Determination in rejected medical school applicants: a 10-year follow-up.
In view of low admission rate to medical schools, a large number of applicants are rejected annually. This population is denied the fulfillment of its occupational goal and must decide either to reapply to medical school or to choose a different occupational path. The present study focused on the possible career paths of rejected applicants, their persistence in reapplication and eventual admittance. The closeness to medicine of the alternative career was examined by two dimensions: the situs and the status. The career paths were viewed with respect to pre-admission cognitive criteria and occupational status of the alternative choices as compared to medicine. The study's random sample comprised one-third of the unaccepted applicants to the Tel-Aviv University School of Medicine for the 1970 academic year. The research follow-up (n = 208) of the applicants was conducted in 1981. The results showed a strong determination on the part of the unaccepted applicants to persist in their choice of medicine: 59% of the subjects reapplied and graduated from medical school either in Israel or in other countries. This group was found to be significantly more persistent in its number of reapplications than subjects who turned to an alternative career path. Thus, persistence was rewarding. When an alternative occupation was chosen, the tendency was towards careers unrelated to medicine but with a similarly high occupational status. No significant differences were found in the pre-admission cognitive criteria between those who studied medicine and those who chose an alternative career. Motivation and determination seemed to be the dominant factors in the attainment of one's choice of medicine as a profession.


The Arabidopsis ORANGE (AtOR) gene promotes carotenoid accumulation in transgenic corn hybrids derived from parental lines with limited carotenoid pools.
The AtOR gene enhances carotenoid levels in corn by promoting the formation of plastoglobuli when the carotenoid pool is limited, but has no further effect when carotenoids are already abundant. The cauliflower orange (or) gene mutation influences carotenoid accumulation in plants by promoting the transition of proplastids into chromoplasts, thus creating intracellular storage compartments that act as metabolic sink. We overexpressed the Arabidopsis OR gene under the control of the endosperm-specific wheat LMW glutenin promoter in a white corn variety that normally accumulates only trace amounts of carotenoids. The total endosperm carotenoid content in the best-performing AtOR transgenic corn line was 32-fold higher than wild-type controls (~25 µg/g DW at 30 days after pollination) but the principal carotenoids remained the same, suggesting that AtOR increases the abundance of existing carotenoids without changing the metabolic composition. We analyzed the expression of endogenous genes representing the carotenoid biosynthesis and MEP pathways, as well as the plastid fusion/translocation factor required for chromoplast formation, but only the DXS1 gene was upregulated in the transgenic corn plants. The line expressing AtOR at the highest level was crossed with four transgenic corn lines expressing different carotenogenic genes and accumulating different carotenoids. The introgression of AtOR increased the carotenoid content of the hybrids when there was a limited carotenoid pool in the parental line, but had no effect when carotenoids were already abundant in the parent. The AtOR gene therefore appears to enhance carotenoid levels by promoting the formation of carotenoid-sequestering plastoglobuli when the carotenoid pool is limited, but has no further effect when carotenoids are already abundant because high levels of carotenoids can induce the formation of carotenoid-sequestering plastoglobuli even in the absence of AtOR.


Left ventricular and coronary angiographic anatomy. Relationship to ventricular irritability in the late hospital phase of acute myocardial infarction.
Late hospital phase ventricular arrhythmias in acute myocardial infarction (MI) have been associated with a high incidence of sudden death following hospital discharge. Thirty-eight patients were studied 10-24 days following onset of symptoms of MI. Each patient had a 24-hour ambulatory ECG tape recording and left ventricular and coronary angiography performed. Patients with complicated ventricular arrhythmias (multiform, coupled, R on T VPCs or ventricular tachycardia), when compared to those with uncomplicated ventricular arrhythmias (unifocal or no VPCs), had a greater number of proximally narrowed major coronary arteries (P less than 0.001), a higher coronary "score" (P less than 0.001), a greater incidence of previous myocardial infarction (P less than 0.005), a greater percentage of abnormal left ventricular segments 86% vs 69% (P less than 0.001) and lower ejection fractions. These data suggest that late hospital phase survivors of MI with complicated ventricular arrhythmias have more extensive coronary artery disease with greater left ventricular dysfunction than survivors with uncomplicated ventricular arrhythmias. This more extensive disease may result in increased areas of ischemic myocardium and may help explain the refractoriness of these arrhythmias to pharmacologic therapy.


Flexibility--the guiding principle for antibody manufacturing.
Ensuring adequate manufacturing capacity for recombinant and monoclonal antibodies is one of the greatest challenges facing the biotech industry. The following factors should be taken into account when designing product development and production strategies.


Expression of the complement C3a and C5a receptors after permanent focal ischemia: An alternative interpretation.
The receptors for the complement anaphylatoxins C3a and C5a are expressed by glial cells and neurons in normal and inflamed brain. Previous studies demonstrated modest elevations in mRNA expression of these receptors in a model of focal cerebral ischemia. Using a similar model system for both mice and rats, we report markedly different patterns of anaphylatoxin receptor mRNA expression in cerebral ischemia. C5a receptor expression was dramatically elevated within 3 h after middle cerebral artery occlusion, while C3aR expression was reduced to 25% of control animals. By 24 h post-occlusion, expression of both receptors was higher than at any other time point examined. This increased expression at late time points after occlusion is most likely the result of massive infiltration of leukocytes expressing the receptors. We also observed increased receptor mRNA expression in sham-operated animals, indicating that the procedures used for arterial occlusion affects mechanisms regulating receptor expression. This latter result highlights the importance of including this important control group in ischemic model systems for proper interpretation of changes in gene expression.


Dietary glycemic index, glycemic load, and renal cancer risk: findings from prostate, lung, colorectal, and ovarian cancer trial.
Dietary glycemic index (GI) or glycemic load (GL) has been associated with the development of many cancers, but the evidence for renal cancer is still limited. The aim of the present study was to investigate the association between GI or GL and renal cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial. The cohort for our analysis consisted of 101,190 participants. GI and GL were calculated from the FFQ data using previously published reference values. Multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression model after adjusting for most known renal cancer risk factors. During a median of 12.2 years of follow-up, 443 incident renal cancer cases occurred. Higher dietary GI was significantly associated with a higher risk of renal cancer (HRQ3vsQ1: 1.38; 95% CI: 1.09-1.74; p for trend = 0.008). There was no significant association between dietary GL and renal cancer risk (HRQ3vsQ1 = 1.12, 95% CI = 0.79-1.59, p for trend = 0.591). Spline regression plot revealed a higher risk of renal cancer with a higher GI but not GL. There was no statistical evidence for nonlinearity (p for nonlinearity >0.05). In summary, findings of this large-scale prospective cohort study suggested that dietary GI may be associated with the risk of renal cancer. If confirmed in other populations and settings, dietary GI could be considered as a modifiable risk factor for renal cancer prevention.


The influence of age and physical activity on the pressure sensitivity of soft tissues of the musculoskeletal system.
The pressure sensitivity of soft tissues is defined as the slightest pressure causing pain. Sex, movement system illnesses, pain ailments may influence the pressure sensitivity. However, there have been few studies on factors determining the level of pressure sensitivity of skeletal muscles. The authors have determined to study the influence of age and physical activity on the pressure sensitivity of skeletal muscles. The examination of pressure sensitivity of trigger points and muscle insertions was carried out using algometry. 76 volunteers (38 students and 38 individuals aged 50-75) participated in the study. The differences in pressure sensitivity between students and people aged 50-75 were not statistically significant. Pressure sensitivity of students differed depending on their level of physical activity. The level of physical activity influenced the pressure sensitivity of skeletal muscles. Age did not significantly influence pressure sensitivity.


Effective prevention of recurrent dislocation following primary cemented Endo-MarkIII/SP2 total hip arthroplasty using a posterior lip augmentation device.
This retrospective study was performed to determine the effectiveness of preventing recurrent dislocation following primary cemented Endo-MarkIII/SP2 total hip replacement using a posterior lip augmentation device (PLAD). Between January 2003 and Dezember 2006, 27 PLADs were used in the treatment of recurrent hip dislocation in 27 patients who had received a cemented primary total hip arthroplasty using Endo-MarkIII/SP2 (Waldemar LINK, Hamburg, Germany) components. The mean number of dislocations prior to stabilization with this specific device was 2.6 (range 2-4, SD ± 0.4) with a mean time to revision surgery of 10 months (IQR 13). The mean age of the patients at time of revision surgery was 81.5 years (range 70-94, SD ± 6.9). The control group evaluating the clinical outcome using the Harris Hip Score (HHS) also received a cemented primary total hip arthroplasty using the same implants. A retrospective clinical and radiological review was carried out at a mean follow-up of 68.5 months (range 30-103, SD ± 17.7). Of the 27 patients, 6 had died at the time of the latest review, with the posterior lip augmentation device still in situ and without reported further dislocation after PLAD application. In 2 of the remaining 21 patients recurrent dislocation occurred, thus a subsequent revision of respective implants had to be performed to achieve persistent joint stability. At latest follow-up no deep infection or implant loosening occurred. Surgical treatment of recurrent dislocation following primary cemented Endo-MarkIII/SP2 total hip replacement using a posterior lip augmentation device is a safe and effective procedure which can lead to a secondary stabilization of the total hip arthroplasty in about 90 % of the patients.


Growth inhibitory effect of grape phenolics against wine spoilage yeasts and acetic acid bacteria.
This paper investigates the in vitro antimicrobial potential of 15 grape phenolic compounds of various chemical classes (phenolic acids, stilbenes and flavonoids) using the broth microdilution method against yeasts and acetic acid bacteria frequently occurring in deteriorated wine. Pterostilbene (MICs=32-128 μg/mL), resveratrol (MICs=256-512 μg/mL) and luteolin (MICs=256-512 μg/mL) are among six active compounds that possessed the strongest inhibitory effects against all microorganisms tested. In the case of phenolic acids, myricetin, p-coumaric and ferulic acids exhibited selective antimicrobial activity (MICs=256-512 μg/mL), depending upon yeasts and bacteria tested. In comparison with potassium metabisulphite, all microorganisms tested were more susceptible to the phenolics. The results revealed the antibacterial and antiyeast effects against wine spoilage microorganisms of several highly potent phenolics naturally occurring in grapes. These findings also provide arguments for further investigation of stilbenes as prospective compounds reducing the need for the use of sulphites in winemaking.


Perineural extension to the skull base from early cutaneous malignancies of the midface.
To document the clinical progression of four patients with a past history of complete removal of early midface cutaneous malignancies that presented years later with isolated recurrence along the distribution of the infraorbital nerve, and to discuss the diagnostic role of early imaging to identify perineural invasion. The study is a retrospective chart review, review of radiographic findings, and review of the literature. The authors report four cases of isolated perineural invasion along the infraorbital nerve resulting from previously excised cutaneous malignancies. Pain followed by anesthesia in the distribution of second division of the trigeminal nerve should alert the practitioner about possible perineural recurrence that may require imaging and open exploration to establish the diagnosis.


Molecular characterization of meiotic recombination across the 140-kb multigenic a1-sh2 interval of maize.
The 140-kb a1-sh2 interval of the maize genome contains at least four genes (a1, yz1, x1, and sh2). Partial sequence analysis of two haplotypes has revealed many single nucleotide polymorphisms and InDel polymorphisms, including several large structural polymorphisms. The physical positions of 101 meiotic recombination breakpoints are not distributed uniformly across the interval and are instead concentrated within three recombination hot spots. Two of these recombination hot spots are genic (a1 and yz1) and one is apparently nongenic. The x1 gene is not a recombination hot spot. Thus, these results suggest that not all hot spots are genes and indicate that not all genes are hot spots. Two of the 101 recombination events arose by means of either noncrossover events involving conversion tract lengths of at least 17 kb or double-crossover events. Only one recombination breakpoint mapped to the approximately 80-kb distal portion of the a1-sh2 interval that contains large amounts of repetitive DNA including retrotransposons; in this region the ratio of genetic to physical distance is less than 0.5% of the genome's average. These results establish that the retrotransposon faction of the maize genome is relatively inert recombinationally.


Biosensor detection of botulinum toxoid A and staphylococcal enterotoxin B in food.
Immunoassays were developed for the simultaneous detection of staphylococcal enterotoxin B and botulinum toxoid A in buffer, with limits of detection of 0.1 ng/ml and 20 ng/ml, respectively. The toxins were also spiked and measured in a variety of food samples, including canned tomatoes, sweet corn, green beans, mushrooms, and tuna.


Resistance mechanisms of Mycobacterium tuberculosis against phagosomal copper overload.
Mycobacterium tuberculosis is an important bacterial pathogen with an extremely slow growth rate, an unusual outer membrane of very low permeability and a cunning ability to survive inside the human host despite a potent immune response. A key trait of M. tuberculosis is to acquire essential nutrients while still preserving its natural resistance to toxic compounds. In this regard, copper homeostasis mechanisms are particularly interesting, because copper is an important element for bacterial growth, but copper overload is toxic. In M. tuberculosis at least two enzymes require copper as a cofactor: the Cu/Zn-superoxide dismutase SodC and the cytochrome c oxidase which is essential for growth in vitro. Mutants of M. tuberculosis lacking the copper metallothionein MymT, the efflux pump CtpV and the membrane protein MctB are more susceptible to copper indicating that these proteins are part of a multipronged system to balance intracellular copper levels. Recent evidence showed that part of copper toxicity is a reversible damage of Fe-S clusters of dehydratases and the displacement of other divalent cations such as zinc and manganese as cofactors in proteins. There is accumulating evidence that macrophages use copper to poison bacteria trapped inside phagosomes. Here, we review the rapidly increasing knowledge about copper homeostasis in M. tuberculosis and contrast those with similar mechanisms in Escherichia coli. These findings reveal an intricate interplay between the host which aims to overload the phagosome with copper and M. tuberculosis which utilizes several mechanisms to reduce the toxic effects of excess copper.


Experimental upregulation of developmentally downregulated ribosomal protein large subunits 7 and 7A promotes axon regeneration after injury in vivo.
Ribosomal proteins are involved in neurodevelopment and central nervous system (CNS) disease and injury. However, the roles of specific ribosomal protein subunits in developmental axon growth, and their potential as therapeutic targets for treating CNS injuries, are still poorly understood. Here, we show that ribosomal protein large (Rpl) and small (Rps) subunit genes are substantially (56-fold) enriched amongst the genes, which are downregulated during maturation of retinal ganglion cell (RGC) CNS projection neurons. We also show that Rpl and Rps subunits are highly co-regulated in RGCs, and partially re-upregulated after optic nerve crush (ONC). Because developmental downregulation of ribosomal proteins coincides with developmental decline in neuronal intrinsic axon growth capacity, we hypothesized that Rpl/Rps incomplete re-upregulation after injury may be a part of the cellular response which attempts to reactivate intrinsic axon growth mechanisms. We found that experimentally upregulating Rpl7 and Rpl7A promoted axon regeneration after ONC in vivo. Finally, we characterized gene networks associated with Rpl/Rps, and showed that Rpl7 and Rpl7A belong to the cluster of genes, which are shared between translational and neurodevelopmental biological processes (based on gene-ontology) that are co-downregulated in maturing RGCs during the decline in intrinsic axon growth capacity.


Affinity labeling mu opioid receptors with novel radioligands.
1. A series of novel opiate ligands based upon 6alpha-naloxamine have been examined in opioid receptor binding assays. 2. Coupling an ethylamine spacer alone to 6-alpha-naloxamine gave a compound with relatively poor affinity for mu opioid receptors compared to naloxone, although it retained high affinity for kappa1 opioid receptors. Coupling a benzoyl group significantly increased the affinity. The presence at the 4-position of the benzoyl moiety of an amino-(NalAmiBen) or an azido-substituent (NalAziBen) did not significantly effect the affinity at mu receptors. However, iodinating the benzoyl moiety at the 3-position increased the affinity of the derivatives. 3. Two compounds were radiolabeled and evaluated in receptor binding assays. Both radioligands labeled sites in CHO cells stably transfected with the mouse MOR-1 clone. The amino coupound [125I]NalAmiBen and the azido derivative [125I]NalAziBen reversibly bound to membranes from CHO cells transfected with MOR-1 with high affinity in the dark. Exposure of [125I]NalAmiBen to UV did not alter the reversibility of binding, but exposure of [125I]NalAziBen to UV light led to the covalent coupling of the radioligand to the receptor. When run on SDS-PAGE, [125I]NalAziBen binding showed a band at approximately 70-80 kDa. A control corresponding to nonspecific binding failed to reveal any labeling. No bands were observed from membranes labeled with [125I]NalAmiBen.


Potential value of guard-wire technology in the interventional treatment for ostial coronary lesions.
To explore potential value of guard-wire technology during percutaneous coronary intervention (PCI) in patients with ostial coronary lesions. Patients, who underwent PCI, were collected between October 2011 and March 2017. Of the 141 patients, 63 (44.7%) have ostial lesions, and 78 (55.3%) have distal bifurcation sites. They were divided into group A (n = 71) and group B (n = 70). Group A received PCI after guard-wire technology. Group B were given balloon dilation and stent after placing guide wire through target lesion vessel. X-ray exposure time, contrast agent dosage, total PCI duration, pressure incarceration times, cases of malignant arrhythmia and cases of failed PCI of all patients were analyzed, respectively. The general clinical characteristics includes patients age, sex ratio, the proportion of complications, smoking ratio and left ventricular ejection fraction of both groups was not significantly different. X-ray exposure time, contrast agent dosage, PCI total time, stent positioning time, pressure infestation frequency, arrhythmia frequency and complication number of group B were higher than those of group A. There is no case of malignant arrhythmia and case of failed PCI in group A, while there were five malignant arrhythmia and four failed PCI in group B. Contrast agent dosage and cases of failed PCI increased in group B compared with group A. The guard wire technology is safer and more feasible to patients with ostial coronary lesions who underwent PCI.


Optical imaging of vascular pathophysiology.
Pathophysiological processes in the vascular system are the major cause of mortality and disease. Atherosclerosis, an inflammatory process in arterial walls, can lead to formation of plaques, whose rupture can lead to thrombus formation, obstruction of vessels (thrombosis), reduction of the blood flow (ischemia), cell death in the tissue fed by the occluded vessel, and depending on the affected vessel, to myocardial infarction or stroke. Imaging techniques enabling visualization of the biological processes involved in this scenario are therefore highly desirable. In recent years, a number of reporter agents and reporter systems have been developed to visualize these processes using different imaging modalities including nuclear imaging techniques, such as positron emission tomography or single photon emission computed tomography, magnetic resonance imaging, and ultrasound. This article comprises a brief overview of optical imaging techniques, such as fluorescence imaging and bioluminescence imaging for the visualization of vascular pathophysiology.


An Empirical Transmitted EPID Dosimetry Method using a Back-Projection Algorithm.
The present study aimed to introduce a rapid transmission dosimetry through an electronic portal-imaging device (EPID) to achieve two-dimensional (2D) dose distribution for homogenous environments. In this Phantom study, first, the EPID calibration curve and correction coefficients for field size were obtained from EPID and ionization chamber. Second, the EPID off-axis pixel response was measured, and the grey-scale image of the EPID was converted into portal dose image using the calibration curve. Next, the scattering contribution was calculated to obtain the primary dose. Then, by means of a verified back-projection algorithm and the Scatter-to-Primary dose ratio, a 2D dose distribution at the mid-plane was obtained. The results obtained from comparing the transmitted EPID dosimetry to the calculated dose, using commercial treatment planning system with gamma function while there is 3% dose difference and 3mm distance to agreement criteria, were in a good agreement. In addition, the pass rates of γ < 1 was 94.89% for the homogeneous volumes. Based on the results, the method proposed can be used in EPID dosimetry.


The epithelial pathology of bovine genital tuberculosis.
The histopathology of the uterine and salpingeal epithelium of five cows affected with genital tuberculosis was studied. Both optical and scanning electron microscopy were used and the results were compared. Various forms and degrees of cellular lesions are described, including hypertrophy, flattening, detachment, nuclear protrusions and alterations of the cilia. In the different sites considered (uterus: intercaruncular and caruncular areas; salpinges: isthmus and ampulla) various characteristic lesions were observed.


A 3D printing personalized percutaneous puncture guide access plate for percutaneous nephrolithotomy: a pilot study.
CT-Urography combined with 3D printing technology, digital design, construction of individualized PCNL puncture guides, and preliminary analyze their efficacy, safety puncture positioning for PCNL. Twenty-two patients with renal calculi were randomly selected at the affiliated Hospital of Xuzhou Medical University during 2017-2018. We randomly divided the patients into two groups: in 10 experimental groups, we used our 3D printing personalized percutaneous puncture guide access plate for PCNL, and in the control group, 12 patients with standard USG guide PCNL. The accuracy of puncture position, puncture time, and intraoperative blood loss was compared. In the experimental group, 10 patients with 3D printing personalized percutaneous puncture guide access plate. The puncture needle was accessed through the guide plate and verified by the color Doppler. The single puncture, needle position, and depth success rate were 100.00% (10/10). The angles were consistent with the preoperative design. In the control group, 12 patients via USG guided PCNL success rate was 75.00% (9/12). The puncture time and amount of hemorrhage was (7.78 ± 0.94) min and (49.31 ± 6.43) mL, and (9.04 ± 1.09) min and (60.08 ± 12.18) mL, respectively. The above data of the two groups were statistically significant (P < 0.05). 3D printing personalized percutaneous nephrolithotomy guide plate for PCNL can improve PCNL renal puncture channel positioning accuracy, shorten puncture time, reduce intraoperative blood loss, bleeding-related complications and provide a new method for PCNL renal puncture positioning, which is worthy of further clinical exploration.


'The Elephant Man' as 'self' and 'other': the psycho-social costs of a misdiagnosis.
'The Elephant Man's Disease' acquired enormous notoriety through the portrayals of the life of Joseph Merrick, 'The Elephant Man', on American stage, screen and television. These portrayals, inspired by Ashley Montagu's book, The Elephant Man (1971) parleyed the designation of Merrick's condition into a household phrase, a metaphor for the grimmest extreme of ugliness. This paper explores the impact of 'The Elephant Man' as the chief referent and role model for persons who believed they shared the condition of neurofibromatosis 1, a neurological genetic disorder, which was erroneously believed at the time his story was popularized to have affected Joseph Merrick. Data were gathered through interviews with sixty affected individuals and families about their responses to the media representations of 'The Elephant Man'. Informants were recruited from three NF Support Groups and two urban hospital caseloads in Northern California.


[A new hetisine-type alkaloid from the stems and leaves of Aconitum coreanum].
To study the chemical constituents of the stems and leaves of Aconitum coreanum (Lèvl.) Rapaics. The constituents of Aconitum coreanum were isolated by using various kinds of modern chromatographic methods. The new alkaloid was identified on the basis of spectral analysis. Two compounds were isolated and identified as: 13-dehydro-1beta-acetyl-2alpha,6beta-dihydroxyhetisine (I) and Guanfu base G (II). Compound I is a new alkaloid.


Nuclear triiodothyronine receptors in the developing rat brain.
This study examines whether the high sensitivity of the developing brain to thyroid hormones and the purported decline in sensitivity in adulthood, are correlated with changes in the density and affinity characteristics of specific nuclear T3 receptors. The authors have found that the nuclei of cerebral hemispheres have a high density of T3 receptors at birth (212 +/-28 X 10(-17) mol/microgram DNA) which declines to adult levels by the end of the second postnatal week (115 +/- 7 X 10(-17) mol/microgram DNA), remaining at this level until 6 months of age. Even though no significant changes were detected in the equilibrium dissociation constant (Kd) during the early period of development, comparison neonatal with the adult brain reveals a decrease in Kd (neonatal, 3.9 X 10(-10) M; adult, 2.3 X 10(-10) M). In the developing animal, neonatal thyroidectomy increased the number of binding sites in the nucleus by 36--44%. It is concluded that the high number of nuclear T3 receptors in the first week of postnatal life is correlated with the high dependence of brain tissue on thyroid hormones and that the decline in brain sensitivity may be associated with the decline in nuclear T3 receptors. The high affinity and density of nuclear receptors in adult brain tissue relative to the developing brain and liver, respectively, point to a continued regulatory role of thyroid hormones in brain.


Selective attention dysfunctions in adult rats neonatally treated with 6-hydoxydopamine.
Adult rats treated intracisternally with 6-hydroxydopamine during the perinatal period were trained on a black-white discrimination. Alterations in cue shape and cue location failed to selectively distinguish differences in response patterns for the treated animals. However, when irrelevant stimuli were added to the discriminative array, the 6-hydroxydopamine group evidenced marked impairment of performance throughout the period of distraction.


Isoflurane impairs odour discrimination learning in rats: differential effects on short- and long-term memory.
Anaesthetics suppress the formation of lasting memories at concentrations that do not suppress perception, but it is unclear which elements of the complex cascade leading from a conscious experience to a lasting memory trace are disrupted. Experiments in conscious humans suggest that subhypnotic concentrations of anaesthetics impair consolidation or maintenance rather than acquisition of a representation (long-term more than short-term memory). We sought to test whether these agents similarly impair learning in rats. We used operant conditioning in rats to examine the effect of isoflurane on acquisition compared with long-term (24 h) memory of non-aversive olfactory memories using two different odour discrimination tasks. Rats learned the 'valences' of odour pairs presented either separately (task A) or simultaneously (task B), under control conditions and under isoflurane inhalation. In a separate set of experiments, we tested the ability of the animals to recall a learning set that had been acquired 24 h previously. Under 0.4% isoflurane inhalation, the average number of trials required to reach criterion performance (18 correct responses in 20 successive trials) increased from 21.9 to 43.5 (P<0.05) and 24.2 to 54.4 (P<0.05) for tasks A and B, respectively. Under 0.3% isoflurane inhalation, only task B was impaired (from 24.2 to 31.5 trials, P<0.05). Recall at 24 h was dose-dependently impaired or prevented by isoflurane for both tasks. Isoflurane interfered with long-term memory of odour valence without preventing its acquisition. This paradigm may serve as a non-aversive animal model of conscious amnesia.


Comparative analysis in different organs and tissue-specific metabolite profiling of Atractylodes lancea from four regions by GC-MS and laser microdissection.
Traditional Chinese medicine is made from the rhizome of Atractylodes lancea (Thunb.) DC. (Compositae), known as Cangzhu. In this study, gas chromatography-mass spectrometry was used to identify and quantify the volatile oils of different organs of A. lancea from four regions of China: Jiangsu, Anhui, Henan, and Hubei provinces. The volatile oils of A. lancea were qualitatively and quantitatively characterized using gas chromatography-mass spectrometry combined with laser microdissection. The results identified 21 components in A. lancea, the majority of the components were found in the rhizomes, followed by the fibrous roots, flowers, leaves, and stems. According to the contents of volatile oils in A. lancea, it was divided into Dabieshan (mainly includes hinesol and β-eudesmol) and Maoshan types (mainly includes atractylon and atractylodin), and the ratios of hinesol:β-eudesmol:atractylon:atractylodin were 17.06:4.55:0:1, 12.66:11.71:0.99:1, 7.43:6.23:0:1, and 0.13:0.16:1.52:1 in A. lancea from AH, HN, HB, and JS, respectively. Tissue-specific study indicated that Dabieshan type mainly includes elemol, hinesol, and β-eudesmol in the periderm and secretory cavities of A. lancea, whereas Maoshan type mainly includes atractylon, atractylodin, little hinesol, and β-eudesmol in the secretory cavities. Conversely, no volatile oils were detected in the cortex, phloem, xylem, vascular ray, or pith. This study provides a foundation for further evaluation and utilization of A. lancea.


Growth and transformation in workplace alcoholism programming.
The origins of contemporary workplace programs to provide constructive assistance to employees with alcohol problems are described. The transformation from industrial alcoholism programming to employee assistance programming is delineated in terms of a seven-component "core technology." The high degree of reported success of these programs is described with general findings from a survey of 480 private-company sites. Increasing rates of self-referral for assistance with alcohol problems are described in terms of factors facilitating such referrals. Basic research knowledge is summarized, together with a projection of new studies considered to be critical for maximizing the effectiveness of alcoholism intervention as it relates to workplace programs. Throughout the chapter the large-scale impact of workplace programming is emphasized, with an urgency for greater attention to be paid to these activities by the alcohol problem research community.


Uptake rates and attitudes to influenza and COVID-19 vaccination in pregnancy - a prospective cohort study.
Influenza and COVID-19 are highly prevalent RNA viruses. Pregnancy increases the frequency of severe maternal morbidity and mortality associated with these viruses. Vaccination plays an important role in protecting pregnant women and their infants from adverse outcomes. In this prospective study, we aimed to determine the vaccination uptake rate for influenza and COVID-19 in a pregnant population and to explore reasons why women remained unvaccinated. A prospective cohort study was conducted over a two-week period in December 2022 in the National Maternity Hospital, Dublin. There were 588 women surveyed over the 2-week period. Overall, 377 (57%) were vaccinated that year for seasonal influenza, a significant rise from 39% in a similar study in 2016. The majority (n = 488, 83%) of women reported receiving at least one COVID-19 vaccine. However only 132 (22%) received a COVID-19 vaccine in pregnancy, despite 76% (n = 466) stating they would be happy to receive it. Factors such as age, obesity, co-morbidities, ethnic group, and type of antenatal care received were shown to influence vaccination rates. We recommend that the importance of vaccination be stressed regularly to eligible patients at their antenatal clinic visits and where possible combining influenza/COVID-19 vaccination on the same day to improve uptake.


Pulmonary stenosis in infants and young children.
Twenty-four patients less than 3 years old underwent operation for pulmonary stenosis. Pulmonary dysplasia was diagnosed preoperatively in only 4 patients; in 20 patients the lesion was categorized simply as pulmonary stenosis. At operation, more severe valve deformities were often present in patients less than 2 years of age. Preoperative evaluation did not reveal the extent of the deformity in 7 additional patients. The deformities included not only valvular dysplasia (thickened redundant valve cusps) but also supravalvular and annular abnormalities. Relief of obstruction was obtained only when all components of the obstructive abnormality were relieved. Patch angioplasty of the right ventricular outflow tract was necessary in 13 patients with complex morphology. Valvotomy was effective only for pulmonary stenosis due to pure commissural fusion. A spectrum of the morphology of pulmonary stenosis is recognized, with more complex lesions than simple commissural fusion identified in younger children. The more complex lesions may require more extensive operations (outflow tract patch) to completely relieve the obstructive pathological condition in the outflow tract.


[New developments in the fight against bacterial infections : Update on antiobiotic research, development and treatment].
Infections caused by pathogens with antimicrobial resistance (AMR) pose a threat to modern healthcare and have triggered the development of comprehensive national and global action plans against the spread of AMR. These include an increasing global network with the focus on rational antibiotic use, innovative strategies on antibiotic research and development, and new therapeutic approaches in antibacterial drug research. In Europe 671,689 infections associated with AMR pathogens and 33,110 deaths directly related to AMR were counted in just 1 year. Globally, resistant Staphylococcus aureus, Escherichia coli, pneumococci, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are the most common pathogens in the context of these deaths. Resistance to antibiotics in major drug classes such as beta-lactams and fluoroquinolones is particularly common. Strategies for overcoming the global AMR crisis address research on AMR emergence and spread, promoting campaigns for responsible antibiotic use, and improving infection prevention. The identification of new antibiotics and treatment approaches and the development of new strategies to contain the spread of AMR are essential. Newly approved substances include delafloxacin, lefamulin, and meropenem-vaborbactam. New antibiotics that are well advanced in clinical trials are aztreonam-avibactam, sulbactam-durlobactam, omadacycline, and type II topoisomerase inhibitors. Much interest is also being shown in the development of new therapeutic approaches such as bacteriophage treatment.


Selective Removal to Soft Dentine versus Full Pulpotomy for Management of Proximal Deep Carious Lesions: A Randomized Controlled Non-Inferiority Trial.
The management of the deep carious lesion with reversible pulpitis is a dilemma for the dentist. The current study compared selective removal to soft dentine (SRSD) and full pulpotomy (FP) for treating proximal deep carious lesions in teeth with reversible pulpitis. Visual-tactile examination and bitewing radiographs were used to determine the depth of carious lesion, and American Association of Endodontists recommendations were used to formulate pulp diagnosis. Sixty mandibular molar teeth from healthy patients between the ages of 16-35 years and a diagnosis of proximal deep carious lesion with reversible pulpitis were included. Teeth were randomly allocated to two study groups. SRSD group (n = 30): soft dentine was preserved over the pulpal aspect. A hard-setting calcium hydroxide cement liner and resin-modified glass ionomer cement base were applied over the remaining soft carious dentine. FP group (n = 30): complete caries removal followed by mineral trioxide aggregate FP was performed. The teeth in both groups were restored with composite resin restoration. The established criteria for outcome assessment of SRSD and pulpotomy were used. Accordingly, only asymptomatic teeth with no radiological evidence of periapical rarefaction were considered successful at the 12-month follow-up. Two-sample t test, Pearson χ2 test/Fisher's exact test, and percentage agreement were used for statistical evaluation. According to the per-protocol analysis, the success rate of both SRSD and FP treatment was 95.45% and 95.65%, respectively, and the actual difference between the two treatments was 1% (95% CI: [-10, 9]). The data suggests that both treatments (SRSD and FP) appear to have a good success rate (>95%) when used to manage permanent mandibular molar teeth with proximal deep carious lesion and reversible pulpitis. As SRSD is a noninvasive procedure, it should be favored over FP in these instances.


A CASSCF/CASPT2 insight into excited-state intramolecular proton transfer of four imidazole derivatives.
Excited-state intramolecular proton transfer (ESIPT) of four imidazole derivatives, 2-(2'-hydroxyphenyl)imidazole (HPI), 2-(2'-hydroxyphenyl)benzimidazole (HPBI), 2-(2'-hydroxyphenyl)-1H-phenanthro[9,10-d]imidazole (HPPI) and 2-(2'-hydroxyphenyl)-1-phenyl-1H-phenanthro[9,10-d]imidazole (HPPPI), were studied by the sophisticated CASSCF/CASPT2 methodology. The state-averaged SA-CASSCF method was used to optimize their geometry structures of S0 and S1 electronic states, and the CASPT2 calculations were used for the calibration of all the single-point energies, including the absorption and emission spectra. A reasonable agreement is found between the theoretical predictions and the available experimental spectral data. The forward ESIPT barriers of four target compounds gradually decrease with the increase of molecular size. On the basis of the present calculations, it is a plausible speculation that the larger the size, the faster is the ESIPT rate, and eventually, HPPPI molecule can undergo a completely barrierless ESIPT to the more stable S1 keto form. Additionally, taking HPI as a representative example, the radiationless decays connecting the S0 and S1 /S0 conical intersection structures were also studied by constructing a linearly interpolated internal coordinate (LIIC) reaction path. The qualitative analysis shows that the LIIC barrier of HPI in the keto form is remarkably lower than that of its enol-form, indicating that the former has a big advantage over the latter in the nonradiative process.


Specificity of purified protein derivative extracts from ten species of Mycobacteria killed with phenol in the haemagglutination and haemagglutination inhibition test.
The specificity of purified protein derivative (PPD) extracts from 10 species of Mycobacteria killed with phenol was evaluated using the haemagglutinin (HA) and haemagglutination inhibition (HI) tests. The HA test showed many cross-reactions with homologous and heterologous antisera. In the HI test, many antisera cross-reacted with most PPD extracts. The PPD extracts from Mycobacterium foruitum and M. smegmatis were the most specific. It was concluded that PPD extracted from unheated bacilli was not sufficiently specific for use in HI tests.


Expressions of resistance and cross-resistance in teniposide-resistant L1210 cells.
Resistance to teniposide (VM-26) by VM-26 selected resistant L1210 cells in culture was attributed to alterations in the flux of VM-26 across the plasma membrane and to functions of homogeneously staining regions that appeared on one or more chromosomes. In the present study, electrophoresis of membrane-cytosol fractions of these resistant sublines demonstrated a protein band, Mr 22 kd, that was not evident in similar fractions of drug-sensitive L1210 cells or three revertant sublines. The distribution of this protein among various cellular fractions could be altered by manipulation of the concentration of calcium ions. A representative subline, LIa5 microM, was observed to have vesicles that reacted with Sudan black B stain, an indication of altered lipid metabolism. The LIa5 microM subline was cross-resistant to etoposide, vincristine, doxorubicin, amsacrine, and actinomycin D. Concentrations of VM-26 that inhibited cell division to the same extent caused an accumulation of fewer cells in the G2 stage of cell division in LIa5 microM cultures than in L1210 cultures. These observations indicate that the LIa5 microM subline expressed multiple drug resistance, as well as changes in the expression of cytotoxicity to VM-26.


Snapshot of an oxygen intermediate in the catalytic reaction of cytochrome c oxidase.
Cytochrome c oxidase (CcO) reduces dioxygen to water and harnesses the chemical energy to drive proton translocation across the inner mitochondrial membrane by an unresolved mechanism. By using time-resolved serial femtosecond crystallography, we identified a key oxygen intermediate of bovine CcO. It is assigned to the PR-intermediate, which is characterized by specific redox states of the metal centers and a distinct protein conformation. The heme a3 iron atom is in a ferryl (Fe4+ = O2-) configuration, and heme a and CuB are oxidized while CuA is reduced. A Helix-X segment is poised in an open conformational state; the heme a farnesyl sidechain is H-bonded to S382, and loop-I-II adopts a distinct structure. These data offer insights into the mechanism by which the oxygen chemistry is coupled to unidirectional proton translocation.


Long-term remission of blastic natural killer-cell lymphoma after autologous peripheral blood stem-cell transplantation.
We report here a case of blastic natural killer (NK)-cell lymphoma treated successfully with autologous peripheral blood stem-cell transplantation (APBSCT). A 57-year-old man had skin tumors and was diagnosed as having blastic NK-cell lymphoma by tumor biopsy. Skin, lymph nodes, left tonsil, and bone marrow were involved at presentation. Chemotherapy led to complete remission (CR). To sustain CR, the patient underwent high-dose chemotherapy in combination with 12 Gy of total-body irradiation (TBI) followed by autologous peripheral blood stem-cell rescue. He showed rapid recovery of hematopoiesis and could tolerate regimen-related toxicity after APBSCT. He has maintained long-term remission for 20 months after APBSCT. From this case, we concluded that APBSCT with preconditioning by TBI-containing regimens might be a cure-attaining treatment for disseminated blastic NK-cell lymphoma and should be considered as a choice of treatment in cases where no suitable donors for allogeneic transplantation are available.


The role of a dental operating microscope in improved nonsurgical treatment of "calcified" canals.
Three cases illustrating successful nonsurgical treatment of "calcified" canals are presented. Careful round bur drilling through dense calcified deposits in the pulp chamber and into the canal may uncover a treatable apical canal remnant. The dental operating microscope (Dentiscope) is an invaluable aid.


A simple procedure for electron microscopy of Golgi-impregnated nerve cells.
Most of the precipitations that normally fill up Golgi impregnated nerve cells can easily be removed by placing the material in a diluted solution of ammonia for several hours. A very fine scattering of electron-dense particles remains. Preparations processed in this way can be studied electron microscopically, in this way rendering fine structural examination of previously identified neurons possible. The method is applicable for silver chromate Golgi techniques and can be used for all parts of the brain.


Solutions for organ perfusion and storage: haemorheologic aspects.
The hydroxyethyl starch (HES) contained in University of Wisconsin (UW) solution causes erythrocyte aggregation. The effect of UW on red blood cell (RBC) deformability is still unclear. HES-free preservation solutions, Celsior (CS) and Custodiol (CU) are available. In this study we evaluated whether they really showed a reduced aggregating and stiffening effect on RBCs when compared with UW. We was also evaluated the effect of these solutions on cellular membranes by measuring acetylcholinesterase (AChE), which is a marker of RBC membrane integrity. The determination of RBC aggregation and deformability was performed by a laser-assisted optical rotation cell analyzer (LORCA). AChE measurement was performed with a spectrophotometric technique. The mean RBC aggregation index (AI) measured in pure blood control samples was 28.00 +/- 0.73%. The AI measured samples containing UW was 38.82 +/- 1.58%. In samples with CS, it was 13.307 +/- 0.64% and in samples with CU the mean AI was 12.47 +/- 0.42%. Also the RBC aggregating time was quicker in presence of UW compared with controls. AChE concentration in blood was 3.043 +/- 0.4 nmol. CS and UW did not produce any significant change; a significant reduction was found when CU was added to blood, namely 1.975 +/- 0.1 nmol (P < .05). The use of UW or CS or CU did not result in any significant change in RBC deformability. CS and CU solutions do not aggregate erythrocytes, whereas Wisconsin does massively. CU causes an alteration of RBC cellular membrane as demonstrated by depletion of AChE.


A network model for blind source extraction in various ill-conditioned cases.
This paper discusses blind source extraction in various ill-conditioned cases based on a simple extraction network model. Extractability is first analyzed for the following ill-conditioned cases: the mixing matrix is square but singular, the number of sensors is smaller than that of sources, the number of sensors is larger than that of sources but the column rank of mixing matrix is deficient, and the number of sources is unknown and the column rank of mixing matrix is deficient. A necessary and sufficient condition for extractability is obtained. A cost function and an unsupervised learning algorithm for the extraction network model are developed. Simulation results are also presented to show the validity of the theoretical results and the performance and characteristics of the learning algorithm.


Three new cytotoxic metabolites from the marine sponge Plakortis halichondrioides.
Three new cytotoxic compounds, one a cyclic-peroxide-containing acid (5) and the two others alkylated dihydroxy alpha,beta-unsaturated C22 and C21 acids (6 and 7), were isolated from the marine sponge Plakortis halichondrioides, which was collected off the coast of Jamaica. The structures were elucidated through mass and mainly 1D and 2D nmr spectral analysis. All three acids are cytotoxic against P-388 murine leukemia.


Posttraining flavor exposure in hungry rats after simultaneous conditioning with a nutrient converts the CS into a conditioned inhibitor.
The present study investigated the decrement in nutrient-based conditioned flavor preference found in hungry rats exposed to a flavor following simultaneous flavor-sucrose conditioning while thirsty. Although a significant decrease in preference was found in the experimental group in each experiment, there was no evidence of either spontaneous recovery (Experiment 1) or reinstatement (Experiment 2). In addition, posttraining flavor exposure weakened the original flavor-sucrose association (Experiment 3). These results suggested that the flavor-US association might have been impaired after posttraining flavor exposure. Two further experiments assessed whether the flavor acquired the properties of a net inhibitor, using the retardation and summation tests for conditioned inhibition. Experiment 4 revealed that the flavor suffered retardation when retraining was conducted after the exposure phase. In Experiment 5, the target flavor decreased the preference shown for a different flavor previously paired simultaneously with sucrose when both were presented forming an unreinforced compound in the summation tests. None of these effects was found in a control group, which had received serial flavor → nutrient presentations during training. Together, these results suggest that a flavor simultaneously paired with sucrose acquires the properties of a net inhibitor when it is subsequently presented outside the compound to hungry animals.


Wear simulation of reverse total shoulder arthroplasty systems: effect of glenosphere design.
Although early results with reverse total shoulder arthroplasty (rTSA) have been promising, concern exists about the high reported rates of scapular notching and the potential for catastrophic failure of glenoid component fixation. Generation of polyethylene wear debris may also contribute to notching and osteolysis of the scapula. A testing model for polyethylene wear is currently unavailable for reverse shoulder prostheses. The goal of this study was to develop a testing protocol using a commercially available hip simulator. Component design may also influence the generation of polyethylene debris. It is hypothesized that increased polyethylene wear occurs in glenospheres with holes in the articulating surface. Custom fixtures were fabricated to simulate both glenohumeral abduction and flexion on a 12-station hip wear simulator. Loading profiles for both abduction and flexion were alternated every 250,000 cycles for a total of 5 million cycles. Gravimetric analysis of humeral cups throughout the test was used to characterize wear. Lubricant fluid was collected throughout the test and digested for polyethylene particle analysis. Comparisons of volumetric wear rates and total volume loss between glenospheres with and without holes and between flexion and abduction loading profiles showed similar results. Particle analysis displayed fibrillar particles with an equivalent circle diameter of 0.3 ± .1 μm and an aspect ratio of 2.5 ± 1.4. This study represents the first wear simulation and particle characterization of reverse shoulder systems. No significant difference in wear was reported between glenospheres with and without holes.


Poisson-based image editing for semi-supervised vitiligo lesion segmentation with limited annotations.
Vitiligo lesion segmentation is crucial for the assessment and treatment of vitiligo. There are two significant challenges in this problem, namely, the availability of dense segmentation annotations and the collection of large amounts of vitiligo images, which are also major challenges in medical image analysis (MIA). However, most existing methods often heavily rely on the availability of large-scale labeled datasets and high-quality annotations. Consequently, the performance of these models may not be easily reproducible or transferable to those domains with limited data availability. As a result, there is a need to develop alternative approaches that can leverage unlabeled datasets for segmentation with a small-scale training set. In this paper, we propose a data augmentation strategy based on image editing, which can synthesize a large number of samples using a small number of annotated data. The synthesized examples are of high visual quality and enforce the segmentation performance without any cost. Besides, we also adapt the Mean-Teacher framework for reliable predictions mining from unlabeled samples to alleviate the demands of densely annotated segmentations. We obtain pseudo-labels for unlabeled samples by utilizing highly confident pixels. On the other hand, we proposed a new Bimodal Vitiligo Lesions Segmentation (BVLS) dataset containing fine-grain segmentation masks and bimodal images usually used for vitiligo diagnosis to mitigate the lack of a vitiligo segmentation dataset. Extensive experiments conducted on the BLVS dataset demonstrate that our approach can achieve significant improvements (+17.27%) compared with previous data augmentation methods on the UNet backbone. Furthermore, the semi-supervised framework can reach an IoU of 49.71% with only 10% annotated images. Our code and dataset are availabel at https://github.com/JcWang20/BLVS.


Cellular and subcellular heterogeneity of glutathione metabolism and transport in rat kidney cells.
Selective permeabilization of plasma membranes with digitonin produced separation of cytosolic and mitochondrial compartments of proximal tubular (PT) and distal tubular (DT) cells from a rat kidney. Subcellular distributions of several intracellular glutathione (GSH)-dependent enzymes were similar in the two cell types but specific activities were significantly higher in PT cells, indicating that DT cells, particularly in their mitochondrial fraction, have a diminished capacity to detoxify reactive oxygen species. To enable isolation of suspensions of mitochondria, renal cells were treated with digitonin followed by the bacterial protease nagarse and were filtered through polycarbonate membranes. Activity distributions of enzymatic markers for subcellular fractions were quantitated and uptake of GSH was studied in suspensions of PT and DT cell mitochondria. While PT cell mitochondria catalyzed rapid uptake of GSH that was inhibited by malate, indicating involvement of dicarboxylate carriers, DT cell mitochondria exhibited limited capacity for GSH uptake that was not inhibited by substrates for the two dicarboxylate carriers. This report provides the first description of methodology for the preparation of mitochondria from renal cells derived from specific nephron cell types and shows that mitochondria from DT cells have a significantly lower capacity to use GSH for detoxification and regulation of redox status.


Fusion of macrophages on an implant surface is associated with down-regulated expression of ligands for galectin-1 and -3 in the rat.
Galectins have a wide range of biological activities which are elicited by binding to appropriate glycoligands. Besides regulation of the expression of the galectins the extent of the presence of suitable binding sites will be relevant to infer the cellular responsiveness to this class of sugar receptors. Thus ligand presentation requires monitoring by the tissue lectin. We demonstrate the expression of galectin-3 by macrophages and foreign-body giant multinucleate cells colonizing a cellophane implant in the rat by the A1D6 monoclonal antibody. The extents of ligand presence are visualized in the same cells by biotinylated galectin-3 and also by galectin-1 which is produced by diverse mammalian cell types and widely distributed. Labeled mistletoe (VAA) and tomato (LEA) lectins are used as tools to assess the degree of similarity of the binding profile between endogenous and exogenous proteins. The presentation of alpha-galactosides is monitored with a natural immunoglobulin G subfraction obtained by two consecutive affinity chromatography steps. The binding of labeled galectins and plant lectins was significantly lower to foreign-body giant multinucleate cells than to mononuclear macrophages. The application of the alpha-galactoside-specific probe yielded no significant staining. The potential problem of epitope accessibility could be excluded by the concomitant positivity obtained with an IgG subfraction with selectivity to beta-galactosides also obtained by affinity chromatography. These results provide no evidence for a role of alpha-galactosides for the binding of galectins in the rat macrophages colonizing the implant. The reduced level of expression of glycoligands for galectin-1 and -3 in foreign-body giant multinucleate cells in contrast with the mononuclear macrophages suggests an inhibitory influence of macrophage fusion on the expression of galectin-reactive molecules.


Response of the hen ovary to eCG treatment: Insight into morphology and expression of genes related to steroidogenesis and vitellogenesis.
The present study aimed to examine the effect of equine chorionic gonadotropin (eCG) treatment on the chicken ovarian folliculogenesis and steroidogenesis. The expression of vitellogenesis-related genes in the liver was also investigated. Laying hens were injected with 75 I.U./kg of body weight/0.2 mL of eCG, once a day for 7 successive days. On day 7 of the experiment hens, including control hens which were receiving vehicle, were euthanized. The liver and ovarian follicles were harvested. Blood was collected daily through the whole experiment. The eCG treatment resulted in the cessation of egg laying after 3 or 4 days. The eCG-treated hens had heavier ovaries with a higher number of yellowish and yellow follicles arranged in a non-hierarchical way in contrast to ovaries of control hens. Moreover, these birds had elevated plasma estradiol (E2) and testosterone (T) concentrations. The molar ratios of E2:progesterone (P4) and T:P4 were increased in chickens injected with eCG. Real-time polymerase chain reaction revealed changes in mRNA abundances of steroidogenesis-associated genes (StAR, CYP11A1, HSD3β, and CYP19A1) in ovarian follicles: white, yellowish, small yellow, and the largest yellow preovulatory (F3-F1) as well as VTG2, apoVLDL II, and gonadotropin receptors in the liver. In general, the abundances of gene transcripts were higher in eCG-treated hens than in control hens. Western blot analyses showed an elevated abundance of aromatase protein in the prehierarchical and small yellow follicles of eCG-treated hens. Unexpectedly, there was presence of both FSHR and LHCGR mRNA in the liver and the level of expression was shifted in eCG-treated hens. In summary, eCG treatment leads to disruption of the ovarian hierarchy with accompanying changes in circulating steroids and ovarian steroidogenesis.


Loss of Regulatory Immune Function in Coronary Artery Disease Patients from the Indian Population.
The pathogenic roles of inflammatory T cells and monocytes subsets have not been explored in different manifestations of coronary artery disease. We studied the frequency of these cells, their response to autoantigens, regulatory cell functional assay, foam cell formation and macrophage differentiation in 181 patients (stable angina, ST-elevated myocardial infarction (STEMI), NSTEMI, and unstable angina), and 34 controls and in samples collected during recurrent cardiac events and from patients showing clinical improvement. The proportion of Th17 cells and monocytes gradually increased in patients with stable angina at one end of the spectrum followed by NSTEMI, STEMI, and unstable angina at other end. Inflammatory cells were positively and inversely associated with recurrent events and clinical improvement, respectively. Patients showed expansion of Th17 cells in response to autoantigen (HSP60) and compromised Treg function. Our results suggest that stress-induced activation of inflammatory cells expands in the absence of regulatory control in CAD patients.


Neurophysiologic predictors of response to atomoxetine in young adults with attention deficit hyperactivity disorder: a pilot project.
Atomoxetine is a non-stimulant medication with sustained benefit throughout the day, and is a useful pharmacologic treatment option for young adults with Attention-Deficit/Hyperactivity Disorder (ADHD). It is difficult to determine, however, those patients for whom atomoxetine will be both effective and advantageous. Patients may need to take the medication for several weeks before therapeutic benefit is apparent, so a biomarker that could predict atomoxetine effectiveness early in the course of treatment could be clinically useful. There has been increased interest in the study of thalamocortical oscillatory activity using quantitative electroencephalography (qEEG) as a biomarker in ADHD. In this study, we investigated qEEG absolute power, relative power, and cordance, which have been shown to predict response to reuptake inhibitor antidepressants in Major Depressive Disorder (MDD), as potential predictors of response to atomoxetine. Forty-four young adults with ADHD (ages 18-30) enrolled in a multi-site, double-blind placebo-controlled study of the effectiveness of atomoxetine and underwent serial qEEG recordings at pretreatment baseline and one week after the start of medication. qEEG measures were calculated from a subset of the sample (N = 29) that provided useable qEEG recordings. Left temporoparietal cordance in the theta frequency band after one week of treatment was associated with ADHD symptom improvement and quality of life measured at 12 weeks in atomoxetine-treated subjects, but not in those treated with placebo. Neither absolute nor relative power measures selectively predicted improvement in medication-treated subjects. Measuring theta cordance after one week of treatment could be useful in predicting atomoxetine treatment response in adult ADHD.


Alternatives to ileostomy after colectomy for inflammatory bowel disease.
Proctocolectomy and Brooke ileostomy have long been the standard surgical procedure for patients with refractory ulcerative colitis or colonic Crohn's disease. Ileorectal anastomosis, ileoanal anastomosis, the continent ileostomy, and the continent ostomy valve are now being used in selected patients as options to the Brooke ileostomy. The indications for and advantages of these procedures and their potential disadvantages and contraindications are discussed in this chapter.


[Dependence of the levels of morbidity with temporary loss of work capacity on the body functional state of those working in hypokinesia].
The study was designed to analyze the relation of body functioning and temporary disability rates in order to identify physiologic indices characterizing health status and its possible variations. As illustrated by the data on health status of female workers engaged in precision assembly work and exposed to hypokinesia it was established that the indices of general physical work capacity could be used for predicting possible changes in workers' health state. The workers with high levels of physical capacity for work had lower morbidity rates, that tendency being especially revealed in workers of older age groups.


Tonically active neurons in the striatum encode motivational contexts of action.
In order to achieve a goal, one procures immediately available rewards, escape from aversive events or endures absence of rewards. The neuronal substrate for these goal-directed actions includes the limbic system and the basal ganglia. In the basal ganglia, classes of projection neurons in the striatum show activity with motivational as well as sensorimotor properties, such as expectation of reward and task schedule for obtaining reward. Tonically active neurons (TANs), presumed cholinergic interneurons in the striatum, respond to reward-associated stimuli, evolve their activity through learning and respond also to aversive event-associated stimuli such as airpuff on the face. A recent study showed that responses to visual cues are less selective to whether the cue instructs reward or no reward. To address this paradox, we asked macaque monkeys to perform a set of visual reaction time tasks while expecting the reward, aversive event or absence of reward. We found that TANs respond to instruction stimuli associated with motivational outcomes but not to unassociated ones, and that they mostly differentiate associated instructions. We also found that the higher percentage of TANs in the caudate nucleus respond to stimuli associated with motivational outcomes than in the putamen, whereas the higher percentage of TANs in the putamen respond to GO signals than in the caudate nucleus especially for an action anticipating a reward. These findings suggest a distinct, pivotal role played by TANs in the caudate nucleus and putamen in encoding instructed motivational contexts for goal-directed action selection and learning in the striatum.


Inhibition of Krebs cycle and activation of glyoxylate cycle in the course of chronological aging of Saccharomyces cerevisiae. Compensatory role of succinate oxidation.
We investigated oxidative processes in mitochondria of Saccharomyces cerevisiae grown on ethanol in the course of chronological aging. We elaborated a model of chronological aging that avoids the influence of exhaustion of medium, as well as the accumulation of toxic metabolites during aging. A decrease in total respiration of cells and, even more, of the contribution of respiration coupled with ATP-synthesis was observed during aging. Aging is also related with the decrease of the contribution of malonate-insensitive respiration. Activities of citrate-synthase (CS), alpha-ketoglutarate dehydrogenase (KGDH) and malate dehydrogenase (MDH) were threefold decreased. The activity of NADP-dependent isocitrate dehydrogenase (NADP-ICDH) decreased more significantly, while the activity of NAD-dependent isocitrate dehydrogenase (NAD-ICDH) fell even greater, being completely inactivated on the third week of aging. In contrast, succinate dehydrogenase (SDH), enzymes of glyoxylate cycle (GCL) (isocitrate lyase (ICL) and malate synthase (MLS)), and enzymes of ethanol oxidation (alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ACDH)), were activated by 50% or more. The behavior of oxidative enzymes and metabolic pathways are apparently inherent to a more viable, long-lived cells in population, selected in the course of chronological aging. This selection allows cells to reveal the mechanism of their higher viability as caused by shunting of complete Krebs cycle by glyoxylate cycle, with a concomitant increased rate of the most efficient energy source, namely succinate formation and oxidation. Thiobarbituric-reactive species (TAR species) increased during aging. We supposed that to be the immediate cause of damage of a part of yeast population. These data show that a greater succinate contribution to respiration in more active cells is a general property of yeast and animal tissues.


Synthesis, Biological Evaluation and in Silico Studies of 3-Hydroxy-N-(2-(substituted phenyl)-4-oxothiazolidin-3-yl)-2-napthamide Derivatives.
In the present study, a series of 3-hydroxy-N-(2-(substituted phenyl)-4-oxothiazolidin-3-yl)-2-napthamide derivatives were synthesized, characterized and evaluated for theirin vitroactivity, i. e., antimicrobial, antioxidant and anti-inflammatory. The target compounds were synthesized by condensation reaction of 3-hydroxy-2-naphthoic acid hydrazide with substituted benzaldehydes which were subjected to cyclization reaction with thioglycolic acid and ZnCl2 to get target compounds. The synthesized 3-hydroxy-N-(2-(substituted phenyl)-4-oxothiazolidin-3-yl)-2-napthamide derivatives were examined for their antimicrobial activity and 3-hydroxy-N-(4-oxo-2-(3,4,5-trimethoxyphenyl)thiazolidin-3-yl)-2-naphthamide (S20) exhibited the highest antimicrobial potential. The N'-(2,3-dichlorobenzylidene)-3-hydroxy-2-naphthohydrazide (S5) displayed good antifungal potential against Rhizopus oryzae, whereas N'-(2,3-dichlorobenzylidene)-3-hydroxy-2-naphthohydrazide (S20) showed the highest antioxidant potential and N-(2-(2,6-dichlorophenyl)-4-oxothiazolidin-3-yl)-3-hydroxy-2-naphthamide (S16) displayed the highest anti-inflammatory activity. The results of molecular docking studies revealed that existence of hydrogen bonding and hydrophobic interactions with their respective proteins. In silico ADMET studies were carried out by Molinspiration, Pre-ADMET and OSIRIS property explorer to predict the pharmacokinetic behaviour of synthesized 3-hydroxy-N-(2-(substituted phenyl)-4-oxothiazolidin-3-yl)-2-napthamide derivatives.


Complex interactions at a GC-rich domain regulate cell type-dependent activity of the ornithine decarboxylase promoter.
Regulation of ornithine decarboxylase (ODC) is critical to the control of cellular growth, differentiation, and carcinogenesis. A GC-rich region in the ODC promoter contains two overlapping protein binding sites that interact to regulate basal level expression in some cell types. A perfect binding motif for transcription factor Sp1 (CCCCGCCCC) is located at nucleotides -114 to -106 relative to the site of transcriptional initiation, binds strongly to purified Sp1 protein, and forms several complexes when incubated with nuclear extracts. Only one of these complexes is recognized by Sp1-specific antibody. A new protein-binding motif (GCCCCTCCCC, located at -110 to -100) partially overlaps with the Sp1 site and analyses by DNase I protection showed that a new protein ("NF-ODC1") and the Sp1-like proteins interact with the ODC promoter in a mutually exclusive manner. Mutation of the NF-ODC1 binding motif strongly enhanced ODC promoter strength in some cell types, but had little or no influence in others. The effect of mutating the Sp1 site also varied with cell type. These cell type specificities did not correlate with the levels of Sp1 and NF-ODC1 binding activities in nuclear extracts. These results show that regulation of the ODC promoter by the Sp1 family is cell type-specific and modulated by a negative effector that we have termed NF-ODC1.


Novel Pd(II)-catalysed N,O-bicyclisation as an efficient route to the 6-oxa-2-azabicyclo[3.2.1]octane skeleton.
1-(Benzyloxycarbonylamino)-hex-5-en-3-ol undergoes a novel Pd(II)/CuCl2-catalysed bicyclisation to furnish the corresponding 6-oxa-2-azabicyclo[3.2.1]octane in good yield.


The need for physiological phenotyping to develop new drugs for airways disease.
Asthma and COPD make up the majority of obstructive airways diseases (OADs), which affects ∼11 % of the population. The main drugs used to treat OADs have not changed in the past five decades, with advancements mainly comprising variations on existing treatments. The recent biologics are beneficial to only specific subsets of patients. Part of this may lie in our inability to adequately characterise the tremendous heterogeneity in every aspect of OAD. The field is currently moving towards the concept of personalised medicine, based on a focus on treatable traits that are objective, measurable and modifiable. We propose extending this concept via the use of emerging clinical tools for comprehensive physiological phenotyping. We describe, based on published data, the evidence for the use of functional imaging, gas washout techniques and oscillometry, as well as potential future applications, to more comprehensively assess and predict treatment response in OADs. In this way, we hope to demonstrate how physiological phenotyping tools will improve the way in which drugs are prescribed, but most importantly, will facilitate development of new drugs for OADs.


Circadian dynamics of vasopressin in mouse selection lines: translation and release in the SCN.
Arg8-vasopressin (AVP), a circadian clock-controlled gene product, is released from the hypothalamic suprachiasmatic nuclei (SCN) in mice in a circadian fashion. Previously reported differences in two mouse lines, initially selected for thermoregulatory nest-building behavior (building small nests (S-mice) or big nests (B-mice)) with different circadian organization of behavior and in number of SCN-AVP immunoreactive neurons, were further investigated. We confirmed and expanded the finding that S-mice exhibited constant high levels of SCN-AVP content with no apparent circadian rhythmicity, whereas B-mice had lower numbers of AVP positive cells which varied with time of day. We found that AVP mRNA expression levels at midnight and midday were similar in both lines, as established by in situ hybridization. When AVP transport and release were blocked by colchicine, SCN-AVP immunoreactivity was similar in both lines. This suggests that differences in SCN-AVP content depend on transport or release. Organotypic SCN cultures of B-mice showed more AVP release per neuron than cultures of S-mice. These results reveal that on a mechanistic level the mouse lines differed in transport and/or release of AVP in the SCN, rather than differential regulation of AVP gene transcription or number of AVP immunoreactive neurons.


1H MR spatially resolved spectroscopy of human tissues in situ.
SPAtially Resolved Spectroscopy (SPARS) has been developed as a method to obtain localized MR spectra in a whole body MRI system. It is based upon a combination of selective and non-selective pulses such that longitudinal magnetization is preserved in a particular volume of interest (VOI), whereas outside this volume the magnetization is dephased in the transversal plane. After this selection phase the spectrum of the VOI can be obtained after a single excitation pulse. In this respect it is similar to the VSE sequence as proposed by Aue et al. The difference is that even by using relatively large body and head coils the SPARS sequence requires much lower rf powers levels, such that it can be implemented on a whole body MRI system.


Comparison of urinary albumin excretion rate in overnight urine and albumin creatinine ratio in spot urine in diabetic patients in general practice.
To evaluate whether measurement of albumin creatinine ratio (ACR) on a spot urine specimen can replace a timed overnight collection of urine albumin excretion rate (UAER) in patients with diabetes in primary care. Patients with diabetes attending Rønvik Health Centre were asked to bring a timed overnight collection of urine for measurement of UAER. They were also asked to void a urine specimen for measurement of albumin creatinine ratio. Primary health care. One-hundred-and-six persons with diabetes (47 women, 59 men) aged 13 to 78 years. The sensitivity and specificity of ACR with cut-off values of 2.5 mg/mmol for men and 3.5 mg/mmol for women compared to UAER with cut-off value of 20 mg/24 h was 90%. Spot urine ACR analysed on a DCA 2000 can replace a timed (overnight) collection of urine and measurement of UAER when diabetic patients are reviewed in general practice. This simplifies procedures for the patient as a timed urine collection is no longer necessary. Another advantage is that the results are available after 7 min.


CT visualization of blood pool in rats by using long-circulating, iodine-containing micelles.
Small, long-circulating particulate carriers of contrast agents, such as micelles, are potentially useful in computed tomographic (CT) blood-pool imaging. An iodine-containing amphiphilic block-copolymer consisting of iodine-substituted poly-L-lysine (MPEG-iodolysine) forms micelles in an aqueous solution. The biodistribution and CT depiction of these radiopaque micelles were therefore studied in rats. MPEG-iodolysine micelles were synthesized and injected into rats via the tail vein at a dose of 170 mg iodine per kilogram. Three animals were used, and tissue enhancement was followed on serial CT scans. MPEG-iodolysine block-copolymer forms particulates with an average diameter of 80 nm and an iodine content of 33.8%. After intravenous injection into rats, the agent produced noticeable and sustained enhancement of the blood pool (aorta and heart), liver, and spleen for least 3 hours. In rats, MPEG-iodolysine micelles were a long-lived blood-pool contrast agent useful for CT.


Clozapine as a first- or second-line treatment in schizophrenia: a systematic review and meta-analysis.
No consensus exists on whether clozapine should be prescribed in early stages of psychosis. This systematic review and meta-analysis therefore focus on the use of clozapine as first-line or second-line treatment in non-treatment-resistant patients. Articles were eligible if they investigated clozapine compared to another antipsychotic as a first- or second-line treatment in non-treatment-resistant schizophrenia spectrum disorders (SCZ) patients and provided data on treatment response. We performed random-effects meta-analyses. Fifteen articles were eligible for the systematic review (N = 314 subjects on clozapine and N = 800 on other antipsychotics). Our meta-analysis comparing clozapine to a miscellaneous group of antipsychotics revealed a significant benefit of clozapine (Hedges' g = 0.220, P = 0.026, 95% CI = 0.026-0.414), with no evidence of heterogeneity. In addition, a sensitivity analysis revealed a significant benefit of clozapine over risperidone (Hedges' g = 0.274, P = 0.030, 95% CI = 0.027-0.521). The few eligible trials on this topic suggest that clozapine may be more effective than other antipsychotics when used as first- or second-line treatment. Only large clinical trials may comprehensively probe disease stage-dependent superiority of clozapine and investigate overall tolerability.


Subjective, anatomical, and functional nasal evaluation of patients with obstructive sleep apnea syndrome.
Studies have shown a high occurrence of nasal alterations in patients with obstructive sleep apnea syndrome (OSAS), but no studies have used different methods to evaluate the nose of patients with OSAS. The objective of this study was to evaluate the nose of patients with OSAS, compare them to controls, and correlate the different methods used to evaluate the nose. Forty-seven patients with moderate/severe OSAS and 20 controls who were matched for gender, age, and body mass index were included. Questionnaires regarding sleep and nasal symptoms, physical examination, rhinoscopy, nasofibroscopy, nasal inspiratory peak flow (NIPF), and acoustic rhinometry (AR) measurements were performed. In the OSAS group, 33 (70.2%) were male, with a mean age of 53.2 ± 9.1 years. In the control group, 13 (65%) were male, with a mean age of 53.7 ± 9.7 years. The OSAS group had a higher score on the nasal symptoms scale (p < 0.01) and a higher frequency of nasal alterations [presence of septal deviation, clinical complaints (p = 0.01) and hypertrophy of the inferior nasal turbinate (p < 0.01)]. The NIPF and AR parameters could not differentiate between the OSAS and control groups. There were no significant correlations among the different methods used to evaluate the nose. Lower NIPF values were capable of predicting higher apnea-hypopnea index scores (p = 0.007). Clinical complaints and nasal alterations as measured by rhinoscopy and nasofibroscopy were associated with the presence of OSAS, which was not the case for the NIPF and AR parameters. The results of different evaluation methods were not correlated with each other.


Pharmacokinetics and pharmacodynamics of a short- and long-acting theophylline medication (theolair and Theolair retard) in normals and asthmatics. Part I: pharmacokinetics.
Plasma concentration and pharmacokinetic data of a sustained-release theophylline (Theolair retard) was compared with that of a short-acting theophylline (Theolair) in six normals and six patients with asthmatic bronchitis. Steady-state plasma levels were reached on day 4 or earlier for both Theolair retard and Theolair. Theolair retard showed stable plasma concentrations. Patients showed lower (maximal) values for the plasma levels for Theolair retard and for Theolair and a shorter elimination half-life time for Theolair. This may perhaps be explained by the larger number of smokers among the patients versus the normals. As for the large interindividual variation in plasma levels and pharmacokinetics it seems advisable to administer theophylline guided by plasma levels estimated on the 4th day of administration, about 3 h after the morning dose.


The association between N-terminal pro B-type natriuretic peptide and lipoprotein particle concentration plateaus at higher N-terminal pro B-type natriuretic peptide values: Multi-Ethnic Study on Atherosclerosis.
The association between N-terminal pro B-type natriuretic peptide (NT-proBNP) and blood levels of small and large LDL- and HDL- particle (P) concentration may not be linear throughout the whole range of NT-proBNP values. Linear spline regression analysis between NT-proBNP and lipoprotein particle concentrations was performed cross-sectionally in 5597 individuals from the Multi-Ethnic Study of Atherosclerosis adjusted for age, race, sex, body mass index, % of energy from saturated fats, intentional exercise, statin use, antihypertensive medication use, diabetes, IL-6 and estimated glomerular filtration rate. Spline knots were selected as the point at which the linear slope changed in these associations. NT-proBNP was positively associated with large LDL-P and HDL-P, but inversely associated with small LDL-P and HDL-P, but only for NT-proBNP values below the knot (range: 100-200 pg/mL). These results suggest the presence of two distinct biological mechanisms above and below the knot determining the association between NT-proBNP and lipoprotein particle concentrations.


Peroperative haemorrhage and epidural anaesthesia in major abdominal surgery. A retrospective study.
The preoperative blood loss during resection of the colon, abdominal-perineal excision of the rectum and cystectomy, according to the method of Bricker, was studied from anaesthetic reports. The period under study was 18 months. A total of 97 patients were divied into two main groups according to the type of anaesthesia (general anaesthesia and general anaesthesia combined with epidural analgesia), as well as into sub-groups according to the type of operation. An evaluation was made of the blood loss, peroperative mean arterial blood pressure and the duration of the operation. In contrast to reports published earlier on other types of operation, we have been unable to demonstrate a significant reduction in the blood loss of patients given general anaesthesia plus epidural analgesia, despite a lower mean arterial blood pressure during the operation. We ignored any possible postoperative beneficial effect of epidural anaesthesia.


Inflammasome assembly in neurodegenerative diseases.
Neurodegenerative disorders are characterized by the progressive dysfunction and death of selectively vulnerable neuronal populations, often associated with the accumulation of aggregated host proteins. Sustained brain inflammation and hyperactivation of inflammasome complexes have been increasingly demonstrated to contribute to neurodegenerative disease progression. Here, we review molecular mechanisms leading to inflammasome assembly in neurodegeneration. We focus primarily on four degenerative brain disorders in which inflammasome hyperactivation has been well documented: Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and the spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We discuss shared and divergent principles of inflammasome assembly across these disorders, and underscore the differences between neurodegeneration-associated inflammasome activation pathways and their peripheral-immune counterparts. We examine how aberrant assembly of inflammasome complexes may amplify pathology in neurodegeneration, including misfolded protein aggregation, and highlight prospects for neurotherapeutic interventions based on targeting inflammasome pathways.


Resolution of viral load in mild COVID-19 patients is associated with both innate and adaptive immune responses.
Over 90% of the COVID-19 patients manifest mild/moderate symptoms or are asymptomatic. Although comorbidities and dysregulation of immune response have been implicated in severe COVID-19, the host factors that associate with asymptomatic or mild infections have not been characterized. We have collected serial samples from 23 hospitalized COVID-19 patients with mild symptoms and measured the kinetics of SARS-CoV-2 viral load in respiratory samples and markers of inflammation in serum samples. We monitored seroconversion during the acute phase of illness and quantitated the amount of total IgG against the receptor-binding domain of SARS-CoV-2 and estimated the virus neutralization potential of these antibodies. Viral load decreased by day 8 in all the patients but the detection of viral RNA in saliva samples did not correlate well with viral RNA detection in nasopharyngeal/oropharyngeal swab samples. 25% of the virus-positive patients had no detectable neutralizing antibodies in the serum and in other cases, the efficiency of antibodies to neutralize SARS-CoV-2 B1.1.7 strain was lower as compared to the circulating virus isolate. Decrease in viral load coincided with increase in neutralizing antibodies and interferon levels in serum. Most patients showed no increase in inflammatory cytokines such as IL-1β or IL-6, however, elevated levels of IL-7 and other inflammatory mediators such as TNF-α and IL-8 was observed. These data suggest that most mild infections are associated with absence of inflammation coupled with an active innate immune response, T-cell activation and neutralizing antibodies.


Improvement of dyslipidemia, insulin sensitivity, and energy balance by a peroxisome proliferator-activated receptor alpha agonist.
Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor family of ligand-activated transcription factors. It plays an important role in the regulation of genes involved in lipid metabolism and transport. Compound A is a potent and orally active PPARalpha agonist that activated both human and rat PPARalpha receptors. The compound induced the expression of genes involved in fatty acid metabolism in a rodent hepatoma cell line and in the liver of db/db mouse. The ability of compound A to stimulate fatty acid beta-oxidation was demonstrated in human hepatocytes and human skeletal muscle cells, which confirmed a functional activation of PPARalpha-mediated activities. Compound A was shown to be a more potent and efficacious antidyslipidemic agent in atherogenic rat and db/db mouse models as compared with fenofibrate. The increase in high-density lipoprotein cholesterol levels by compound A was at least partially due to an increase in serum apolipoprotein A-I protein concentrations in human PPARalpha transgenic mouse. The triglyceride-lowering effect was further confirmed in a higher species, obese dog models. In addition, compound A dose-dependently ameliorated hyperglycemia and hyperinsulinemia, and improved glucose tolerance in db/db mice. In a diet-induced obesity mouse model, compound A decreased body weight mainly by increasing energy expenditure and reducing fat deposition. In conclusion, the novel and potent PPARalpha agonist improves lipid profile, insulin sensitivity, and energy balance in animal models.


Sex differences in the associations of socioeconomic status with undiagnosed diabetes mellitus and impaired glucose tolerance in the elderly population: the KORA Survey 2000.
Sex differences in the associations of socioeconomic status (SES) with prevalence of undiagnosed diabetes mellitus, impaired glucose tolerance (IGT) and known risk factors of type 2 diabetes mellitus were investigated in an elderly population. Oral glucose tolerance tests were carried out in 1354 randomly selected subjects (697 men, 657 women) aged 55-74 years in the population-based KORA Survey 2000, Augsburg, Germany. Odds ratios (ORs) and 95% confidence intervals (CIs) for undiagnosed diabetes or IGT by education, occupation and income were estimated using logistic regression controlling for age, waist circumference, blood pressure, triglycerides, physical activity, smoking and alcohol intake. All three SES variables were significantly inversely related to body mass index, waist circumference and low physical activity in women (P < 0.05). In men, these associations were weaker or absent. Using the lowest category as reference, occupational status was significantly associated with undiagnosed diabetes in women (adjusted OR 0.5; 95% CI 0.3-0.8) after controlling for risk factors in multivariate regression. The OR was also reduced with higher income in women (adjusted OR, diabetes: 0.7; 95% CI 0.5-1.03). Among men, no significant relations of the SES indicators with unknown diabetes were observed. However, the odds of having IGT was lower with higher occupational status in men (adjusted OR 0.7; 95% CI 0.5-0.9). Undiagnosed type 2 diabetes was related to low SES defined by occupation or income in women only. In men, low occupational status was independently associated with higher IGT risk. Educational level was not related to glucose disorders in both sexes in the elderly population.


Long Non-coding RNA SPAG5-AS1 Attenuates Diabetic Retinal Vascular Dysfunction by Inhibiting Human Retinal Microvascular Endothelial Cell Proliferation, Migration, and Tube Formation by Regulating the MicroRNA-1224-5p/IRS-1 Axis.
Diabetic retinopathy (DR) is causal for visual impairment and blindness. The research aimed at whether and how lncRNA SPAG5-AS1 (SPAG5-AS1) is involved in retinal vascular dysfunction under diabetic conditions. After determination of SPAG5-AS1, miR-1224-5p, and IRS-1 expression in high glucose (HG)-treated human retinal microvascular endothelial cells (hRMECs), their respective influences on retinal vascular dysfunction was explored by cell counting kit-8, Transwell, wound-healing assay, and tube formation assay. SPAG5-AS1/miR-1224-5p/IRS-1 interaction was identified through bioinformatics analysis and luciferase reporter gene assays. As tested, SPAG5-AS1 and IRS-1 levels were induced, while miR-1224-5p was enhanced in HG-treated hRMECs. Up-regulating SPAG5-AS1 or downregulating miR-1224-5p could inhibit hRMECs proliferation, migration, and tube formation, and vice versa. SPAG5-AS1 can promote IRS-1 expression by miR-1224-5p, and depletion of IRS-1 was functional for the reversal of up-regulated SPAG5-AS1-modified influences on HG-treated hRMECs. Additionally, in diabetic rats, SPAG5-AS1 can alleviate retinal vascular dysfunction. All in all, SPAG5-AS1 attenuates diabetic retinal vascular dysfunction through miR-1224-5p/IRS-1 axis, providing a potential therapeutic strategy for DR.


Enhanced potency of perfluorinated thalidomide derivatives for inhibition of LPS-induced tumor necrosis factor-alpha production is associated with a change of mechanism of action.
Perfluorination of phthalimides leads to dramatically increased potency as inhibitors of TNF-alpha production. We examined the enantiodependence for several tetrafluorophthalimides and alpha-methylthalidomide, 3. Only 3 exhibited strikingly enantiodependent activity. The key structural determinant for the enhanced activity is the tetrafluorophthaloyl group, which confers enhanced potency and a change in the mechanism of inhibition.


Ticarcillin serum and tissue concentrations in gynecology and obstetrics.
Ticarcillin tissue concentrations were determined in 77 patients following an infusion of 5 g over 30 min. The tissues studied in gynecology were endometrium, tube, ovary and myometrium. The relative tissue levels ranged from 17% to 30% of the corresponding serum concentrations when ticarcillin was administered once, and from 22% to 32% when the drug was infused repeatedly. In no case did these tissue levels exceed the serum concentrations. The mean relative tissue levels in early pregnancy (decidua, placenta, embryo) were 10% of the corresponding serum concentrations. Levels in late pregnancy were determined in the placenta, amniotic fluid and in serum from the umbilical cord artery and vein immediately after delivery. Maximal placenta concentrations of 30 mg/kg were determined; these declined exponentionally with half-lives of 2.8 and 1.3 h, respectively, following single and repeated dosings. Amniotic fluid levels increased from 10 mg/l immediately after the first infusion to 60 mg/l after the seventh infusion. Individual umbilical cord levels in the artery and vein were significantly different, indicating that the fetus has properties of a deep compartment. The total amount of ticarcillin excreted daily in the mother's milk was strictly correlated to its volume and ranged from 2-2.5 mg/l.


Multiple molecular logic gate arrays in one system of (2-(2'-pyridyl)imidazole)Ru(ii) complexes and trimeric cyclophanes in water.
Shape-switchable cyclophane hosts allow the controlled capture and release of reactive polypyridineRu(ii) complexes in water. This gives rise to a network of host-guest binding, acid-base reactions in ground and excited states, and chemical redox interconversions. In the case of (2-(2'-pyridyl)imidazole)Ru(ii) complexes, several molecular logic gate arrays of varying complexity emerge as a result. Cyclophane-induced 'off-on' switching of luminescence in neutral solution is found to originate from two features of these aromatic hosts: enhancement of radiative decay by the polarizable host and the suppression of nonradiative decay involving deprotonation by reducing the water content within the deep host cavity. These are examples of nanometric coordination chemistry/physics being controlled by inclusion in an open box. The aromatic units of the macrocycle are also responsible for the shape-switching mechanism of wall collapse/erection.


Computed tomography of the pancreas: a preliminary experience.
CT appears to be an excellent non-invasive method for the evaluation of pancreatic disease, particularly when ultrasonography is inconclusive. The authors review their preliminary experience and analyze the results in 34 patients.


Feasibility of exclusive enteral feeds from birth in VLBW infants >1200 g--an RCT.
To evaluate the feasibility of initiation of exclusive enteral feeds on first day of life in very low birthweight infants >1200 g. Haemodynamically stable infants with birthweights 1200-1500 g irrespective of gestational age were randomized into two groups. Enteral feeds 80 mL/kg/day started within 1 h of birth and increased by 20 mL/kg/day to 180 mL/kg/day. No intravenous fluids given. Intravenous fluids 50 mL/kg/day started along with enteral feeds 30 mL/kg/day within 1 h of birth and increased by 20 mL/kg/day to 180 mL/kg/day. The outcome measures were - primary: time to regain birthweight and secondary: duration of hospital stay, incidence of necrotizing enterocolitis and sepsis. Twenty three babies randomized in each group. Infants in study group regained birthweight earlier [mean 5.52 days, SD ± 2.94] compared to those in control group [mean 12.7 days, SD ± 2.25] (p < 0.0001). Duration of hospital stay was lower in study group [mean 15.04 days, SD ± 5.26] compared to those in control group [mean 28.04 days, SD ± 6.76] (p < 0.0001). No necrotizing enterocolitis detected. It is feasible to initiate exclusive enteral feeds from first day of life in stable infants with birthweight between 1200 and 1500 g without any parenteral fluid support. It leads to twice as faster regaining of birthweight and halves duration of hospital stay.