationship between endocytosis and transcytosis. These newly developed CMCNP have the potential to be used in pulmonary drug delivery applications to potentially enhance NP internalization and transport into and across the pulmonary epithelium.


Synthesis and physical characterization of DNA fragments containing N4-methylcytosine and 5-methylcytosine.
The synthesis of N4-methyl-2'-deoxycytidine and its fully protected mononucleotide, suitable for the oligonucleotide synthesis by phosphotriester method is described. A set of octanucleotides - d(CGCGCGCG), d(CG5mCGCGCG), d(CG4mCGCGCG) and dodecanucleotides - d(GGACCCGGGTCC), d(GGA5mCCCGGGTCC), d(GGA4mCCCGGGTCC) has been synthesized in a solution. Physical characterization of the oligonucleotide duplexes by means of UV and CD spectrometry provides the evidence that 4mC similarly to 5mC favours the B--greater than Z transition, although both of these methylated cytosines inhibit the B--greater than A conformational change. N4-Methylcytosine in contrast to 5-methylcytosine reduces the DNA double helix thermal stability.


ATP and endogenous agonists inhibit evoked [3H]-noradrenaline release in rat iris via A1 and P2y-like purinoceptors.
Effects of ATP, adenosine and purinoceptor antagonists on field stimulation-evoked (3 Hz, 2 min) [3H]-noradrenaline overflow were investigated in the rat isolated iris. ATP and adenosine inhibited the evoked overflow of [3H]-noradrenaline. 1,3-Dipropyl-8-cyclopentylxanthine (DPCPX) shifted the concentration-response curve of ATP to the right in a concentration-dependent manner, but with a potency (-log KB = 7.88) much lower than expected for an A1 adenosine receptor. In the continuous presence of DPCPX, the ATP-induced prejunctional inhibition was unaffected by suramin (100 mumol/l) and DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, 50 mumol/l) but was antagonized by the P2Y-receptor antagonist cibacron blue (= reactive blue 2; 30 and 100 mumol/l, -log KB = 4.7) and alpha,beta-methylene-ATP (10 mumol/l). Whereas the evoked [3H]-noradrenaline overflow was unaffected by suramin and DIDS, cibacron blue and alpha,beta-methylene-ATP caused a small and transient increase. Cibacron blue at 30 mumol/l failed to antagonize the inhibition of evoked [3H]-noradrenaline overflow that adenosine produced in the absence of DPCPX. Basal [3H]-noradrenaline overflow was enhanced by cibacron blue, not changed by alpha,beta-methylene-ATP and DIDS, and decreased by suramin. The results show that exogenous ATP inhibits sympathetic neurotransmission in the rat iris via A1 and P2Y-like purinoceptors. The latter have a low apparent affinity for cibacron blue and probably are blocked by alpha,beta-methylene-ATP. Under the present conditions, endogenous purines exert a tonic inhibition not only via A1- but also via these P2Y-receptors.


Preparative isolation of sargachromanol E from Sargassum siliquastrum by centrifugal partition chromatography and its anti-inflammatory activity.
Centrifugal partition chromatography (CPC) can be used to isolate various bioactive compounds from natural materials by one-step. We confirmed antioxidative compounds existed in chloroform (CHCl3) fraction of Sargassum siliquastrum using online-HPLC. Fractions (A, B, C, D and E) were separated from the CHCl3 fraction by preparative CPC (n-hexane:ethyl acetate:methanol:water, 5:5:7:3, v/v). In this study, we proved that the isolated compounds exhibit anti-inflammatory activities using lipopolysaccharide (LPS) stimulated RAW 264.7 macrophages. The fraction A which exhibited the strongest inhibitory effect on nitric oxide (NO) production level, was confirmed as sargachromanol E by LC-MS-ESI, (1)H NMR and (13)C NMR data. The sargachromanol E significantly reduced the inflammatory response in LPS induced macrophages, decreasing LPS-induced transcription factor of pro-inflammatory cyclooxygenase-2, NO synthase, phosphate P38, phosphate ERK1/2, LPS-stimulated tumor-necrosis factor alpha, interleukin-1 beta and prostaglandin E2 release. In conclusion, it was suggested that sargachromanol E inhibited inflammation in LPS induced RAW 264.7 cells via MAPK pathway.


Physical Activity and Cerebral Small Vein Integrity in Older Adults.
Identifying promoters of cerebral small vein integrity is important to counter vascular contributions to cognitive impairment and dementia. In this preliminary investigation, the effects of a randomized 24-month physical activity (PA) intervention on changes in cerebral small vein integrity were compared to those of a health education (HE) control. Cerebral small vein integrity was measured in 24 older adults (n = 8, PA; n = 16, HE) using ultra-high field MRI before and at the end of the 24-month intervention. Deep medullary veins were defined as straight or tortuous; percent change in straight length, tortuous length, and tortuosity ratio were computed. Microbleed count and white matter hyperintensities were also rated. Accelerometry-based values of PA increased by 17.2% in the PA group but declined by 28.0% in the HE group. The PA group, but not the HE group, had a significant increase in straight vein length from baseline to 24-month follow-up (P = 0.02 and P = 0.21, respectively); the between-group difference in percent change in straight length was significant (increase: median, 93.6%; interquartile range, 112.9 for PA; median, 28.4%; interquartile range, 90.6 for HE; P = 0.07). Between group differences in other markers were nonsignificant. Increasing PA in late-life may promote cerebral small vein integrity. This should be confirmed in larger studies.


Bank Voles Show More Impulsivity in IntelliCage Learning Tasks than Wood Mice.
Impulsivity is a personality trait of healthy individuals, but in extreme forms common in mental disorders. Previous behavioral testing of wild-caught bank voles and wood mice suggested impulsiveness in bank voles. Here, we compared behavioral performance of bank voles and wood mice in tests for response control in the IntelliCage. In the reaction time task, a test similar to the five-choice serial-reaction time task (5CSRTT), bank voles made more premature responses. Impulsivity in the reaction time task was associated with smaller medial habenular nucleus in bank voles. Additional tests revealed reduced behavioral flexibility in the self-paced flexibility task in bank voles, but equal spatial and reversal learning in the chaining/reversal task in both species. Expression of immediate early gene Arc after behavioral testing was low in medial prefrontal cortex, but high in hypothalamic supraoptic and paraventricular nucleus in bank voles. Wood mice showed the opposite pattern. Numbers of Arc-positive cells in the dorsal hippocampus were higher in bank voles than wood mice. Due to continuous behavioral testing (24/7), associations between behavioral performance and Arc were rare. Corticosterone measurements at the end of experiments suggested that IntelliCage testing did not elicit a stress response in these wild rodents. In summary, habenular size differences and altered activation of brain areas after testing might indicate differently balanced activations of cortico-limbic and cortico-hypothalamic circuits in bank voles compared to wood mice. Behavioral performance of bank voles suggest that these rodents could be a natural animal model for investigating impulsive and perseverative behaviors.


Uracil Nucleosides with Reactive Group at C5 Position: 5-(1-Halo-2-sulfonylvinyl)uridine Analogues.
The transition-metal-catalyzed or radical-mediated halosulfonylation of 5-ethynyluridine provided (E)-(1-halo-2-tosylvinyl)uridines. These (β-halo)vinyl sulfones undergo efficient stereoselective addition-elimination with amines or thiols to provide Z-β-aminovinyl or E-β-thiovinyl sulfones tethered to the C5 position of the uracil ring.


Trends in use of herbal and nutritional supplements in cardiovascular patients.
Use of herbs and nutritional supplements (known as naturoceuticals) is increasing in the USA, with about 50% of Americans taking naturoceuticals and spending over 10 billion dollars per year for them. This raises concerns regarding their use instead of proven therapies, their side effects, and drug interaction potential. The study sought to characterize cardiology patients who used supplements and to examine whether their use was diagnosis or doctor dependent, whether it affected patients' compliance, and what supplements were used. In all, 187 patients attending our cardiology clinic were interviewed, examined, and followed for up to 1 year. The users and nonusers of naturoceuticals were compared. Supplements were used in 106 patients (an average of 3.1 naturoceutical per patient). There were no significant differences in their use by gender, age, primary care doctor specialty, or cardiovascular medications prescribed (except for statins). Patients with a history of myocardial infarction, coronary revascularization, hyperlipidemia, and a family history of coronary artery disease were more likely to use the supplements. Average low-density lipoprotein (106 vs. 108 mg/dl), average blood pressure (132/77 vs. 138/78 mmHg), and average hemoglobin (Hb)A1c (8.7 vs. 7.7%) showed no statistically significant differences between users and nonusers. Patients most commonly took multivitamins, vitamin E, vitamin C, vitamin B, folate, garlic, calcium, coenzyme Q10, and gingko. This study indicates that naturoceutical use is widespread among cardiovascular patients and it is difficult to predict clinically who the users are. Fortunately, according to our limited compliance measures, it appears that the naturoceutical use has not affected patients' compliance with traditional medications. Also, possibly a detrimental interaction potential between traditional medications and naturoceuticals has been demonstrated.


Modulation of the frequency of glucose-dependent bursts of electrical activity by HCO3/CO2 in rodent pancreatic B-cells: experimental and theoretical results.
The burst pattern of electrical activity recorded from pancreatic B-cells in response to 11 mM glucose shows a large islet to islet variability. The relationship between burst frequency and glucose sensing (the threshold for electrical activity and the graded increase in electrical response to glucose, i.e. active phase %) has not been investigated within the same islet. In this work, we show that low HCO3 (5 mM) Hepes buffered solutions reversibly reduce the frequency of bursts compared to control (25 mM) HCO3 buffered solutions in the same islet. There was no change in the threshold or active phase (%). Using the mathematical model of Sherman et al. 1988, we explored mechanisms for a change in frequency independent of a change in active phase (%). Increased exchangeable calcium pool size and increased cell to cell coupling were the two theoretical treatments which could reproduce the experimental data. We conclude that burst frequency can be modulated independent of the active phase and that alteration of a calcium pool size best fits the experimental data.


Preclinical epigenetic models for screening epigenetic drugs for schizophrenia.
Schizophrenia is an important psychiatric disorder for which effective drugs are available. However, there are problems with current drug therapy of schizophrenia in that some patients do not respond adequately. Moreover, some patients show treatment resistance and some patients show cognitive decline despite treatment. Hence new and effective drugs will be useful for the treatment of this disorder. Since there is increasing evidence that epigenetic mechanisms of gene expression are defective in schizophrenia, drugs that correct epigenetic defects, epigenetic drugs, could be useful in the treatment of this disorder. This paper discusses preclinical epigenetic models for screening epigenetic drugs for schizophrenia. It also discusses how such models could be useful for the discovery and development of such drugs.


Parental marital relationship satisfaction is associated with glycemic outcomes in children with type 1 diabetes.
We hypothesized that glycemic outcomes in children with type 1 diabetes are linked to marital satisfaction of primary caregivers above and beyond parent neuroticism and child effortful control. We evaluated a cross-sectional sample of 73 married parent families with a child (ages 7-18 years) with type 1 diabetes of at least 2 years duration. We assessed marital relationship satisfaction, parent neuroticism, and child effortful control through the use of validated questionnaires. We used univariate comparisons and multivariable models to determine whether marital relationship satisfaction was associated with hemoglobin A1c [HbA1c] and whether this association persisted after adjusting for demographic factors and parent neuroticism/child effortful control. In univariate analyses, HbA1c was associated with marital relationship satisfaction of the primary caregiver. In multivariable models adjusting for demographic factors, marital satisfaction remained associated with HbA1c, whereas none of the other factors tested (including family income and race/ethnicity) retained significance. In univariate analyses, child effortful control was also associated with HbA1c. When child effortful control was added to the multivariable model, marital satisfaction remained associated with HbA1c with similar coefficient and confidence intervals describing the relationship between marital satisfaction and hemoglobin A1c. Higher levels of marital satisfaction of the primary diabetes caregiver are associated with glycemic outcomes for children with type 1 diabetes. Interventions to improve spousal relationships may have downstream benefits that could include promoting more optimal child HbA1c levels.


Prospective multicentre study on barbed reposition pharyngoplasty standing alone or as a part of multilevel surgery for sleep apnoea.
The aim of this study was to demonstrate in a prospective multicentre study that Barbed Reposition Pharyngoplasty (BRP) procedure is safe and effective in management of obstructive sleep apnoea/hypopnea syndrome (OSAHS) patients. Prospective study. Multicentre study. Patients suffering from obstructive sleep apnoea. Values of postoperative apnoea-hypopnea index (AHI), oxygen desaturation index (ODI), epworth sleepiness scale (ESS). 111 Barbed Reposition Pharyngoplasty procedures standing alone or as a part of multilevel surgery for OSAHS, performed between January and September 2016, were analysed in 15 different centres. The average hospitalisation period was 2.5 ± 0.5 days. The mean patient age was 46.3 ± 10.5 years. The average body mass index at the time of the procedure was 27.9 ± 3.2, and the majority of the patients were men (83%). The mean preoperative and postoperative apnoea/hypopnea index was 33.4 ± 19.5 and 13.5 ± 10.3, respectively (P < .001). The mean preoperative and postoperative ESS score was 10.2 ± 4.5 and 6.1 ± 3.6, respectively (P < .001). The mean preoperative and postoperative ODI were 29.6 ± 20.7 and 12.7 ± 10.8, respectively (P < .001). Patients undergoing BRP standing alone or as part of a multilevel approach for the treatment of OSAHS have a reasonable expectation for success with minimal morbidity.


Pulse oximetry for monitoring during ward analgesia: epidural morphine versus parenteral narcotics.
A pulse oximeter was used to monitor oxygen saturation in 20 women following cesarean delivery. The patients were randomly assigned to one of two groups. Group A received conventional parenteral narcotics for relief of postoperative pain and group B received epidural morphine. All patients were monitored overnight, and data were stored continuously. There were no statistically significant differences in the low saturation values between the two groups. However, the group A desaturation episodes occurred an average of 2.7 +/- 1.9 hours after the parenteral narcotics were administered, and the group B desaturation episodes occurred an average of 13.7 +/- 5.9 hours after the epidural morphine was administered.


KCTD17-related myoclonus-dystonia syndrome: clinical and electrophysiological findings of a patient with atypical late onset.
Myoclonus-dystonia is a rare syndrome typically occurring during childhood or adolescence, mainly due to SGCE pathogenic variants. Early-onset, atypical presentations of myoclonus-dystonia have recently been associated with KCTD17 variants. In these cases, laryngeal involvement was reported in the advanced stages. We evaluated a 52-year-old man with myoclonus-dystonia and positive family history. He underwent an electromyographic investigation of vocal cord and forearm muscles. Whole-exome sequencing was also performed. Onset of symptoms was at 51 years with dysphonia and vocal tremor. Electromyography disclosed abductor spasmodic dysphonia and laryngeal myoclonus. The patient later developed writer's cramp, upper limb myoclonus, and blepharospasm. Botulinum toxin injection led to improvement of the writer's cramp and to a lesser extent of the spasmodic dysphonia. Genetic analysis identified a heterozygous missense variant in exon 2 of KCTD17: c.229 C > A (p.Leu77Ile), consistently predicted as damaging. We suggest that the KCTD17-associated phenotypic spectrum may include late onset (even in late adulthood) as well as early and prominent laryngeal involvement.


Reduced notch activity is associated with an impaired marginal zone B cell development and function in Sly1 mutant mice.
MZ B cells represent a distinct lineage of naive B lymphocytes, apart from FO B cells and peritoneal B1 cells, and mediate humoral immune responses against blood-borne type 2 T-independent antigens. Regulation of MZ B cell development involves the Notch receptor signaling, the intensity of B cell receptor signals, and cell compartmentalization by adhesion and chemokine receptors. Our previous work showed that gene-targeted mice expressing a truncated form of the putative signaling adapter protein SLy1 exhibit reduced numbers of a splenic B cell population enriched in MZ B cells. Here, we demonstrate that Sly1(d/d) mice exhibit a partial, but selective, block in the transition from pre-MZ to mature MZ B cells. Development of both T1 and T2 precursor subsets and FO B cells was normal in Sly1(d/d) mice. Consistent with the loss of MZ B cells, the production of antigen-specific IgM antibodies following immunization with pneumococcal polysaccharides was severely impaired in Sly1(d/d) mice. Importantly, expression of the Notch signaling mediator RBP-J and the Notch target genes Hes-1 and Hes-5 was markedly reduced in MZ but not FO B cells of Sly1(d/d) mice. In contrast, B cell receptor signaling, expression and function of LFA-1 and alpha4-integrins, and expression of chemokine receptors appeared intact in Sly1(d/d) cells. Collectively, these results provide strong evidence that SLy1 is important for the generation and function of MZ B cells and suggest a novel link between SLy1 and the activity of the Notch pathway in the development of MZ B cells.


Hepatozoonosis of Dogs and Cats.
Hepatozoon canis and Hepatozoon americanum are tick-borne infections of dogs transmitted by different tick species, with dissimilar geographic distributions, target organs, and clinical syndromes. H canis is transmitted mostly by the brown dog tick Rhipicephalus sanguineus sensu lato, affects hemolymphoid organs, is associated with anemia and other hematologic abnormalities, and is widely prevalent globally, whereas H americanum is transmitted by the Gulf Coast tick Amblyomma maculatum, causes severe myositis, and is an emerging parasite in the southern United States. Treatment of these 2 infections decreases the parasitic load without elimination. Domestic cats are infected with 3 Hepatozoon species.


Genetic analysis of phenylpropanoids and antioxidant capacity in strawberry fruit reveals mQTL hotspots and candidate genes.
Phenylpropanoids are a large class of plant secondary metabolites, which play essential roles in human health mainly associated with their antioxidant activity. Strawberry (Fragaria × ananassa) is a rich source of phytonutrients, including phenylpropanoids, which have been shown to have beneficial effects on human health. In this study, using the F. × ananassa '232' × '1392' F1 segregating population, we analyzed the genetic control of individual phenylpropanoid metabolites, total polyphenol content (TPC) and antioxidant capacity (TEAC) in strawberry fruit over two seasons. We have identified a total of 7, 9, and 309 quantitative trait loci (QTL) for TPC, TEAC and for 77 polar secondary metabolites, respectively. Hotspots of stable QTL for health-related antioxidant compounds were detected on linkage groups LG IV-3, LG V-2 and V-4, and LG VI-1 and VI-2, where associated markers represent useful targets for marker-assisted selection of new varieties with increased levels of antioxidant secondary compounds. Moreover, differential expression of candidate genes for major and stable mQTLs was studied in fruits of contrasting lines in important flavonoids. Our results indicate that higher expression of FaF3'H, which encodes the flavonoid 3'-hydroxylase, is associated with increased content of these important flavonoids.


Subgroup Analysis Can Optimize the Relapse-Prediction Cutoff Value for WT1 Expression After Allogeneic Hematologic Stem Cell Transplantation in Acute Myeloid Leukemia.
High WT1 expression after allogeneic hematologic stem cell transplantation (allo-HSCT) can strongly predict relapse in acute myeloid leukemia (AML). However, the cutoff values obtained have been inconsistent. Precise cutoff values may be optimized through subtype analysis; the RUNX1-RUNX1T1 fusion transcript provides an ideal reference. RUNX1-RUNX1T1 and WT1 transcript levels were simultaneously measured in 1299 bone marrow samples serially collected from 176 t(8;21) AML patients after allo-HSCT. The upper limit of the normal bone marrow WT1 level was 0.6%, which we previously reported to be the cutoff value for significant relapse prediction in AML as a whole. WT1 cutoff values of 0.6%, 1.2%, and 1.8% significantly differentiated patients in relapse after allo-HSCT. Nonetheless, patients with WT1 levels of 0.6% to 1.2% and those with levels of >1.2% and 1.8% after HSCT had rates of cumulative incidence of relapse similar to those with a continuous WT1 level of ≤0.6%, and both were significantly lower than that in patients with a WT1 level of >1.8%. WT1 expression was significantly related to RUNX1-RUNX1T1 transcript levels at WT1 levels of >1.8% but not at levels of 0.6% to 1.2% or >1.2% to 1.8%. Therefore, subgroup analysis can optimize the relapse-prediction cutoff value of WT1 expression. A cutoff level of 1.8% more accurately differentiates t(8;21) AML patients in relapse after allo-HSCT than does a cutoff level of 0.6%.


Marital coital rates and dominance.
Are heterosexual pairings in which the male is dominant more satisfactory? Coital rates of couples in which husbands were younger than their wives were contrasted with those in which husbands were older, but there was no significant difference. However, the data were not controlled for duration of marriage, and for a constant spouse-age-sum, couples with the husband the younger marry later on average than do the others. So whether younger-husband couples have lower coital rates is undecided.


Dpp/BMP transport mechanism is required for wing venation in the sawfly Athalia rosae.
The pattern of wing venation varies considerably among different groups of insects and has been used as a means of species-specific identification. However, little is known about how wing venation is established and diversified among insects. The decapentaplegic (Dpp)/bone morphogenetic protein (BMP) signaling pathway plays a critical role in wing vein formation during the pupal stages in Drosophila melanogaster. A key mechanism is BMP transport from the longitudinal veins (LVs) to the posterior crossvein (PCV) by the BMP-binding proteins, short gastrulation (Sog) and twisted gastrulation2/crossveinless (Tsg2/Cv). To investigate whether the BMP transport mechanism is utilized to specify insect wing vein patterns in other than Drosophila, we used the sawfly Athalia rosae as a model, which has distinct venation patterns in the fore- and hindwings. Here, we show that Ar-dpp is ubiquitously expressed in both the fore- and hindwings, but is required for localized BMP signaling that reflects distinct wing vein patterns between the fore- and hindwings. By isolating Ar-tsg/cv in the sawfly, we found that Ar-Tsg/Cv is also required for BMP signaling in wing vein formation and retains the ability to transport Dpp. These data suggest that the BMP transport system is widely used to redistribute Dpp to specify wing venation and may be a basal mechanism underlying diversified wing vein patterns among insects.


Safe esophageal bougie placement for laparoscopic hiatal hernia repair.
The increased use of laparoscopy for treatment of reflux esophagitis has been associated with a 1-8% complication rate. Perforation of the esophagus from bougie placement, wrap breakdown or too tight a wrap are some of the complications seen from this surgery. An esophageal dilator system was developed to overcome these problems. Thirty patients had an esophageal dilator system used whereby a 48 F or 58 F dilator was placed over a 18 F orogastric tube. Intraoperative gastroscopy documented a properly created wrap. There were no esophageal perforations or morbidity associated with the dilator.


Separation of different types of afterpotentials following penicillin-induced paroxysmal depolarization shifts of neurons in the motor cortex of the rat.
Afterpotentials of penicillin-induced paroxysmal depolarization shifts (PDS) of neurones in the motor cortex of the rat in vivo were investigated with intracellular recordings. Following the PDS, 4 different types of afterpotentials were observed: fast afterhyperpolarizations with an average duration of 600 ms, fast afterdepolarizations with an average duration of 700 ms, slow afterhyperpolarizations with an average duration of 1.9 s and slow afterdepolarizations with an average duration of 1.8 s. The fast and slow afterpotentials could occur in various combinations with the exception of a fast afterhyperpolarization followed by a slow afterdepolarization. Neurones displaying afterdepolarizations had higher resting membrane potentials than those displaying afterhyperolarizations, i.e. the polarity of the afterpotential depended on membrane potential. Experiments with intracellular Cl- injection indicated that the fast but not the slow afterpotentials are associated with an increase in membrane Cl- conductance. The slow afterhyperpolarizations are suggested to result from a calcium-dependent or a synaptically generated potassium current.