Two Filtering Methods of Forecasting Linear and Nonlinear Dynamics of Intensive Longitudinal Data.
With the advent of new data collection technologies, intensive longitudinal data (ILD) are collected more frequently than ever. Along with the increased prevalence of ILD, more methods are being developed to analyze these data. However, relatively few methods have yet been applied for making long- or even short-term predictions from ILD in behavioral settings. Applications of forecasting methods to behavioral ILD are still scant. We first establish a general framework for modeling ILD and then extend that frame to two previously existing forecasting methods: these methods are Kalman prediction and ensemble prediction. After implementing Kalman and ensemble forecasts in free and open-source software, we apply these methods to daily drug and alcohol use data. In doing so, we create a simple, but nonlinear dynamical system model of daily drug and alcohol use and illustrate important differences between the forecasting methods. We further compare the Kalman and ensemble forecasting methods to several simpler forecasts of daily drug and alcohol use. Ensemble forecasts may be more appropriate than Kalman forecasts for nonlinear dynamical systems models, but further forecasting evaluation methods must be put into practice.


Antagonism of estrogenic effects on feeding behavior by central implants of anisomycin.
The following experiment determined whether the estrogenic suppression of food intake is dependent upon changes in protein synthesis within neurons of the paraventricular nucleus of the hypothalamus (PVN). Ovariectomized rats were treated centrally with anisomycin-filled or empty (control) cannulae in the PVN. Females were injected with either 2.0 micrograms of estradiol benzoate (EB) or the oil vehicle and the inner cannulae were removed 2 h later. EB injections significantly lowered food and water intake in the central control group but not in animals given PVN implants of anisomycin. Body weight gain decreased for all females. EB induced comparable levels of female sexual behavior in both groups, demonstrating that anisomycin implants did not affect the ability of estradiol to stimulate lordosis. These findings indicate that the effects of estradiol on food intake require the activation of protein synthesis in estrogen-sensitive PVN neurons.


Method validation revisited: a chemometric approach.
A validation procedure is presented that satisfies the FDA requirements of accuracy (including precision repeatability), sensitivity, linearity, dynamic range, and homoscedasticity, all with a single set of data. The procedure utilizes the corrigible error correction (CEC) technique comprised of three response curves--standard, Youden one-sample, and method of standard additions (MOSA) plots, from a total of 15 to 18 X,Y data pairs. For the bias component of accuracy, the systematic bias error of the method is quantitatively separated into its constant and proportional error components. The overall constant systematic error is further separated into the system (blank) and analyte-matrix (sample) components. The CEC data also provide an internal, i.e., in situ corrected assay for the sample for comparison with alternative method data. Statistical diagnostic tests are used for the final evaluation of the method acceptability, specifically in deciding whether or not the systematic error indicated requires a root source search for its removal or is simply a calibration constant of the method.


Possible implementation of salicylate anions in lead detoxification.
The water-soluble coordination polymer of formula {[Pb(Sal)2(H2O)]n} (SaLead), was obtained from the reaction between Pb(NO3)2 and the potassium salt of salicylic acid (SalH), an anti-inflammatory drug, which is also use as food preservation, in cosmetics etc. The compound was characterized by melting point, Attenuated Total Reflectance-Fourier Transform Infra-Red (ATR-FTIR) spectroscopy and X-ray diffraction crystallography (XRD) in solid state and in solution by Ultra Violet (UV) and 1H NMR spectroscopies. The binding affinity of SalK to Pb(II) ions towards SaLead was determined in order to examine its possible implementation in lead detoxification. The in vitro non-toxic behaviour of SalK and its complex SaLead was evaluated against normal human fetal lung fibroblast cells (MRC-5). The corresponding IC50 values are 260 ± 13 and > 1600 μM respectively. The non-genotoxic in vitro activity of SaLead was confirmed with the micronucleus (MN) assay, while its in vivo non-toxicity behaviour was evaluated with Allium cepa and Artemia salina assays.


Age-related susceptibility to hepatotoxicants.
Limited information is available regarding age-associated events that lead to differences in vulnerability to chemicals that injure the liver. For some agents, such as allyl alcohol, alterations in metabolic activation, by liver biotransformation enzymes, are responsible for age-associated changes in severity of liver damage. For other toxicants, such as carbon tetrachloride, there appears to be no relation between changes in activation/detoxification processes and the effects of aging on the extent of liver injury. With diquat, a rise in iron content seems to explain the increased toxicity observed in hepatocytes of old rats compared with those of young-adult rats. Additional research is needed to identify the mechanisms responsible for age-dependent differences in sensitivity to environmental chemicals.


Direct observation in the millisecond time range of fluorescent molecule asymmetrical interaction with the electropermeabilized cell membrane.
Interaction of two stains (propidium iodide and ethidium bromide) with electropermeabilized living Chinese hamster ovary cells is observed using an ultrafast fluorescence image acquisition system. The computing process is linked to an ultra-low-light intensifying camera working with a very short time resolution (3.33 ms per image). Altered parts of the cell membrane were identified via the enhancement in fluorescence intensity of the dyes. They reflect the electropermeabilized part of the membrane in which free flow of dye occurred. Images of the fluorescence interaction patterns of the two dyes, in a maximum 20-ms time lag after pulsation, reveal asymmetrical permeabilization of the cell membrane. For electric field intensities higher than a first threshold value, permeabilization is always observed on the anode-facing side of the cell. For electric field intensities over a second higher threshold value, the two electrode-facing hemispheres of the cell are permeabilized, the hemisphere facing the anode being most permeable. These data support the conclusion that electropermeabilization of living cell membrane is affected by its resting potential. The asymmetrical pattern of the dye interaction is not dependent on the nature or concentration of the dye, the ionic strength of the pulsing buffer, or the duration of the pulse. The field intensity determines the fraction of the membrane in which molecular alterations can occur. The extent of alteration in this localized region is determined by the duration of the pulse when a single pulse in the millisecond time range is applied.


Liraglutide improves vascular dysfunction by regulating a cAMP-independent PKA-AMPK pathway in perivascular adipose tissue in obese mice.
Perivascular adipose tissue (PVAT) attenuates its anti-contractile effect through an endothelial-dependent mechanism that aggravates endothelial dysfunction in obesity. The present study was conducted to explore whether liraglutide could improve vascular dysfunction, including the anti-contractile effect of PVAT and endothelial function, by modulating PVAT-related signaling pathways in obesity. C57BL/6 mice were fed a normal-chow diet or a high-fat diet (HFD) with or without liraglutide treatment. Vascular function of the thoracic aorta with or without PVAT were measured. Protein levels of components of the PKA-AMPK-PGC1α and antioxidant signaling pathway in PVAT were determined by western blotting. Brown adipose tissue-related gene in PVAT was measured by qRT-PCR. Metabolic profiles of HFD-fed mice were improved after treatment with liraglutide. Liraglutide improved PVAT-induced anti-contractile capability and PVAT-induced endothelial dysfunction in HFD-fed mice both in vivo and ex vivo. However, blocking PKA, or AMPK, but not cAMP, attenuated these beneficial effects of liraglutide. Treating HFD-fed mice with liraglutide activated the AMPK/eNOS pathway and induced browning-related gene expression. Moreover, liraglutide increased antioxidant capability. The protective effects were related to activation of a cAMP-independent PKA-AMPK pathway, as demonstrated by western blot and PCR. Liraglutide improved vascular dysfunction by modulating a cAMP-independent PKA-AMPK pathway in PVAT in HFD-induced obese mice. The findings provide a novel mechanism for the cardiovascular protection of liraglutide by modulating PVAT function in obesity.


Cholesterol mass efflux capacity and coronary artery calcium: The Multi-Ethnic Study of Atherosclerosis.
We assessed the cross-sectional and longitudinal relationships of high-density lipoprotein (HDL)-mediated cholesterol mass efflux capacity (CMEC) with coronary artery calcium (CAC) score and CAC density. CMEC was measured in 1626 Multi-Ethnic Study of Atherosclerosis (MESA) participants in samples obtained between 2000 and 2002 as part of two nested case-control studies, one with cases of incident cardiovascular disease and the other with cases of carotid plaque progression by ultrasound. Cardiac CT examinations for the presence of CAC were performed at baseline and at two additional examinations. CAC scores (Agatston and volume) and density scores (for those with positive CAC) were calculated. Multivariable linear regression modeling per SD increment of CMEC was used to estimate the associations of CMEC with each of these CAC measures. We found no association between higher CMEC and either lower CAC scores or a higher CAC density. We also found no association between higher CMEC and progression of any of these CAC measures. These findings suggest that HDL-mediated cholesterol efflux may be associated with cardiovascular risk via mechanisms unrelated to burden of calcified plaque.


Nonconvulsive status epilepticus due to cefepime in a patient with normal renal function.
Status epilepticus and encephalopathy have been reported with use of cephalosporins in patients with renal failure. We here report the case of a 79-year-old patient with normal renal function who developed subtle mental status changes during cefepime therapy for urinary tract infection. Emergent electroencephalography revealed evidence of nonconvulsive status epilepticus (NCSE), which responded initially to lorazepam. Later, the patient's NCSE gradually resolved only after cefepime was discontinued, with mental status returning to baseline as the electroencephalography changes resolved. It should be recognized that cefepime therapy can cause NCSE even in the presence of normal renal function. Measurement of serum concentrations and changes in dosing guidelines can probably prevent NCSE during cefepime therapy.


Identification of methane cycling pathways in Quaternary alluvial-lacustrine aquifers using multiple isotope and microbial indicators.
Groundwater rich in dissolved methane is often overlooked in the global or regional carbon cycle. Considering the knowledge gap in understanding the biogeochemical behavior of methane in shallow aquifers, particularly those in humid alluvial-lacustrine plains with high organic carbon content, we investigated methane sources and cycling pathways in groundwater systems at the central Yangtze River basins. Composition of multiple stable isotopes (2H/18O in water, 13C in dissolved inorganic carbon, 13C/2H in methane, and 13C in carbon dioxide) was combined with the characteristics of microbes and dissolved organic matter (DOM) in the study. The results revealed significant concentrations of biogenic methane reaching up to 13.05 mg/L in anaerobic groundwater environments with abundant organic matter. Different pathways for methane cycling (methanogenic CO2-reduction and acetate-fermentation, and methane oxidation) were identified. CO2-reduction dominated acetate-fermentation in the two methanogenic pathways primarily associated with humic DOM, while methane oxidation was more closely associated with microbially derived DOM. The abundance of obligate CO2-reduction microorganisms (Methanobacterium and Methanoregula) was higher in samples with substantial CO2-reduction, as indicated by isotopic composition. The obligate acetate-fermentation microorganism (Methanosaeta) was more abundant in samples exhibiting evident acetate-fermentation. Additionally, a high abundance of Candidatus Methanoperedens was identified in samples with apparent methane oxidation. Comparing our findings with those in other areas, we found that various factors, such as groundwater temperature, DOM abundance and types, and hydrogeological conditions, may lead to differences in groundwater methane cycling. This study offered a new perspective and understanding of methane cycling in worldwide shallow alluvial-lacustrine aquifer systems without geothermal disturbance.


Examining trends in gun violence injuries before and during the COVID-19 pandemic across six trauma centers.
The onset of the national stay-at-home orders accompanied by a surge in firearm sales has elevated the concerns of clinicians and public health authorities. The purpose of this study was to examine the impact of the stay-at-home orders among gunshot wound (GSW) trauma admissions. This was a retrospective cohort study at six level I trauma centers across four states. Patients admitted after the onset of COVID-19 restrictions (March 16, 2020-June 30, 2020) were compared with those admitted during the same period in 2019. We compared (1) rate of patients with GSW and (2) characteristics of patients with GSW, by period using Χ2 tests or Fisher's exact tests, as appropriate. There were 6996 trauma admissions across the study period; 3707 (53%) in 2019 and 3289 (47%) in 2020. From 2019 to 2020, there was a significant increase in GSW admissions (4% vs. 6%, p=0.001); 4 weeks specifically had significant increases (March 16-March 23: 4%, April 1-April 8: 5%, April 9-April 16: 6%, and May 11-May 18: 5%). Of the 334 GSWs, there were significant increases in patients with mental illness (5% vs. 11%, p=0.03), alcohol use disorder (2% vs. 10%, p=0.003), substance use disorder (11% vs. 25%, p=0.001), and a significant decrease in mortality (14% vs. 7%, p=0.03) in 2020. No other significant differences between time periods were identified. Our data suggest that trauma centers admitted significantly more patients with GSW following the national guidelines, including an increase in those with mental illness and substance use-related disorders. This could be attributable to the stay-at-home orders. Level III, retrospective study.


Adjustment disorder in cancer patients after treatment: prevalence and acceptance of psychological treatment.
To investigate the prevalence of adjustment disorder (AD) among cancer patients and the acceptance of psychological treatment, in relation to sociodemographic, clinical, and psychological factors. Breast, prostate, and head and neck cancer patients of all stages and treatment modalities (N = 200) participated in this observational study. Patients completed the Hospital Anxiety and Depression Scale, Checklist Individual Strength, Distress Thermometer and problem list. Patients with increased risk on AD based on these questionnaires were scheduled for a diagnostic interview. Patients diagnosed with AD were invited to participate in a randomized controlled trial on the cost-effectiveness of psychological treatment. Participation in this trial was used as a proxy of acceptance of psychological treatment. Logistic regression analyses were used to investigate associated factors. The overall prevalence of AD was estimated at 13.1%. Sensitivity analyses showed prevalence rates of AD of 11.5%, 15.0%, and 23.5%. Acceptance of psychological treatment was estimated at 65%. AD was associated both with being employed (OR = 3.3, CI = 1.3-8.4) and having a shorter time since diagnosis (OR = 0.3, CI = 0.1-0.8). Taking sensitivity analysis into account, the prevalence of AD among cancer patients is estimated at 13 to 15%, and is related to being employed and having a shorter time since diagnosis. The majority of cancer patients with AD accept psychological treatment.


A Fuzzy Reasoning Design for Fault Detection and Diagnosis of a Computer-Controlled System.
A Fuzzy Reasoning and Verification Petri Nets (FRVPNs) model is established for an error detection and diagnosis mechanism (EDDM) applied to a complex fault-tolerant PC-controlled system. The inference accuracy can be improved through the hierarchical design of a two-level fuzzy rule decision tree (FRDT) and a Petri nets (PNs) technique to transform the fuzzy rule into the FRVPNs model. Several simulation examples of the assumed failure events were carried out by using the FRVPNs and the Mamdani fuzzy method with MATLAB tools. The reasoning performance of the developed FRVPNs was verified by comparing the inference outcome to that of the Mamdani method. Both methods result in the same conclusions. Thus, the present study demonstratrates that the proposed FRVPNs model is able to achieve the purpose of reasoning, and furthermore, determining of the failure event of the monitored application program.


Open surgical treatment of subclavian artery pseudoaneurysm after endovascular repair: a case report.
Subclavian artery aneurysms are rare but may cause life-threatening complications. Surgical repair has been performed as a treatment of choice, but recently, with the development of endovascular treatment, many endovascular repairs have been performed to prevent surgical complications. A patient undergoing endovascular repair with a subclavian artery aneurysm was diagnosed with a type II endoleak with an enlarged aneurysmal sac. Surgical repair was performed to remove the aneurysmal sac compressing the adjacent organs. The highly mobile subclavian artery has abundant collaterals. Therefore, regular follow-up is essential for endovascular repair. Surgical repair is effective when adjacent organs are compressed by the aneurysm sac.


Correlation of Histomorphometric Changes with Diffusion Tensor Imaging for Evaluation of Blast-Induced Auditory Neurodegeneration in Chinchilla.
In the present study, we have evaluated the blast-induced auditory neurodegeneration in chinchilla by correlating the histomorphometric changes with diffusion tensor imaging. The chinchillas were exposed to single unilateral blast-overpressure (BOP) at ∼172dB peak sound pressure level (SPL) and the pathological changes were compared at 1 week and 1 month after BOP. The functional integrity of the auditory system was assessed by auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE). The axonal integrity was assessed using diffusion tensor imaging at regions of interests (ROIs) of the central auditory neuraxis (CAN) including the cochlear nucleus (CN), inferior colliculus (IC), and auditory cortex (AC). Post-BOP, cyto-architecture metrics such as viable cells, degenerating neurons, and apoptotic cells were quantified at the CAN ROIs using light microscopic studies using cresyl fast violet, hematoxylin and eosin, and modified Crossmon's trichrome stains. We observed mean ABR threshold shifts of 30- and 10-dB SPL at 1 week and 1 month after BOP, respectively. A similar pattern was observed in DPAOE amplitudes shift. In the CAN ROIs, diffusion tensor imaging studies showed a decreased axial diffusivity in CN 1 month after BOP and a decreased mean diffusivity and radial diffusivity at 1 week after BOP. However, morphometric measures such as decreased viable cells and increased degenerating neurons and apoptotic cells were observed at CN, IC, and AC. Specifically, increased degenerating neurons and reduced viable cells were high on the ipsilateral side when compared with the contralateral side. These results indicate that a single blast significantly damages structural and functional integrity at all levels of CAN ROIs.


Concurrent chemoradiotherapy with carboplatin and uracil-f tegafur (UFT) for patients with poor performance status with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
Concurrent chemoradiotherapy with carboplatin and uracil-f tegafur (UFT) seems to be a promising and appropriate regimen for patients with poor performance status (PS) with locally advanced squamous cell carcinoma of the head and neck (SCCHN). We designed a regimen based on divided low-dose administration to reduce toxicity for patients with poor PS with locally advanced SCCHN. Sixty-two patients with previously untreated stage III-IV SCCHN and PS of 2 or 3 were entered into this study. They received radiotherapy: 70 Gy/35 fractions. The chemotherapy consisted of a combination of carboplatin (Calvert's formula: (GFR+25) x AUC (=5)/4 mg/week; where AUC area under the curve and GFR = glomerular filtration rate) and UFT (300 mg/day, per os). The overall clinical response rate and the pathological complete response (CR) were 90% (56/62) and 61% (38/62), respectively. Grade > or =3 mucositis occurred in only 6% of patients (4/62) and grade 2 > or =3 leukocytopenia and neutropenia occurred in only 5% (3/62).


Extra-osseous Ewing sarcoma of the thyroid gland mimicking lymphoma recurrence: a case report.
Extra-osseous Ewing sarcomas/peripheral primitive neuroectodermal tumors (EOES/pPNETs) are high-grade malignant tumors found in various organs, such as the lung, skin, intestine, kidney and female genital tract; however, to the best of our knowledge, only two cases have previously been identified in the thyroid gland. We describe a case of primary EOES/PNET of the thyroid gland in a 66-year-old man with a previous history of large B cell lymphoma. During a routine follow-up examination, the patient underwent an ultrasound cervical scan showing a solid nodule of the left thyroid lobe. The fine-needle aspiration biopsy of the nodule suggested a neuroendocrine tumor. Histological and immunohistochemical examination of the surgical specimen supported a diagnosis of EOES/PNET, which was further confirmed by the demonstration of EWSR1 gene translocation by means of fluorescent in situ hybridization and by the detection of glycogen particles and neurosecretory granules by means of electron microscopy. Total body computed tomography and magnetic resonance imaging excluded the involvement of other sites, and therefore a diagnosis of primary EOES/PNET of the thyroid gland was made.This paper also discusses the main differential diagnoses, including lymphoma recurrence, other small round cell tumors (primary or metastatic), and a thyroid localization of an EWS/PNET from another organ.


[MR imaging of the Achilles tendon: evaluation of criteria for the differentiation of asymptomatic and symptomatic tendons].
The purpose of this study was to develop quantitative and qualitative MRI criteria to differentiate between healthy and pathological Achilles tendons. 364 Achilles tendons were examined on a 1.5 T MRI scanner. 264 patients had Achilles tendon complaints, 100 asymptomatic Achilles tendons served as a control. T 1-weighted, T 2-weighted and a STIR sequence were performed in sagittal and axial orientation. Images were evaluated in consensus by two radiologists. Quantitative and qualitative criteria were assessed. A Mann-Whitney-U-Test and a regression analysis were used for statistical analysis. There were statistically significant differences between the patients with disorders and the control group concerning the depth (12.0 mm and 6.3 mm, p < 0.001) and length (83.2 mm and 45.9 mm, p < 0.001) of the tendon, the area of the tendon cross section (1.60 mm (2) and 061 mm (2), p < 0.001), as well as the length of the bursa retrocalcanea (8.3 mm and 5.3 mm, p < 0.001). There was a sensitivity of 97 % and a specificity of 91 % using a formula including the 3 criteria: tendon depth (A4), length of bursa (A5) and area of tendon (F). The measurement of the Achilles tendon and the binary-logistic regression analysis allow differentiation between normal and pathological Achilles tendons.


Puzzling Out Synaptic Vesicle 2 Family Members Functions.
Synaptic vesicle proteins 2 (SV2) were discovered in the early 80s, but the clear demonstration that SV2A is the target of efficacious anti-epileptic drugs from the racetam family stimulated efforts to improve understanding of its role in the brain. Many functions have been suggested for SV2 proteins including ions or neurotransmitters transport or priming of SVs. Moreover, several recent studies highlighted the link between SV2 and different neuronal disorders such as epilepsy, Schizophrenia (SCZ), Alzheimer's or Parkinson's disease. In this review article, we will summarize our present knowledge on SV2A function(s) and its potential role(s) in the pathophysiology of various brain disorders.


Immunofluorescence localization of calmodulin in human polymorphonuclear leukocytes.
Human polymorphonuclear leukocytes (PMNs) were purified (approximately equal to 99%) from peripheral blood of normal, adult volunteers. The indirect immunofluorescence technique was used to investigate the presence and the localization of calmodulin in human PMNs. The cellular distribution of calmodulin has been evaluated using an affinity chromatography-purified sheep IgG anti-calmodulin and fluorescein-conjugated rabbit anti-sheep IgG. The anti-calmodulin immunofluorescence pattern suggests that calmodulin is evenly distributed throughout the cytoplasm of human PMNs.


Genetic studies of the pyrimidine permeases from Saccharomyces cerevisiae: lack of intragenic complementation.
A search for intragenic complementation of mutants of the cytosine and uracil permeases of Saccharomyces cerevisiae was made. Among numerous diploid pairs of mutants of the cytosine permease gene no complementation was found. Similarly negative results were obtained with pairs of mutants of the uracil permease. The significance of these results is discussed.


Three-Dimensional (3D) Culture Models in Cancer Investigation, Drug Testing and Immune Response Evaluation.
Preclinical models for the definition of anti-cancer drug safety and efficacy are constantly evolving [...].


Does an auditory distractor sequence affect self-paced tapping?
This study investigated whether an auditory distractor (D) sequence affects the timing of self-paced finger tapping. To begin with, Experiment 1 replicated earlier findings by showing that, when taps are synchronized with an isochronous auditory target (T) sequence, an isochronous D sequence of different tempo and pitch systematically modulates the tap timing. The extent of the modulation depended on the relative intensity of the T and D tones, but not on their pitch distance. Experiment 2 then used a synchronization-continuation paradigm in which D sequences of different tempi were introduced only during continuation tapping. Although the D sequences rarely captured the taps completely, they did increase the tapping variability and deviations from the correct tempo. Furthermore, they eliminated the negative correlation between successive inter-tap intervals and led to intermittent phase locking when the tapping period was close to the period of the D sequence. These distractor effects occurred regardless of whether or not the taps generated auditory feedback tones. The distractor effects thus depend neither on the intention to synchronize with a T sequence nor on the simultaneous perception of two auditory sequences. Rather, they seem to reflect a basic attraction of rhythmic movement to auditory rhythms.


[Depressive symptoms and related risk factors in old and oldest-old elderly people with arthritis].
This study was to investigate the prevalence of depressive symptoms and risk factors in elderly people (old vs oldest-old) with arthritis. The Korean Longitudinal Study of Aging (KLoSA) was used with a sample of 1,084 elderly people with arthritis aged 65 or above. We found that the prevalence of depressive symptom was greater for oldest-old people (66.7%) compared to old people (56%). Significant differences between old people and oldest-old people were found for education, living with spouse, number of generation, regular exercise, body mass index (BMI), ADL limitation, self-rated health, and depression. Significant differences existed between depression and non-depression in terms of all variables except region and BMI among old people. But, among the oldest people, ADL limitation and self-rated health showed differences. The Logistic regression analysis revealed that religion, medical comorbidity, ADL limitation, self-rated health were significantly associated with depressive symptoms in old people. But, in oldest-old people, none of the variables were associated with depressive symptoms. The findings show that there are age differences in depression and related factors in elderly people with arthritis. Longitudinal studies, which covered depressive symptom severity and which are controlled for a large number of potential confounders, will need to complement the results of this study in the future.


DFT studies of the structure and vibrational spectra of 8-hydroxyquinoline N-oxide.
The geometry, frequency and intensity of the vibrational bands of 8-hydroxyquinoline N-oxide (8-HQNO) and its deuterated derivative (8-DQNO) were obtained by the density functional theory (DFT) with the BLYP and B3LYP functionals and 6-31G(d,p) basis set. The optimized bond lengths and bond angles are in good agreement with the X-ray data. The IR and INS spectra of 8-HQNO and 8-DQNO computed at the DFT level reproduce the vibrational wavenumbers and intensities with an accuracy, which allows reliable vibrational assignments.


Cardiovascular and neuromuscular responses to high-dose pancuronium-metocurine in pediatric burned and reconstructive patients.
The efficacy of the combined use of pancuronium and metocurine (Pm-MTC) in high doses to produce rapid-onset muscle paralysis was evaluated in 15 patients with acute burns and 18 recovered burned patients scheduled for reconstructive surgery. Two and three times the previously determined ED95 of the combination for each group was used. (ED95 for Pm-MTC combination is 0.032/0.129 mg/kg for acute burns and 0.013/0.051 mg/kg for reconstructive patients.) Doubling ED95 produced 95% paralysis in 3.1 +/- 0.9 min in acutely burned children and in 4.3 +/- 0.7 min in reconstructive children (mean +/- SEM). These onset times were not significantly different from each other. Tripling the ED95 of the combination in burned children reduced the onset time to 1.3 +/- 0.14 min, but this was not significantly different from 2 X ED95 onset time in burned patients. The administration of 3 X ED95 to the reconstructive group, however, resulted in a significantly more rapid onset time of 1.8 +/- 0.4 min compared with 2 X ED95 in the same population. With 3 X ED95 the onset times between burn and reconstructive patients were not significantly different. Time for recovery of twitch to 25% of control twitch height (75% twitch depression) was significantly prolonged in burned patients compared with reconstructive patients for equipotent doses administered. Although the occasional patient showed prominent changes in heart rate and blood pressure, overall cardiovascular stability was impressive.(ABSTRACT TRUNCATED AT 250 WORDS)


An in vitro evaluation of PCL-TCP composites as delivery systems for platelet-rich plasma.
In this study, we first investigated the in vitro degradation properties of biodegradable, bioresorbable polycaprolactone-20% tricalcium phosphate (PCL-TCP) composites immersed in simulated body fluid (SBF) and phosphate buffered saline (PBS). Then, the release profiles of the growth factors present in platelet-rich plasma (PRP) loaded onto the composites incubated in SBF and PBS were compared. Composites immersed in both buffers showed water uptake of 13.7%+/-0.75 at day 1, followed by a constant uptake of 12.1%+/-0.3 until day 12. Henceforth the water uptake declined for SBF- and increased for PBS-soaked composites. The weight loss data did not reveal any trend. SBF- and PBS-soaked samples displayed 1-2% weight loss for 2 and 5 of the ten time points measured respectively. The original protein retention (PR) of the composites was 49.1%+/-1.50. After immersion in SBF and PBS for 4 weeks, the PR was augmented to 88.5%+/-1.40 and 69.1%+/-1.40 correspondingly. PRP after activation contained 164.7+/-24.8, 194+/-43 and 18.3+/-4.75 ng/ml of TGF-beta1, PDGF-BB and IGF-1. Microscopic analysis verified the attachment of PRP to the rods and pores of the composites. Interestingly, the buffers played an important role in determining the release profiles of TGF and PDGF. Firstly, PBS-soaked composites manifested a tri-phasic burst-like profile that was absent in SBF. Secondly, SBF-soaked composites experienced delayed release of the growth factors and total release was not achieved (64.4% for TGF and 60.5% for PDGF), whereas total release was realized for PBS-soaked composites. Lastly, release profiles from SBF-soaked composites were growth factor mediated in terms of their amounts and sizes. This was not observed for PBS-soaked composites. IGF-1, on the other hand, exhibited a progressive reduction in levels over the entire experimental period for both buffers. The mechanisms of release were theorized to be a combination of diffusion, degradation and bioactivity. Since SBF is analogous to our body fluids in terms of its ionic constituents, we expect the elution profiles derived from SBF-soaked samples to more accurately emulate the in vivo situation. In conclusion, this study has deemed PCL-TCP composites as suitable delivery systems for platelet-rich plasma.


Pipecolic acid levels and transport in developing mouse brain.
The regional distribution of pipecolic acid (PA) in newborn mouse brain, measured by a new sensitive high performance liquid chromatography with electrochemical detection (HPLC-EC) method, shows a two-fold difference among various areas. Diencephalon, olfactory bulb and anterior telencephalon show the highest PA levels, while the lowest PA levels are seen in mesencephalon and rhombencephalon. The pattern of regional distribution of PA is identical to the regional accumulation in brain of the newborn seen by us following i.p. injections of D,L-[3H]PA9. The highest levels of PA are seen in both brain and serum during the perinatal period of development. Pipecolic acid levels decrease in brain and serum at one day of age and reach adult values within two weeks postnatal. The brain/serum PA ratio (2.9-3.5) during the perinatal period declines gradually after birth to adult values (0.7-0.8) at 30 days. The liver and kidney follow the same pattern with higher levels of PA seen during the perinatal period; however, these levels decreased rapidly to adult levels within one week postnatal. Following injections (250 mg/kg, i.p. and s.c. in the adult and newborn, respectively), D,L-PA accumulates for up to 24 h in the newborn mouse brain. In adult, the cerebral concentration of PA increases rapidly and reaches its peak level in 5-10 min. It remains relatively constant up to 5 h and then declines slowly to 24 h. Pipecolic acid levels in serum show essentially the same pattern of accumulation between adult and newborn mice with some quantitative differences.(ABSTRACT TRUNCATED AT 250 WORDS)


Angina following myocardial revascularization. Does time of recurrence predict etiology and influence results of operation?
To assess the operative mortality and long-term results in patients undergoing repeat revascularization for recurrent angina, we analyzed 48 consecutive patients operated upon at New York University Medical Center between 1970 and 1978. Between January, 1970, and July, 1973, 15 patients underwent repeat revascularization with five operative deaths (33 percent). Thirty-three patients underwent similar operations from July, 1973, to July, 1978, with only one operative death (3 percent). Technical factors and improved methods of myocardial protection during the operation directly influence this decrease in operative mortality rate. The indication for reoperation was incapacitating angina developing within 2 months of the inital operation in 18 patients (early failures) and after more than 2 months in 30 patients (late failures). The early failures were most commonly attributed to technical factors (33 percent) and graft occlusion by exuberant pericardial scarring (33 percent). The late failures were commonly related to the development of new native coronary lesions (47 percent) and selection of an incorrect site for distal anastomoses (23 percent). The prognostic and therapeutic implications of these findings will be discussed in detail. Angina was abolished or significantly decreased in 90 percent of the survivors, and there were only two late deaths occuring 18 and 20 months postoperatively. These data indicate that patients undergoing repeat myocardial revascularization can be operated upon with low operative mortality rates and symptomatic improvement comparable to that of patients undergoing coronary artery bypass for the first time.


Anxiety and depression in patients with vocal fold nodules, edema and polyps.
To compare the prevalence and severity of depression and anxiety among patients with vocal fold (VF) nodules, polyps and edema. At the same time the aim was to analyse association between severity of distress and the level of vocal handicap as well as to identify other factors related to severity of depression and anxiety in these patients. To all participants were given five questionnaires: (1) questionnaire on socio-demographic and some other characteristics of patient; (2) Beck's Depression Inventory (BDI); (3) State-Trait Anxiety Inventory (STAI) 1 (State Anxiety); (4) STAI 2 (Trait Anxiety); and (5) Voice Handicap Index (VHI)-10. A total of 205 patients were included in this study. Mild-to-severe depression, according to BDI was present in 79 (38.6%) patients. Mild-to-severe state anxiety and trait anxiety were present in 199 (97.1%) and 200 (97.6%) patients, respectively. Only 10 patients had VHI-10 score ≤ 11. Multivariate analyses showed that there were no significant differences in the level of depression and anxiety between patients with VF nodules, polyps and edema. The VHI-10 score was significantly higher in patients with VF edema in comparison with VF nodule patients (p = 0.001), as well as in comparison with VF polyp patients (p = 0.001). The present study identified a high prevalence of psychological and vocal distress among patients with vocal disorders. Severity of depression and anxiety did not differ between patients with VF nodules, polyps and edema, and it was not related to the level of vocal handicap.


A comparison of calibration methods for stereo fluoroscopic imaging systems.
Stereo (biplane) fluoroscopic imaging systems are considered the most accurate and precise systems to study joint kinematics in vivo. Calibration of a biplane fluoroscopy system consists of three steps: (1) correction for spatial image distortion; (2) calculation of the focus position; and (3) calculation of the relative position and orientation of the two fluoroscopy systems with respect to each other. In this study we compared 6 methods for calibrating a biplane fluoroscopy system including a new method using a novel nested-optimization technique. To quantify bias and precision, an electronic digital caliper instrumented with two tantalum markers on radiolucent posts was imaged in three configurations, and for each configuration placed in ten static poses distributed throughout the viewing volume. Bias and precision were calculated as the mean and standard deviation of the displacement of the markers measured between the three caliper configurations. The data demonstrated that it is essential to correct for image distortion when sub-millimeter accuracy is required. We recommend calibrating a stereo fluoroscopic imaging system using an accurately machined plate and a calibration cube, which improved accuracy 2-3 times compared to the other calibration methods. Once image distortion is properly corrected, the focus position should be determined using the Direct Linear Transformation (DLT) method for its increased speed and equivalent accuracy compared to the novel nested-optimization method. The DLT method also automatically provides the 3D fluoroscopy configuration. Using the recommended calibration methodology, bias and precision of 0.09 and 0.05 mm or better can be expected for measuring inter-marker distances.


Genomic background selection to reduce the mutation load after random mutagenesis.
Random mutagenesis is a standard procedure to increase allelic variation in a crop species, especially in countries where the use of genetically modified crops is limited due to legal constraints. The chemical mutagen EMS is used in many species to induce random mutations throughout the genome with high mutation density. The major drawback for functional analysis is a high background mutation load in a single plant that must be eliminated by subsequent backcrossing, a time and resource-intensive activity. Here, we demonstrate that genomic background selection combined with marker-assisted selection is an efficient way to select individuals with reduced background mutations within a short period. We identified BC1 plants with a significantly higher share of the recurrent parent genome, thus saving one backcross generation. Furthermore, spring rapeseed as the recurrent parent in a backcrossing program could accelerate breeding by reducing the generation cycle. Our study depicts the potential for reducing the background mutation load while accelerating the generation cycle in EMS-induced winter oilseed rape populations by integrating genomic background selection.


Contractile effect of vanadate and other vanadium compounds on the rat vas deferens.
Sodium metavanadate (NaVO3), vanadium pentoxide (V2O5) and vanadyl sulphate (VOSO4), evoked rhythmic and tonic contractions of the normal and reserpinized rat isolated vas deferens. Contractions were not observed by the use of vanadium trichloride (VCl3) The order of potency of these compounds, for their maximum contractile effects was NaVO3 greater than V2O5 greater than VOSO4 greater than VCl3. Differences in pD2 values were less than 0.5 long units in relation to the first compound. Vanadium-induced contractions were blocked by Ca2+ deprivation, nifedipine, Mg2+, Mn2+, Ni2+ and Co2+, indicating the involvement of a loosely bound or extracellular calcium-dependent mechanism. It is still unclear whether this calcium translocation was related, or not, to changes in Na+, K+-ATPase activity. Since ouabain blocked the action of vanadyl or vanadate non-competitively, it is concluded that vanadium compounds and ouabain induce their effects by interacting with different sites in vas deferens, both of which may or may not be located on the (Na+, K+)ATPase enzyme complex.


Temporal changes in radiological and chemical composition of Cambrian-Vendian groundwater in conditions of intensive water consumption.
Intensive groundwater uptake is a process at the intersection of the anthroposphere, hydrosphere, and lithosphere. In this study, groundwater uptake on a peninsula where only one aquifer system - the Cambrian-Vendian (CmV) - is available for drinking water uptake is observed for a period of four years for relevant radionuclides and chemical parameters (Cl, Mn, Fe, δ18O). Intensive groundwater uptake from the CmV aquifer system may lead to water inflow either from the sea, through ancient buried valleys or from the under-laying crystalline basement rock which is rich in natural radionuclides. Changes in the geochemical conditions in the aquifer may in turn bring about desorption of Ra from sediment surface. Knowing the hydrogeological background of the wells helps to predict possible changes in water quality which in turn are important for sustainable groundwater management and optimization of water treatment processes. Changes in Cl and Ra concentrations are critical parameters to monitor for sustainable management of the CmV groundwater. Radionuclide activity concentrations in groundwater are often considered rather stable, minimum monitoring frequency of the total indicative dose from drinking water is set at once every ten years. The present study demonstrates that this is not sufficient for ensuring stable drinking water quality in case of aquifer systems as sensitive as the CmV aquifer system. Changes in Cl concentrations can be used as a tool to predict Ra activity concentrations and distribute the production between different wells opening to the same aquifer system.


Anthropological studies in Assam, India. 1. Observations on five Mongoloid populations.
Five Mongoloid population groups from Upper Assam (Ahom, Chutia, Deuri, Mishing and Moran) have been investigated for the distribution of anthropometric and dermatoglyphic traits as well as for that of ABO blood groups and PTC taste sensitivity. The results are discussed with special reference to extent and causes of intergroup variability.


Imaging findings of granulocyte colony-stimulating factor-producing tumors: a case series and review of the literature.
Granulocyte colony-stimulating factor (G-CSF)-producing tumors have an aggressive clinical course. Here, we report five cases of G-CSF-producing tumors and review the literature, focusing on imaging findings related to tumor-produced G-CSF. In addition to our cases, we identified 30 previous reports of G-CSF-producing tumors on which 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)/CT, bone scintigraphy, or evaluation of bone marrow MR findings was performed. White blood cell count, serum C-reactive protein, and serum interleukin-6 were elevated in all cases for which these parameters were measured. G-CSF-producing tumors presented large necrotic masses (mean diameter 83.2 mm, range 17-195 mm) with marked FDG uptake (mean maximum standardized uptake value: 20.09). Diffuse FDG uptake into the bone marrow was shown in 28 of the 31 cases in which FDG-PET/CT was performed. The signal intensity of bone marrow suggested marrow reconversion in all seven MRI-assessable cases. Bone scintigraphy demonstrated no significant uptake, except in two cases with bone metastases. Splenic FDG uptake was increased in 8 of 10 cases in which it was evaluated. These imaging findings may reflect the effects of tumor-produced G-CSF. The presence of G-CSF-producing tumors should be considered in patients with cancer who show these imaging findings and marked inflammatory features of unknown origin.


Potent and selective adenosine A(2A) receptor antagonists: [1,2,4]-triazolo[4,3-c]pyrimidin-3-ones.
Antagonism of the adenosine A(2A) receptor affords a possible treatment of Parkinson's disease. In the course of investigating pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A(2A) antagonists, we prepared [1,2,4]-triazolo[4,3-c]pyrimidin-3-ones with potent and selective (vs A(1)) A(2A) antagonist activity. Structure-activity relationships are described for this series.


Revisiting the diversity of Ludioctenus Fairmaire (Elateridae: Agrypninae), with description of a new species from Afghanistan, and discussion on the systematic position of Tetrigusina.
The genus Ludioctenus Fairmaire, 1893 hitherto included only L. cyprius (Baudi di Selve, 1871) from the eastern Mediterranean and L. pakistanicus Schimmel Tarnawski, 2012 from Pakistan. Here, we describe L. afghanicus sp. nov. from the Nuristan Province in eastern Afghanistan. The distribution and morphological diversity of Ludioctenus is discussed, main diagnostic characters for all species are figured, and an identification key to the species of this genus is provided. Female pregenital segments and genitalia are figured for the first time for Ludioctenus, and the systematic position of this genus and its relatives is discussed.


New Drugs for Heart Failure: What is the Evidence in Older Patients?
Heart failure (HF) is a major public health concern, with a high prevalence in the older population. The majority of randomized clinical trials evaluating new emerging pharmacologic agents for HF (eg, angiotensin receptor-neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, intravenous iron for deficiency treatment, transthyretin stabilizers, soluble guanylate cyclase stimulators, cardiac myosin activators, and new potassium binders) have found positive results on various clinical outcomes, particularly in patients with reduced ejection fraction. These treatments might have an important role in the management of older patients as well. Nevertheless, trials demonstrating benefit of these drugs have involved patients significantly younger (on average, approximately 10 years) and fewer comorbidities than those commonly encountered in clinical practice. We describe the recent evidence regarding the newest HF drugs and their applicability to older individuals in terms of efficacy and safety, and we discuss their effects on outcomes particularly valuable to older patients, such as preservation of cognitive function, functional status, independence, and quality of life. Although available subgroup analyses seem to confirm efficacy and safety across the age spectrum for some of these drugs, their effects on older patients centered outcomes often have been neglected. Future HF trials should be designed to include older patients more representative of the real clinical practice, to overcome generalizability biases.


Gamma interferon induces monocyte killing of Listeria monocytogenes by an oxygen-dependent pathway; alpha- or beta-interferons by oxygen-independent pathways.
Human peripheral blood monocytes purified by counterflow centrifugal elutriation were treated with recombinant interferons-gamma (IFN-gamma), alpha (IFN-alpha), or beta (IFN-beta)--and tested for their capacity to kill Listeria monocytogenes. All three IFNs increased the monocyte bactericidal activity in a dose-dependent fashion. Exogeneous catalase, an inhibitor of monocyte-generated hydrogen peroxide, did not affect bactericidal activity. However, exogenous superoxide dismutase inhibited killing by IFN-gamma-activated monocytes, but not by IFN-alpha- or IFN-beta-activated monocytes. By contrast, exogenous soybean trypsin inhibitor inhibited killing by IFN-alpha or IFN-beta-activated monocytes, but not by IFN-gamma-activated monocytes. Combinations of IFN-gamma and IFN-alpha resulted in no increase in bactericidal activity. Finally, treatment with IFN-gamma resulted in different receptiveness of the cell to subsequent oxidative burst-stimulating signals than did treatment with either IFN-alpha or IFN-beta. These results suggest that monocytes treated with IFN-gamma kill L. monocytogenes by an oxygen-dependent mechanism, but treatment with IFN-alpha or IFN-beta elicits principally oxygen-independent mechanisms.


Non-apoptotic function of apoptotic proteins in the development of Malpighian tubules of Drosophila melanogaster.
Drosophila metamorphosis is characterized by the histolysis of larval structures by programmed cell death, which paves the way for the establishment of adult-specific structures under the influence of the steroid hormone ecdysone. Malpighian tubules function as an excretory system and are one of the larval structures that are not destroyed during metamorphosis and are carried over to adulthood. The pupal Malpighian tubules evade destruction in spite of expressing apoptotic proteins, Reaper, Hid, Grim, Dronc and Drice. Here we show that in the Malpighian tubules expression of apoptotic proteins commences right from embryonic development and continues throughout the larval stages. Overexpression of these proteins in the Malpighian tubules causes larval lethality resulting in malformed tubules. The number and regular organization of principal and stellate cells of Malpighian tubules is disturbed, in turn disrupting the physiological functioning of the tubules as well. Strikingly, the localization of beta-tubulin, F-actin and Disclarge (Dlg) is also disrupted. These results suggest that the apoptotic proteins could be having non-apoptotic function in the development of Malpighian tubules.


Lead optimization of thiazolo[5,4-c]piperidines: 3-cyclobutoxy linker as a key spacer for H(3)R inverse agonists.
The simpler, the better: H(3) histamine receptor (H(3)R) are of interest as therapeutic targets in cognitive and somnolence disorders. Here, lead optimization of H(3)R inverse agonists bearing a thiazolo[5,4-c]piperidine group gave rise to a clinical candidate with a much simpler unprecedented benzamide scaffold, displaying decreased hERG activity while maintaining high brain receptor occupancies.


Work Disability in Axial Spondyloarthritis.
Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that typically affects people of working age. Work-related outcomes are therefore important to study, both from an individual but also a societal perspective. Through this review of the literature, we explore the impact of axSpA on key work outcomes including work and productivity loss and predictors for these. Recent evidence confirms that axSpA is associated with substantial consequences on the ability to work. Reassuringly, early treatment and use of biologics have been associated with improved wok outcomes highlighting the importance of prompt diagnosis and management. High disease activity, labour-intensive jobs, poor physical function and impaired spinal mobility are among identified predictors of adverse work outcomes in axSpA. The impact of axSpA on work outcomes is considerable and necessitates optimal intervention, including suppression of disease activity, to enhance people's chances of remaining in work.


Small-cell lung cancer metastasis to a meningioma: Case report and review of the literature.
Tumor-to-tumor metastasis is a rare event with meningioma as the recipient tumor accounting for 20% of the reported cases. The most common primary cancers showing this phenomenon are lung and breast cancer. Most lung cancers metastasizing to a meningioma are due to lung adenocarcinoma with the literature containing only 3 prior reports of small-cell lung cancer showing this pattern of spread. Herein, we present the case of a 67-year-old-patient with small-cell lung cancer that developed a metastasis to a meningioma.


Diffusion-weighted imaging with histogram analysis of the apparent diffusion coefficient maps in the diagnosis of parotid tumours.
The aim of this study was to investigate the role of diffusion-weighted imaging (DWI) with histogram analysis of apparent diffusion coefficient (ADC) maps in the characterization of parotid tumours. This prospective study included 39 patients with parotid tumours. All patients underwent magnetic resonance imaging with DWI, and ADC maps were generated. The whole lesion was selected to obtain histogram-related parameters, including the mean (ADCmean), minimum (ADCmin), maximum (ADCmax), skewness, and kurtosis of the ADC. The final diagnosis included pleomorphic adenoma (PA; n=18), Warthin tumour (WT; n=12), and salivary gland malignancy (SGM; n=9). ADCmean (×10-3mm2/s) was 1.93±0.34 for PA, 1.01±0.11 for WT, and 1.26±0.54 for SGM. There was a significant difference in whole lesion ADCmean among the three study groups. Skewness had the best diagnostic performance in differentiating PA from WT (P=0.001; best detected cut-off 0.41, area under the curve (AUC) 0.990) and in discriminating WT from SGM (P=0.03; best detected cut-off 0.74, AUC 0.806). The whole lesion ADCmean value had best diagnostic performance in differentiating PA from SGM (P=0.007; best detected cut-off 1.16×10-3mm2/s, AUC 0.948). In conclusion, histogram analysis of ADC maps may offer added value in the differentiation of parotid tumours.


The anorectic action of peripherally administered 5-HT is enhanced by vagotomy.
Peripherally administered 5-HT produced a greater suppression of food intake in rats with subdiaphragmatic vagotomy than in sham-operated controls. The enhanced anorexia to 5-HT in vagotomised rats and the anorexia in sham-operated controls were reversed by methysergide, indicating the involvement of 5-HT receptors in the observed anorexia in both groups of animals. Thus the increased suppression of food intake in vagotomised rats cannot be explained in terms of non-specific effects of 5-HT. Both vagotomised and sham-operated rats showed an equivalent degree of anorexia when treated with fenfluramine suggesting that the receptor mechanism responsible for the anorectic action of 5-HT plays little or no part in the action of fenfluramine. Systemic administration of 5-HT was found to slow the rate of gastric clearance. Unlike the anorexia induced by 5-HT this effect was not reversed by methysergide. Thus it appears that peripherally administered 5-HT interacts with the vagus nerve but the mechanism responsible for 5-HT anorexia is independent of any action on gastric clearance.


Increase in liver microsomal glutathione S-transferase activity by phenobarbital treatment of rats. Possible involvement of oxidative activation via cytochrome P450.
The possible involvement of oxidative activation of liver microsomal glutathione (GSH) S-transferase by the cytochrome P450 system was investigated. When rats were given phenobarbital (PB) intraperitoneally for 3 days, liver microsomal GSH S-transferase activity was stimulated 1.3-1.4-fold and the effect of PB on the transferase was potentiated by combination with a catalase inhibitor, 3-amino-1,2,4-triazole. Immunoblotting of microsomal proteins from PB-treated rats with anti-microsomal GSH S-transferase antibody after SDS-PAGE showed the presence of a dimer of the transferase. When microsomal suspensions prepared from PB-treated rats were placed on ice without GSH, the microsomal GSH S-transferase activity gradually increased with time and reached 200% of the initial level at 3 hr when activation of the transferase by N-ethylmaleimide was lost. The time-dependent increase in GSH S-transferase activity in PB-treated microsomes was prevented by addition of 0.1 mM GSH. The increase in microsomal GSH S-transferase activity by NADPH was depressed by cytochrome P450 inhibitors such as SKF 525-A (2-diethylaminoethyl-2,2-diphenylvalerate), metyrapone or isoniazid in agreement with the concomitant decrease in generation of hydrogen peroxide in microsomes. These results indicate that the increase in GSH S-transferase activity in liver microsomes by PB treatment of rats is due to the oxidative modification of the enzyme by reactive oxygen species which are concomitantly increased following induction of cytochrome P450.


Practical behavior change counseling in primary care.
Unhealthy behaviors lead to significant preventable morbidity and mortality in the United States. Primary care providers are in a unique position to address these issues with patients. Despite the importance and opportunity for health behavior counseling in primary care, reported rates are low. This article presents a practical model for health behavior counseling in everyday clinical practice.


Study of online information for anxious patients requiring dental extractions.
Introduction Standard practice for dental extractions is to provide treatment under local anaesthesia (LA) without additional sedation or general anaesthesia. Even in oral surgery departments, the majority of patients receive this anxiety-provoking treatment under LA alone. All patients undergoing extractions could benefit from information on relaxation and anxiety management. This study aims to perform an in-depth analysis of the quality of websites that provide information on dental extractions and anxiety.Materials and methods Key phrases were searched on Google. The content, reliability and readability of the top ten websites for each key phrase were qualitatively evaluated using three tools: DISCERN, Flesch-Kincaid, and a specialised oral surgery website checklist (OSWC).Results Patient education was limited, with 70% of websites being either advertisements, forums or articles for healthcare professionals. The majority of websites poorly described treatment such as sedation and only 16% provided methods for relaxation. Readability was poor, with 92% above average UK adult literacy ability.Conclusion Extraction patients should be signposted to effective resources before treatment or referral. Dental anxiety advice can easily be incorporated into all treatment plans, with recommended website links included in digital communication, such as text messages or practice websites.


A review of mast cells and liver disease: What have we learned?
Mast cells are recognized as diverse and highly complicated cells. Aside from their notorious role in allergic inflammatory reactions, mast cells are being implicated in numerous disease processes from heart disease to cancer. Mast cells have been implicated in liver pathogenesis including hepatitis and host allograft rejection after liver transplantation. The aim of this review is to discuss the traditional function of mast cells, their location and anatomy with regards to hepatic vasculature and the role of mast cells in hepatic diseases including liver regeneration and rejection. Finally, we will touch on the role of mast cells in liver cancer. In conclusion, we hope that the reader comes away with a better understanding of the diverse and potential role(s) that mast cells may play in liver pathologies.


How does the skeletal muscle communicate with the brain in health and disease?
Endocrine mechanisms have been largely associated with metabolic control and tissue cross talk in mammals. Classically, myokines comprise a class of signaling proteins released in the bloodstream by the skeletal muscle, which mediate physiological and metabolic responses in several tissues, including the brain. Recent exciting evidence suggests that myokines (e.g. cathepsin B, FNDC5/irisin, interleukin-6) act to control brain functions, including learning, memory, and mood, and may mediate the beneficial actions of physical exercise in the brain. However, the intricate mechanisms connecting peripherally released molecules to brain function are not fully understood. Accumulating findings further indicates that impaired skeletal muscle homeostasis impacts brain metabolism and physiology. Here we review recent findings that suggest that muscle-borne signals are essential for brain physiology and discuss perspectives on how these signals vary in response to exercise or muscle diseases. Understanding the complex interactions between skeletal muscle and brain may result in more effective therapeutic strategies to expand healthspan and to prevent brain disease. This article is part of the special Issue on 'Cross Talk between Periphery and the Brain'.


Measuring Alzheimer's Disease and Other Dementias in Diverse Populations Using Medicare Claims Data.
We examined how methods used for identifying dementia in administrative claims affected dementia incidence across racial/ethnic populations using a 100% sample of Medicare beneficiaries (n = 23,793,452). We found levels differed by method from 3.1% annual incidence to 3.6% in 2014. Dementia incidence declined from 2007 to 2014, but choice of method differentially impacted levels and trends by race/ethnicity. Methods using codes for dementia diagnosis and drugs to treat symptoms identified proportionally more Hispanics and Asians with dementia than other race/ethnicities, while codes for dementia diagnosis, drugs, and symptoms identified proportionally more whites and American Indians/Alaska Natives with dementia than other race/ethnicities.


N-of-1 clinical trials. A technique for improving medical therapeutics.
This discussion was selected from the weekly Grand Rounds in the Department of Medicine, University of Washington School of Medicine, Seattle. Taken from a transcription, it has been edited by Paul G. Ramsey, MD, Associate Professor of Medicine, and Philip J. Fialkow, MD, Professor and Chair of the Department of Medicine.


Effect of a Multi-Layer, Extended-Release Methylphenidate Formulation (PRC-063) on Sleep in Adults with ADHD: A Randomized, Double-Blind, Forced-Dose, Placebo-Controlled Trial Followed by a 6-month Open-Label Extension.
The effects of stimulant treatment on sleep in adults with attention-deficit/hyperactivity disorder (ADHD) are complex and varied, with some individuals experiencing worsening of sleep but others experiencing improvement. Data from previously reported trials of the clinical efficacy and safety of the long-acting methylphenidate formulation PRC-063 (Adhansia XR® in the USA; Foquest® in Canada) in adults with ADHD were used to evaluate patient-reported sleep outcomes, as captured using the Pittsburgh Sleep Quality Index (PSQI) and adverse events of insomnia. The trials comprised 4 weeks of randomized, forced-dose PRC-063 treatment at a dose of 0 (placebo), 25, 45, 70, or 100 mg/day followed by an optional 6 months of open-label PRC-063 treatment at an individually optimized dose of 25-100 mg/day. At the end of double-blind treatment, PRC-063 (all doses combined; N = 297) showed no significant difference versus placebo (N = 78) in least squares mean change in global PSQI score from baseline (- 0.7 vs. - 1.3; P = 0.0972) or in scores for each of the seven subscales of the PSQI. For patients enrolled in the open-label extension (N = 184), mean ± standard deviation global PSQI score improved from 7.8 ± 3.55 at the end of double-blind treatment to 5.8 ± 3.11 at 1 month and 5.4 ± 3.21 at 6 months (P < 0.0001). A greater proportion of patients were good sleepers (global PSQI score ≤ 5) at the end of the open-label extension (57.3%) than at baseline (20.9%) or at the end of double-blind treatment (26.0%). In a logistic regression analysis, baseline global PSQI score (odds ratio 1.491; P < 0.0001), but not randomized study treatment (P = 0.1428), was a significant predictor of poor sleep (global PSQI score > 5) at the end of double-blind treatment. Adverse event rates for insomnia (15.8 vs. 3.8%) and initial insomnia (6.1 vs. 1.3%) during double-blind treatment were higher for PRC-063 (all doses combined) than for placebo. Two patients receiving PRC-063 in the double-blind study and one patient in the open-label study were withdrawn because of insomnia adverse events. Our findings indicate that, on average, PRC-063 had no significant impact on overall sleep quality in adults with ADHD. Although insomnia was observed as an adverse event, when sleep was measured over time as an outcome in its own right for patients receiving dose-optimized PRC-063 open-label, more patients showed improvement in sleep than deterioration. CLINICALTRIALS. NCT02139124 and NCT02168127.


Early development of the thoracic discs ofDrosophila.
We estimate the number of blastoderm cells which generate the thoracic imaginal discs ofDrosophila. At hatching the wing disc is twice the size of the haltere disc, but the results suggest that both discs develop from a similar number of blastoderm cells. Two homeotic mutations, which transform the haltere into wing, affect embryonic growth but not the primordial number. All the segmental primordia may be of similar size and each may be similarly subdivided into a larger anterior, and a smaller posterior polyclone.


Multicenter analysis of stereotactic radiotherapy of the resection cavity in patients with brain metastases.
Brain metastases show a recurrence rate of about 50% after surgical resection. Adjuvant radiotherapy can prevent progression; however, whole-brain radiotherapy (WBRT) can be associated with significant side effects. Local hypofractionated stereotactic radiotherapy (HFSRT) is a good alternative to provide local control with minimal toxicity. In this multicenter analysis, we evaluated the treatment outcome of local HFSRT after resection brain metastases in 181 patients. Patient's characteristics, treatment data as well as follow-up data were collected and analyzed with special focus on local control, locoregional control and survival. After a median follow-up of 12.6 months (range 0.3-80.2 months), the crude rate for local control was 80.5%; 1- and 2-year local recurrence-free survival rates were 75% and 70% (median not reached). Resection cavity size was a significant predictor for local recurrence (P = 0.033). The median overall survival was 16.0 months. Both graded prognostic assessment score and recursive partitioning analysis were accurate predictors of survival. HFSRT leads to excellent local control and has a high potential to consolidate results after surgery; acute and late toxicity is low. Distant intracerebral metastases occur frequently during follow-up, and therefore, a close patient monitoring needs to be warranted if whole-brain radiotherapy is omitted.


The molecular pathogenesis of collagen-induced arthritis in mice--a model for rheumatoid arthritis.
The most widely used model for rheumatoid arthritis is the collagen-induced arthritis (CIA) in mice. This model has gained acceptance since it is reproducible, well defined and has proven useful for development of new therapies for rheumatoid arthritis, as exemplified by the most recent advancement using TNFalpha neutralization treatment. The collagen-induced arthritis model, however, represents only certain pathways leading to arthritis and there is no consensus on how they operate. Nevertheless, we are beginning to understand the immune recognition structures, such as MHC molecules, lymphocyte receptors and type II collagen epitopes, which are of crucial importance for the development of this disease. These provide useful tools for further investigations of the pathogenesis of CIA as well as for understanding the pathogenesis of rheumatoid arthritis.


The rate by which mortality increase with age is the same for those who experienced chronic disease as for the general population.
Mortality doubles approximately every 6-7 years during adulthood. This exponential increase in death risk with chronological age is the population-level manifestation of ageing, and often referred to as the rate-of-ageing. We explore whether the onset of severe chronic disease alters the rate-of-ageing. Using Swedish register data covering the entire population of the birth cohorts 1927-30, we analyse whether being diagnosed with myocardial infarction, diabetes or cancer results in a deviation of the rate-of-ageing from those of the total population. We also quantify the long-term mortality effects of these diseases, using ages with equivalent mortality levels for those with disease and the total population. None of the diseases revealed a sustained effect on the rate-of-ageing. After an initial switch upwards in the level of mortality, the rate-of-ageing returned to the same pace as for the total population. The time it takes for the rate to return depends on the disease. The long-term effects of diabetes and myocardial infarction amount to mortality levels that are equivalent to those aged 5-7 years older in the total population. For cancer, the level of mortality returns to that of the total population. Our results suggest an underlying process of ageing that causes mortality to increase at a set pace, with every year older we become. This process is not affected by disease history. The persistence of the rate-of-ageing motivates a critical discussion of what role disease prevention can play in altering the progression of ageing.


Static balance in patients with patellofemoral pain syndrome.
The relationship between one-leg static standing balance (OLSSB) and patellofemoral pain syndrome (PFPS) is unknown. OLSSB decreases in patients with PFPS. Prospective case series. Fifty-two women with unilateral PFPS were enrolled in this study. OLSSB was evaluated with a stabilometer. Q angle was measured with a lengthened-arm universal goniometer. Lower extremity alignment was analyzed with full-length standing anteroposterior teleroentgenograms. Quadriceps and hamstring strength was measured on an isokinetic dynamometer. There were significant differences in OLSSB, Q angle, and strength of quadriceps and hamstring between the symptomatic and asymptomatic sides. There was a correlation between the strength of the quadriceps and hamstring and OLSSB, while there was no correlation between OLSSB and the severity of pain, lower extremity alignment, and Q angle on the symptomatic side. OLSSB and quadriceps and hamstring strength decreased and Q angle increased on the symptomatic side in PFPS patients. A relationship between OLSSB and pain, Q angle, and lower extremity alignment was not detected, while there was a correlation between the strength of the quadriceps and hamstring and OLSSB. A quadriceps and hamstring strengthening may be beneficial to improve OLSSB in patients with PFPS.


Application of Ullmann and Ullmann-Finkelstein reactions for the synthesis of N-aryl-N-(1H-pyrazol-3-yl) acetamide or N-(1-aryl-1H-pyrazol-3-yl) acetamide derivatives and pharmacological evaluation.
Ullmann-type reactions are becoming a major tool in medicinal chemistry. In this article, we describe the use of these Copper-catalyzed reactions with various precursors, acyl-heteroarylamines or pyrazoles of interest for pharmacomodulation. To the medicinal chemist they offer new, usually untapped disconnection approaches to compounds of interest. They thus open the way to new original analogues of bioactive compounds possibly not patented, from common building-blocks. They also allow C to N bioisosteric replacements, which sometimes are synthetically challenging. We report for the first time the critical effect of acetylamino substituents on the regioselective arylation of unsymmetrical pyrazoles that are useful for medicinal chemists. Finally, we have applied this strategy to the design of novel AT(1) receptor antagonists. Though this family has been extensively investigated in the past 30 years, N-arylation and C to N replacement made possible by Ullmann chemistry, can produce original antagonists.


Contemporary management of diabetic neuropathic foot ulceration: a study of 917 consecutively treated limbs.
For patients with diabetic neuropathic foot ulceration, the current treatment paradigm is heavily weighted toward limb revascularization; aligning incentives to perform more surgery and less ulcer management/prevention. Our purpose was to perform an analysis of functional outcomes to assess this current treatment paradigm. Nine hundred and seventeen neuropathic ulcerated feet in 706 patients with diabetes were analyzed. Four hundred and sixty limbs (50.2%) had concomitant ischemia, 219 of which were revascularized (137 angioplasty and 82 open surgery). Outcomes measured included ulcer healing, survival, limb salvage, amputation-free survival, maintenance of ambulation, and independence. Independent predictors of outcomes were measured using an Extended Cox Model. Overall outcomes (n = 917) were: ulcer healed, n = 250 (27%; mean time to healing 33 weeks); functionally healed, n = 488 (53%; mean time to functional healing 29 weeks); 5-year limb salvage, 68%; survival, 38%; amputation-free survival, 30%; maintenance of ambulation, 64%; and maintenance of independence, 74%. There was little difference in ulcer healing rates for patients with or without ischemia (28.5% versus 26%; p = 0.4). However, ischemia was a significant marker of poor outcomes (nonischemic ulcer, ischemic ulcer revascularized, and ischemic ulcer not revascularized: 5-year limb salvage of 80%, 61%, and 51%; p < 0.001); survival (47%, 37%, and 24%; p = 0.03); amputation-free survival (37%, 28%, and 17%; p < 0.001); maintenance of ambulation (74%, 55%, and 55%; p < 0.001); and maintenance of independence (82%, 72%, and 58%; p = 0.01). Wound healing was an independent predictor of survival and amputation-free survival (survival: hazard ratio = 0.58; 95% CI,0.46-0.73; amputation-free survival: hazard ratio = 0.42; 95% CI, 0.33-0.53). The current treatment paradigm is associated with relatively poor healing rates and substantial late morbidity and mortality. Although revascularization is effective treatment for ischemia, it is probably overvalued when compared with the potential improvement afforded by better medical foot wound management.


Progressive Response to Repeat Application of Capsaicin 179 mg (8% w/w) Cutaneous Patch in Peripheral Neuropathic Pain: Comprehensive New Analysis and Clinical Implications.
To investigate the efficacy of repeated application of capsaicin 179 mg cutaneous patch in nonresponders to the first application. Post hoc, as-treated analysis of two prospective trials (STRIDE and PACE) with 52-week follow-up. Open-label. Multicenter clinical trial. STRIDE: nondiabetic neuropathic pain; PACE: painful diabetic peripheral neuropathy. Patients were divided according to number of applications needed before attainment of a ≥30% reduction in average pain intensity (question 5 of the Brief Pain Inventory [BPI-Q5]). We assessed the change from baseline in average pain intensity (BPI-Q5), mean "interference with sleep" score, Patient Global Impression of Change, quality of life (QOL) via the EuroQol 5-dimension, and Self-Assessment of Treatment. In STRIDE and PACE, respectively, n = 306 and n = 313 received the capsaicin patch; n = 60 and n = 96 had a response after the first application, n = 33 and n = 68 after the second, and n = 11 and n = 43 after the third. Among patients without a ≥30% reduction in pain intensity at 3 months, in STRIDE and PACE, respectively, 23.3% and 28.1% achieved a ≥30% reduction at 6 months, increasing to 33.9% and 45.7% at 12 months. Similar results were obtained when a decrease of ≥50% was used as the responder definition. Progressive improvements in pain intensity in slower responders reached levels similar to those in early responders at month 12 and were accompanied by improvements in sleep, QOL, and patient satisfaction. Although some patients with peripheral neuropathic pain experience rapid improvements with a single treatment of capsaicin 179 mg patch, some may require two or three treatments before an initial response is observed. Similar benefits for pain, sleep, and QOL can be achieved in early and late responders.


Does sorting by color using visible and high-energy violet light improve classification of taxa in honey bee pollen pellets?
Pollen collected by honey bees from different plant species often differs in color, and this has been used as a basis for plant identification. The objective of this study was to develop a new, low-cost protocol to sort pollen pellets by color using high-energy violet light and visible light to determine whether pollen pellet color is associated with variations in plant species identity. We identified 35 distinct colors and found that 52% of pollen subsamples (n = 200) were dominated by a single taxon. Among these near-pure pellets, only one color consistently represented a single pollen taxon (Asteraceae: Cichorioideae). Across the spectrum of colors spanning yellows, oranges, and browns, similarly colored pollen pellets contained pollen from multiple plant families ranging from two to 13 families per color. Sorting pollen pellets illuminated under high-energy violet light lit from four directions within a custom-made light box aided in distinguishing pellet composition, especially in pellets within the same color.


Export of ice-nucleating particles from watersheds: results from the Amazon and Tocantins river plumes.
We examined ice-nucleating particles (INPs) in the plumes of the Tocantins and Amazon rivers, which drain watersheds with different proportions of degraded land. The concentration of INPs active at -15°C (INP-15) was an order of magnitude lower in the Tocantins (mean = 13.2 ml-1; s.d. = 7.8 ml-1), draining the more degraded watershed, compared with the Amazon (mean = 175.8 ml-1; s.d. = 11.2 ml-1), where the concentration was also significantly higher than in Atlantic surface waters (mean = 3.2 ml-1; s.d. = 2.3 ml-1). Differences in heat tolerance suggest that INPs emitted by the Amazon rainforest to the atmosphere or washed into the river might originate from contrasting sources on top of and below the rainforest canopy, respectively. For the Amazon River, we estimate a daily discharge of 1018 INP-15 to Atlantic waters. Rivers in cooler climate zones tend to have much higher concentrations of INPs and could, despite a smaller water volume discharged, transfer even larger absolute numbers of INP-15 to shelf waters than does the Amazon. To what extent these terrestrial INPs become aerosolized by breaking waves and bubble-bursting remains an open question.


Vascular endothelial growth factor (VEGF)-D stimulates VEGF-A, stanniocalcin-1, and neuropilin-2 and has potent angiogenic effects.
The mature form of human vascular endothelial growth factor-D (hVEGF-D(ΔNΔC)) is an efficient angiogenic factor, but its full mechanism of action has remained unclear. We studied the effects of hVEGF-D(ΔNΔC) in endothelial cells using gene array, signaling, cell culture, and in vivo gene transfer techniques. Concomitant with the angiogenic and proliferative responses, hVEGF-D(ΔNΔC) enhanced the phosphorylation of VEGF receptor-2, Akt, and endothelial nitric oxide synthase. Gene arrays, quantitative reverse transcription-polymerase chain reaction, and Western blot revealed increases in VEGF-A, stanniocalcin-1 (STC1), and neuropilin (NRP) 2 expression by hVEGF-D(ΔNΔC) stimulation, whereas induction with hVEGF-A(165) altered the expression of STC1 and NRP1, another coreceptor for VEGFs. The effects of hVEGF-D(ΔNΔC) were seen only under high-serum conditions, whereas for hVEGF-A(165), the strongest response was observed under low-serum conditions. The hVEGF-D(ΔNΔC)-induced upregulation of STC1 and NRP2 was also evident in vivo in mouse skeletal muscle treated with hVEGF-D(ΔNΔC) by adenoviral gene delivery. The importance of NRP2 in hVEGF-D(ΔNΔC) signaling was further studied with NRP2 small interfering RNA and NRP antagonist, which were able to block hVEGF-D(ΔNΔC)-induced survival of endothelial cells. In this study, the importance of serum and upregulation of NRP2 and STC1 for VEGF-D(ΔNΔC) effects were demonstrated. Better knowledge of VEGF-D(ΔNΔC) signaling and regulation is valuable for the development of efficient and safe VEGF-D(ΔNΔC)-based therapeutic applications for cardiovascular diseases.


Escherichia coli transport in porous media: influence of cell strain, solution chemistry, and temperature.
Packed bed column and complementary characterization experiments were carried out with two Escherichia coli strains (D21 g and XL1-Blue) under a range of ionic strength (IS) and valence (KCl, CaCl(2), and artificial groundwater) to determine the role of bacterial strain and solution chemistry on cell adhesion. Increasing IS and valence had a marked effect on the electrokinetic and surface properties of bacteria and quartz grains; hence resulting in a greater rate of deposition. Distinct deposition trends were observed for the two cell strains, with greater retention observed for D21 g versus XL1-Blue across the range of IS. Selected transport and characterization experiments were also conducted with the D21 g cells, finding deposition also increasing with IS and valence. In the presence of Ca(2+) bacterial deposition behavior deviated from anticipated trends and it is concluded from additional analysis that Ca(2+) ions influence bacterial surface charge, hydrophobicity, and extracellular polymers. Further transport experiments were conducted with the D21 g cells and colloids to establish the role of temperature (4, 10 and 25 degrees C). Results suggested that a combination of specific and non-specific interactions occurring between the cells and quartz determines the extent of deposition, rather than transport from the bulk to the collector surface.


Trimetallic Spinel NiCo2-x Fex O4 Nanoboxes for Highly Efficient Electrocatalytic Oxygen Evolution.
The development of efficient and low-cost electrocatalysts toward the oxygen evolution reaction (OER) is critical for improving the efficiency of several electrochemical energy conversion and storage devices. Here, we report an elaborate design and synthesis of porous Co-based trimetallic spinel oxide nanoboxes (NiCo2-x Fex O4 NBs) by a novel metal-organic framework engaged strategy, which involves chemical etching, cation exchange, and subsequent thermal oxidation processes. Owing to the structural and compositional advantages, the optimized trimetallic NiCo2-x Fex O4 NBs (x is about 0.117) deliver superior electrocatalytic performance for OER with an overpotential of 274 mV at 10 mA cm-2 , a small Tafel slope of 42 mV dec-1 , and good stability in alkaline electrolyte, which is much better than that of Co-based bi/monometallic spinel oxides and even commercial RuO2 .


[Benefits of flexible visitation in the intensive care units for the family of critical patients].
To identify, analyze and summarize the main effects that may be related to flexible visitation policies for the relatives of critically ill adults. A review of the literature was conducted in the following databases: PubMed, CINAHL, PsycINFO, Cochrane Library and CUIDEN. Thematic content analysis was used to evaluate selected articles. Fifteen articles were included in this review. Four main themes emerged from the thematic content analysis. Themes included the main effects of flexible visitation policies for the family of the critical patients such as: improvement of satisfaction, reduction of anxiety and stress, satisfaction regarding their own family needs, and the role of the family in the patient's care. According to the existing evidence, flexible visitation policies appear to be both beneficial and decisive. It seems to be necessary to favor the participation of the family in the care of the intensive patient as well as the acquisition of a more prominent role the visitation context and in their relationship with the patient.


Fatty acid composition of myelin lipids from developing rat forebrain and spinal cord: influence of experimental hyperphenylalaninaemia.
The fatty acid composition of individual myelin lipids from rat forebrain and spinal cord was analysed at 20 and 30 days p.p. During this phase of rapid myelination the proportions of C 16:0 and C 18:0 fatty acids decreased whereas the relative amounts of long chain and unsaturated fatty acids increased in most lipid classes. This developmental shift was more pronounced in the forebrain and was different with respect to both magnitude and direction for each myelin lipid. The experimental induction of chronic hyperphenylalaninaemia (hyper-Phe) from day 3 p.p. lead to alterations in the rate of myelination, which were most pronounced in the forebrain. At 20 days, especially in the forebrain, chain elongation and desaturation of fatty acids were delayed. This delay was maximal in sphingomyelin fatty acids, C 18:0 and C 24:1. In hydroxycerebrosides, the shift in the fatty acid composition from C 16:0 to C 22:0 was accelerated in hyper-Phe rats. No significant difference in the fatty acid composition of any myelin lipid was found in the more mature myelin (spinal cord, 30 days p.p.). No evidence was found of a primary effect of hyper-Phe on myelination.


Inhibition of penicillin-induced EEG discharges by low doses of morphine or naloxone in the rabbit. Evidence for a possible non-opioid receptor-mediated mechanism at the sensorimotor cortex.
In rabbits, pretreatment by intravenous (IV) and intracortical (IC) routes with low doses of morphine (250 micrograms/kg IV or 60 pmoles/rabbit IC) and naloxone (1-50 micrograms/kg IV or 0.3 pmoles/rabbit IC) antagonizes the EEG and behavioural seizures due to the IC injection of penicillin (150 Units) at the level of the sensorimotor cortex. Pretreatment with naloxone (20 micrograms/kg IV) did not alter the anticonvulsant effect of morphine (250 micrograms/kg IV). The similar anticonvulsant effect of the two drugs together with the absence of any antagonism by naloxone on the effect of morphine seem to suggest that both drugs act through a non-opioid receptor-mediated mechanism. Further, in light of the low effective doses of the drugs and of the absence of any additive effect after their combined administration, one might speculate that morphine and naloxone do not act through different pharmacological receptors. However, the presence of distinct EEG patterns with either morphine or naloxone, injected IC and IV, in animals fully protected against penicillin-induced seizures, does not seem to be in favour of the latter possibility.


The concentration of plasma fibronectin in burns patients treated with fresh frozen plasma or plasma protein fraction.
A group of 10 patients with 30-70% burns were given intravenous infusions during the first 48 h following hospital admission either with fresh frozen plasma (FFP) or human plasma protein fraction ( HPPF ). FFP contained 300-400 mg/dl plasma fibronectin whereas none was detectable in HPPF . Circulating plasma fibronectin levels fell quickly in those patients receiving HPPF and levels remained low for 2-3 weeks. In those receiving FFP, plasma fibronectin remained normal during the 48-h transfusion period but fell subsequently. Fibronectin may be an important determinant in the resistance to shock and infections. Consideration should therefore be given to the use of blood products which contain fibronectin and to the monitoring of plasma levels both during the acute and recovery periods after burn injury.


Coniochaeta fungus benefits from its intracellular bacteria to form biofilm and defend against other fungi.
During cultivation of a gastric fungus, Coniochaeta polymorpha, growth of Nocardia colonies on top of the fungal culture raised the question whether bacteria originated from inside of fungus. In this study, the likelihood of intracellular origin of bacteria as well as interaction of two microorganisms was assessed. Fluorescence and electron microscopy showed occurrence of several bacterial cells in fungal cytoplasm. A thick biofilm was observed on the surface of co-culture compared with thin one on bacterial and none on fungal monocultures. Field emission scanning electron microscopy (FESEM) micrographs of co-culture showed a dense network of fungal and bacterial cells embedded in a slime-like layer. Dual cultures revealed antagonistic activity of both fungus and bacteria against three Candida species. These findings indicate that Nocardia isolate identified in this study originated from the inside of fungus C. polymorpha. Intracellular bacteria could benefit the fungal host by producing a rigid biofilm and an antifungal compound.


Diagnosis and management of lumbar spinal stenosis in primary care in France: a survey of general practitioners.
Lumbar spinal stenosis (LSS) is a common spinal condition and the most frequent indication for spinal surgery in elderly people. General practitioners (GPs) are on the 1st line for its diagnosis and treatment. We aimed to assess how GPs diagnose and treat people with LSS in France. We conducted a cross-sectional survey in a primary care setting. French GPs were selected by a random draw from the French Medical Board. The questionnaire was designed by 3 physicians specialized in physical and rehabilitation medicine and a resident in general practice. A provisional questionnaire was tested in a pilot survey of 11 French GPs. Participants' feedbacks served to build the final questionnaire. This latter was submitted by e-mail or mail to 330 GPs. GPs were surveyed about the 3 main domains relevant to the management of people with LSS in primary care: 1/ diagnosis, 2/ pharmacological treatments and 3/ non-pharmacological treatments, using self-administered open- and closed-ended questions and visual analog scales. Overall, 90/330 (27.3%) GPs completed the survey. 51/89 (57.3%) GPs were confident with managing people with LSS. Low back pain 51/87 (58.6%), neurogenic claudication 38/87 (43.7%) and paresthesia in the lower limbs 31/87 (35.6%) were the 3 most frequently cited clinical signs leading to the diagnosis of LSS. Improvement with lumbar flexion was mentioned by 9/87 (10.3%) GPs. 85/86 (98.8%) would consider prescribing lumbar imaging, 60/84 (71.4%) corticoid spinal injections and 42/79 (53.2%) would never prescribe lumbar flexion-based endurance training. All GPs would refer people with LSS to another specialist. French GPs lack confidence with diagnosing LSS and prescribing pharmacological and non-pharmacological treatments for people with LSS.


Olfactory and gustatory dysfunctions in SARS-CoV-2 infection: A systematic review.
Among Coronavirus Disease 2019 (COVID-19) manifestations, Olfactory (OD) and Gustatory (GD) Dysfunctions (OGD) have drawn considerable attention, becoming a sort of hallmark of the disease. Many have speculated on the pathogenesis and clinical characteristics of these disturbances; however, no definite answers have been produced on the topic. With this systematic review, we aimed to collect all the available evidence regarding the prevalence of OGD, the timing of their onset and their resolution, their rate of recovery and their role as diagnostic and prognostic tools for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. A systematic review comprising all the observational studies that reported the prevalence and/or the longitudinal trajectories of OGD in COVID-19 patients, as self-reported by patients or measured through objective psychophysical tests. After the selection process, 155 studies were included, with a total of 70,920 patients and 105,291 not-infected individuals. Prevalence reports were extremely variable across studies, with wide ranges for OD (0%-98%) and GD (0-89%) prevalence. OGD occurred early during the disease course and only rarely preceded other symptoms; out of 30 studies with a follow-up time of at least 20 days, only in 5 studies OGD fully resolved in more than 90% of patients. OGD had low sensitivity and high specificity for SARS-CoV-2 infection; accuracy of OD and GD for infection identification was higher than 80% in 10 out of 33 studies and in 8 out of 22 studies considered, respectively. 28 out of 30 studies that studied the association between OGD and disease severity found how OGD were associated with lower rates of severe pneumonia, hospitalization and mortality. OGD seem to be highly prevalent in SARS-CoV-2 infection. They occur early, concomitantly with other symptoms and often persist after recovery, in some cases for months; whether a full recovery eventually occurs in all cases is not clear yet. OGD are good predictors of SARS-CoV-2 infection and are associated with a milder disease course.


Narrative learning in the virtual landscape: a model from a baccalaureate program.
This article explores the implications of presenting a medical humanities curriculum in a virtual format, using as a model a fully online humanities course taught in both traditional 15-week and accelerated 5-week formats. The course explores narrative competency and allows baccalaureate students to deepen their practical skills with increased awareness of narrative constructions. The online course design fosters growth in many areas of communication that have otherwise been absent in face-to-face courses taught by this educator. In the virtual format, students showed increased investment in the course content and an openness to communicating their experience as well as to critically challenging their colleagues on narrative-based dilemmas, such as those centered around building empathy, remaining nonjudgmental when challenged with ethical dilemmas, and awareness of signs within themselves of disengagement and burnout.


Hammock mitral valve: a rare cause of congenital mitral regurgitation--a case report.
Hammock valve, also known as anomalous mitral arcade is a rare mechanism for congenital mitral insufficiency. We report a case of a two-week-old neonate who presented with features of heart failure and an apical systolic murmur. Echocardiogram showed severe mitral regurgitation and abnormal mitral valve with direct attachment of mitral leaflets to papillary muscle without intervening chordae tendinae, typical of hammock valve. Heart failure was controlled with ionotrpes and diuretics. The literature on the hammock mitral valve is reviewed.


The importance of adult life-span perspective in explaining variations in political ideology.
As a comment on Hibbing et al.'s paper, we discuss the evolution of political and social views from more liberal to more conservative over the span of adulthood. We show that Hibbing et al.'s theoretical model creates a false prediction from this developmental perspective, as increased conservatism in the adult life-span trajectory is accompanied by the avoidance of negative bias.


Cytology versus calcitonin assay in fine-needle aspiration biopsy wash-out fluid (FNAB-CT) in diagnosis of medullary thyroid microcarcinoma.
Widespread use of sensitive ultrasound examination led to an increasing detection of medullary thyroid microcarcinoma (micro-MTC). This prospective study evaluated the diagnostic accuracy of Fine-needle Aspiration Biopsy Cytology (FNAB-C) and calcitonin assay in Fine-needle Aspiration Biopsy wash-out fluid (FNAB-CT) in thyroid nodules less than 1 cm with elevated serum calcitonin(sCT). 87 thyroid nodules from 60 patients with elevated sCT (>10 pg/ml) were included and 51 were thyroid nodules less than 1cm. FNAB-CT and FNAB-C were performed to distinguish medullary thyroid carcinoma (MTC) lesions before surgery, histopathologic diagnoses served as main reference standards. FNAB-CT had a greater performance over FNAB-C for preoperative diagnosis of MTC (diagnostic accuracy: 98.85 vs 61.90%, sensitivity: 98.55 vs 55.07%, specificity: 100 vs 97.44%), especially for micro-MTC: FNAB-C established a sensitivity and diagnostic accuracy of 48.78 and 58% respectively, while FNAB-CT reached 97.56% sensitivity and 98.04% diagnostic accuracy. FNAB-CT demonstrated high diagnostic accuracy in diagnosing micro-MTC. Patients with microscopic thyroid nodules and elevated sCT level should perform FNAB-CT to exclude the diagnosis of MTC lesions.