The Continuum of Prostate Cancer Care: An Integrated Population Based Model of Health Care Delivery.
We present a comprehensive model for population based prostate cancer management that is scalable, and has improved quality and outcomes. Kaiser Permanente Southern California is an integrated health care system that provides comprehensive care for 3.7 million members. Beginning in 2003 we put programs into place to improve the spectrum of care related to prostate cancer. These programs addressed screening, shared decision making for treatment after diagnosis, and care improvement for men with localized and advanced disease. These were implemented with traditional quality improvement techniques and outcomes were evaluated in collaboration with research groups embedded in the organization. Prostate cancer screening in men 75 years old or older decreased 50% from 30% to 15%. The Safety Net program identified nearly 1,200 men with prostate cancer who had not been seen for followup from 2006 to 2010. There was a reduction in blood loss in surgical procedures that obviated the need for transfusion while maintaining a low positive margin rate. Hormonal therapy was changed to a dosing approach that was based on circulating testosterone levels, preventing some of the side effects of this therapy. Coupled with a systems approach to osteoporosis prevention, this approach resulted in a dramatic reduction in fracture rates in this high risk population. These data demonstrate that a systems approach to a population based prostate cancer program can lead to efficient and reliable care that can be successfully disseminated through an integrated health plan.


IL-1ra polymorphisms and risk of epidural-related maternal fever (EPIFEVER-2): study protocol for a multicentre, observational mechanistic cohort study.
Laboratory data suggest that insufficient circulating levels of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra) are associated with intrapartum inflammation and epidural-related maternal fever, both of which increase the rate of obstetric interventions and antibiotic use during labour. Genetic polymorphisms strongly influence IL-1ra levels in the general population. We aim to examine the association between IL-1ra polymorphisms and epidural-related maternal fever using Mendelian randomization analysis. EPIFEVER-2 is a multicentre UK trial enrolling 637 women receiving epidural analgesia for labour. Blood samples obtained no later than four hours after epidural insertion will provide deoxyribonucleic acid for Taqman single-nucleotide polymorphism genotyping for presence/absence of rs6743376, rs1542176 alleles for IL-1ra, to establish the genetic score. The absence of both alleles is associated with the lowest IL-1ra levels. The primary outcome is pyrexia (>38°C) or intrapartum antibiotic administration. Secondary outcomes include mode of delivery, maternal and neonatal healthcare interventions. The EPIFEVER-2 study was prospectively registered (ISRCTN99641204) following ethical approval. Participant recruitment began in May 2021, with 221 women recruited across three centres as of November 21, 2021. EPIFEVER-2 will generate the largest prospective dataset detailing the incidence and consequences of epidural-related maternal fever. Using Mendelian randomisation analysis, a causative role for lower IL1-ra levels in determining the risk of epidural-related maternal fever and/or antibiotic administration before delivery will be examined.


α-Smooth Muscle Actin and ACTA2 Gene Expressions in Vasculopathies.
α-smooth muscle actin, encoded by ACTA2 gene, is an isoform of the vascular smooth muscle actins, typically expressed in the vascular smooth muscle cells contributing to vascular motility and contraction. ACTA2 gene mutations cause a diversity of diffuse vasculopathies such as thoracic aortic aneurysms and dissections as well as occlusive vascular diseases, including premature coronary artery disease and ischemic stroke. Dynamics of differentiation-specific α-smooth muscle actin in arterial smooth muscle cells and proliferation of the proteins have been well described. Although a variety of research works have been undertaken in terms of modifications of α-smooth muscle actin and mutations of ACTA2 gene and myosin, the underlying mechanisms towards the pathological processes by way of gene mutations are yet to be clarified. The purpose of the present article is to describe the phenotypes of α-smooth muscle actin and implications of ACTA2 mutations in vasculopathies in order to enhance the understanding of potential mechanisms of aortic and coronary disorders.


Immobilization of pectinmethylesterase from acerola (Malpighia glabra L.) in porous silica.
The total and partially purified enzyme pectinmethylesterase from acerola fruit was covalently immobilized on porous silica particles. These efficiency values were 114% for the total PME and 351% for the partially purified PME. In both forms the immobilization resulted in compounds with high thermal stability.


Utility of fractional exhaled nitric oxide (F(E)NO) measurements in diagnosing asthma.
To facilitate the use of fractional exhaled nitric oxide (F(E)NO) as a clinical test, F(E)NO measurements need more clarification. We sought to evaluate the yield of F(E)NO measurement for the diagnosis of asthma and identify the determinants of F(E)NO in children. Two hundred forty five consecutive steroid-naïve patients aged 8-16 years with symptoms suggestive of asthma were included. Children were evaluated using F(E)NO measurements, questionnaires, skin prick tests, spirometries, and methacholine challenge tests. Asthma was diagnosed in 167 children. The sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) of F(E)NO measurements for the diagnosis of asthma at the best cutoff value of 22 ppb were 56.9%, 87.2%, 90.5%, and 48.6%, respectively. At a cutoff value of 42 ppb, specificity and PPV were all 100% but at the cost of very low sensitivity (23.4%) and NPV (37.9%). Both atopy and asthma were identified as independent risk factors associated with high F(E)NO. The association of asthma with high F(E)NO was found only in atopic children because F(E)NO was low in non-atopic children regardless of asthma status. Although highest F(E)NO was observed in atopic asthmatic patients, 28% of these patients had F(E)NO values lower than 22 ppb. Atopic asthmatic patients with low F(E)NO values and non-atopic asthmatic patients were responsible for false-negative cases that might contribute to low sensitivity of F(E)NO measurements in diagnosing asthma. High specificity of F(E)NO measurements may help identify patients with atopic asthma among subjects with respiratory symptoms.


Facile synthesis of high iron content activated carbon-supported nanoscale zero-valent iron for enhanced Cr(VI) removal in aqueous solution.
Nanoscale zero-valent iron (nZVI) based materials are considered as one of the most promising in situ remediation materials in the remediation of groundwater contaminated by a variety of pollutants. Supporting nZVI on activated carbon (AC) could reduce the aggregation of nZVI and lead to better utilization during application. The most used method for synthesizing nZVI/AC is liquid-phase reduction synthesis. However, the problem of nZVI shedding during the synthesis remains unsolved. In this study, an improved liquid-phase reduction synthesis method of nZVI/AC was developed. Compared to the conventional method, the improved method could significantly increase the Fe content of the obtain nZVI/AC (from 3.8% to 5.9%) and the utilization of reactant FeSO4·7H2O (from 49% to 77%) easily by changing the addition order and form of reactants, while using the same reaction precursors. The improved method reduced the shedding of nZVI from AC by taking advantage of the different solubility of FeSO4 in ethanol and water, and the different reactivity of NaBH4 in ethanol and water. The characterization results demonstrated that more nZVI was supported to the pores and outer surface of AC. The removal experiments of Cr(VI) (5.0 mg/L) from water showed that the nZVI/AC synthesized using the improved method exhibited better removal efficiency (85.6%) than that of the nZVI/AC synthesized using the conventional method (67.4%). These results suggested that selecting the appropriate solvent and optimizing the synthesis process may greatly improve the performance of nZVI-based materials.


Correlation analysis of polyamine metabolism and reproductive hormone levels in goose ovarian follicles.
To investigate the relationship between polyamine metabolism and reproductive hormones in ovarian follicles of Sichuan white geese, follicle polyamine content and reproductive hormone levels and gene expressions related to polyamine metabolism, steroidogenesis and steroid hormone receptors were detected by HPLC, ELISA and RT-qPCR. The results showed that the overall trend of spermidine and spermine levels increased first and then decreased as increasing follicle size, with the highest level in F3 and F5 follicles (P < 0.05). Putrescine and 17β-estradiol (E2) levels in hierarchical follicles were significantly lower than those in prehierarchical follicles (P < 0.05). Progesterone (P4) first increased and then decreased, with the highest level in the F5 follicle (P < 0.05). The expression levels of estrogen receptor 1 (ER1) showed an overall increase as increasing follicle size (except in F3 follicles), while estrogen receptor 2 (ER2) in hierarchical follicles was significantly lower than that in the prehierarchical follicles (P < 0.05). In addition, the overall expression level of progesterone receptor (PR) decreased, with no significant differences among F1, F2 and F3 follicles (P > 0.05). Yolk putrescine contents were positively correlated with yolk E2 concentrations and PR expression levels (P < 0.05), A significant positive correlation of spermidine levels with yolk P4 concentrations and PR expressions was also observed, as well as the spermine levels with yolk P4 concentrations (P < 0.05). In summary, polyamines were involved in the regulation of follicular development in geese, and this regulation played a role in affecting steroidogenesis and the expression of genes related to hormone receptors.


Mitochondria express α7 nicotinic acetylcholine receptors to regulate Ca2+ accumulation and cytochrome c release: study on isolated mitochondria.
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that mediate synaptic transmission in the muscle and autonomic ganglia and regulate transmitter release in the brain. The nAChRs composed of α7 subunits are also expressed in non-excitable cells to regulate cell survival and proliferation. Up to now, functional α7 nAChRs were found exclusively on the cell plasma membrane. Here we show that they are expressed in mitochondria and regulate early pro-apoptotic events like cytochrome c release. The binding of α7-specific antibody with mouse liver mitochondria was revealed by electron microscopy. Outer membranes of mitochondria from the wild-type and β2-/- but not α7-/- mice bound α7 nAChR-specific antibody and toxins: FITC-labeled α-cobratoxin or Alexa 555-labeled α-bungarotoxin. α7 nAChR agonists (1 µM acetylcholine, 10 µM choline or 30 nM PNU-282987) impaired intramitochondrial Ca(2+) accumulation and significantly decreased cytochrome c release stimulated with either 90 µM CaCl(2) or 0.5 mM H(2)O(2). α7-specific antagonist methyllicaconitine (50 nM) did not affect Ca(2+) accumulation in mitochondria but attenuated the effects of agonists on cytochrome c release. Inhibitor of voltage-dependent anion channel (VDAC) 4,4'-diisothio-cyano-2,2'-stilbene disulfonic acid (0.5 µM) decreased cytochrome c release stimulated with apoptogens similarly to α7 nAChR agonists, and VDAC was co-captured with the α7 nAChR from mitochondria outer membrane preparation in both direct and reverse sandwich ELISA. It is concluded that α7 nAChRs are expressed in mitochondria outer membrane to regulate the VDAC-mediated Ca(2+) transport and mitochondrial permeability transition.


Tumor bed extending to margins in breast cancer specimens after neoadjuvant chemotherapy: Incidence and clinical significance.
Pathologic examination of post-neoadjuvant chemotherapy (NAC) breast surgical specimens includes assessment of margins. It has been recommended that tumor bed (TB) changes extending to margins should be documented; however, its' incidence and clinical significance have not yet been established. The aim of our study was to gather prognostic data on this histological finding. We retrospectively identified all cases where TB was reported at margin. Cases where margins were also positive for invasive carcinoma or DCIS were excluded. From 2016 to 2019, 115 cases of NAC treated breast cancers were identified with 21 having at least one margin positive for TB after initial surgery (incidence of 18.3 %). Five cases were estrogen receptor (ER)-/HER2-, 9 were HER2+ and 7 were ER+/HER2-. Nineteen patients underwent partial mastectomy and 2 underwent total mastectomy. Nine patients had a pathological complete response (pCR).Ten cases had more than one positive margin for TB. None of the 21 patients underwent a second surgery for margin re-excision. Twenty patients received adjuvant therapy. With an average follow-up of 28.1 months, there has been one local recurrence. Four other patients developed metastatic disease, one of which died of the disease. The rates of locoregional and distant recurrence and mortality were statistically similar to those from patients whose margins were negative for TB. Our results suggest low risk of local recurrence when a positive margin for TB is not re-excised. Further data and follow-up will be needed to confirm the adequacy of conservative management in this setting.


Treatment duration affects cytoprotective efficacy of positive allosteric modulation of α7 nAChRs after focal ischemia in rats.
To minimize irreversible brain injury after acute ischemic stroke (AIS), the time to treatment (i.e., treatment delay) should be minimized. However, thus far, all cytoprotective clinical trials have failed. Analysis of literature identified short treatment durations (≤72 h) as a common motif among completed cytoprotective clinical trials. Here, we argue that short cytoprotective regimens even if given early after AIS may only slow down the evolution of ischemic brain injury and fail to deliver sustained long-term solutions leading to relapses that may be misinterpreted for conceptual failure of cytoprotection. In this randomized blinded study, we used young adult male rats subjected to transient 90 min suture middle cerebral artery occlusion (MCAO) and treated with acute vs. sub-chronic regimens of PNU120596, a prototypical positive allosteric modulator of α7 nicotinic acetylcholine receptors with anti-inflammatory cytoprotective properties to test the hypothesis that insufficient treatment durations may reduce therapeutic benefits of otherwise efficacious cytoprotectants after AIS. A single acute treatment 90 min after MCAO significantly reduced brain injury and neurological deficits 24 h later, but these effects vanished 72 h after MCAO. These relapses were avoided by utilizing sub-chronic treatments. Thus, extending treatment duration augments therapeutic efficacy of PNU120596 after MCAO. Furthermore, sub-chronic treatments could offset the negative effects of prolonged treatment delays in cases where the acute treatment window after MCAO was left unexploited. We conclude that a combination of short treatment delays and prolonged treatment durations may be required to maximize therapeutic effects of PNU120596, reduce relapses and ensure sustained therapeutic efficacy after AIS. Similar concepts may hold for other cytoprotectants including those that failed in clinical trials.


Conformation of oxytocin studied by laser Raman spectroscopy.
The peptide backbone conformation and salient structural details of oxytocin were examined by laser Raman spectroscopy. Spectra were obtained in the solid phase, water, 2H2O, and dimethyl sulfoxide solutions. A distinct Amide I band was obtained at 1663 cm-1 for aqueous and deuterated samples and 1666 cm-1 for the solid sample. A relatively high frequency Amide III band at 1260 cm-1 was obtained. It is concluded that these Amide I and III bands arise from the "beta-turn"-like conformation of oxytocin. The tyrosine side chain, according to the I850 cm-1/I830 cm-1 intensity ratio, is exposed to the solvent. The S-S stretching vibration at 512 cm-1 indicates the conformation of C-C-S-S-C-C in the disulfide bridge of oxytocin in the ring is gauche-gauche-gauche.


An open-label, rater-blinded, 8-week trial of bupropion hydrochloride extended-release in patients with major depressive disorder with atypical features.
The present study aimed at investigating the effectiveness and tolerability of -bupropion hydrochloride extended release (XL) in major depressive disorder (MDD) patients with atypical features (AF).51 patients were prescribed bupropion XL for 8 weeks (6 visits: screening, baseline, weeks 1, 2, 4 and 8). The primary efficacy measure was a change of the Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version (SIGH-SAD) from baseline to endpoint. Secondary efficacy measures included the SIGH-SAD atypical symptoms subscale, Clinical Global Impression-Severity (CGI-S), Sheehan Disability Scale (SDS) and Epworth Sleepiness Questionnaire (ESQ). Response or remission was defined as ≥50% reduction or ≤7 in SIGH-SAD total scores, respectively, at end of treatment.The HAM-D-29 total score reduced by 55.3% from baseline (27.3±6.5) to end of treatment (12.2±6.3) (p<0.001). Atypical symptom subscale scores also reduced by 54.5% from baseline (9.2±3.0) to end of treatment (4.2±2.8) (p<0.001). At the end of treatment, 24.4% (n=10) and 51.2% (n=21) subjects were classified as remitters and responders, respectively. The most frequently reported AEs were headache (13.7%), dry mouth (11.8%), dizziness (9.8%), and dyspepsia (9.8%).Our preliminary study indicates that bupropion XL may be beneficial in the treatment of MDD with atypical features. Adequately powered, randomized, double-blind, placebo-controlled trials are necessary to determine our results.


Role of bone 1stem cell-seeded 3D polylactic acid/polycaprolactone/hydroxyapatite scaffold on a critical-sized radial bone defect in rat.
Osteoconductive biomaterials were used to find the most reliable materials in bone healing. Our focus was on the bone healing capacity of the stem cell-loaded and unloaded PLA/PCL/HA scaffolds. The 3D scaffold of PLA/PCL/HA was characterized by scanning electron microscopy (SEM), rheology, X-ray diffraction (XRD), and Fourier transform-infrared (FT-IR) spectroscopy. Bone marrow stem cells (BMSCs) have multipotential differentiation into osteoblasts. Forty Wistar male rats were used to organize four experimental groups: control, autograft, scaffold, and BMSCs-loaded scaffold groups. qRT-PCR showed that the BMSCs-loaded scaffold had a higher expression level of CD31 and osteogenic markers compared with the control group (P < 0.05). Radiology and computed tomography (CT) scan evaluations showed significant improvement in the BMSCs-loaded scaffold compared with the control group (P < 0.001). Biomechanical estimation demonstrated significantly higher stress (P < 0.01), stiffness (P < 0.001), and ultimate load (P < 0.01) in the autograft and BMSCs-loaded scaffold groups compared with the untreated group and higher strain was seen in the control group than the other groups (P < 0.01). Histomorphometric and immunohistochemical (IHC) investigations showed significantly improved regeneration scores in the autograft and BMSCs-loaded scaffold groups compared with the control group (P < 0.05). Also, there was a significant difference between the scaffold and control groups in all tests (P < 0.05). The results depicted that our novel approach will allow to develop PLA/PCL/HA 3D scaffold in bone healing via BMSC loading.


Inspiratory-to-expiratory ratio during ventilation for idiopathic respiratory distress syndrome.
We have studied the effects of changes in inspiratory-to-expiratory ratios (I/E ratios) on transcutaneous blood gases in a group of 30 infants receiving respiratory support for the idiopathic respiratory distress syndrome (IRDS). Following the use of a reversed I/E ratio (inspiration exceeding expiration), changes in oxygenation were very variable but improvements were seen most consistently in babies weighing greater than 1,750 g and less than 850 g. The use of reversed I/E ratios seemed less efficient than positive end-expiratory pressure in raising TcPO2 for the same increase in mean airway pressure. Changes from a 1:1 ratio to a normal I/E ratio, in which expiratory time exceeded inspiratory time by 50-100%, led to more marked and consistent falls in TcPO2. We conclude that a flexible attitude toward the use of I/E ratios should be adopted to avoid raising mean airway pressure needlessly.


Novel and selective potentiometric membrane sensor for amiloride determination in pharmaceutical compounds and urine.
A new PVC membrane sensor is described as a potentiometric sensor for amiloride. The sensor having amiloride-sodium tetraphenyl phthalate (ion-pair) as an electroactive material and dibutyl phthalate (DBP) as an anion excluder in PVC matrix in the percentage ratio of 4:66:30 (ion-pair: DBP:PVC) (w/w). The membrane sensor exhibits suitable response to amiloride in a concentration range of 1.0 x 10(-2) to 1.0 x 10(-6)mol L(-1) with a limit of detection of 9.9 x 10(-7)mol L(-1). The slope of the system was -54.3+/-1.0 mV decade(-1) over pH range of 2.0-7.0. Selectivity coefficients for amiloride relative to a numbers of potential interfering substances were investigated. The sensor was highly selective for amiloride over a large number of similar compounds. The sensor showing a fast response time of 6s and was used over a period of 2 months with a good reproducibility. The sensor was successfully applied to determination of amiloride in pharmaceutical samples with satisfactory results.


An Update on Screening and Prevention for Breast and Gynecological Cancers in Average and High Risk Individuals.
Breast and gynecological cancers affect almost 900,000 women and therefore most health care providers will be involved at some point in the management of women with cancer. As the prognosis of all cancers is much more favorable when diagnosed in early stages, it is imperative that all health care providers are familiar not only with current screening guidelines for the average population, but also with the identification of high risk individuals who may benefit from more intense screening as well as available interventions to prevent disease or decrease risk. The purpose of this review article is to provide relevant information to physicians and other health care providers to aid in identifying patients that are classified as "high risk" for developing breast or a gynecologic cancer, outlining what interventions exist for adequate screening and risk reduction strategies, and to provide an update on current screening guidelines for individuals at average and high risk.


Cutting costs while maintaining quality: how the VA has leveraged simulation.
Simulation training in the Department of Veterans Affairs has saved money and improved outcomes and is now being used throughout the organization.


Characterization of the biotransformation pathways of clomiphene, tamoxifen and toremifene as assessed by LC-MS/(MS) following in vitro and excretion studies.
The use of selective oestrogen receptor modulators has been prohibited since 2005 by the World Anti-Doping Agency regulations. As they are extensively cleared by hepatic and intestinal metabolism via oxidative and conjugating enzymes, a complete investigation of their biotransformation pathways and kinetics of excretion is essential for the anti-doping laboratories to select the right marker(s) of misuse. This work was designed to characterize the chemical reactions and the metabolizing enzymes involved in the metabolic routes of clomiphene, tamoxifen and toremifene. To determine the biotransformation pathways of the substrates under investigation, urine samples were collected from six subjects (three females and three males) after oral administration of 50 mg of clomiphene citrate or 40 mg of tamoxifen or 60 mg of toremifene, whereas the metabolizing enzymes were characterized in vitro, using expressed cytochrome P450s and uridine diphosphoglucuronosyltransferases. The separation, identification and determination of the compounds formed in the in vivo and in vitro experiments were carried out by liquid chromatography coupled with mass spectrometry techniques using different acquisition modes. Clomiphene, tamoxifen and toremifene were biotransformed to 22, 23 and 18 metabolites respectively, these phase I reactions being catalyzed mainly by CYP3A4 and CYP2D6 isoforms and, to a lesser degree, by CYP3A5, CYP2B6, CYP2C9, CYP2C19 isoforms. The phase I metabolic reactions include hydroxylation in different positions, N-oxidation, dehalogenation, carboxylation, hydrogenation, methoxylation, N-dealkylation and combinations of them. In turn, most of the phase I metabolites underwent conjugation reaction to form the corresponding glucuro-conjugated mainly by UGT1A1, UGT1A3, UGT1A4, UGT2B7, UGT2B15 and UGT2B17 isoenzymes.


Minor surgery for the repair of retinal detachment emanating from retinoschisis.
To propose a mechanism for the development of the outer layer retinal tears that occur with retinoschisis and the detachment emanating from it that is consistent with the limited extent of the detachment and the response to binocular occlusion and local buckles. A consecutive series of 24 patients with retinoschisis, collected over 15 years, was analysed. Seven patients developed a symptomatic retinal detachment emanating from breaks in the outer layers of retinoschisis. The detachments responded to binocular occlusion, a sponge buckle, or a temporary balloon buckle and laser coagulation to the edges of the breaks. Two retinas attached completely after 48 hr of binocular occlusion, four responded to local sponge buckles and one to a temporary balloon buckle. All attached without drainage of subretinal fluid. Final visual acuity was 20/20 in six eyes and 20/25 in one eye. The detachment emanating from retinoschisis responds to ocular rest or a local buckle to breaks in the outer layers. It is proposed that the mechanism for the detachment that emanates from retinoschisis is intraretinal traction by residual transretinal fibres at the edge of the schisis cavity.


Psychometric qualities of the patient rated Wrist/Hand evaluation (PRWHE) in dutch primary care patients with wrist complaints.
Knowledge on the course, disability and functionality of wrist complaints is still compendious in primary care guidelines, despite the high prevalence in primary care. Valid questionnaires can facilitate the monitoring of patients in primary care and research initiatives. In this study, we aimed to study the psychometric qualities of the Dutch version of the Patient Rated Wrist/Hand Evaluation (PRWHE-DLV) among adults with (sub)acute wrist complaints in primary care. An observational cohort of 35 adults with (sub)acute wrist complaints in Dutch primary care was established. The content validity of the PRWHE-DLV was validated by assessing the floor and ceiling effects at baseline (T0). Reproducibility was assessed by the test-retest reliability between T0 and T1 (2-5 days after T0), using the Intra-class Correlation Coefficient. The construct validity was assessed based on the correlation between the PRWHE-DLV and the Quick-DASH, Physical Component Score (SF-12), VAS-function, Physical Functioning (SF-12), VAS-pain and Bodily Pain (SF-12) at T0. Responsiveness was defined as the ability of the PRWHE-DLV to measure change 3 weeks after T0 (internal) and the relation of these changes to clinically important outcomes (external). Psychometric qualities of the PRWHE-DLV demonstrated high content validity with no floor or ceiling effects, excellent reliability (Intra-class correlation coefficient = 0.90; 95% CI 0.80-0.95), high construct validity with the validated Quick-DASH and VAS score (r = 0.85 with Quick-DASH, r = 0.75 with VAS-function and r = 0.78 with VAS-pain) and high responsiveness. The PRWHE-DLV provided reliable and adequate information for primary care clinical practice.


Novel modification of voice prosthesis.
The undesired dilatation of the tracheooesophageal shunt after surgical implantation of voice prosthesis is a typical complication of this procedure. Temporary removal of the prosthesis and reinsertion after a short period of time is a first-line therapeutical option aiming shrinkage of the shunt. Failure of this measure generally is an indication of revision surgery. We present first experiences treating leakage problems with novel modified voice prosthesis without surgical intervention in specified cases. 11 patients (1 female, 10 male) aging between 51 and 71 years were presented with shunt leakage between 11/2008 and 11/2012 in the ENT-Department of the University Hospital of Homburg/Saar after a custom built voice prosthesis had been used initially successfully. A "Provox 2"(®) voice prosthesis was modified with two discs made of silicone each on the tracheal and oesophageal side and additionally reinforcing the diameter of the prosthesis by a silicone tube. The modified prosthesis was inserted in a retrograde way under general anesthesia, analogical to the approach used with the "Provox 1"(®)-prosthesis. The period of observation ranged between 12 and 48 months. As a measure of control swallowing of methylene blue was used. In all cases leakage suspended. Durability of the modified prosthesis ranged between 2 and 6 months. Neither the patients' complained about, nor did the physicians notice subjectively an impairment of the voice quality. Modifications of "Provox 2"(®)-prosthesis should be regarded in individual cases and constitute a reasonable alternative to revision surgery. A surgical approach is more intricate and costly, more taxing for the patient and susceptible to failure. We regard the necessity of general anesthesia for the insertion of the modified prosthesis as a disadvantage.


A computational model of inner speech supporting flexible goal-directed behaviour in Autism.
Experimental and computational studies propose that inner speech boosts categorisation skills and executive functions, making human behaviour more focused and flexible. In addition, many clinical studies highlight a relationship between poor inner-speech and an executive impairment in autism spectrum condition (ASC), but contrasting findings are reported. Here we directly investigate the latter issue through a previously implemented and validated computational model of the Wisconsin Cards Sorting Tests. In particular, the model was applied to explore potential individual differences in cognitive flexibility and inner speech contribution in autistic and neurotypical participants. Our model predicts that the use of inner-speech could increase along the life-span of neurotypical participants but would be reduced in autistic ones. Although we found more attentional failures (i.e., wrong behavioural rule switches) in autistic children/teenagers and more perseverative behaviours in autistic young/older adults, only autistic children and older adults exhibited a lower performance (i.e., fewer consecutive correct rule switches) than matched control groups. Overall, our results corroborate the idea that the reduced use of inner speech could represent a disadvantage for autistic children and autistic older adults. Moreover, the results suggest that cognitive-behavioural therapies should focus on developing inner speech skills in autistic children as this could provide cognitive support throughout their whole life span.


An instrument for measuring blood pressure and assessing cardiovascular health from the fingertip.
Despite blood pressure being one the leading modifiable risk factors for cardiovascular disease and death, it is severely under-monitored. For this challenge we propose a finger artery non-invasive tono-oscillometric monitor (FANTOM) which is an automated low-cost instrument for measuring blood pressure and hemodynamic parameters from the fingertip. The sensing technology is highly scalable and could be integrated to a pulse oximeter probe for increased patient comfort. A tonometric cuff-less mechatronic system is used to apply pressure on the fingertip for (i) measuring oscillometric blood pressure, (ii) recording arterial waveform and for (iii) constructing central blood pressure (CBP) waveform. Clinical study on volunteers (n = 33) was performed against a commercially available arm cuff device yielding systolic and diastolic readings ((mean±SD) mmHg) of (-0.9 ± 7.3) mmHg and (-3.3 ± 6.6) mmHg respectively. The results comply with the Association for the Advancement of Medical Instrumentation (AAMI) standard for non-invasive blood pressure monitors. The arterial pulse recording morphology was compared against a volume clamp device (CNSystems CNAP 500) (n = 3) resulting in similar performance. Comparison of CBP against a pulse wave analysis (PWA) device (Atcor Medical Sphygmocor XCEL) (n = 5) revealed central aortic systolic pulse (CASP) and central augmentation index (cAIx) estimates with precision and accuracy of (2.0 ± 3.7) mmHg and (1.4 ± 6.2)% respectively. In conclusion, the results indicate that the proposed technology could be useful in the development of new portable or wearable blood pressure monitors. The sensing technology is highly scalable and could be integrated to a pulse oximeter probe for increased patient comfort.


Biomimetic synthesis of cannabispiran.
Total synthesis of cannabispiran (1) was accomplished by a biomimetic-type cyclization of the bibenzyl 2, using K3Fe(CN)6 or MoCl4.


Can Education and Enhanced Medical Director Oversight Improve Definitive Airway Control in the Prehospital Environment?
Endotracheal intubation (ETI) is the most definitive technique for airway management. However, supraglottic airway (SGA) may be used when ETI is not feasible. The purpose of this study was to determine the effect of updated field sedation protocols, simulation teaching, robust Quality Assurance/Continuing Quality Improvement (QA/CQI) program, and enhanced emergency medical services (EMSs) medical director oversight on ETI and SGA usage at a Level 1 trauma center. After the transition of EMS directors in May 2016, field sedation protocols were updated, a new QA/CQI was instituted, and multiple teaching and simulation sessions were conducted. A retrospective review of EMS data was conducted on all prehospital airway interventions performed by EMS personnel. Intubations occurring from July 2013 to May 2016 served as controls. Intubations from May 2016 to December 2017 served as the comparison group. Data collected included intubation type/indication, age, and successful or unsuccessful. There were 967 ETI and SGA performed on 84% and 15% of patients, respectively. Success rates were 75% for ETI and 82% for SGA. ETI increased from 83% in the control group to 88% in the study group, and SGA decreased from 16% in the control group to 11% in the study group (P = .029). The success rate for ETI increased by 2% in the study group (P = .539). This study showed that definitive airway control could be positively impacted by incorporating education and medical director oversight into EMS training. ETI increased and SGA decreased after implementation.


Analysis of the role of DPB1-encoded amino acids in the genetic predisposition to type I diabetes mellitus.
The role of the DPB1 gene in genetic susceptibility to type I diabetes has yet to be elucidated. Studies of DPB1 alleles are conflicting. Analysis at the amino acid level, rather than consideration of allelic polymorphism, has been informative in determining disease susceptibility encoded by the DRB1 and DQ genes. In this study, therefore, amino acid variation at polymorphic sites of the DPbeta peptide chain encoded by the second exon of the DPB1 gene was analyzed in diabetic and control subjects from white Caucasian, North Indian Asian, and Jamaican populations. Human leukocyte antigen genotypes and haplotypes were analyzed using a logistic-regression approach and the data were conditioned for the effects on disease risk of the DRB1, DQA1, and DQB1 genes. Eight DPbeta amino acid residues were significantly associated with type I diabetes independent of DR and DQ (DPbeta 9, 33, 35, 36, 55, 56, 57, and 69). None of these residues, however, correlated consistently with disease risk in all three racial groups. This contrasts with findings for the DRbeta, DQalpha and DQbeta peptide chains, where the identity of the amino acid at particular sites has been found to correlate with predisposition to type I diabetes.


Localization of olivo-cerebellar fibers in inferior cerebellar peduncle in man.
The localization of the olivo-cerebellar fibers in the inferior cerebellar peduncle was examined in a patient who showed severe degeneration of the left olivary nucleus due to an old hemorrhagic infarct in the contralateral cerebellum. Other precerebellar nuclei which send their cerebellipetal axons to the inferior cerebellar peduncle, such as the external cuneate nucleus, the lateral reticular nucleus and the arcuate nucleus, were normally preserved. The dorsal spino-cerebellar tract and the vestibular nuclei, together with the juxtarestiform body were also intact. Degeneration of the inferior cerebellar peduncle was noted only in its ventromedial portion contralateral to the olivary lesion. As a result, it is concluded that the olivo-cerebellar fibers seem to be located in this portion of the inferior cerebellar peduncle.


Advances in the understanding of the clinically relevant genetic pathways and molecular aspects of canine mammary tumours. Part 2: invasion, angiogenesis, metastasis and therapy.
Significant advances have been made recently in the understanding of the molecular events and critical pathways associated with and driving cancer of the mammary gland in humans and dogs. The study of canine mammary tumour biology, particularly the interactions of neoplastic cells with stromal and immune cells, is crucial for the development of novel effective therapeutic agents and strategies. This second part of a two-part review discusses some of the latest advances in the understanding of the clinically relevant genetic and molecular pathways involved in metastasis and in the interactions between tumour and stromal cells, including inflammatory and immune cells, cancer-associated fibroblasts, and endothelial cells. Recent experimental data on the role of matrix-degrading proteases and angiogenic factors are also discussed. Finally, the clinical utility of different non-surgical therapeutic modalities is reviewed.


CapsNetYY1: identifying YY1-mediated chromatin loops based on a capsule network architecture.
Previous studies have identified that chromosome structure plays a very important role in gene control. The transcription factor Yin Yang 1 (YY1), a multifunctional DNA binding protein, could form a dimer to mediate chromatin loops and active enhancer-promoter interactions. The deletion of YY1 or point mutations at the YY1 binding sites significantly inhibit the enhancer-promoter interactions and affect gene expression. To date, only a few computational methods are available for identifying YY1-mediated chromatin loops. We proposed a novel model named CapsNetYY1, which was based on capsule network architecture to identify whether a pair of YY1 motifs can form a chromatin loop. Firstly, we encode the DNA sequence using one-hot encoding method. Secondly, multi-scale convolution layer is used to extract local features of the sequence, and bidirectional gated recurrent unit is used to learn the features across time steps. Finally, capsule networks (convolution capsule layer and digital capsule layer) used to extract higher level features and recognize YY1-mediated chromatin loops. Compared with DeepYY1, the only prediction for YY1-mediated chromatin loops, our model CapsNetYY1 achieved the better performance on the independent datasets (AUC [Formula: see text]). The results indicate that CapsNetYY1 is an excellent method for identifying YY1-mediated chromatin loops. We believe that the CapsNetYY1 method will be used for predictive classification of other DNA sequences.


Antigenic similarities among estuarine soft-bottom benthic taxa.
Antisera prepared against whole-organism extracts of benthic invertebrates from Puget Sound, Washington, and North Inlet, South Carolina, were tested for specificity with extracts from both coasts. Immunological similarities among taxa reflected conventional phylogenetic relationships both within each of these areas and also between both areas. Antisera also cross-reacted with extracts to a lesser degree at higher taxonomic levels. The existence of common antigens among phylogenetically related taxa makes feasible the use of serological methods to document trophic interactions in environments where it is difficult to obtain sufficient material to serve as immunogen for production of highly specific antisera. Deep-sea or other high diversity food webs may be investigated using serological methods that are already well-developed for use in terrestrial and shallow-water environments.


Quantum mechanical effects in plasmonic structures with subnanometre gaps.
Metallic structures with nanogap features have proven highly effective as building blocks for plasmonic systems, as they can provide a wide tuning range of operating frequencies and large near-field enhancements. Recent work has shown that quantum mechanical effects such as electron tunnelling and nonlocal screening become important as the gap distances approach the subnanometre length-scale. Such quantum effects challenge the classical picture of nanogap plasmons and have stimulated a number of theoretical and experimental studies. This review outlines the findings of many groups into quantum mechanical effects in nanogap plasmons, and discusses outstanding challenges and future directions.


[Single-lead VDD pacing with sensing dipole in the coronary sinus: a case of implantation through persistent left superior vena cava].
We report the case of a VDD single-lead pacemaker implantation through a persistent left superior vena cava in a 48-year-old male patient with recurrent episodes of syncope due to paroxysmal atrioventricular block. VDD lead insertion through the anomalous venous structure led to positioning of the floating sensing dipole into the coronary sinus, in a very large and stable sensed atrial signal due to the close anatomic relationship between the coronary sinus and the left atrium. Shortness of the sensed atrioventricular interval allowed VDD stimulation to occur only in the case of paroxysmal atrioventricular block.


Modulation of Streptococcus mutans virulence by dental adhesives containing anti-caries agents.
The aim of this in vitro study was to analyze the effect of the incorporation of two anti-caries agents into dental adhesives on the reduction of the virulence of Streptococcus mutans and on the adhesion to dentin. Apigenin (1mM) and tt-Farnesol (5mM) were added separately and in combination to a self-etch adhesive (CS3 - Clearfil S3 Bond Plus) and to an each-and-rinse adhesive (OPT - OptiBond S). Biofilm of S. mutans was grown on adhesive-coated hydroxyapatite disks for 115h and bacterial viability, dry-weight, alkali soluble, water soluble, intracellular polysaccharides and protein were quantified. Bond strength and dentin-adhesive interface were performed to analyze the effects of the incorporation on the physical properties and to identify changes in hybrid layer morphology. Addition of Apigenin and Apigenin+tt-Farnesol to CS3, and Apigenin or tt-Farnesol to OPT reduced the dry-weight of S. mutans biofilm. Insoluble polysaccharide decreased with the addition of Apigenin to CS3 and tt-Farnesol to OPT. Intracellular polysaccharide decreased with addition of Apigenin and Apigenin+tt-Farnesol to CS3. No changes in dentin bond strength, resin-dentin interfacial morphology, total amount of protein and soluble polysaccharide were observed with the additions. Biofilms that are less cariogenic around dental restorations could decrease secondary caries formation; in addition, the reduction of virulence of S. mutans without necessarily killing the microorganism is more unlikely to induce antimicrobial resistance.


The Effects of Primary Unconjugated Bile Acids on Nanoencapsulated Pharmaceutical Formulation of Hydrophilic Drugs: Pharmacological Implications.
In a recent study, in our laboratory, primary unconjugated bile acids, commonly found in humans, chenodeoxycholic acid (CDCA), have been shown to improve stability of nanoencapsulated lipophilic drugs and improve their release profile after oral administration likely via electrokinetic stabilisation. Hence, this study aimed to examine the effects of CDCA on exerting similar effects on hydrophilic drugs. Various CDCA-based formulations were produced for the orally administered hydrophilic drug, metformin. Analyses of these formulations included electrokinetic potentials, topography, drug and CDCA formulation contents, nano size distribution, heat-induced deformation and outer-core expansion indices, release profiles, shell-resistance ratio, and thermal and chemical indices. With the drug's main target being pancreatic beta-cells, the formulations' effects on cell viability, functions and inflammatory profiles were also investigated. CDCA-based metformin formulations exhibited improved stability and release profiles via thermal, chemical and electrokinetic effects, which were formulation-dependent suggesting potential applications of CDCA in the oral targeted delivery of hydrophilic drugs.


Interprofessional communication between community pharmacists and general practitioners: a qualitative study.
Background While collaboration between community pharmacists (CPs) and general practitioners (GPs) is essential to provide comprehensive patient care, their communication often is scarce and hampered by multiple barriers. Objective We aimed to assess both professions' perceptions of interprofessional communication with regard to content and methods of communication as a basis to subsequently develop best-practice recommendations for information exchange. Setting Ambulatory care setting in Germany. Method CPs and GPs shared their experience in focus groups and in-depth interviews which were conducted using a semi-structured interview guideline. Transcribed recordings were assessed using qualitative content analysis according to Mayring. Main outcome measure Specification of existing barriers, CPs'/GPs' general perceptions of interprofessional communication and similarities and differences regarding prioritization of specific information items and how to best communicate with each other. Results Four focus groups and fourteen interviews were conducted. Seven internal (e.g. professions were not personally known to one another) and nine external barriers (e.g. mutual accessibility) were identified. Ten organizational, eight medication-related, and four patient-related information items were identified requiring interprofessional communication. Their relevance varied between the professions, e.g. CPs rated organizational issues higher than GPs. Both professions indicated communication via phone to be the most frequently used method of communication. Conclusion CPs and GPs opinions often differ. However, communication between CPs and GPs is perceived as crucial suggesting that a future concept has to offer standardized recommendations, while leaving CPs and GPs room to adjust it to their individual needs.


The analysis of pathological findings for cervical lymph node biopsies in eastern Saudi Arabia.
Lymphadenopathy is a common medical problem. A lymph node biopsy may be necessary for definitive diagnosis in selected cases. The study group included a retrospective, hospital-based series of patients who had a cervical lymph node biopsy at the Saudi Aramco Medical Services organization between 1997 and 2008. During the study period, there were a total of 452 cervical lymph node biopsies. Biopsies were performed on 122 (27%) children ≤18 years and 81 (18%) patients >60 years. The most common histopathological diagnosis was reactive disease (52.2%, n=236), which was followed by granulomatous disease (15.5%, n=70). We detected carcinoma in 14.6% of the patients (n=66), Hodgkin's lymphoma in 8.8% (n=40) and non-Hodgkin's disease in 8.8% (n=40). Malignancy was more common in adults than children (19.5% vs. 1.6%, respectively and reactive disease was more common in children than adults (65.3% vs. 47.3%, respectively). Metastatic disease was more likely in the older age group (17.7% vs. 0%), Hodgkin's disease was found in 12.5% of the adolescents, and non-Hodgkin's disease was present in 10.3% of the adults and elderly. The most common histopathological findings for cervical lymph node biopsies in eastern Saudi Arabia were reactive disease and granulomatous disease.


Extrinsic venous compression secondary to spine osteophytes.
This study aims to report two cases of symptomatic extrinsic compression of the inferior vena cava and left iliac vein caused by vertebral osteophytes. We present two case reports of extrinsic venous compression by vertebral osteophytes. Both cases were endovascularly treated, with a successful outcome. A review of the literature of this unusual condition is also presented. The first patient is an 80-year-old woman who presented to the vascular surgery clinic with bilateral lower extremity edema and pain. A computed-tomography angiography (CTA) revealed extrinsic compression of the inferior vena cava from enlarged osteophytes. Venography and intravascular ultrasound were performed, confirming the diagnosis. A self-expanding venous stent was successfully deployed in the inferior vena cava relieving the extrinsic compression. The edema resolved the following day and was discharged without complications. The second patient is a 61-year-old male that presented to the emergency department with a left iliofemoral deep venous thrombosis. CTA showed left iliac vein compression by a lumbar osteophyte. Percutaneous thrombectomy was successfully achieved and an expanding stent was deployed covering the entire lesion. One month after the procedure the patient died from COVID-19-associated respiratory failure. Osteophytes must be considered when dealing with extrinsic venous compression, especially in elderly people.


MRI of vaginal conditions.
Magnetic resonance imaging (MRI) has become an important part of the assessment of suspected vaginal pathology. This pictorial review demonstrates the MRI features and some of the histopathological findings of a variety of vaginal conditions. These may be congenital (total vaginal agenesis, partial vaginal agenesis, longitudinal vaginal septum, transverse vaginal septum), benign (Bartholin's cyst, diffuse vaginal inflammation, invasive endometriosis, ureterovaginal fistula, post-surgical appearances with the formation of a neovagina and adhesions) or malignant, usually due to extension or recurrence from another pelvic malignancy. In this paper, examples of the above are described and illustrated together with examples of the much rarer primary vaginal malignancies.


Multiple intratendinous ossified deposits of the Achilles tendon: Case report of an unusual pattern of ossification.
True ossification of the Achilles tendon is a rare condition as compared to calcification. The etiology of ossification is multifactorial, however, previous surgery, trauma and degenerative changes have been attributed to be the major causes. Three different patterns of ossification have been described within the Achilles tendon based on their location. We present a case of multiple discrete deposits of ossification within the main substance of the Achilles tendon in a young male with a previous history of clubfoot surgery in childhood. The pattern of ossification was different than all the previously reported cases. Pain was the predominant symptom. He was investigated by using plain radiographs, ultrasonography, computed tomography and magnetic resonance imaging. Surgical excision of all the bony lumps lead to satisfactory outcome without any complications.


The Ubiquity of Chronic Illness.
This is a review of five different books dealing with some aspect of what might be termed a "chronic illness" - Alzheimer's disease, lupus, addiction, erectile dysfunction, and leprosy. The array of different subjects examined in these books points to the negotiable limits of this hugely open category. What exactly constitutes an "illness"? Why not use a less biomedical term instead: "disturbance", "problem", or simply "condition"? And how are we to understand "chronic" - simply as the flipside of "acute" or "curable"?


Elevated red cell distribution width contributes to a poor prognosis in patients with esophageal carcinoma.
The red cell distribution width (RDW) has also been reported to reliably reflect the inflammation and nutrition status and predict the prognosis across several types of cancer, however, the prognostic value of RDW in esophageal carcinoma has seldom been studied. A retrospective study was performed to assess the prognostic value of RDW in patients with esophageal carcinoma by the Kaplan-Meier analysis and multivariate Cox regression proportional hazard model. All enrolled patients were divided into high RDW group (≧15%) and low RDW group (<15%) according to the detected RDW values. Clinical and laboratory data from a total of 179 patients with esophageal carcinoma were retrieved. With a median follow-up of 21months, the high RDW group exhibited a shorter disease-free survival (DFS) (p<0.001) and an unfavorable overall survival (OS) (p<0.001) in the univariate analysis. The multivariate analysis revealed that elevated RDW at diagnosis was an independent prognostic factor for shorter PFS (p=0.043, HR=1.907, 95% CI=1.020-3.565) and poor OS (p=0.042, HR=1.895, 95% CI=1.023-3.508) after adjustment with other cancer-related prognostic factors. The present study suggests that elevated preoperative RDW(≧15%) at the diagnosis may independently predict poorer disease-free and overall survival among patients with esophageal carcinoma.


[Impact of onsite or dispatched automated external defibrillator use on early survival after sudden cardiac arrest occurring in international airports].
Out-of-hospital cardiac arrest (OHCA) is a major public health challenge. Use of automated external defibrillators (AED) by laypersons improves survival of patient's victim of OHCA. The aim of our study was to compare onsite AED vs. dispatched AED management of cardiac arrest occurring in international airports. We conducted a retrospective, observational, comparative, study on data collected from three international airports: Paris-Charles-de-Gaulle (CDG), Chicago and Madrid-Barajas. We included patients with OHCA occurring inside the airport between 2009 and 2013. Group public access (PUB) included airports where AED were available to laypersons and group dispatched (SEC) was represented by Paris-CDG airport where AED was provided by paramedic teams. The primary endpoint was successful resuscitation defined as survival at time of hospital admission. We included 150 consecutive patients victim of OHCA in the three airports. The time between collapse and AED setting was significantly shorter in the PUB vs. SEC group (4±3minutes vs. 11±11, P=0.0006). The total duration of resuscitation was shorter in the PUB group (10±10minutes vs. 36±25minutes, P<0.0001). Survival at time of hospital admission was higher in the PUB group (62% vs. 38%, P=0.01). The availability of public access AEDs in international airports seems to allow a quicker defibrillation and an increased success rate of resuscitation.


Investigation of catalytic effect on carbon-carbon bond formation by Baylis-Hillman (BH) reaction between (2/3/4)-nitro-arylaldehyde and alkylacrylates and computational approaches through DFT functional.
The 4-diazabicyclo[2. 2. 2] octane, DABCO, had widely established with gigantic and celestial applications on catalysis for carbon-carbon bond formation reactions. Thus, it has been employed to synthesize the alkyl 2-(hydroxyl (nitrophenyl) methyl)acrylate by the reaction of arylaldehydes and alkylacrylates under a mild condition with good yields. First of all, reaction was examined effect of various solvents, such as water, MeOH, Dioxane, DMSO, t-Butanol, DMF, Toluene, and THF and THF was the best solvent in term of yield. Next, the room temperature (R.T) was the optimized condition than 60 °C and 80 °C. The overall reaction progress was monitored in presence of DABCO, Et3N, C2H5ONa, C4H9OK, (CH3)3COK and pyridine catalysts with THF solvents at room temperatures, and calculated the amount for superior of catalyst. There was no product obtained in presence of catalysts, such as Et3N, C2H5ONa, C4H9OK, (CH3)3COK and pyridine. But in present of DABCO, this reaction has proceeded and monitored the concentration of catalyst and various temperature effects on reaction progress. In addition, the computational approaches for speculative investigation of solvents effect has employed for predicating and comparatively verified with the proposed reaction mechanism in presence of DABCO catalyst through the Density Functional Theory (DFT). The most acceptable tools for the thermodynamic had been illustrated to get the reaction kinetics by formation energy, entropy, enthalpy for reactant, product and transition state. Finally, the Gibbs free energy for reactions from the reactants and product has calculated to predict the occurring spontaneously possibility with and without solvents, and it is said that the reaction is spontaneously occurred through the water, DMSO, THF solvent although it is opposed fact without solvent even other solvents. It might be concluded that the optimization conditions of reaction are the THF solvent in presence of 20% DABCO catalyst at room temperature with high (about 90%) throughout 6-8 h where the 4- position of nitro group in arylaldehyde is the most preferable in case of time and yield.


Investigation of the possible role of endotoxin, TXA2, PGI2 and PGE2 in experimentally induced rumen acidosis in cattle.
Rumen acidosis was induced experimentally with 70 g barley/kg b.w. in 2 rumen fistulated cows. The cows were followed for 80 h after the grain engorgement. Endotoxin was monitored in cell-free ruminal fluid and peripheral plasma together with inflammation mediators TXA2, PGI2 and PGE2 and several clinical and clinical-chemical parameters. The results do not support the theory of systemical endotoxemia due to a large increase in rumen endotoxin concentration in cattle suffering from rumen acidosis. However, both clinical and clinical-chemical data suggest that an endotoxicosis developed, but the levels of inflammation mediators TXB2, FGI2 and PGE2 were not significantly elevated in the peripheral circulation. An absorbtion of endotoxins and synthesis of inflammation mediators are therefore suggested to take place prehepatically.


Non-alcoholic fatty liver disease is associated with a worse prognosis in patients with heart failure: A pool analysis.
Non-alcoholic fatty liver disease (NAFLD) is associated with a higher risk of heart failure (HF) than those without NAFLD. However, the prognostic impact of NAFLD in HF is still controversial. This meta-analysis aimed to explore the association between NAFLD and the risk of adverse outcomes in patients with HF. We searched multiple electronic databases (Embase, PubMed, and Google Scholar) for potentially related studies up to June 30, 2022. Cohort studies reported multivariable adjusted relative risks and 95% confidence intervals (CIs) of adverse outcomes in HF patients with NAFLD comparing those without NAFLD were included for analysis. A total of six studies involving 12,374 patients with HF were included for analysis, with a median follow-up duration of 2.5 years. The pooled analysis showed that HF patients with NAFLD were associated with a significantly increased risk of major composite adverse outcomes (HR 1.61, 95% CI 1.25-2.07), all-cause mortality (HR 1.66, 95% CI 1.39-1.98), and HF hospitalization or re-hospitalization (HR 1.71, 95% CI 1.03-2.86). NAFLD is associated with a worse prognosis in patients with HF. Effective screening and treatment strategies are needed to improve the prognosis in HF patients with NAFLD.


Randomized trial of adjuvant chemotherapy after curative resection for gastric cancer.
The aim of the study was to evaluate the efficacy of adjuvant chemotherapy on survival after resection for gastric cancer. Patients were enrolled if they underwent resection of gastric cancer but had lymph node or serosal involvement or both. Surgical resection was either total or partial gastrectomy according to the site of the tumor, and surgeons were allowed to perform either D1 or D2 gastrectomy. The subjects were random assigned in two treatment groups as follows: surgery alone as the control group, or surgery and adjuvant chemotherapy. Nine cycles of 5 days protocol every 4 weeks was proposed to the patients of the chemotherapy group. The protocol included a daily administration of 200 mg/m(2) of folinic acid, 5-fluorouracil (375 mg/m(2) during the first session increasing 25 mg by session until reaching 500 mg/m(2)) and CDDP 15 mg/m(2). Two hundred patients were required. Kaplan-Meier survival curves were compared according to the log-rank and the Mantel-Haenszel methods. In all, 205 patients were enrolled in the study; 104 had surgery alone and 101 had surgery and adjuvant chemotherapy. The patients' characteristics were similar except for the mean age, which was 4 years less in the control group. Because of toxicity, 54% of the patients stopped the protocol before the end of the nine courses, and 46% of the patients received the nine courses including 32% with a decreased dose and 14% with a full dose. The 5-year survival rate was 39% in the control group and 39% in the chemotherapy group. This protocol of adjuvant chemotherapy failed to improve the 5-year survival after resection for gastric cancer.


Drugs in development for hepatitis B.
The management of chronic hepatitis B (CHB) has improved dramatically over the last decade with the development of new drugs such as lamivudine and adefovir dipivoxil, in addition to the now standard interferon (IFN)-alpha therapy. These new drugs can achieve a significant reduction or inhibit replication of hepatitis B virus (HBV) DNA during therapy. However, in the majority of patients, particularly in those who are hepatitis B e antigen (HBeAg)-negative, the sustained off-therapy suppression of HBV DNA is rare. For this reason, several new antiviral and immunomodulatory agents are currently being evaluated. Among the immunomodulatory agents, pegylated IFNalpha (peginterferon-alpha) has been shown to be more effective for HBeAg-positive CHB than either lamivudine or standard IFNalpha monotherapy, particularly in those patients infected by HBV genotypes A and B. The new antivirals entecavir, tenofovir disoproxil fumarate and telbivudine exhibit a more potent viral inhibitory effect than the currently approved drugs (IFNs, lamivudine and adefovir dipivoxil). However, the emergence of viral resistance has been witnessed and this could be one of the major limitations to the clinical use of these new drugs, particularly during prolonged therapy. In HBeAg-negative patients it is more and more common for oral antiviral therapy to be administered for prolonged periods, as the sustained off-therapy response rates of short-term therapy are very low. Different studies are currently evaluating combination therapy, using lamivudine with adefovir dipivoxil or peginterferon-alpha with lamivudine; the preliminary results show virological responses no better than those achieved by monotherapy. However, as combination therapy is associated with a low likelihood of developing HBV drug resistance, this could result in a higher virological response during prolonged therapy. In the near future the most realistic therapeutic option for the majority of patients with CHB will be long-term use of these new, more potent antiviral drugs, if they can achieve good safety profiles while maintaining low resistance rates at affordable costs.


Rabbit blastocyst: allocation of cells to the inner cell mass and trophectoderm.
The proportion of total cells in the blastocyst allocated to the inner cell mass (ICM) and trophectoderm (TE) is important for future development and may be sensitive indicator to evaluate culture conditions. The number of cells and their distribution within the two primary cell lineages were determined for the rabbit embryo developing in vivo after superovulation or nonsuperovulation or embryo transfer and compared with embryos developing in vitro. Comparisons were made with cultured embryos or embryos grown in vivo until 3.5, 4.0, and 4.5 days of age. Embryos from superovulated rabbits developed in vivo for 3.5, 4.0, and 4.5 days, respectively, had 361, 758, and 902 total cells (P < 0.05), and in nonsuperovulated rabbits 130, 414, and 905 total cells (P < 0.05), with increasing proportions of ICM cells over time (P < 0.05). One-cell embryos recovered from superovulated females and transferred to nonsuperovulated recipients developed more slowly with 70, 299, and 550 total cells after 3.5, 4.0, and 4.5 days of culture (P < 0.05), respectively. The proportion of ICM cells increased with age of the embryo. Corresponding values for one-cell embryos cultured in vitro resulted in 70, 299, and 550 total cells (P < 0.05). However, in vitro culture of morula-stage embryos in the presence of fetal bovine serum for 24 hr did not delay growth. In addition, the proportions of ICM/total cells were 0.17, 0.25, and 0.29 for embryos developing in vitro at 3.5, 4.0, and 4.5 days respectively, similar to those for embryos developing in vivo at each of the three recovery times.(ABSTRACT TRUNCATED AT 250 WORDS)


BVA Council regional vacancies.
Are you aware of BVA Council's role in ensuring that the Association fulfils its representational function? Do you care about issues affecting the profession and could you help ensure they are heard at the highest level? There are vacancies for seven regional representatives on Council and elections will take place early next year.


Sleep loss alters synaptic and intrinsic neuronal properties in mouse prefrontal cortex.
Despite sleep-loss-induced cognitive deficits, little is known about the cellular adaptations that occur with sleep loss. We used brain slices obtained from mice that were sleep deprived for 8h to examine the electrophysiological effects of sleep deprivation (SD). We employed a modified pedestal (flowerpot) over water method for SD that eliminated rapid eye movement sleep and greatly reduced non-rapid eye movement sleep. In layer V/VI pyramidal cells of the medial prefrontal cortex, miniature excitatory post synaptic current amplitude was slightly reduced, miniature inhibitory post synaptic currents were unaffected, and intrinsic membrane excitability was increased after SD.


Possible existence of Na(+)-coupled amino acid transport in the pigmented rabbit conjunctiva.
The objective of the present study was to determine whether Na(+)-amino acid cotransport contributed to the short-circuit current (ISC) in the isolated pigmented rabbit conjunctiva. Glycine, L-arginine, D-arginine, and L-glutamic acid were the amino acids tested, and bioelectric measurements were made in the Using chamber. The ISC was increased from 4% (L-glutamic acid) to 44% (L-arginine). The EC50 was 0.35 mM for glycine, 0.06 mM for L-arginine, 0.16 mM for D-arginine, and 1 mM for L-glutamic acid. No elevation in ISC was seen in the absence of Na+ in the mucosal bathing fluid. The above findings are consistent with the possible existence of a Na(+)-amino acid cotransport process on the apical side of the pigmented rabbit conjunctiva.


Metabolic stasis in an ancient symbiosis: genome-scale metabolic networks from two Blattabacterium cuenoti strains, primary endosymbionts of cockroaches.
Cockroaches are terrestrial insects that strikingly eliminate waste nitrogen as ammonia instead of uric acid. Blattabacterium cuenoti (Mercier 1906) strains Bge and Pam are the obligate primary endosymbionts of the cockroaches Blattella germanica and Periplaneta americana, respectively. The genomes of both bacterial endosymbionts have recently been sequenced, making possible a genome-scale constraint-based reconstruction of their metabolic networks. The mathematical expression of a metabolic network and the subsequent quantitative studies of phenotypic features by Flux Balance Analysis (FBA) represent an efficient functional approach to these uncultivable bacteria. We report the metabolic models of Blattabacterium strains Bge (iCG238) and Pam (iCG230), comprising 296 and 289 biochemical reactions, associated with 238 and 230 genes, and 364 and 358 metabolites, respectively. Both models reflect both the striking similarities and the singularities of these microorganisms. FBA was used to analyze the properties, potential and limits of the models, assuming some environmental constraints such as aerobic conditions and the net production of ammonia from these bacterial systems, as has been experimentally observed. In addition, in silico simulations with the iCG238 model have enabled a set of carbon and nitrogen sources to be defined, which would also support a viable phenotype in terms of biomass production in the strain Pam, which lacks the first three steps of the tricarboxylic acid cycle. FBA reveals a metabolic condition that renders these enzymatic steps dispensable, thus offering a possible evolutionary explanation for their elimination. We also confirm, by computational simulations, the fragility of the metabolic networks and their host dependence. The minimized Blattabacterium metabolic networks are surprisingly similar in strains Bge and Pam, after 140 million years of evolution of these endosymbionts in separate cockroach lineages. FBA performed on the reconstructed networks from the two bacteria helps to refine the functional analysis of the genomes enabling us to postulate how slightly different host metabolic contexts drove their parallel evolution.


Surgery Insight: orthopedic treatment options in rheumatoid arthritis.
Longstanding rheumatoid arthritis (RA) leads to disability, caused mainly by joint destruction. The current goals of surgical intervention are to restore function and quality of life, prevent joint deterioration, relieve pain, and correct deformity. A number of different surgical treatment options are available to patients with RA, including synovectomy, arthrodesis, joint replacement, and soft tissue and special hand surgery; nonoperative management is also important. Decision-making and timing for orthopedic intervention are complex issues because of polyarticular involvement. Functional impairment, pain, and the subsequent loss of quality of life and inability to work have become the main considerations for surgical reconstruction. Early referral for orthopedic treatment can lead to improved functional benefit for patients with RA. The decision for orthopedic intervention should be established by an interdisciplinary team that includes rheumatologists and orthopedic surgeons experienced in the surgery of RA. Priority should be given to the joint that causes the greatest disability and pain. Disease progression and pharmaceutical treatment options should be taken into consideration when establishing an orthopedic intervention protocol.


Osteosarcoma: pathology and classification.
Osteosarcoma encompasses many different clinical, roentgenographic, and pathologic entities. Some of the tumors, but not all, have prognostic implications that have to be considered during the evaluation of the results of new treatment regimens.


The value of psychiatric team screening of candidates for jejunoileal bypass surgery.
The relationship between successful outcome of jejunoileal bypass surgery and the results of evaluation by a psychiatric team is reported on. In a surgical group of sixty-one patients, the recommendations of the team were found to be significantly related to the outcome of surgery and correctly identified the emotional hazards so common in this procedure.


Incidence of major structural cardiac defects associated with increased nuchal translucency but normal karyotype.
To examine the association between increased nuchal translucency thickness and major cardiac defects in chromosomally normal fetuses. Tertiary referral unit for fetal medicine and fetal cardiology. During a 4-year period (January 1997 to January 2001), detailed echocardiography was performed in 1319 chromosomally normal fetuses with increased nuchal translucency thickness at 10-14 weeks of gestation. The incidence of major cardiac defects was examined in relation to the fetal NT at the 10-14-week scan. Major cardiac defects were diagnosed in 60 (4.5%) of the 1319 fetuses. In fetuses with a nuchal translucency thickness in the range of 2.5-3.4 mm, the incidence of major cardiac defects was 2.5% (18/722; 95% confidence interval, 1.5-3.9) and in those with a nuchal translucency thickness > or =3.5 mm, it was 7% (42/597; 95% confidence interval, 5.1-9.4). Specialist echocardiography is indicated in all fetuses with increased nuchal translucency thickness because, in such fetuses, the incidence of major cardiac defects is substantially higher than in pregnancies with maternal diabetes, family history and exposure to drugs, where fetal echocardiography is widely considered to be necessary.


Frailty criteria and cognitive performance are related: data from the FIBRA study in Ermelino Matarazzo, São Paulo, Brazil.
To assess the relationship between the CHS frailty criteria (Fried et al., 2001) and cognitive performance. Cross sectional and population-based. Ermelino Matarazzo, a poor sub district of the city of São Paulo, Brazil. 384 community dwelling older adults, 65 and older. Assessment of the CHS frailty criteria, the Brief Cognitive Screening Battery (memorization of 10 black and white pictures, verbal fluency animal category, and the Clock Drawing Test) and the Mini-Mental State Examination (MMSE). Frail older adults performed significantly lower than non-frail and pre frail elderly in most cognitive variables. Grip strength and age were associated to MMSE performance, age was associated to delayed memory recall, gait speed was associated to verbal fluency and CDT performance, and education was associated to CDT performance. Being frail may be associated with cognitive decline, thus, gerontological assessments and interventions should consider that these forms of vulnerability may occur simultaneously.


Coordination of chemical analyses under the European Human Biomonitoring Initiative (HBM4EU): Concepts, procedures and lessons learnt.
The European Human Biomonitoring Initiative (HBM4EU) ran from 2017 to 2022 with the aim of advancing and harmonizing human biomonitoring in Europe. More than 40,000 analyses were performed on human samples in different human biomonitoring studies in HBM4EU, addressing the chemical exposure of the general population, temporal developments, occupational exposure and a public health intervention on mercury in populations with high fish consumption. The analyses covered 15 priority groups of organic chemicals and metals and were carried out by a network of laboratories meeting the requirements of a comprehensive quality assurance and control system. The coordination of the chemical analyses included establishing contacts between sample owners and qualified laboratories and monitoring the progress of the chemical analyses during the analytical phase, also addressing status and consequences of Covid-19 measures. Other challenges were related to the novelty and complexity of HBM4EU, including administrative and financial matters and implementation of standardized procedures. Many individual contacts were necessary in the initial phase of HBM4EU. However, there is a potential to develop more streamlined and standardized communication and coordination in the analytical phase of a consolidated European HBM programme.


The combined ratio of estrogen, progesterone, Ki-67, and P53 to predict the recurrence of endometrial cancer.
We aimed to explore the capacity of the combined ratio of biomarkers to predict the recurrence of Stage I-III endometrial cancer (EC). A total of 473 patients were enrolled after screening. The cut-off value of the ratio was calculated by the receiver operating characteristic curve (ROC). The univariate and multivariate Cox regression analysis was used to assess the correlation between the combined ratio and the recurrence of EC. The differences of clinicopathological parameters between the two groups divided based on the threshold were compared. The ROC curve showed that 0.92 was the optimal cut-off value of the ratio ([ER + PR]/[P53 + Ki67]). The multivariate analysis demonstrated that only International Federation of Gynecology and Obstetrics stage (p = .031) and the combined ratio (p = .004) were independent risk factors of recurrence. The 3-year recurrence-free survival (RFS) and overall survival of patients in the low-ratio group were 54.1% and 66.8%, respectively; while in the high-ratio group were 94.9% and 97.9%, respectively (p < .001). The 3-year RFS of 194 patients, who did not receive the adjuvant therapy, was 54.7% and 97.2% between two groups (p < .001). The optimal cut-off value (0.92) of the combined ratio was demonstrated to be better to predict the recurrence of EC than a single immunohistochemical marker.


Origin and early evolution of the plant terpene synthase family.
As a midsized gene family conserved more by lineage than function, the typical plant terpene synthases (TPSs) could be a valuable tool to examine plant evolution. TPSs are pivotal in biosynthesis of gibberellins and related phytohormones as well as in formation of the extensive arsenal of specialized plant metabolites mediating ecological interactions whose production is often lineage specific. Yet the origin and early evolution of the TPS family is not well understood. Systematic analysis of an array of transcriptomes and sequenced genomes indicated that the TPS family originated after the divergence of land plants from charophytic algae. Phylogenetic and biochemical analyses support the hypothesis that the ancestral TPS gene encoded a bifunctional class I and II diterpene synthase producing the ent-kaurene required for phytohormone production in all extant lineages of land plants. Moreover, the ancestral TPS gene likely underwent duplication at least twice early in land plant evolution. Together these two gave rise to three TPS lineages leading to the extant TPS-c, TPS-e/f, and the remaining TPS (h/d/a/b/g) subfamilies, with the latter dedicated to secondary rather than primary metabolism while the former two contain those genes involved in ent-kaurene production. Nevertheless, parallel evolution from the ent-kaurene–producing class I and class II diterpene synthases has led to roles for TPS-e/f and -c subfamily members in secondary metabolism as well. These results clarify TPS evolutionary history and provide context for the role of these genes in producing the vast diversity of terpenoid natural products observed today in various land plant lineages.


Generalized microsporum audoninii infection and depressed cellular immunity associated with a missing plasma factor required for lymphocyte blastogenesis.
Described herein is a 15 year old girl with a generalized, possibly systemic Microsporum audouinni infectin associated with anergy and defective lymphocyte transformation as a consequence of a deficiency of an uncharacterized plasma factor. Intravenous administration of plasma, obtained from normal donors, has produced consistent although incomplete clinical improvement. Defective lymphocyte transformation to M. audiouinii antigen cultured in autologous plasma became normal after infusions of normal plasma were instituted. Systemic administrations of griseofulvin, clotrimazole and miconazole produced transient and incomplete clinical improvement. Clearing of the cutaneous infection and stabillization of the neurologic status was finally achieved with plasma infusions combined with parenterally administered amphotericin B.


Epoetin-alfa induced pruritic maculopapular eruption: Case report and literature review.
Erythropoiesis-stimulating agents (ESA) are commonly used in clinical practice to improve anaemia. Despite a number of patients successfully treated without adverse events, the complications have been previously reported. To report and review the characteristics and management of ESA hypersensitivities. Case reports and related articles associated with ESA use, published between January 1999 and December 2018, were retrieved through Electronic databases (MEDLINE® and PubMed®). Forty-seven ESA patients with various immediate and delayed hypersensitivity reactions caused by epoetin and pharmaceutical excipients were identified from nineteen studies and one case report in this paper. Fatal hypersensitivity to ESA and ESA-allergic cross-reactivities have been documented. Desensitization or change of EPO molecular structure has been reported as successful methods of re-introducing the drug. ESA hypersensitivity in the various allergic reactions and cross-reactivity have been documented. Desensitization and Epoetin structural changes could be successful methods to re-introduce the drug.


Preoperative sleep quality affects postoperative pain and function after total joint arthroplasty: a prospective cohort study.
The relationship between preoperative sleep quality and postoperative clinical outcomes after total joint arthroplasty (TJA) is unclear. We performed a prospective cohort study to determine whether preoperative sleep quality was correlated with postoperative outcomes after TJA. In this prospective cohort study, 994 patients underwent TJA. Preoperative sleep measures included scores on the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), and a ten-point sleep quality scale. The primary study outcome measured was the visual analog scale (VAS) pain score to 12 weeks postoperation. The consumption of analgesic rescue drugs (oxycodone and parecoxib) and postoperative length of stay (LOS) were recorded. We also measured functional parameters, including range of motion (ROM), Knee Society Score (KSS), and Harris hip score (HHS). The mean age for total knee and hip arthroplasties was 64.28 and 54.85 years, respectively. The PSQI scores were significantly correlated with nocturnal and active pain scores and ROM and functional scores from postoperative day 1 (POD1) to POD3. In addition, significant correlation was noted between the correlation between the active pain scores and ESS scores in the TKA group at postoperative 3 months. The consumption of analgesics after joint arthroplasty was significantly correlated with the PSQI scores. Moreover, significant correlations were noted between the sleep parameters and postoperative length of hospital stay (LOS). Preoperative sleep parameters were correlated with clinical outcomes (i.e., pain, ROM, function, and LOS) after TJA. Clinicians should assess the sleep quality and improve it before TJA.


Outcomes based on prior therapy in the phase 3 METEOR trial of cabozantinib versus everolimus in advanced renal cell carcinoma.
In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) versus everolimus in patients with advanced renal cell carcinoma (RCC), after prior antiangiogenic therapy. Outcomes were evaluated for subgroups defined by prior therapy with sunitinib or pazopanib as the only prior VEGFR inhibitor, or prior anti-PD-1/PD-L1 therapy. For the prior sunitinib subgroup (N = 267), median PFS for cabozantinib versus everolimus was 9.1 versus 3.7 months (HR 0.43, 95% CI 0.32-0.59), ORR was 16% versus 3%, and median OS was 21.4 versus 16.5 months (HR 0.66, 95% CI 0.47-0.93). For the prior pazopanib subgroup (N = 171), median PFS for cabozantinib versus everolimus was 7.4 versus 5.1 months (HR 0.67, 95% CI 0.45-0.99), ORR was 19% versus 4%, and median OS was 22.0 versus 17.5 months (HR 0.66, 95% CI 0.42-1.04). For prior anti-PD-1/PD-L1 therapy (N = 32), median PFS was not reached for cabozantinib versus 4.1 months for everolimus (HR 0.22, 95% CI 0.07-0.65), ORR was 22% versus 0%, and median OS was not reached versus 16.3 months (HR 0.56, 95% CI 0.21-1.52). Cabozantinib was associated with improved clinical outcomes versus everolimus in patients with advanced RCC, irrespective of prior therapy, including checkpoint inhibitor therapy.


Two pathways for the activation of small-conductance potassium channels in neurons of substantia nigra pars reticulata.
Neurons in substantia nigra pars reticulata express the messenger RNA for SK2 but not for SK3 subunits that form small-conductance, Ca2+-dependent K+ channels in dopamine neurons. To determine pathways for the activation of small-conductance, Ca2+-dependent K+ channels in substantia nigra pars reticulata neurons of rats and mice, we studied effects of the selective blocker of small-conductance, Ca2+-dependent K+ channels, apamin (0.01 or 0.3 microM). Apamin diminished the afterhyperpolarization following each action potential and induced burst discharges in substantia nigra pars reticulata neurons. Apamin had a robust effect already at a low (10 nM) concentration consistent with the expression of the SK2 subunit. Afterhyperpolarizations were also reduced by the Ca2+ channel blockers Ni2+ (100 microM) and omega-conotoxin GVIA (1 microM). Depletion of intracellular Ca2+ stores did not change the afterhyperpolarization. However, we observed outward current pulses that occurred independently from action potentials and were abrogated by apamin. Apart from a faster time course, they shared all properties with spontaneous hyperpolarizations or outward currents that ryanodine receptor-mediated Ca2+ release from intracellular stores induces in juvenile dopamine neurons. Sensitization of ryanodine receptors by caffeine silenced substantia nigra pars reticulata neurons. This effect was abolished by the depletion of intracellular Ca2+ stores. We conclude that SK2 channels in substantia nigra pars reticulata neurons are activated by Ca2+ influx through at least two types of Ca2+ channels in the membrane and by ryanodine receptor-mediated Ca2+ release from intracellular stores. Ryanodine receptors do not amplify small-conductance, Ca2+-dependent K+ channel activation by the Ca2+ influx during a single spike. Yet, ryanodine receptor-mediated Ca2+ release and, thereby, an activation of small-conductance, Ca2+-dependent K+ channels by intracellular Ca2+ are available for excitability modulation in these output neurons of the basal ganglia system.


Quantitative CTA vascular calcification, atherosclerosis burden, and stroke mechanism in patients with ischemic stroke.
Vascular calcification is recognized as the advanced stage of atherosclerosis burden. We hypothesized that vascular calcium quantification in CT angiography (CTA) would be helpful to differentiate large artery atherosclerosis (LAA) from other stroke etiology in patients with ischemic stroke. We studied 375 acute ischemic stroke patients (200 males, mean age 69.9 years) who underwent complete CTA images of the aortic arch, neck, and head. The automatic artery and calcification segmentation method measured calcification volumes in the intracranial internal carotid artery (ICA), cervical carotid artery, and aortic arch using deep-learning U-net model and region-grow algorithms. We investigated the correlations and patterns of vascular calcification in the different vessel beds among stroke etiology by age category (young: <65 years, intermediate: 65-74 years, older ≥75 years). Ninety-five (25.3%) were diagnosed with LAA according to TOAST criteria. Median calcification volumes were higher by increasing the age category in each vessel bed. One-way ANOVA with Bonferroni correction showed calcification volumes in all vessel beds were significantly higher in LAA compared with other stroke subtypes in the younger subgroup. Calcification volumes were independently associated with LAA in intracranial ICA (OR; 2.89, 95% CI 1.56-5.34, P = .001), cervical carotid artery (OR; 3.40, 95% CI 1.94-5.94, P < .001) and aorta (OR; 1.69, 95%CI 1.01-2.80, P = .044) in younger subsets. By contrast, the intermediate and older subsets did not show a significant relationship between calcification volumes and stroke subtypes. Atherosclerosis calcium volumes in major vessels were significantly higher in LAA compared to non-LAA stroke in younger age.


Density- and size-dependent spacing of ant nests: evidence for intraspecific competition.
We present three lines of evidence which each suggest that intraspecific competition has significantly influenced the spacing patterns of Formica altipetens colonies. First, nearest-neighbor analysis of nest spacing patterns detected significant uniformity in six of eight plots. Second, there was a signifcant increase in the distance separating nearest neighbors as ant nest diameters increased. Third, ant nest density predicted substantial variation in the colony dispersion index, indicating the existence of a dispersion continuum at our study site.


Clinical outcome and follow-up of sonographically suspected in utero urinary tract anomalies.
We determined the outcome of pregnancy and long-term renal function in cases of sonographically detected fetal urinary tract anomalies (UTAs). This was a retrospective cohort study done at an academic hospital (tertiary referral center). All records of prenatal sonographic examinations done between January 1985 and October 1994 that indicated a suspicion for UTA were examined for perinatal mortality, postnatal confirmation of sonographic diagnosis, postnatal management, and calculated creatinine clearance to determine the ultimate renal function. Of 99 cases with suspected UTAs, 28 pregnancies were terminated because the UTA was considered fatal, and 32 fetuses died perinatally. Twenty-one children are alive with good renal function, 4 with moderate renal function, and 2 with poor renal function. The prenatal diagnosis was not confirmed after birth in 12 children, all of whom are alive with good renal function. The prognosis for prenatally suspected UTA was worse in cases of bilateral involvement and in cases with associated multiple malformations. The prognosis of prenatally diagnosed UTAs depends on the specific anomaly suspected. Abnormal karyotype, other associated malformations, and bilateral involvement are unfavorable determinants of the prognosis in individual cases.


Characterization of UMP synthase in dairy cattle heterozygous for a lethal recessive trait.
UMP synthase was characterized biochemically in dairy cattle heterozygous for a deficiency of this enzyme. Both activities comprising this bifunctional enzyme are decreased, with OMP decarboxylase more affected than orotate phosphoribosyltransferase. Immunotitration of UMP synthase activity revealed the presence of the protein product of the mutant allele in the heterozygous animals. UMP synthases from normal and deficient cattle were not distinguished from one another by kinetic constants, responses to inhibitors, pH profiles, or thermal lability. It was concluded that the 50% reduction in enzyme activity in heterozygous cattle is the result of the presence of only half the normal level of catalytically active UMP synthase.


Expression and distribution of Kv4 potassium channel subunits and potassium channel interacting proteins in subpopulations of interneurons in the basolateral amygdala.
The Kv4 potassium channel α subunits, Kv4.1, Kv4.2, and Kv4.3, determine some of the fundamental physiological properties of neurons in the CNS. Kv4 subunits are associated with auxiliary β-subunits, such as the potassium channel interacting proteins (KChIP1 - 4), which are thought to regulate the trafficking and gating of native Kv4 potassium channels. Intriguingly, KChIP1 is thought to show cell type-selective expression in GABA-ergic inhibitory interneurons, while other β-subunits (KChIP2-4) are associated with principal glutamatergic neurons. However, nothing is known about the expression of Kv4 family α- and β-subunits in specific interneurons populations in the BLA. Here, we have used immunofluorescence, co-immunoprecipitation, and Western Blotting to determine the relative expression of KChIP1 in the different interneuron subtypes within the BLA, and its co-localization with one or more of the Kv4 α subunits. We show that all three α-subunits of Kv4 potassium channel are found in rat BLA neurons, and that the immunoreactivity of KChIP1 closely resembles that of Kv4.3. Indeed, Kv4.3 showed almost complete co-localization with KChIP1 in the soma and dendrites of a distinct subpopulation of BLA neurons. Dual-immunofluorescence studies revealed this to be in BLA interneurons immunoreactive for parvalbumin, cholecystokin-8, and somatostatin. Finally, co-immunoprecipitation studies showed that KChIP1 was associated with all three Kv4 α subunits. Together our results suggest that KChIP1 is selectively expressed in BLA interneurons where it may function to regulate the activity of A-type potassium channels. Hence, KChIP1 might be considered as a cell type-specific regulator of GABAergic inhibitory circuits in the BLA.


Sodium taurocholate cotransporting polypeptide inhibition efficiently blocks hepatitis B virus spread in mice with a humanized liver.
Sodium taurocholate cotransporting polypeptide (NTCP) is a recently discovered hepatitis B virus (HBV) receptor. In the present study, we used TK-NOG mice with a humanized liver to examine the impact of endogenous NTCP expression on HBV infection. Upon inoculation with HBV, these mice exhibited clear viremia in 2 weeks, and serum HBV DNA levels gradually increased. The frequency of HBsAg-positive hepatocytes in the liver was 5.1 ± 0.6% at 2 weeks and increased with increasing HBV DNA levels, reaching 92.9 ± 2.8% at 10 to 12 weeks. In vivo siRNA-mediated NTCP knockdown before and after HBV inoculation significantly suppressed the levels of HBV replication and the frequency of HBsAg-positive hepatocytes at 2 weeks, whereas NTCP knockdown 13 weeks after infection did not affect these parameters. Similar to the humanized mouse livers in the early phase of HBV infection, human liver samples from chronic hepatitis B patients, especially those treated with nucleos(t)ide analogues, contained a considerable number of hepatocytes that were negative for the anti-HBs antibody. In conclusion, NTCP inhibition prevents the spread of HBV-infected hepatocytes in mice with a humanized liver. NTCP-targeted therapy has potential for regulating HBV infection in patients with chronic hepatitis B.


Combination of liquid-phase hollow fiber membrane microextraction with gas chromatography-negative chemical ionization mass spectrometry for the determination of dichlorophenol isomers in water and urine.
A method for the determination of trace amount of dichlorophenol isomers in urine samples using the combination of liquid-phase hollow fiber microextraction (LPME-HF) with gas chromatography-negative chemical ionization mass spectrometry (GC-NCI-MS) has been demonstrated. The method has been optimized with respect to several parameters including the effects of negative chemical ionization (NCI) reagent pressure, the hollow fiber length, extraction time, stirring rate, sample pH and salt concentration for the determination of dichlorophenol isomers in water. The correlation coefficient (r2) of the calibration curves for 2,5-dichlorophenol, 2,3-dichlorophenol, 2,6-dichlorophenol, 3,5-dichlorophenol and 3,4-dichlorophenol were 0.988, 0.981, 0.985, 0.971 and 0.994, respectively. The average recovery rates for 2,5-dichlorophenol, 2,3-dichlorophenol, 2,6-dichlorophenol, 3,5-dichlorophenol and 3,4-dichlorophenol were 0.97, 0.93, 0.96, 0.95 and 0.95, respectively (n=3 for each dichlorophenol) indicate that the methodology is feasible for the determination of trace amounts of dichlorophenol isomers in water and urine samples. Limits of detection (LOD) have been found to be in the range of 5-20 ng/ml. In addition, differentiation of the five dichlorophenol isomers is an easy task using the current approach of combining LPME-HF with NCI-GC-MS technique since they exhibit different NCI spectra.


Calcium in rat peripheral nerve during chronic alterations in plasma calcium.
The calcium content in desheathed tibial nerve was compared to that in cerebellum in rats fed diets containing either 0.01% (low), 0.67% (control) or 3.0% (high) Ca, for 8 weeks. For changes in concentration of plasma ionized Ca, 48% below and 35% above the control mean, percent change in endoneurial Ca content is linearly related, with a slope of 0.80, to percent change in plasma ionized Ca. A line with a slope of 0.21 describes the relation between percent change in cerebellum Ca and percent change in plasma ionized Ca. Plasma, cerebellum and nerve concentrations of Na, K and Cl were similar in the control compared with the two experimental groups of animals. The concentration of plasma Mg varied 20% below and 17% above the control mean, inversely with plasma Ca, but nerve and cerebellum Mg did not change from control values. The results of this study fail to demonstrate Ca homeostasis in rat peripheral nerve endoneurium during chronic hypo- and hypercalcemia. Endoneurial Mg, however, appears to be regulated.


Stereocontrolled synthesis of 1,3-diols from enones: cooperative Lewis base-mediated intramolecular carbonyl hydrosilylations.
A streamlined synthesis of β-hydroxy ketone substrates has been developed to further investigate a recently discovered cooperative Lewis base-mediated intramolecular carbonyl hydrosilylation reaction. The synthesis features an enone β-borylation/oxidation sequence that has proven to be quite general and high-yielding. This has allowed for additional investigations into the diastereoselectivity of the hydrosilylation reaction through the preparation of important polyketide fragments.