Micro-Tomographic Investigation of Ice and Clathrate Formation and Decomposition under Thermodynamic Monitoring.
Clathrate hydrates are inclusion compounds in which guest molecules are trapped in a host lattice formed by water molecules. They are considered an interesting option for future energy supply and storage technologies. In the current paper, time lapse 3D micro computed tomographic (µCT) imaging with ice and tetrahydrofuran (THF) clathrate hydrate particles is carried out in conjunction with an accurate temperature control and pressure monitoring. µCT imaging reveals similar behavior of the ice and the THF clathrate hydrate at low temperatures while at higher temperatures (3 K below the melting point), significant differences can be observed. Strong indications for micropores are found in the ice as well as the THF clathrate hydrate. They are stable in the ice while unstable in the clathrate hydrate at temperatures slightly below the melting point. Significant transformations in surface and bulk structure can be observed within the full temperature range investigated in both the ice and the THF clathrate hydrate. Additionally, our results point towards an uptake of molecular nitrogen in the THF clathrate hydrate at ambient pressures and temperatures from 230 K to 271 K.


Post-stimulation effects on the auditory brain stem response partial-masking and enhancement.
The auditory brain stem response (ABR) was recorded in human subjects using the stimulus configuration of a tone-on-tone forward-masking paradigm, but with all stimuli at suprathreshold levels. A masking stimulus preceded, by delta t msec, the probe stimulus which elicited the ABR. The latency vs. delta t functions for waves III and V were essentially parallel to each other and were interpreted in terms of a partial forward-masking effect, possibly originating in the cochlea. Likewise, the amplitude function for wave III showed varying degrees of decrement as a function of delta t that was also compatible with a partial forward-masking interpretation. In contrast, wave V showed an amplitude increment relative to the unmasked wave that was maximal for delta t values of 15 and 45 msec. The amplitude increment in wave V was termed enhancement and was interpreted as a central process governed by the timing of sound sequences.


Association of the FTO rs9939609 single nucleotide polymorphism with C-reactive protein levels.
Adipose tissue is a key factor determining C-reactive protein (CRP) plasma levels. Variation at the fat-mass and obesity-associated (FTO) gene locus has been reported to be associated with increased body fat. We investigated whether the FTO rs9939609 T>A single nucleotide polymorphism might alter CRP levels in a population-based sample of 2,415 participants from a large prospective cohort study. Genotype/phenotype relationships were studied by linear trend analysis stratified by sex. The rs9939609 A-allele was significantly associated with CRP levels in both genders (men, +21%, P = 0.002; women, +14%, P = 0.01 per A-allele). The association was attenuated, but remained statistically significant after additional adjustment for BMI, waist-to-hip ratio, and other potential confounding factors (men, +14%, P = 0.03; women, +12%, P = 0.02; per A-allele). Similar results were obtained when subjects with CRP levels higher then 10 mg/l were excluded. Our data provide preliminary evidence that the FTO rs9939609 T>A polymorphism contributes to variation in plasma CRP levels independently of obesity indices.


Childhood infections and the risk of inflammatory bowel disease.
Adults with inflammatory bowel disease from North Carolina were questioned during 1986 and 1987 to assess risk due to a variety of childhood infections and treatments with antibiotics. Responses were compared with those of neighbor controls. Persons with Crohn's disease were more likely to report an increased frequency of childhood infections in general (odds ratio 4.67, 95% CI 2.65-8.23) and pharyngitis specifically (odds ratio 2.14, 95% CI 1.30-3.51). This was validated by an increased frequency of tonsillectomy (odds ratio 1.53, 95% CI 1.07-2.20). Crohn's cases were more likely to report frequent treatment with antibiotics for both otitis (odds ratio 2.07, 95% CI 1.03-4.14) and pharyngitis (odds ratio 2.14, 95% CI 1.20-3.84). Although Crohn's cases were more likely to report frequent exposure to penicillin (odds ratio 1.81, 95% CI 0.98-3.31), there did not appear to be excess risk conferred by penicillin after controlling for frequency of infections. Persons with ulcerative colitis also reported an excess of infections generally (odds ratio 2.37, 95% CI 1.19-4.71), but not an excess of specific infections or treatments with antibiotics. Persons who reported an increased frequency of infections tended to have an earlier onset of Crohn's disease (P < 0.0001) and ulcerative colitis (P = 0.04). Finally, it was noted that urban living in childhood increased the risk for Crohn's disease. We conclude that childhood infections may be a risk factor for Crohn's disease and may presage the early onset of disease.


New 3' elements control Pax6 expression in the developing pretectum, neural retina and olfactory region.
Pax6 is a key transcriptional regulator in eye, olfactory system, forebrain, pituitary cerebellum, spinal cord and pancreas development. Alternative splicing, promoter usage and multiple enhancers regulate the complex Pax6 spatio-temporal expression pattern. Chromosomal rearrangements which abolish PAX6 gene expression have been characterised downstream of the coding region. Through evolutionary sequence comparison and transgenic reporter studies, we have identified a new Pax6 3' cis-regulatory region. This region, C1170 Box 123, contains three distinct modules of human-mouse sequence conservation, while only Box 1 is conserved to Fugu. Both the human and the orthologous Fugu sequence direct similar reporter gene expression in the developing pretectum, neural retina and olfactory region, indicating evolutionary conservation of Pax6 regulatory mechanisms despite the low level of overall sequence conservation.


[Posterior reinforcement behind hepatic angiomas. Mirror artefact as a possible source of error].
Posterior enhancement beyond liver hemangiomas was retrospectively assessed on 89 hemangiomas of all size and localization with in the liver. This enhancement is seen only beyond big and complex lesions, containing hypoechoic or anechoic zones. Conversely, it seems to be very rare beyond little hyperechoic lesions. It is necessary to distinguish true enhancement and a mirror artefact beyond lesions of all sizes but localized just near the diaphragma. In the lesions of less than 2 cm, no clear posterior enhancement was discovered, but some of them showed a very clear mirror artifact.


[Middle-aged and elderly patients with hydronephrosis induced by ureteric obstruction: etiology and diagnosis].
To improve the etiologic diagnosis of middle-aged and elderly patients with ureteric obstruction. The etiology and diagnosis were retrospectively studied in 141 middle-aged and elderly patients with hydronephrosis in recent 10 years. 59 patients had ureterolithiasis, 51 ureteric cancer, 11 ureteric tuberculosis, 9 UPJ stricture, 6 uretero-cyst and 5 ureteric polyp. Ureterolithiasis and ureteric cancer contribute greatly to ureteric obstruction in middle-aged and elderly patients. Etiologically, B ultrasonography is suggested to be used as the first choice in diagnosis and follow-up of the middle-aged and elderly patients with hydronephrosis, especially those accompanied with hematuria.


Extensive loss of Wnt genes in Tardigrada.
Wnt genes code for ligands that activate signaling pathways during development in Metazoa. Through the canonical Wnt (cWnt) signaling pathway, these genes regulate important processes in bilaterian development, such as establishing the anteroposterior axis and posterior growth. In Arthropoda, Wnt ligands also regulate segment polarity, and outgrowth and patterning of developing appendages. Arthropods are part of a lineage called Panarthropoda that includes Onychophora and Tardigrada. Previous studies revealed potential roles of Wnt genes in regulating posterior growth, segment polarity, and growth and patterning of legs in Onychophora. Unlike most other panarthropods, tardigrades lack posterior growth, but retain segmentation and appendages. Here, we investigated Wnt genes in tardigrades to gain insight into potential roles that these genes play during development of the highly compact and miniaturized tardigrade body plan. We analyzed published genomes for two representatives of Tardigrada, Hypsibius exemplaris and Ramazzottius varieornatus. We identified single orthologs of Wnt4, Wnt5, Wnt9, Wnt11, and WntA, as well as two Wnt16 paralogs in both tardigrade genomes. We only found a Wnt2 ortholog in H. exemplaris. We could not identify orthologs of Wnt1, Wnt6, Wnt7, Wnt8, or Wnt10. We identified most other components of cWnt signaling in both tardigrade genomes. However, we were unable to identify an ortholog of arrow/Lrp5/6, a gene that codes for a Frizzled co-receptor of Wnt ligands. Additionally, we found that some other animals that have lost several Wnt genes and are secondarily miniaturized, like tardigrades, are also missing an ortholog of arrow/Lrp5/6. We analyzed the embryonic expression patterns of Wnt genes in H. exemplaris during developmental stages that span the establishment of the AP axis through segmentation and leg development. We detected expression of all Wnt genes in H. exemplaris besides one of the Wnt16 paralogs. During embryo elongation, expression of several Wnt genes was restricted to the posterior pole or a region between the anterior and posterior poles. Wnt genes were expressed in distinct patterns during segmentation and development of legs in H. exemplaris, rather than in broadly overlapping patterns. Our results indicate that Wnt signaling has been highly modified in Tardigrada. While most components of cWnt signaling are conserved in tardigrades, we conclude that tardigrades have lost Wnt1, Wnt6, Wnt7, Wnt8, and Wnt10, along with arrow/Lrp5/6. Our expression data may indicate a conserved role of Wnt genes in specifying posterior identities during establishment of the AP axis. However, the loss of several Wnt genes and the distinct expression patterns of Wnt genes during segmentation and leg development may indicate that combinatorial interactions among Wnt genes are less important during tardigrade development compared to many other animals. Based on our results, and comparisons to previous studies, we speculate that the loss of several Wnt genes in Tardigrada may be related to a reduced number of cells and simplified development that accompanied miniaturization and anatomical simplification in this lineage.


[Binding pancreaticojejunostomy: clinical report of 150 cases].
To study the safety and feasibility of a new operative procedure called binding pancreaticojejunostomy (BPJ) used to prevent anastomotic leakage following pancreatoduodenectomy (PD). From 1996 to 2001, a newly developed operative procedure, binding pancreaticojejunostomy, was performed upon 150 cases undergoing PD. The remnant of pancreas was sutured with and invaginated into the jejunum, with the suture needle only penetrating the mucosa and not the seromuscular layer. The mucosa of jejunum near the pancreatic remnant was destroyed by electric coagulation or phenol. The pancreas and jejunum were bound together so that they were pressed close to each other. The clinical data were reviewed and analysed. The operation of BPJ was performed smoothly on all 150 patients. No pancreatic leakage occurred. The BPJ procedure is effective in avoiding anastomotic leakage following PD.


[The conservative therapy of urolithiasis (author's transl)].
Some common conservative treating methods of urolithiasis are critically discussed. Based on physico-chemical relationships of solubility and cristallisation of stone-forming compounds our own methods of conservative treatment of urolithiasis is presented.


A pathogen-like antigen-based vaccine confers immune protection against SARS-CoV-2 in non-human primates.
Activation of nucleic acid sensing Toll-like receptors (TLRs) in B cells is involved in antiviral responses by promoting B cell activation and germinal center responses. In order to take advantage of this natural pathway for vaccine development, synthetic pathogen-like antigens (PLAs) constructed of multivalent antigens with encapsulated TLR ligands can be used to activate B cell antigen receptors and TLRs in a synergistic manner. Here we report a PLA-based coronavirus disease 2019 (COVID-19) vaccine candidate designed by combining a phage-derived virus-like particle carrying bacterial RNA as TLR ligands with the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein as the target antigen. This PLA-based vaccine candidate induces robust neutralizing antibodies in both mice and non-human primates (NHPs). Using a NHP infection model, we demonstrate that the viral clearance is accelerated in vaccinated animals. In addition, the PLA-based vaccine induces a T helper 1 (Th1)-oriented response and a durable memory, supporting its potential for further clinical development.


Validity and Reliability of Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2) in Iranian People with Parkinson's Disease.
Pain is one of the nonmotor symptoms of Parkinson's disease (PD) that, in order to be better managed, requires to be evaluated. Evaluations are done using pain assessment scales such as the Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2). The goal of this study was to assess the psychometric properties of SF-MPQ-2 to measure pain in people with PD. Four hundred and twenty-eight PD patients with a mean (SD) age of 60.11 (11.44) years were included. Accessibility was measured through floor and ceiling effects. Dimensionality was estimated by exploratory factor analysis. The association between SF-MPQ-2 and other scales such as Neuropathic Pain Symptom Inventory, Douleur Neuropathic 4, Brief Pain Inventory, King's Pain Parkinson's Disease Scale, and Visual Analog Scale-Pain was considered to calculate convergent validity. Internal consistency and test-retest reliability were assessed by Cronbach's alpha and intraclass correlation coefficient (ICC), respectively. A noticeable floor effect was found. Dimensionality results indicated four factors for this scale. A strong relationship was found between the SF-MPQ-2 total score and other scales (r = 0.55 to 0.85). In reliability analysis, Cronbach's alpha and ICC were 0.93 and 0.94 for SF-MPQ-2, respectively. The results of this study showed that SF-MPQ-2 has adequate validity and reliability to measure pain in people with Parkinson's disease.


Next-generation sequencing for simultaneous determination of human papillomavirus load, subtype, and associated genomic copy number changes in tumors.
Human papillomavirus (HPV) infection in cases of squamous cell carcinoma of the oropharynx is a powerful predictive and prognostic biomarker. We describe how the use of next-generation sequencing can provide a novel method for the detection of HPV in DNA isolated from formalin-fixed paraffin-embedded tissues. Using this methodology in a cohort of 44 head and neck tumors, we identified the samples that contained HPV sequences, the viral subtype involved, and a direct readout of viral load. Specificity of HPV detection by sequencing compared to traditional detection methods using either PCR or p16 immunohistochemistry was 100%. Sensitivity was 50% when either compared to PCR [confidence interval (CI) = 29% to 71%] or 75% when compared to p16 (CI = 47% to 91%). In addition, we demonstrate the ability of next-generation sequencing to detect other HPV subtypes that would not have been detected by traditional methods, and we demonstrated the ability to apply this method to any tumor and any virus in a panel of eight human cancer cell lines. This methodology also provides a tumor genomic copy number karyogram, and in the samples analyzed here, a lower level of chromosome instability was detected in HPV-positive tumors compared to HPV-negative tumors, as observed in previous studies. Thus, the use of next-generation sequencing for the detection of HPV provides a multiplicity of data with clinical significance in a single test.


Laminin-1 promotes enteric nervous system development in mouse embryo.
Neuronal development is regulated by extracellular environmental factors including nerve growth factor (NGF) and laminin. We have previously demonstrated that laminin-1 promotes neurite outgrowth of dorsal root ganglion cells by modulating NGF and integrin signaling. However, information about their effects on the enteric nervous system (ENS) is limited. Recently, we succeeded in visualizing enteric neural crest-derived cell (ENCC) migration using SOX10-Venus transgenic mice, in which ENCC are labeled with a green fluorescent protein, Venus. In this study, we examine the effects of NGF and laminin-1 in ENCC migration using SOX10-Venus mice gut. Pregnant SOX10-Venus mice were killed on day 12.5 of gestation. The colorectum was dissected from embryos (n = 10) and placed in culture medium including NGF with or without laminin-1 for 12 h. Extension rates of ENCC migration, colorectum and ENCC migration per colorectum were calculated. Venus positive-ENCC extension rate was significantly higher in the laminin group (n = 5) compared to control (n = 5), 22.84 and 13.96 %, respectively (p < 0.05). The extension rate of the colorectum was not significantly different between the two groups. Our results suggest that laminin promotes ENCC migration in mice. This technique allowed us to visualize the effects of extracellular molecules on ENCC migration and it potentially provides us with an insight into the pathophysiology of developmental disorders of the ENS, such as Hirschsprung's disease.


Long-term exposure to PM2.5 and cardiovascular disease incidence and mortality in an Eastern Mediterranean country: findings based on a 15-year cohort study.
Evidence concerning the impact of long-term exposure to fine Particulate Matter ≤2.5 μm (PM2.5) on Cardio-Vascular Diseases (CVDs) for those people subject to ambient air pollution in developing countries remains relatively scant. This study assessed the relationship of 15-year PM2.5 exposure with cardiovascular incidence and mortality rate in Isfahan province, Iran. The cohort comprised 3081 participants over 35 years old who were free of CVDs. They were selected through multi-stage cluster sampling in Isfahan, Iran. PM2.5 exposure was determined separately for each individual via satellite-based spatiotemporal estimates according to their residential addresses. In this context, CVD is defined as either fatal and non-fatal Acute Myocardial Infarctions (AMI) or stroke and sudden cardiac death. The incidence risk for CVD and the ensuing mortality was calculated based on the average PM2.5 exposure within a study period of 15 years using the Cox proportional hazards frailty model upon adjusting individual risk factors. The mean annual rate of PM2.5 and the follow-up data of each residential area were combined. Mean three-year PM2·5 exposure for the cohort was measured at 45.28 μg/m3, ranging from 20.01 to 69.80 μg/m3. The median time period for conducting necessary follow-ups was 12.3 years for the whole population. Notably, 105 cardiovascular and 241 all-cause deaths occurred among 393,786 person-months (27 and 61 per 100,000 person-months, respectively). In well-adjusted models, 10 μg/m3 increase in PM2.5 corresponded to a 3% increase in the incidence rate of CVDs [0.95 CI = 1.016, 1.036] (in case of p = 0.000001 per 10 μg/m3 increase in PM2.5, the Hazard Ratio (HR) for AMI and Ischemic Heart Disease (IHD) was 1.031 [0.95 CI = 1.005, 1.057] and 1.028 [0.95 CI = 1.017, 1.039]), respectively. No consistent association was observed between PM2.5 concentration and fatal CVD (fatal AMI, fatal stroke, SCD (Sudden Cardiac Death)) and all-cause mortality. Results from analyses suggest that the effect of PM2.5 on cardiovascular disease occurrence was stronger in the case of older people, smokers, and those with high blood pressure and diabetes. The final results revealed that long-term exposure to ambient PM2.5 with high concentrations positively correlated with IHD incidence and its major subtypes, except for mortality. The outcome accentuates the need for better air quality in many countries.


Heavy metal concentrations and arsenic speciation in animal manure composts in China.
A nationwide survey of animal manure-based composts was carried out in China. Two hundred and twelve samples were collected and analyzed for the concentrations of 9 heavy metals or metalloids and arsenic (As) speciation. The concentrations of heavy metals vary widely (Zn 11.8-3692, Cu 3.6-916, Cr 0.7-6603, Ni 0.7-73, Pb 0.05-189, As 0.4-72, Co 0.1-94, Cd 0.01-8.7 and Hg 0.01-1.9mgkg-1 dry weight). Compared with the maximum permissible values of the Chinese standard for organic fertilizers, 13.7% and 2.4% of the composts exceeded the limits for As (15mgkg-1) and Cd (3mgkg-1), respectively. Some samples contained very high concentrations of Zn and Cu, although no limits have been set for these two metals in China. Further analysis showed that As was present mainly as arsenate (AsⅤ), with dimethylarsenate (DMA) and monomethylarsenate (MMA) as the minor species in composts. There were significant correlations between the concentrations of Zn, Cu and As, suggesting co-contamination of these elements in some composts. Monte Carlo simulations based on the distributions of metal concentrations and application rate showed that repeated applications of compost likely increase the concentrations of Zn, Cu, Cd and Hg in soil significantly compared with the soil background levels. This study highlights a need to minimize the concentrations of Zn, Cu, Cd, Hg and As in animal manures to ensure their safe recycling to agricultural soils.


Functional Radiotherapy Targeting using Focused Dose Escalation.
Various quantitative and semi-quantitative imaging biomarkers have been identified that may serve as valid surrogates for the risk of recurrence after radiotherapy. Tumour characteristics, such as hypoxia, vascularity, cellular proliferation and clonogen density, can be geographically mapped using biological imaging techniques. The potential gains in therapeutic ratio from the precision targeting of areas of intrinsic resistance makes focused dose escalation an exciting field of study. This overview will explore the issues surrounding biologically optimised radiotherapy, including its requirements, feasibility, technical considerations and potential applicability.


Mechanisms underlying the loss of mitochondrial membrane potential in glutamate excitotoxicity.
Glutamate excitotoxicity amplifies neuronal death following stroke. We have explored the mechanisms underlying the collapse of mitochondrial potential (Deltapsi(m)) and loss of [Ca(2+)](c) homeostasis in rat hippocampal neurons in culture following toxic glutamate exposure. The collapse of Deltapsi(m) is multiphasic and Ca(2+)-dependent. Glutamate induced a decrease in NADH autofluorescence which preceded the loss of Deltapsi(m). Both the decrease in NADH signal and the loss of Deltapsi(m) were suppressed by Ru360 and both were delayed by inhibition of PARP (by 3-AB or DPQ). During this period, addition of mitochondrial substrates (methyl succinate and TMPD-ascorbate) or buffering [Ca(2+)](i) (using BAPTA-AM or EGTA-AM), rescued Deltapsi(m). These data suggest that mitochondrial Ca(2+) uptake activates PARP which in turn depletes NADH, promoting the initial collapse of Deltapsi(m). After > approximately 20 min, buffering Ca(2+) or substrate addition failed to restore Deltapsi(m). In neurons from cyclophilin D-/- (cypD-/-) mice or in cells treated with cyclosporine A, removal of Ca(2+) restored Deltapsi(m) even after 20 min of glutamate exposure, suggesting involvement of the mPTP in the irreversible depolarisation seen in WT cells. Thus, mitochondrial depolarisation represents two consecutive but distinct processes driving cell death, the first of which is reversible while the second is not.


Interrater Reliability of a Novel Goniometric Technique to Measure Scapular Protraction and Retraction.
Scapular protraction and retraction are often essential for occupational performance; however, clinical assessment of these movements is uniquely challenging. To analyze the interrater reliability of a novel goniometric method to measure scapular protraction and retraction. An observational, descriptive design was implemented to evaluate interrater reliability between two experienced occupational therapists who were also certified hand therapists. Academic institution. Convenience sample of graduate students (N = 80). Outcomes and Measures: The hypothesis, developed before study implementation, was that the technique would demonstrate clinically acceptable interrater reliability, defined as a standard error of measurement (SEM) <8°. Goniometric measurements of the scapula at rest, in maximal protraction, and in maximal retraction were independently obtained from each participant by each evaluator. The goniometer was aligned on the scapula using the superior angle as the axis of motion to measure the movement of the acromion relative to the frontal plane. The SEM was calculated in each position using the intraclass correlation coefficient values and the average of the standard deviations from the two raters. The SEM values between the two evaluators for the resting, protracted, and retracted positions were 3.46°, 2.93°, and 2.74°, respectively. The SEM between the two evaluators for each scapular position was <4°, suggesting that the technique may be clinically reliable. However, additional research regarding the reliability and validity of the technique is recommended. What This Article Adds: The findings of this study support the use of goniometry to measure scapular protraction and retraction in relation to occupational performance. The technique provides a way to quantify baseline scapular mobility and track progress.


Lipolysis in Brown Adipocytes Is Not Essential for Cold-Induced Thermogenesis in Mice.
Lipid droplet (LD) lipolysis in brown adipose tissue (BAT) is generally considered to be required for cold-induced nonshivering thermogenesis. Here, we show that mice lacking BAT Comparative Gene Identification-58 (CGI-58), a lipolytic activator essential for the stimulated LD lipolysis, have normal thermogenic capacity and are not cold sensitive. Relative to littermate controls, these animals had higher body temperatures when they were provided food during cold exposure. The increase in body temperature in the fed, cold-exposed knockout mice was associated with increased energy expenditure and with increased sympathetic innervation and browning of white adipose tissue (WAT). Mice lacking CGI-58 in both BAT and WAT were cold sensitive, but only in the fasted state. Thus, LD lipolysis in BAT is not essential for cold-induced nonshivering thermogenesis in vivo. Rather, CGI-58-dependent LD lipolysis in BAT regulates WAT thermogenesis, and our data uncover an essential role of WAT lipolysis in fueling thermogenesis during fasting.


The influence of vasoactive substances on blood flow and contractile responses of cat gastrocnemius.
1 The effects of several vasoactive substances have been studied on blood flow and acetylochline-induced contraction of the vascularly isolated gastrocnemius of the cat. All substances, including acetylcholine, were administered intra-arterially to the muscle. Blood flow and contractile tension were monitored simultaneously.2 All substances which increased blood flow, enhanced the contractile responses to acetylcholine; angiotensin, which decreased blood flow, attenuated them.3 Histamine was typical of the vasodilators in doses up to 1 mug (9 nmol), but in a dose tenfold higher it produced only a small and transient increase in blood flow and little or no enhancement of the acetylcholine-induced contractions. These paradoxical effects were brought about by that portion of the high dose of histamine which re-entered the cat's systemic circulation.4 The order of potency of the vasodilators was the same for their potentiating effect on the acetylcholine-induced contractile responses as for their enhancing effect on muscle blood flow: bradykinin >histamine>>papaverine>>NaH(2)PO(4) >KCl. Median effective doses (ED(50)S) determined only for bradykinin, histamine and papaverine were, respectively, 20.5, 49.8, and 3,352 pmol as potentiators, and 13.4, 199.8 and 85,000 pmol as vasodilators.5 In general, the effect of a given vasoactive substance on the contractile response to acetylcholine was dose-dependent and correlated well with its effect on muscle blood flow at the moment the acetylcholine was injected. Two important exceptions were, firstly, that the highest dose of papaverine was only moderately effective as a potentiator even though highly effective as an increaser of muscle blood flow; and, secondly, that histamine produced its greatest potentiating effect 10 s after it was injected, at which time its effect on muscle blood flow was quite small.6 It is suggested that these exceptions and, indeed, the much greater potentiating effectiveness of histamine and bradykinin versus papaverine may be due to the ability of histamine and bradykinin to increase the permeability of the muscle's capillaries as well as increasing blood flow through them, thus facilitating much better than mere vasodilators the access of bloodborne acetylcholine to its receptors on the muscle fibres.


Ia afferents of the antagonist are inhibited presynaptically before the onset of a ballistic muscle contraction in man.
The aim of the present investigation was to study whether the pre-movement inhibition of the H reflex in the antagonist of a ballistic voluntary contraction was due to a reduced activity of the motoneuronal pool of the antagonist, or to a reduced excitatory effect of the afferent volley reaching these motoneurons. Human subjects performed visually conditioned ballistic dorsal flexions of the ankle. The inhibition of the H reflex in the antagonist (soleus muscle) was similar if the muscle was initially relaxed or if there was a preexisting level of motor discharge. Since the soleus muscle was inhibited before movement onset in parallel with the H reflex inhibition, the relation between the level of a background activity and the size of superimposed H reflexes was studied. The finding that H reflexes were only slightly reduced in size with decreasing steady EMG levels could not explain the pre-movement inhibition, and it was concluded than an increased presynaptic inhibition of Ia terminals was the source of the H reflex inhibition.


GJB2 mutations in Iranians with autosomal recessive non-syndromic sensorineural hearing loss.
Hereditary hearing loss (HHL) is an extremely common disorder. About 70% of HHL is non-syndromic, with autosomal recessive forms accounting for approximately 85% of the genetic load. Although very heterogeneous, the most common cause of HHL in many different world populations is mutations of GJB2, a gene that encodes the gap junction protein connexin 26 (Cx26). This study investigates the contribution of GJB2 to the autosomal recessive non-syndromic deafness (ARNSD) load in the Iranian population. One hundred sixty eight persons from 83 families were studied. GJB2-related deafness was diagnosed in 9 families (4, 35delG homozygotes; 3, 35delG compound heterozygotes; 1, W24X homozygote; 1, non-35delG compound heterozygote). The carrier frequency of the 35delG allele in this population was approximately 1% (1/83). Because the relative frequency of Cx26 mutations is much less than in the other populations, it is possible that mutations in other genes play a major role in ARNSD in Iran.


A Review of the Key Clinical Trials of 2015: Results and Implications.
Multiple significant, potentially practice changing clinical trials in cardiology have been conducted and subsequently presented throughout the past year. In this paper, the authors have reviewed and contextualized significant cardiovascular clinical trials presented at major international conferences of 2015 including American College of Cardiology, European Association for Percutaneous Cardiovascular Interventions, American Diabetes Association, European Society of Cardiology, Transcatheter Cardiovascular Therapeutics, Heart Rhythm Congress, and the American Heart Association Scientific Sessions. The authors describe new trial data for heart failure (including eplerenone, finerenone, patiromer, sacubitril/valsartan, the beta 3 agonist mirabegron, sitagliptin, empagliflozin, alginate-hydrogel LV epicardial implant), anticoagulation (idarucizumab and andexanet alfa reversal agents, adherence programmes, practice in ablation), transcatheter aortic valve replacement (long-term data, valve-in-valve use, the TriGuard embolic deflecting device), patent foramen ovale closure, cardiovascular prevention (PCSK9 inhibitors, hypertension treatment) and antiplatelets strategies (extended duration therapy with clopidogrel or ticagrelor). Trial data are also described for contemporary technologies including the Biofreedom polymer-free drug coated stent, bioabsorbable stents, PCI strategies, left main treatment, atrial fibrillation ablation techniques, leadless pacemakers and the role of coronary computed tomographic angiography. This paper summarizes and contextualizes multiple pertinent 2015 clinical trials and will be of interest to both clinicians and cardiology researchers.


Ketamine metabolite (2R,6R)-hydroxynorketamine reverses behavioral despair produced by adolescent trauma.
Early life trauma dramatically increases the risk of developing major depressive disorder (MDD), and is associated with a markedly decreased adult treatment response to antidepressants. Novel treatment approaches are required to treat childhood trauma-associated MDD. Recent studies suggest that the (R,S)-ketamine (ketamine) metabolite, (2R,6R)-hydroxynorketamine (HNK), exerts fast- and long-lasting antidepressant-like effects without ketamine's NMDAR-inhibition-associated adverse side-effect profile. We investigated the therapeutic potential of (2R,6R)-HNK against behavioral despair produced by a novel live-predator stress exposure during adolescence. Male and female C57BL/6J mice were exposed to a live snake or control conditions at post-natal (PND) days 31, 45 and 61. In order to assess the enduring consequences of trauma-exposure, at a minimum of 14 days following the last exposure, mice received inescapable shocks followed by a session with available escape options twenty-four hours later. Mice that manifested enduring escape deficits (helplessness) were treated with vehicle or (2R,6R)-HNK (20 mg/kg, i.p.), 24 h prior to retesting for reversal of escape deficits. We found that a significantly greater number of mice developed the helpless phenotype when they were exposed to the live predator and that the helpless phenotype was reversed in mice treated with (2R,6R)-HNK. There were no sex differences in the response to predator-stress exposure or (2R,6R)-HNK treatment. The live-predator model developed in this study provides an opportunity to further refine our understanding of the neurobiological substrates impacted by adolescent trauma and improve treatment strategies. The demonstrated efficacy of (2R,6R)-HNK in this model suggests a novel therapeutic intervention for a treatment-resistant population.


Association of lymphotoxin alpha polymorphism with systemic lupus erythematosus and rheumatoid arthritis: a meta-analysis.
The aim of this study was to perform a meta-analysis of eligible studies to derive precise estimation of the associations of lymphotoxin alpha (LTA) 252 A>G polymorphism (rs909253) with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) risk. Data were collected from the following electronic databases, including EMBASE, PubMed and China National Knowledge Infrastructure (CNKI). A total of 19 studies (13 studies involving 1346 SLE patients and 1951 controls, six studies involving 1079 RA patients and 1057 controls) were included. This meta-analysis showed no evidence of significant association of the A allele with SLE susceptibility (odds ratio [OR] 1.26; 95% confidence interval [CI] 0.98-1.62, P = 0.073), but it showed a weaker association under an additive model (OR 1.63, 95%CI 1.01-2.65, P = 0.047). Stratification by ethnicity indicated that the variant A allele carriers increased the risk of SLE in Asians (OR 1.91, 95%CI 1.44-2.53, P < 0.001). However, we failed to reveal any association between LTA gene 252 A>G polymorphism and RA risk under all models (for A vs. G: OR 1.02, 95%CI 0.79-1.33, P = 0.853; for AA + AG vs. GG: OR 0.86, 95%CI 0.52-1.41, P = 0.542; for AA vs. AG + GG: OR 1.19, 95%CI 0.80-1.78, P = 0.394, for AA vs. GG: OR 1.03, 95%CI 0.58-1.84, P = 0.919). Similar results were obtained in the subgroup analysis based on ethnicity. The present study suggests that LTA 252 A>G polymorphism is associated with SLE susceptibility in Asians, and there is no significant association between LTA 252 A>G polymorphism and RA.


Can cycling safety be improved by opening all unidirectional cycle paths for cycle traffic in both directions? A theoretical examination of available literature and data.
Many studies have found bicycle-motor vehicle crashes to be more likely on bidirectional cycle paths than on unidirectional cycle paths because drivers do not expect cyclists riding at the right side of the road. In this paper we discuss the hypothesis that opening all unidirectional cycle paths for cycle traffic in both directions prevent this lack of expectancy and accordingly improves cycling safety. A new national standard requires careful consideration because a reversal is difficult once cyclists are used to their new freedom of route choice. We therefore explored the hypothesis using available data, research, and theories. The results show that of the length of cycle paths along distributor roads in the Netherlands, 72% is bidirectional. If drivers would become used to cyclists riding at the left side of the road, this result raises the question of why bidirectional cycle paths in the Netherlands still have a poor safety record compared to unidirectional cycle paths. Moreover, our exploration suggested that bidirectional cycle paths have additional safety problems. It increases the complexity of unsignalized intersections because drivers have to scan more directions in a short period of time. Moreover, there are some indications that the likelihood of frontal crashes between cyclists increases. We reject the hypothesis that opening all unidirectional cycle paths for cycle traffic in both directions will improve cycle safety. We recommend more attention for mitigating measures given the widespread application of bidirectional cycle paths in the Netherlands.


Nitrogen, boron-doped Ti3C2 MXene quantum dot-based ratiometric fluorescence sensing platform for point-of-care testing of tetracycline using an enhanced antenna effect by Eu3.
The Ti3C2 MXene quantum dots (Ti3C2 MQDs) derived from Ti3C2 MXene have received much attention because of their remarkable advantages in biosensing. Nevertheless, the functionalization of Ti3C2 MQDs to improve their properties is just in its infant stage. Herein, we firstly synthesized nitrogen and boron co-doped Ti3C2 MQDs (N, B-Ti3C2 MQDs) with good water solubility, strong stability, and high optical characteristics. The N, B-Ti3C2 MQDs exhibit excitation wavelength-dependent blue photoluminescence with optimal excitation/emission peaks at 335/439 nm. Nowadays, the development of fast and real-time detection of tetracycline (TC) in animal derived food is very essential. In this work, a novel point-of-care testing (POCT) platform was established based on ratiometric fluorescence method using N, B-Ti3C2 MQDs coupled with Eu3+. Upon addition of TC in the Eu3+/N, B-MQDs system, blue fluorescence emission of N, B-Ti3C2 MQDs was quenched and red fluorescence emission of Eu3+ was enhanced gradually, which was ascribed to the synergistic inner filter effect and antenna effect. Moreover, we prepared test papers with N, B-Ti3C2 MQDs and Eu3+ for TC detection based on the change of fluorescence color, which could be recognized by color recognizer app installed in the smartphone. Therefore, great promise for POCT of TC is given with the merits of simplicity and visible detection possibility. The proposed method demonstrated a low detection limit of 20 nM. Application of the platform for TC quantification in milk samples opened a novel means for the potential use of N, B-Ti3C2 MQDs in food safety.


Reaction strategies for the enzymatic synthesis of neopentyl glycol diheptanoate.
This work describes for the first time the green synthesis of neopentyl glycol diheptanoate in a solvent-free medium via an enzymatic pathway. The process has been carried out in an open-air reactor in order to ease water removal through evaporation and shift the chemical equilibrium towards product formation. The inhibiting effect of high concentrations of heptanoic acid has been put into evidence by a reduction of initial reaction rate when esterification was performed with stoichiometric amounts of substrates. Therefore, in this work different strategies for the stepwise addition of heptanoic acid are proposed, and best results were obtained when stoichiometric quantities of acid were divided in four equal amounts and added when previous batch was consumed. Biocatalyst Novozym® 435 concentration and temperature were optimised, giving yields of 90% in neopentyl glycol diheptanoate when 7.5% (w/w) and 70 °C were used. With a remaining 7% of heptanoic acid (probably caused by the alcohol evaporation) the addition of neopentyl glycol led to a conversion of 95%. Thus, product can be used in cosmetics without further purification and can be labelled as environmentally-friendly synthesized because of its enzymatic origin.


Sensilla on antenna and maxillary palp of Neoceratitis asiatica (Diptera: Tephritidae).
Neoceratitis asiatica (Diptera: Tephritidae) is a disastrous pest for wolfberry production in China. In our preliminary field trapping experiment, both female and male N. asiatica adults were captured by male-produced sex attractant. To provide a solid background for studying mechanism of olfaction, the sensilla of antenna and maxillary palp of N. asiatica adults were studied by means of scanning electron microscopy. Both sexes have 3 antennal segments, including scape, pedicel, and flagellum, while arista is arisen from the proximal dorsal ridge of the flagellum. Two types of sensilla were found on the scape and pedicel, sensilla microtrichia (AnMi) and sensilla chaetica (AnCh). There are five types of sensilla on the flagellum, sensilla basiconica (AnB), clavate sensilla (AnCl), sensilla trichoidea (AnTr), sensilla coeloconica (AnCo), and AnMi. Three types of sensilla were observed on maxillary palp, sensilla basiconica (MpB), sensilla microtrichia (MpMi), and sensilla chaetica (MpCh). AnMi and MpMi are the most abundant sensilla type on antenna and maxillary palp, respectively. With the exception of having longer flagellum in females, the dimension of antennal segments, type and number of sensilla, density of pores on the shaft of AnCl, AnCh, AnB and MpB, and at the base area of AnCh and MpCh didn't show differences between sexes. This lack of inter-sexual differences may be related to chemoreception of male-emitted sex pheromone and of host plant volatiles by both female and male adults.


Genetic mapping and comparative analysis of seven mutants related to seed fiber development in cotton.
Mapping of genes that play major roles in cotton fiber development is an important step toward their cloning and manipulation, and provides a test of their relationships (if any) to agriculturally-important QTLs. Seven previously identified fiber mutants, four dominant (Li (1), Li (2), N (1) and Fbl) and three recessive (n (2), sma-4(h (a)), and sma-4(fz)), were genetically mapped in six F(2) populations comprising 124 or more plants each. For those mutants previously assigned to chromosomes by using aneuploids or by linkage to other morphological markers, all map locations were concordant except n (2), which mapped to the homoeolog of the chromosome previously reported. Three mutations with primary effects on fuzz fibers (N (1), Fbl, n (2)) mapped near the likelihood peaks for QTLs that affected lint fiber productivity in the same populations, perhaps suggesting pleiotropic effects on both fiber types. However, only Li (1) mapped within the likelihood interval for 191 previously detected lint fiber QTLs discovered in non-mutant crosses, suggesting that these mutations may occur in genes that played early roles in cotton fiber evolution, and for which new allelic variants are quickly eliminated from improved germplasm. A close positional association between sma-4(h ( a )), two leaf and stem-borne trichome mutants (t (1) , t (2)), and a gene previously implicated in fiber development, sucrose synthase, raises questions about the possibility that these genes may be functionally related. Increasing knowledge of the correspondence of the cotton and Arabidopsis genomes provides several avenues by which genetic dissection of cotton fiber development may be accelerated.


Phenytoin cumulation kinetics.
Four male subjects were given phenytoin orally in single or twice-daily doses. Subjects were on 2 or 3 different dosing rates from 260 to 600 mg phenytoin sodium daily. Predose blood samples were obtained almost daily. The resulting serum levels, measured by gas-liquid chromatography, ranged from 1 to 18 micrograms/ml. Serum phenytoin concentration-time data were fit to a 1-compartment open model with zero-order input and Michaelis-Menten elimination. The resulting computer-generated parameter estimates (Vmax, 5.28 to 8.41 mg/kg/day; Km, 0.83 to 4.18 mg/1; Vd, 0.74 to 0.97 1/kg) are in agreement with the ranges of values in the literature. The time course of phenytoin cumulation is compatible with the presence of a major elimination pathway exhibiting Michaelis-Menten kinetic behavior.


Comprehensive analysis of human IL-4 receptor subunits shows compartmentalization in steady state and dupilumab treatment.
Insight into the pathomechanism of atopic diseases demonstrated a pivotal role of the cytokines interleukin-4 (IL-4) and IL-13, which has spurred the development of tailored therapeutics targeting their common IL-4 receptor (IL-4R). However, several aspects of the IL-4R system remain ill-defined in humans. We used multicolor spectral flow cytometry to characterize IL-4R subunit expression in 28 human immune cell subsets on protein and mRNA levels and assessed their subcellular distribution by applying a specifically adapted protocol that avoided influence of fixation and permeabilization on fluorochrome and antibody performance. In patients, we investigated possible changes in IL-4Rα distribution before and during treatment with dupilumab, a monoclonal antibody-targeting IL-4Rα. Whereas all immune cell subsets investigated expressed IL-4Rα and common γ chain protein and mRNA, expression of IL-13Rα1 was restricted to myeloid and B cells. Interestingly, some cells contained considerably more intracellular IL-4R protein than on their surface. Naive B cells were found to carry the highest levels of IL-4Rα distributed evenly between surface and intracellular space, whereas IL-4Rα was found predominantly in intracellular pools in neutrophils. In patients with atopic diseases treated with dupilumab, we observed that engagement of IL-4Rα by dupilumab resulted in internalization of the antibody and decreased total IL-4Rα expression. Notably, even after months of treatment not all intracellular IL-4Rα molecules were occupied by dupilumab, indicating the presence of a "dormant" intracellular IL-4Rα pool that could be mobilized upon certain extrinsic or intrinsic cues. Collectively, our findings suggest that distinct human immune cell subsets contain surface and intracellular IL-4R pools, which are differently affected by targeted biologic treatment.


Anisotropies in the perception of stereoscopic surfaces: the role of orientation disparity.
We measured stereoscopic slant detection thresholds for surfaces slanting about a horizontal or a vertical axis. For random-dot covered surfaces, 1.25 deg of slant was required to detect slant about a horizontal axis, whereas 2.1 deg of slant was required to detect slant about a vertical axis. This anisotropy could be due to the fact that orientation disparities, which contain information about surface slant, are generally smaller for surfaces slanting about a vertical axis. To test this possibility, slant thresholds were measured for surfaces whose orientation disparity content was manipulated independently of the other slant information present. When the magnitude of orientation disparity was the same for surfaces slanting about a horizontal and a vertical axis, both surface orientations required about 1.5 deg of slant to be detected; thus the anisotropy became negligible. In contrast, when the orientation disparity content of a surface slanting about a vertical axis was zero, 3-4 deg of slant was required for detection; thus the anisotropy became larger. Under the conditions of these experiments, it appears that the visual system utilizes orientation disparities.


Detecting trypsin at liquid crystal/aqueous interface by using surface-immobilized bovine serum albumin.
We report a new mechanism for liquid crystal (LC)-based sensor system for trypsin detection. In this system, bovine serum albumin (BSA) was immobilized on gold grids as the enzymatic substrate. When the BSA-modified grid was filled with LC and immersed in the solution containing trypsin, the peptide bonds of BSA were hydrolyzed and peptide fragments were desorbed from the surface of gold grid, which disrupted the orientation of LC at the vicinity and resulted in a dark-to-bright transition of optical image of LCs. By using this mechanism, the limit of detection (LOD) of trypsin is 10 ng/mL, and it does not respond to thrombin and pepsin. Besides, the cleavage behavior on gold surfaces was directly visualized by the scanning photoelectron microscopy (SPEM), in particular for the chemical composition identification and element-resolved image. The loss of BSA fragments and the enhancement of Au photoelectron signal after trypsin cleavage were corresponding to the proposed mechanism of the LC-based sensor system. Because the signals reported by LC can be simply interpreted through the human naked-eye, it provides a simple method for fast-screening trypsin activity in aqueous solution.


A new upper limit for effective dose in patient administered with 18F-FDG for PET/CT whole-body imaging with diagnostic CT parameters.
The aim of present study is to estimate effective dose in patient undergoing 18F-FDG for whole body PET/CT imaging with diagnostic CT parameters and identify the lowest achievable total effective dose. A total of 2247 PET/CT patients with normal glucose level underwent 18F-FDG-whole body imaging procedures. The 18F-FDG dose of 3.7MBq per kg of patient weight administered via intravenous infusion. For CT parameters, kilovoltage of 140keV and current of 40 mAs were used for all studies. All the acquired images collected retrospectively and the effective dose was calculated for each patient using algorithm adapted from ICRP Publication 106, modified for patient weight and patient blood volume. The estimated effective doses were evaluated for patients' body weight and BMI. The mean of total effective dose and standard deviation is approximately 15.08(4.52) mSv using ICRP algorithm. 56% of total patient has normal BMI and their average total effective dose is 13.6mSv. Underweight patients' effective dose can be as low as 9.6mSv even using diagnostic CT protocols. The effective dose of PET/CT procedure in present study is one of the lowest although using diagnostic parameters for CT acquisition compared to published data worldwide. This is due to the improved sensitivity of PET and complex reconstruction technique that maintains the image quality. A significant association between body weight, BMI and effective dose is reported in present study. Therefore, it is suggested that attention must be given for underweight and ideal BMI patients while prescribing FDG activity and CT imaging parameters in order to minimize the effective dose. The effective dose reported in present study can be considered as an upper limit for effective dose in PET/CT patients with normal BMI. This upper limit can be treated as a standard limit when optimizing imaging parameters, developing algorithm for image reconstruction and prescribing activity for patients. This practice could fulfill ALARA principle that could reduce cancer risk.


Practical recommendations for the management of hyperlipidemia.
Hyperlipidemia is a risk factor for atherosclerosis. Raised low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) levels are severe risk factors for atherosclerosis. The role of high-density lipoprotein cholesterol (HDL-C) is controversial. Total cholesterol, LDL-C, HDL-C, triglycerides and lipoprotein(a) levels should be determined in a fasting state. The basis of treating hyperlipidemia remains diet, physical exercise and weight reduction. Olive oil and nuts have been shown to be beneficial. Statins remain first line drug treatment. Further treatment options are ezetimibe, bile acid sequestrants, fibrates and fish oil. Side effects of statins include myopathies and, as shown during the last years, also an increased risk of diabetes mellitus. In patients with statin-related myopathies first results of a gene analysis have been published showing a means of predicting which statin can be administered at which dose for the individual patient with least risk of side effects. Most convincing data have been shown for simvastatin. Patients with renal insufficiency have been shown to have a raised cardiovascular risk. In the SHARP Study the combination of simvastatin plus ezetimibe was effective in reducing cardiovascular events in patients with severe renal insufficiency (especially before dialysis but also in dialysis dependent patients). Important aspects of treating patients with chylomicronemia syndrome are illustrated. Treating young patients with hyperlipidemia as primary prevention remains problematic.


Long-term prevention of vagal atrial arrhythmias by atrial pacing at 90/minute: experience with 6 cases.
Six patients (5 men, 1 woman) with a history ranging from 3-16 years of resistant vagal atrial arrhythmias were treated by atrial pacing at a rate of 90/Min. These patients have been followed up for an average of 5.5 years (range 2-11 years) with favorable results. The arrhythmias were characterized by daily or weekly attacks of typical atrial flutter and atrial fibrillation occurring mainly or exclusively at night, at rest, or in the digestive periods in otherwise normal hearts of middle-aged patients (first attack between 25 and 54, mean 40). The arrhythmias were resistant to quinidine, and were usually aggravated by digitalis, beta-blockers and verapamil. Amiodarone is usually the only effective drug in this syndrome, but was not used before pacing in the 2 first cases, and was ineffective in the other 4 cases. Electrophysiologic studies confirmed the absence of sick sinus syndrome, and the close relationship between relative bradycardia and the onset of the arrhythmia. Atrial pacing alone totally controlled the arrhythmia in 1 patient; amiodarone was used in conjunction with pacing in 3 patients. In 1 patient the improvement was clear but incomplete, and in 1 patient permanent atrial fibrillation occurred shortly after pacemaker implantation.


Molecular and cytogenetic description of somatic hybrids between Gentiana cruciata L. and G. tibetica King.
Somatic hybridization provides an opportunity to create cells with new genetic constitution. Here, the interspecific somatic hybrid plants regenerated in vitro following fusion of cell suspension-derived protoplasts of tetraploid Cross Gentian (Gentiana cruciata L., 2n = 52) with protoplasts released from mesophyll tissue of another tetraploid species, Tibetan Gentian (G. tibetica King, 2n = 52), were studied. According to the results of genome analyses with AFLP, ISSR, and CAPS markers, all somatic hybrids were genetically closer to "suspension" fusion partner G. cruciata than to "mesophyll" partner G. tibetica, but they got G. tibetica chloroplasts. Chromosome counting revealed little variation in the number of chromosomes in hybrid's cells (2n = 88 or 2n = 90), although all plants possessed similar nuclear DNA content which remained stable even after 2 years of in vitro culture. Fluorescence in situ hybridization (FISH) showed that hybrids possessed 4 to 7 chromosomes bearing 5S rDNA sites and 6 or 7 chromosomes with 35S rDNA sites. A part of FISH signals was smaller than those observed in the parental species, which could indicate the loss of rDNA sequences. Genomic in situ hybridization (GISH) showed the predominance of the number of G. cruciata chromosomes over chromosomes of G. tibetica. However, a significant level of cross-hybridization was observed for about one-third of hybrid chromosomes, indicating a high degree of homeology between the genomes of G. cruciata and G. tibetica.


Patients with high-risk differentiated thyroid cancer have a lower I-131 ablation success rate than low-risk ones in spite of a high ablation activity.
To examine success rates in strictly defined high-risk differentiated thyroid cancer (DTC) patients who received a high-activity (≥5550 MBq) adjuvant postoperative I-131 therapy and compare these to the rates found in highest risk and low-risk patients. Retrospective database study. We examined 377 patients with DTC who received I-131 ablation. Patients with distant metastases were classified as very high risk. Patients with primary tumours >4 cm, extensive extrathyroidal invasion (pT4a or pT4b in accordance with the 7th edition of the TNM system), and patients with ≥5 lymph node metastases or any lateral compartment lymph node metastases were considered high risk. All other patients were considered low risk. Ablation success rate at first TSH-stimulated follow-up. The ablation success rate was 72·6% in low-risk patients, 51·7% in high-risk patients and 13·8% in highest risk patients (all differences P < 0·001). In none of the groups, a significant difference in the initial I-131 activity was found between patients with successful and unsuccessful ablation (low risk: P = 0·16, high risk: P = 0·91 and highest risk: P = 0·48). Furthermore, there was no difference in ablation success between patients who received <5550 MBq and those who received ≥5550 Mbq (low risk: P = 0·31, high risk: P = 0·69 and highest risk: P = 0·22). Patients with high-risk DTC have a significantly reduced I-131 ablation success rate compared to low-risk ones in spite of high initial I-131 activities. As successful ablation is prognostically important, efforts should be made to improve outcome in these patients.


High mobility emissive organic semiconductor.
The integration of high charge carrier mobility and high luminescence in an organic semiconductor is challenging. However, there is need of such materials for organic light-emitting transistors and organic electrically pumped lasers. Here we show a novel organic semiconductor, 2,6-diphenylanthracene (DPA), which exhibits not only high emission with single crystal absolute florescence quantum yield of 41.2% but also high charge carrier mobility with single crystal mobility of 34 cm(2) V(-1) s(-1). Organic light-emitting diodes (OLEDs) based on DPA give pure blue emission with brightness up to 6,627 cd m(-2) and turn-on voltage of 2.8 V. 2,6-Diphenylanthracene OLED arrays are successfully driven by DPA field-effect transistor arrays, demonstrating that DPA is a high mobility emissive organic semiconductor with potential in organic optoelectronics.


Paediatric anterior larynx: presentations, associations and a review of the literature.
The literature on the entity of the anterior larynx (AL) is restricted to little evidence on the difficulty encountered in exposing the larynx for intubation, perioperative morbidity and mortality, and scant reports on its prevalence in general adults and children. Here, we describe the prevalence of AL in a series of children presenting with aerodigestive symptoms and explore its association with functional abnormalities, congenital and structural anomalies or conditions. Tertiary paediatric centre. We conducted a retrospective case-control study. Using a prospectively collected surgical database, we identified patients diagnosed with AL (Grades IIb-III-IV Modified Cormack-Lehane scale) and sex and age-matched controls who had undergone full airway endoscopy for aerodigestive symptoms. We collected the demographics, presentations, associated diagnoses and investigations. We compared the proportion of patients with large airway abnormalities and dysmorphism and estimated the prevalence of AL. Over a 5.5-year period, 58 children with AL (28 females, mean age 0.38 years) were matched with 58 controls (mean age 0.42 years). Although both groups presented with permutations of stridor, respiratory failure, cyanotic spells, swallowing and feeding difficulties and SDB, AL presented much more with swallowing and feeding problems (33 vs. 20, p < .05). There were significantly more children with dysmorphism in the AL group (29 vs. 9, p < .05). The prevalence of AL was 4.9% (SE 0.0063). AL was detected in 4.9% of a sample of children who had undergone airway examination for aerodigestive symptoms. It is significantly associated with dysmorphism, and swallowing difficulties that warrant instrumental evaluation.


Evidence for the release of 1-methyl-4-phenylpyridinium (MPP+) from rat striatal neurons in vitro.
[3H]MPP+ (1-[methyl-3H]4-phenylpyridinium) is taken up into rat striatal slices in a temperature-, time- and Na+-dependent process blocked by dopamine (DA) uptake inhibitors. Once taken up, authentic [3H]MPP+ is released at 37 degrees C by 15 mM KCl. This release is inhibited by (-)N-propyl-norapomorphine and enhanced by (-)sulpiride, as observed under the same conditions for [3H]DA release. Thus, rat striatal DA-ergic nerve endings do not discriminate between DA and MPP+ for their active transport and DA autoreceptor-regulated release.


Bullying involvement and self-reported mental health in elementary school children across Europe.
Bullying behavior is recognized internationally as a serious issue associated with mental health and functioning problems among children. The present study sought to determine the associations between bullying involvement and self-reported mental health among elementary school children across seven European countries. The School Children Mental Health in Europe study was conducted in Bulgaria, Germany, Italy, Lithuania, the Netherlands, Romania and Turkey in 2010 using similar methodology to collect cross-sectional data from children, parents, and teachers. The study focused on children who had completed the Dominic Interactive and whose mother and/or teacher had completed the Strengths and Difficulties Questionnaire (n = 5,183). Overall 14.3 % of children were identified as bullies, 18.2 % as victims and, 19.0 % as both bullies and victims. Despite the low threshold for defining bullying status, children identified as being involved were highly likely to present with self-reported mental health problems: 31.6 % of bully-victims reported any disorder, while 25.4 % of bullies and 23.1 % of victims did. Adjusting for key factors, bullies and bully-victims were significantly more likely to present with any externalizing disorder, while victims were not. Additionally, bully-victim status was associated with significantly greater odds of presenting with each internalizing disorder: phobia (AOR = 1.48, 95 %CI = 1.01-2.19), GAD (AOR = 2.54, 95 %CI = 1.67-3.87), separation anxiety (AOR = 1.88, 95 %CI = 1.43-2.47) and depression (AOR = 2.52, 95 %CI = 1.61-3.93). However, victim status was only associated with GAD (AOR = 1.63, 95 %CI = 1.07-2.48) and bully status with separation anxiety (AOR = 1.44, 95 %CI = 1.07-1.93). The results highlight the association of bullying involvement and child mental health in elementary school children across Europe.


Molecular characterization of metabolic subtypes of gastric cancer based on metabolism-related lncRNA.
Increasing evidence has demonstrated that lncRNAs are critical regulators in diverse biological processes, but the function of lncRNA in metabolic regulation remains largely unexplored. In this study, we evaluated the association between lncRNA and metabolic pathways and identified metabolism-related lncRNAs. Gastric cancer can be mainly subdivided into 2 clusters based on these metabolism-related lncRNA regulators. Comparative analysis shows that these subtypes are found to be highly consistent with previously identified subtypes based on other omics data. Functional enrichment analysis shows that they are enriched in distinct biological processes. Mutation analysis shows that ABCA13 is a protective factor in subtype C1 but a risk factor in C2. Analysis of chemotherapeutic and immunotherapeutic sensitivity shows that these subtypes tend to display distinct sensitivity to the same chemical drugs. In conclusion, these findings demonstrated the significance of lncRNA in metabolic regulation. These metabolism-related lncRNA regulators can improve our understanding of the underlying mechanism of lncRNAs and advance the research of immunotherapies in the clinical management of gastric cancer.


Mechanisms implicated in the growth regulatory effects of vitamin D compounds in breast cancer cells.
The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)D3), has been recognized for over 2 decades as a modulator of cell proliferation and differentiation in many cell types, including breast cancer. However, any potential anti-tumour properties displayed by 1,25(OH)D3 are limited by the tendency to cause hypercalcaemia when administered at high doses. Because of this, synthetic vitamin D analogues have been developed that retain the anti-tumour effects seen with 1,25(OH)D3 but which have reduced calcaemic activity. However, it is still unclear as to how 1,25(OH)D3 and its synthetic analogues act within breast cancer cells to elicit the effects on cellular proliferation and differentiation. In this chapter we review the advances that have been made in trying to answer this question. It has been found so far that 1,25(OH)D3 has an effect on the expression of certain cell cycle regulators and in this way can bring about G1 arrest. Evidence has also emerged that vitamin D compounds can also affect the growth-promoting pathways initiated by two important factors involved in breast cancer cell promotion; namely the insulin-like growth factor I (IGF-I) and oestrogen-receptor (ER) pathways. Vitamin D compounds have also been implicated in promotion of apoptosis in breast cancer cells and evidence suggests that 1,25(OH)D3 and its synthetic analogues may potentiate responsiveness of breast cancer cells to conventional cytotoxic agents. Although much remains to be learned about the associated underlying mechanisms, ongoing research suggests that vitamin D analogues are a new class of compounds with potential in breast cancer treatment and prevention.


Thermal Stability Estimation of Single Domain Antibodies Using Molecular Dynamics Simulations.
In this chapter, we describe a protocol to estimate the thermal stability of single domain antibodies (sdAbs) using molecular dynamics (MD) simulations. This method measures the Q-value, the fraction of the native contacts, along the trajectory of high-temperature MD simulations starting from the experimental X-ray structure. We show a good correlation between the Q-value and the experimental melting temperature (Tm) in seven sdAbs. Assessing the Q-value on a per-residue level enabled us to identify residues that contribute to the instability and thus demonstrate which residues could be mutated to improve the stability and have later been validated by experiments. Our protocol extends beyond the application on sdAbs, as it is also suitable for other proteins and to determine the interfacial stability between protein and ligand.


Endocrine effects of testosterone undecanoate as a supplementary treatment to menopausal gonadotropins or tamoxifen citrate in idiopathic oligozoospermia.
To evaluate the effects of T undecanoate given as a supplementary treatment with tamoxifen citrate (TAM) or hMG on pituitary and Leydig cell function in men with idiopathic oligozoospermia. A total of 48 normogonadotropic men with idiopathic oligozoospermia were allocated in to six groups (n = 8 per group) treated with placebo, 40 mg T undecanoate three times per day, 10 mg TAM two times per day, T undecanoate and TAM, 75 IU/d hMG, and T undecanoate and hMG. All groups were evaluated with standard GnRH, thyrotropin-releasing hormone, and hCG tests before and on the final day of 3 months on treatment with measurements of FSH, LH, thyroid-stimulating hormone (TSH), PRL, T, E2, 17-hydroxyprogesterone, sex hormone-binding globulin, and seminal analyses (at least twice each time). Basal and stimulated concentrations and incremental FSH and LH values showed no differences among TAM or hMG and TAM + T undecanoate or hMG + T undecanoate treated groups. Basal, stimulated, and incremental values for TSH and PRL were elevated markedly during treatment in most groups in comparison to placebo. Basal, stimulated, and incremental T and E2 values were similar in active treatment groups except that higher T concentration was found in TAM + T undecanoate as compared with T undecanoate only treated men. Finally, significant improvements were noted in important seminal parameters and particularly in the functional sperm fraction of the TAM + T undecanoate group as compared with single treatment with TAM. These results indicate that T undecanoate in combination with TAM or hMG not only had no adverse effects on pituitary and Leydig cell activity but also seemed to improve important seminal parameters and signify that androgens may be tried as a supplementary treatment to conventional regimes in idiopathic oligozoospermia.


The potential impact of increased recombinant zoster vaccine coverage on the burden of herpes zoster among adults aged 50-59 years.
Recombinant zoster vaccine (RZV) is recommended in the US for prevention of herpes zoster (HZ) in adults aged ≥50 years. Vaccination rates remain suboptimal for adults 50-59 years compared with adults ≥50 years overall. The objective of this study was to model changes in outcomes associated with improved RZV vaccination coverage in US adults 50-59 years. A multicohort Markov model compared a scenario using real-world vaccination coverage for US adults 50-59 years in 2020 versus scenarios assuming higher coverage. Outcomes, based on a lifetime horizon, included HZ cases and complications avoided, quality-adjusted life-years (QALY), and costs. Model inputs included HZ epidemiology, RZV vaccine efficacy, coverage, adverse events, and costs, based on published literature and US sources. Some inputs were updated from previous models, including real-world estimates of RZV coverage, series completion, and reflecting longer-term data on waning of vaccine efficacy. The model utilized a cohort size of 42,756,488 individuals based on the 2020 US population census. The model projected that increasing RZV coverage in adults 50-59 years from 7.3 % to 14.6 % (to coverage for adults 60-64 years in 2020) would avoid an additional 504,468 HZ cases, 42,077 postherpetic neuralgia cases, and 56,247 cases of other HZ-associated complications. The increase in vaccine coverage would result in higher vaccination-related costs of $1,172,411,566, but the avoided HZ cases and complications would be expected to result in direct cost savings of $721,973,386 and indirect cost savings of $593,497,480 from avoided productivity loss. Overall, a gain of 5,230 discounted QALYs and cost savings of $143,059,299 from a societal perspective would be realized. Modestly higher RZV coverage in US adults 50-59 years could reduce the clinical burden associated with HZ and may result in societal cost savings. These findings demonstrate the potential value of increasing RZV vaccination in this population.


Ion Velocity Measurements for the Ionospheric Connections Explorer.
The Ionospheric Connections Explorer (ICON) payload includes an Ion Velocity Meter (IVM) to provide measurements of the ion drift motions, density, temperature and major ion composition at the satellite altitude near 575 km. The primary measurement goal for the IVM is to provide the meridional ion drift perpendicular to the magnetic meridian with an accuracy of 7.5 ms-1 for all daytime conditions encountered by the spacecraft within 15° of the magnetic equator. The IVM will derive this parameter utilizing two sensors, a retarding potential analyzer (RPA) and an ion drift meter (IDM) that have a robust and successful flight heritage. The IVM described here incorporates improvements in the design and operation to produce the most sensitive device that has been fielded to date. It will specify the ion drift vector, from which the component perpendicular to the magnetic field will be derived. In addition it will specify the total ion density, the ion temperature and the fractional ion composition. These data will be used in conjunction with measurements from the other ICON instruments to uncover the important connections between the dynamics of the neutral atmosphere and the ionosphere through the generation of dynamo currents perpendicular to the magnetic field and collisional forces parallel to the magnetic field. Here the configuration and operation of the IVM instrument are described as well as the procedures by which the ion drift velocity is determined. A description of the subsystem characteristics, which allow a determination of the expected uncertainties in the derived parameters, is also given.


Fulminant type 1 diabetes in Korea: high prevalence among patients with adult-onset type 1 diabetes.
The aim of this study was to investigate the prevalence of fulminant type 1 diabetes and the clinical characteristics of the disease among newly diagnosed Korean patients. Using data retrieved from the Seoul National University Hospital database, we identified all patients newly diagnosed with type 1 diabetes from 1 January 1999 to 31 July 2006. Information on clinical manifestations and laboratory data, including the presence of islet autoantibodies detected at diagnosis, were obtained by reviewing medical records. We identified 99 patients newly diagnosed with type 1 diabetes. Seven patients (7.1%) fulfilled the criteria for fulminant type 1 diabetes. Among the patients aged > or =18 years at onset, 30.4% had fulminant type 1 diabetes. Patients with this diabetes subtype tested negative for islet autoantibodies, had a higher age of onset (median 28 vs 10 years, p < 0.001) and a markedly shorter duration from onset of hyperglycaemic symptoms to first hospital visit (median 3 vs 30 days, p < 0.001) than patients with non-fulminant type 1 diabetes, and showed trends of increased serum aspartate aminotransferase and amylase levels and a decreased glucagon-stimulated serum C-peptide response. In Korea, the prevalence of fulminant type 1 diabetes was 7.1% among all patients newly diagnosed with type 1 diabetes and 30.4% among patients with adult-onset diabetes. The clinical and metabolic characteristics of the patients with fulminant type 1 diabetes were similar to those reported in Japanese studies.


Human bioavailability of propranolol from a matrix-in-cylinder system with a HPMC-Gelucire core.
The bioavailability of propranolol from a matrix-in-cylinder system for sustained drug delivery, consisting of a hot-melt extruded ethylcellulose pipe surrounding a drug-containing HPMC-Gelucire 44/14 core, was determined. An oral dose of 80 mg propranolol hydrochloride was administered to healthy volunteers (n = 10) in a randomized cross-over study design either as a commercial pellet formulation (Inderal retard mitis) or as a matrix-in-cylinder system. The influence of concomitant food intake on drug release from the matrix-in-cylinder system was also studied. During the first 10 h after administration, the matrix-in-cylinder system resulted in similar plasma levels as the reference formulation Inderal. The concomitant intake of a high-fat, high-calorie breakfast did not cause dose-dumping. Between 10 h and 24 h after administration of the matrix-in-cylinder system, a remarkable increase of the propranolol plasma levels was noticed (compared to Inderal). This effect was even more pronounced under fed conditions. The matrix-in-cylinder system had a relative bioavailability of 156% (fasted conditions) and 222% (fed conditions) compared to the marketed reference product. In order to elucidate the origin of this increased bioavailability, Caco-2 experiments and dog lymph studies were performed. However, none of these experiments was able to provide a conclusive answer.


[Phototherapy in the era of biologicals].
The development of biologicals had led to a dramatic change in the therapy of psoriasis, making necessary a re-evaluation of conventional therapeutic strategies. Four parameters must be evaluated: efficacy, economic burden, side effects and practicability. As for efficacy, according to published meta-analyses Infliximab reaches the efficiency of PUVA therapy, whereas the other biologicals, although being very effective, are inferior. Biologicals have a clear advantage in treating psoriatic arthritis. All published pharmacoeconomic studies demonstrate a significant advantage of phototherapy over biologicals. Severe and atypical (masked) infections, demyelinizing diseases, possible induction of lymphomas (not definitely established), and autoimmune phenomena are troublesome and feared side effects of biologicals. The risk of photocarcinogenesis after long-term use is the most significant side effect of phototherapy. However, considering the experience of 5 decades of good controlled clinical evaluation of phototherapy, this option has to be considered as safer than Biologicals. Looking at practicability, biologicals have undoubtedly a significant advantage compared to phototherapy.


Current Approach to the Management of Eosinophilic Esophagitis in Adults.
Eosinophilic esophagitis (EoE) is an increasingly diagnosed, immune-mediated disease characterized by inflammation of the esophagus in both children and adult, causing significant morbidity. Adults typically present with dysphagia and a history of food impaction. Diagnosis should be considered in patients with histological evidence of eosinophilia (≥15 eosinophils per high-power field) on esophageal biopsy. More recently, it has been observed that a significant percentage of patients with esophageal eosinophilia respond both clinically and histologically to PPI therapy. This disorder has been named PPI-responsive esophageal eosinophilia (PPI-REE). Recent studies suggest that patients with PPI-REE have similar clinical and endoscopic features of patients with EoE. Specifically, both PPI-REE and EoE patients have a strong disposition to allergy compared to patients without eosinophilia. As such, PPI-REE may represent a subset or variant of EoE. Effective treatment of EoE requires a multidisciplinary approach with gastroenterologists, pathologists, allergists, and nutritionists. Treatments include elimination and elemental diets, topical glucocorticoids (fluticasone and budesonide), and endoscopic dilation.


Sensitive diagnosis of cardiac allograft rejection by detection of cytokine transcription in situ.
In situ transcription of cytokines which are important in the development of cardiac rejection has not been evaluated for diagnosing rejection. The objective was to evaluate the usefulness of in situ reverse transcriptase polymerase chain reaction (RT-PCR) for sensitive detection of acute cardiac rejection. We studied interferon (IFN)-gamma and interleukin (IL)-2 expression using immunohistochemistry and in situ RT-PCR in murine cardiac transplant models. Hearts were heterotopically transplanted (BALB/c to C3H/He) and some mice were not treated (n = 23); others were treated with anti-intercellular adhesion molecule (ICAM)-1 and anti-lymphocyte function associated antigen (LFA)-1 monoclonal antibodies (mAbs) (n = 23). Allografts were removed at days 1 to 7. For control, isografts were harvested at day 7 (n = 2). Mice without treatment rejected allografts within 7 days, while all mAb-treated recipients accepted allografts for the same period. At day 1, allografts of both groups showed scattered myocardial cell infiltration which increased in non-treated allografts, but remained stable in mAb-treated grafts thereafter. In situ RT-PCR showed that IL-2 and IFN-gamma mRNA positive cells were present in non-treated allografts, while few mRNA positive cells were expressed in infiltrating cells in the mAb-treated allografts (IL-2, day 3: 88.8 +/- 28.3 vs. 7.2 +/- 6.4, p < 0.05, positive cells within 10 fields per section). However, immunohistochemistry could not reveal the difference at day 3. In situ RT-PCR is a sensitive method for diagnosing acute rejection, and it reveals the characteristics of myocardial infiltrate cells to determine their role in the process of rejection.


Circulating Gremlin-1 is elevated in systemic sclerosis patients.
Systemic sclerosis is an autoimmune connective tissue disease in which there is activation of the immune system, vascular disease and fibrosis. Activation of quiescent fibroblasts to myofibroblasts is key to disease pathogenesis. Gremlin-1 is a bone morphogenetic protein antagonist which is important in development and we recently reported in skin fibrosis. The aim of this study was to determine the serum circulating levels of Gremlin-1 in early diffuse systemic sclerosis. Twenty-one early diffuse systemic sclerosis patients (less than 2 years from first non-Raynaud's symptom) were included and age and sex-matched healthy controls. Serum was isolated from blood and measured with a specific enzyme-linked immunoassay for Gremlin-1. Clinical variables were also measured. Significantly elevated Gremlin-1 was found in sera of early diffuse systemic sclerosis patients (p < 0.001). In patients with interstitial lung disease, this compared to systemic sclerosis without evidence of interstitial lung disease, Gremlin-1 was significantly elevated (p < 0.0007). A correlation was found between circulating Gremlin-1 and modified Rodnan Skin Score, albeit weak. In early diffuse systemic sclerosis patients, elevated Gremlin-1 is found in serum. This is particularly prominent in systemic sclerosis-associated interstitial lung disease. This suggests that Gremlin-1 may be a biomarker for systemic sclerosis interstitial lung disease.


The number of examinations required for the accurate prediction of the progression of the central 10-degree visual field test in glaucoma.
The purpose of the study was to investigate the number of examinations required to precisely predict the future central 10-degree visual field (VF) test and to evaluate the effect of fitting non-linear models, including quadratic regression, exponential regression, logistic regression, and M-estimator robust regression model, for eyes with glaucoma. 180 eyes from 133 open angle glaucoma patients with a minimum of 13 Humphrey Field Analyzer 10-2 SITA standard VF tests were analyzed in this study. Using trend analysis with ordinary least squares linear regression (OLSLR), the first, second, and third future VFs were predicted in a point-wise (PW) manner using a varied number of prior VF sequences, and mean absolute errors (MAE) were calculated. The number of VFs needed to reach the minimum 95% confidence interval (CI) of the MAE of the OLSLR was investigated. We also examined the effect of applying other non-linear models. When predicting the first, second, and third future VFs using OLSLR, the minimum MAE was obtained using VF1-12 (2.15 ± 0.98 dB), VF1-11 (2.33 ± 1.10 dB), and VF1-10 (2.63 ± 1.36 dB), respectively. To reach the 95% CI of these MAEs, 10, 10, and 8 VFs were needed for the first, second and third future VF predictions, respectively. No improvement was observed by applying non-linear regression models. As a conclusion, approximately 8-10 VFs were needed to achieve an accurate prediction of PW VF sensitivity of the 10-degree central VF.


Decomposition of a Mixed-Valence [2Fe-2S] Cluster to Linear Tetra-Ferric and Ferrous Clusters.
Despite the ease of preparing di-ferric [2Fe-2S] clusters, preparing stable mixed-valence analogues remains a challenge, as these clusters have limited thermal stability. Herein we identify two decomposition products of the mixed-valence thiosalicylate-ligated [2Fe-2S] cluster, [Fe2S2(SArCOO)2]3- ((SArCOO)2- = thiosalicylate).


[Intracranial insertion of a nasogastric tube in a patient with severe head injuries].
The accident intracranial insertion of a nasogastric tube is a well known complication. We report the case of 19-year-old girl with a severe craniofacial trauma who had a nasogastric tube inserted at the site of the traffic accident. The aspiration gave issue of haemorrhagic fluid. At admission the X-ray of the skull showed the intracerebral penetration of the tube. It was removed but the patient died two days later. The various means of prevention and treatment of this complication are discussed.


Glutathione is involved in the early cadmium cytotoxic response in human lung carcinoma cells.
Depletion of cellular glutathione (GSH) has been shown to sensitize A549-T27 human tumor cells to the cytotoxic effects of Cd2+. In this study the temporal and quantitative relationships between reduced cellular GSH levels and cadmium cytotoxic response in these cells were further investigated. Exposure of A549-T27 cells to 10 mM buthionine sulfoximine (BSO) for 8 h decreased their GSH level by 65%. This GSH level remained relatively constant for 8 h in the presence or absence of BSO, but recovered to 83% of the normal cellular level 24 h after removal of BSO. Exposure to 5 microM Cd2+ for 8 h did not significantly change cellular GSH levels. Pretreatment of the A549-T27 cells with 10 mM BSO for 8 h and subsequent exposure of the cells to Cd2+ for 10 days, with or without concurrent treatment of 10 mM BSO during the first 8 h of Cd2+ exposure, resulted in disappearance of the 5 microM Cd2+ threshold for cytotoxic response and reduction of the LC50 from 31 microM Cd2+ to 21 microM. Similar results were obtained when BSO pretreated cells were exposed to Cd2+ for 8 h. The threshold for cytotoxic response of 10 microM Cd2+ disappeared and the LC50 was reduced from 60 microM to 29 microM Cd2+ (with concurrent BSO treatment) and 30 microM (BSO pretreatment only). The results show that GSH plays an important role in early cellular protective responses to Cd2+.


Secular trends in cesarean delivery rates among macrosomic deliveries in the United States, 1989 to 2002.
We describe national trends in cesarean delivery rates among macrosomic infants during 1989 to 2000 and evaluate the maternal characteristics and risk factors for macrosomic infants delivered by cesarean section as compared to macrosomic infants delivered vaginally. We analyzed US 1989 to 2000 Natality files, selecting term (37 to 44 week) single live births to U.S. resident mothers. We compare macrosomic infants (4000 to 4499, 4500 to 4999 and 5000+ g infants) to a normosomic (3000 to 3999 g) control group. The proportion of cesarean deliveries among 5000+ g infants increased significantly over the time period. The adjusted odds ratio of cesarean delivery increased for all macrosomic categories over the 12-year period, as compared to normal birth weight infants. Rates of cesarean delivery among macrosomic infants continue to increase despite a lack of evidence of the benefits of cesarean delivery within this population. Further exploration of the rationale for this trend is warranted and should include the development of an optimal delivery strategy for such patients.


Nyctanthes arbor-tristis alkaloids activates p53 independent cell death receptor and necroptosis pathways in HepG2 cells.
Nyctanthes arbor-tristis is a traditional medicinal plant with potential anti-cancer properties. In this study, crude and alkaloid extracts were prepared from different parts of the plant, and their cytotoxicity was evaluated on four different cancer cell lines. The alkaloid extracts from the leaf and fruit showed promising results, with the HepG2 cell line exhibiting significant cytotoxicity. The promising extracts were further studied for their apoptotic potential using various methods, including DNA fragmentation, TUNEL, Caspase-3 activity, Giemsa, and Hoechst staining. Our results indicated that the fruit extract had the highest apoptotic potential, with clear nuclear condensation, fragmentation, and apoptotic bodies observed. We also investigated the alteration of the Bax/Bcl-2 ratio both at the mRNA and protein levels. Our results showed a significant upregulation of the Bax gene and downregulation of the Bcl-2 gene for the fruit alkaloid extract. This indicates that the phenomenon of cell death expression might be following a p53-independent extrinsic pathway and Bax-activated caspase-independent AIF-mediated necroptosis in the HepG2 cancer cell line. Overall, our findings suggest that Nyctanthes arbor-tristis has potential as a therapeutic option for cancer treatment. The alkaloid extracts from the leaf and fruit may hold promise as a source of bioactive compounds for further development into anti-cancer agents. Further studies are needed to explore the underlying mechanisms of their cytotoxic and apoptotic effects and to evaluate their safety and efficacy in animal models and clinical trials.


Effects of morphine and D-Ala2-D-Leu5-enkephalin in the seizure-susceptible El mouse.
Opioid agonists were used to investigate the modulation of seizures in the seizure-susceptible El mouse. Morphine and D-Ala2-D-Leu5-enkephalin (DADLE) were injected subcutaneously or intracisternally as prototypic agonists for mu and delta opioid receptors. Systemic or intracisternal injection of both morphine and DADLE decreased the incidence of seizures and the seizure score in El mice in a dose-dependent manner. The anticonvulsant effects of morphine and DADLE were reversed by naloxone (2 mg/kg, s.c.). This implies that opioid agonists have anticonvulsant properties which are mediated by mu and delta opioid receptors. In conclusion, a deficit in endogenous opioid peptides, which act as anticonvulsants may play a significant role in the etiology or pathophysiology of seizures in the El mouse.


Decomposition of inequity determinants of healthcare utilization, Iran.
To investigate and decompose the determinants of healthcare utilization in a central province in Iran. Data from 2711 individuals were gathered through interview in a cross-sectional study in Markazi province, Iran, as part of the Healthcare Utilization Survey in 2008. The household economic index (HEI) was created using principal component analysis, and data were analyzed according to the type of healthcare utilization. In addition, the generalized estimation equation model was used to identify the determinants, and the concentration index was calculated and decomposed based on the healthcare utilization determinants. HEI was a fixed determinant for all three types of healthcare utilization (general physician, specialist and health worker); however, other determinants changed with the type of health care. The greatest contributors to inequity in the use of general physician, specialist and health worker care were HEI quintile (41.4%), housewife/retired (32.8%) and living in an urban area (47%), respectively. The concentration index was highest for specialist care and lowest for health worker care. The pattern of utilization differed between the types of health care. Nevertheless, inequity in healthcare utilization is related to government health policies, including the role of the system in reducing inequity by application of policies such as the family physician and rural insurance programme; and factors which are beyond the health system authorities, and are related to population living standards and need intersectoral cooperation.


Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis.
N-methyl-D-aspartate (NMDA) glutamate receptor antagonists are reported to induce schizophrenia-like symptoms in humans, including cognitive impairments. Shortcomings of most previous investigations include failure to maintain steady-state infusion conditions, test multiple doses and/or measure antagonist plasma concentrations. This double-blind, placebo-controlled, randomized, within-subjects comparison of three fixed subanesthetic, steady-state doses of intravenous ketamine in healthy males (n = 15) demonstrated dose-dependent increases in Brief Psychiatric Rating Scale positive (F[3,42] = 21.84; p < 0.0001) and negative symptoms (F[3,42] = 2.89; p = 0.047), and Scale for the Assessment of Negative Symptoms (SANS) total scores (F[3,42] = 10.55; p < 0.0001). Ketamine also produced a robust dose-dependent decrease in verbal declarative memory performance (F[3,41] = 5.11; p = 0.004), and preliminary evidence for a similar dose-dependent decrease in nonverbal declarative memory, occurring at or below plasma concentrations producing other symptoms. Increasing NMDA receptor hypofunction is associated with early occurring memory impairments followed by other schizophrenia-like symptoms.


Contemporary cost-analysis comparison of direct-to-consumer vs. traditional prescriptions of phosphodiesterase-5 inhibitors.
After a focused telehealth visit, patients can now access phosphodiesterase-5 inhibitor (PDE5 inhibitor) prescriptions through online direct-to-consumer (DTC) healthcare companies. This study seeks to quantify the cost of DTC PDE5 inhibitor treatment compared to a traditional physician visit and local pharmacy prescription. Two DTC companies, two compounding pharmacies with national reach, three online Canadian pharmacies, and sixteen American pharmacy chains were queried for prices of 90-day regimens of common PDE5 inhibitors. Prices for chains were determined using their publicly available price on GoodRx® with coupon. Cost of physician visit was determined using 2020 Center for Medicare and Medicaid Services reimbursement for a level 3 new patient visit. For sildenafil 20 mg, a physician visit and local prescription cost a low of $125.45 compared to $144.35 for compounding, $169.34 for Canadian, and $195.00 for DTC. For sildenafil 100 mg, a physician visit and local prescription cost a low of $137.16 compared to $289.35 for compounding, $200.36 for Canadian, and $900.00 for DTC. For tadalafil 5 mg, a physician visit and local prescription cost a low of $125.80 compared to $169.35 for compounding, $195.34 for Canadian, and $720.00 for DTC. For tadalafil 20 mg, a physician visit and local prescription cost a low of $161.00 compared to $289.35 for compounding, $229.00 for Canadian, and $2880.00 for DTC. Thus, local pharmacies, in conjunction with online coupons, consistently provide a markedly less-expensive option for fulfillment of PDE5 inhibitor prescriptions than online DTC services.


Parent-of-Origin inference for biobanks.
Identical genetic variations can have different phenotypic effects depending on their parent of origin. Yet, studies focusing on parent-of-origin effects have been limited in terms of sample size due to the lack of parental genomes or known genealogies. We propose a probabilistic approach to infer the parent-of-origin of individual alleles that does not require parental genomes nor prior knowledge of genealogy. Our model uses Identity-By-Descent sharing with second- and third-degree relatives to assign alleles to parental groups and leverages chromosome X data in males to distinguish maternal from paternal groups. We combine this with robust haplotype inference and haploid imputation to infer the parent-of-origin for 26,393 UK Biobank individuals. We screen 99 phenotypes for parent-of-origin effects and replicate the discoveries of 6 GWAS studies, confirming signals on body mass index, type 2 diabetes, standing height and multiple blood biomarkers, including the known maternal effect at the MEG3/DLK1 locus on platelet phenotypes. We also report a novel maternal effect at the TERT gene on telomere length, thereby providing new insights on the heritability of this phenotype. All our summary statistics are publicly available to help the community to better characterize the molecular mechanisms leading to parent-of-origin effects and their implications for human health.