Hemolytic disease of the newborn as an unusual consequence of drug abuse. A case report.
Severe Rhesus isoimmunization occurred in a primigravida following self-injection of her partner's blood as a consequence of drug abuse. This case demonstrated the value of the true sinusoidal fetal heart rate pattern as an indicator of severe fetal compromise.


[Inhibition of ovulation with 17-alpha-ethinyl-18-methyl-11-methylene-4-estren-17-ol plus ethinylestradiol].
A combined oral application of 30 micrograms ethinylestradiol with 50 micrograms 17 alpha-ethinyl-18-methyl-11-methylene-4-estren-17-ol (a newly developed progestagen) -- for 21 days resulted in a distinct antigonadotrophic effect, shown by hormone analysis (LH, FSH, estradiol and progesterone) in serum samples of three healthy and fertile women. A final recommendation on the daily dosage, however, depends on the results of clinical experimental investigation still in progress.


Surgical treatment of localized renal cell carcinoma in von Hippel-Lindau's disease.
From 1981 to 1986, 10 patients with von Hippel-Lindau's disease underwent an operation for bilateral nonmetastatic renal cell carcinoma. Of the patients 9 underwent unilateral partial nephrectomy and contralateral radical nephrectomy, and 1 underwent bilateral nephrectomy with subsequent hemodialysis and cadaver renal transplantation. Pathologically, the tumor was stage I in 9 patients and stage III in 1. Currently, 8 patients are alive after partial nephrectomy (5 to 56 months) with good renal function (mean serum creatinine 2.0 mg. per dl.) and no evidence of malignancy; 1 of these patients underwent excision of a cerebral metastasis 2 years after partial nephrectomy. One patient is alive on dialysis after removal of the renal remnant for local tumor recurrence. The patient who underwent transplantation is free of tumor with a well functioning allograft. The distinctive features of renal cell carcinoma in von Hippel-Lindau's disease that influence the management of these patients are reviewed.


Correction of aphakia with contact lenses.
The correction of unilateral and bilateral aphakia with contact lenses has given good results. The contact lens of choice today is either the hard corneal lens or the soft hydrophilic lens. High-water-content lenses have excellent oxygen permeability which permits continuous wear. Experience with the 'Sauflon 85' lens is described.


The mouse communal nest: investigating the epigenetic influences of the early social environment on brain and behavior development.
Among the epigenetic factors shaping brain and behavior during early postnatal life, social experiences have a major impact. Early social experiences are mainly of two kinds: mother-offspring and peer interaction. In rodents, the latter has so far been rarely studied. The communal nest (CN) is an innovative experimental strategy that favors an exhaustive investigation of the long-term effects not only of mother-offspring but also of peer interaction. CN is a rearing condition employed by up to 90% of mouse females in naturalistic settings and consists of a single nest where two or more mothers keep their pups together and share care-giving. Mice reared in a communal nest display relevant changes in brain function and behavior, including high levels of neural plasticity markers, such as brain-derived neurotrophic factor (BDNF), and elaborate adult social competencies. Overall, CN appears as an experimental strategy different and complementary to the ones currently used for studying how the early environment determines developmental trajectories.


A versatile genetic tool: haploid cells.
Haploid cells are excellent tools to study gene function as they contain a single copy of the genome and are thus unable to mask the effect of mutations. Recently, haploid embryonic stem cells, which are capable of self-renewal and potentially differentiating into other cell types despite having only one set of chromosomes, have been established in several species. These unique haploid cells allow us to seek recessive gene functions in mammals, and have had a profound influence on the field of genetic screening and drug target identification. In this review, we briefly introduce advances and breakthroughs in haploid cell line research and broadly discuss the versatile application thereof.


Impact of cervical excisional dimensions on endocervical margins status in adenocarcinoma in situ of the uterine cervix: A multicenter study from the FRANCOGYN group.
Excisional procedures have a central role in the management of adenocarcinoma in situ of the cervix (AIS). We aimed to evaluate the relationship between the excisional specimen dimensions and the endocervical margin status. We conducted a multicentric retrospective study in seven French centers. All cases with proven AIS on a colposcopic biopsy and undergoing an excisional procedure afterwards were included in the analysis. We evaluated the impact of excision length, along with the lateral and anteroposterior diameters on the endocervical margin status. An additional subgroup analysis of the impact of maternal age on endocervical margin status was also conducted. Of the 101 cases of AIS diagnosed on initial biopsy, 95 underwent a primary excisional procedure, among which 80% (n = 76/95) had uninvolved endocervical margins and 20% (n = 19/95) had positive endocervical margins. The excisional specimen length was not significantly related to the endocervical margin status. Conversely, both lateral and antero-posterior diameters were significantly correlated with the negative endocervical margins status: OR = 1,19, 95% CI [1.03, 1.40], p = 0.025, for the lateral diameter and OR = 1.34, 95% CI [1.14, 1.64], p = 0.001 for the antero-posterior diameter. The median lateral diameter was 20 mm, IQR (18, 24) in case of endocervical negative margins vs. 18 mm IQR (15, 24) in case of positive endocervical margins (p = 0.039), and the median anteroposterior diameter was 17 mm IQR (15, 20) in case of negative endocervical margins vs 14 mm IQR (11, 15) in case of positive endocervical margins (p = 0.004), respectively. Additionally, in patients over 45 years old, endocervical margin were more likely to be positive despite similar excisional dimensions (7/17 (41%) of positive endocercival margins before 45 years old vs 12/78 (15%) after, p = 0.039) CONCLUSIONS: Endocervical margin statues were significantly related to the transverse diameters (lateral and anteroposterior diameters), but not to the excision specimen length. Reducing the excised length may lead to fewer post-procedure complications but would still allow to obtain a large proportion of negative endocervical margins.


Is alexithymia associated with sleep problems? A systematic review and meta-analysis.
Alexithymia, a difficulty identifying and expressing emotions experienced by oneself or others, measurably harms quality of sleep. Research has observed the association between alexithymia and sleep problems; however, the cumulative effect of this association is still unknown. Therefore, this systematic review and meta-analysis was conducted to present scientific evidence regarding the relationship between alexithymia and sleep quality. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline, and using relevant keywords, we searched six databases: Scopus, PubMed Central, ProQuest, ISI Web of Knowledge, EMBASE, and Science Direct. We selected observational studies on the association between alexithymia and sleep. We conducted meta-analysis using a random-effect model to calculate the effect size (ES) with Fisher's z transformation. Eligible studies (N = 26) in 24 papers included 7546 participants from 12 countries. The entire ES for the association between alexithymia and sleep was 0.44 (95 % CI: 0.31, 0.56). Additionally, patient populations had a larger ES (ES = 0.55; 95 % CI: 0.30, 0.79) than healthy populations (ES = 0.30; 95 % CI: 0.20, 0.41). The results of the present systematic review and meta-analysis revealed a significant association between alexithymia and sleep problems, especially among people with any medical condition.


Treatment of post-herpetic neuralgia. A review of 77 consecutive cases.
The treatment of 77 consecutive cases of post-herpetic neuralgia is reviewed. Stellate blockade proved helpful in 75% of patients with pain of less than 1 year's duration; 40% became virtually pain free. Drug treatment and electrical counterirritation methods gave improvement in 60% of cases but only 15% became pain free. Stellate block carried out after 1 year of pain proved helpful in only 44% of patients, and only 22% became pain free. Stellate blockade carried out within 1 year of the onset of symptoms would appear to be one of the treatments of choice for post-herpetic neuralgia. It would be of interest to see the results of a controlled randomised trial.


On the mechanism of immunosympathectomy.
The effects in vivo and in vitro of the antiserum to mouse nerve growth factor (NGF) are independent of the presence of complement. These results are consistent with the view that the antiserum acts by neutralizing endogenous NGF.


Primitive neuroectodermal tumor (neuroepithelioma) of spinal nerve root -- Report of an adult case and establishment of a cell line.
A case of primitive neuroectodermal tumor arising in the cervical nerve root of a 28-year-old man is presented. Histologically, the tumor was characterised by proliferation of primitive neuroectodermal cells and formation of numerous Homer-Wright type rosettes. A cell line (Nagai line) was established from the tumor. Electron microscopic examination of Nagai cells revealed numerous microrosette formation with microvilli-like cytoplasmic processes projecting into the central lumina. Neurosecretory granules appeared in the cytoplasmic processes when Nagai cells were treated with dibutyryl cyclic AMP. Primitive satellite cells which completely surrounded other tumor cells with their tongue-like slender cytoplasmic processes were also found. Histogenesis of this unique tumor was discussed comparing with the neuroblastoma of sympathetic nervous system, medulloblastoma of the central nervous system, and with the tumors induced by Adenovirus type 12 in animals. It was concluded that the tumor was neuroepithelioma derived from a primitive stem cell of neural crest origin which possesses the bipotency to differentiate toward either neuroblastic or neurilemmal line.


Ultrasound classification of breast masses using a comprehensive Nakagami imaging and machine learning framework.
In this study we investigate the potential of parametric images formed from ultrasound B-mode scans using the Nakagami distribution for non-invasive classification of breast lesions and characterization of breast tissue. Through a sliding window technique, we generated seven types of Nakagami images for each patient scan in our dataset using basic and as well as derived parameters of the Nakagami distribution. To determine the suitable window size for image generation, we conducted an empirical analysis using 4 windows, which includes 3 column windows of lengths 0.1875 mm, 0.45 mm and 0.75 mm and widths of 0.002 mm, along with the standard square window with sides equal to three times the pulse length of incident ultrasound. From the parametric image sets generated using each window, we extracted a total of 72 features that consisted of morphometric, elemental and hybrid features. To our knowledge no other literature has conducted such a comprehensive analysis of Nakagami parametric images for the classification of breast lesions. Feature selection was performed to find the most useful subset of features from each of the parametric image sets for the classification of breast cancer. Analyzing the classification accuracy and Area under the Receiver Operating Characteristic (ROC) Curve (AUC) of the selected feature subsets, we determined that the selected features acquired from Nakagami parametric images generated using a column window of length 0.75 mm provides the best results for characterization of breast lesions. This optimal feature set provided a classification accuracy of 93.08%, an AUC of 0.9712, a False Negative Rate (FNR) of 0%, and a very low False Positive Rate (FPR) of 8.65%. Our results indicate that the high accuracy of such a procedure may assist in the diagnosis of breast cancer by helping to reduce false positive diagnoses.


Plasma haemostatic factors and diabetic retinopathy.
Plasma coagulation factors were measured in twelve male insulin-dependent diabetics with no retinopathy, ten with background and ten with proliferative retinopathy and ten non-diabetics. Factor VIII pro-coagulant activities (VIII:C), ristocetin cofactor activities and factor VIII-related antigen concentrations (VIIIR:ag) were significantly related to the severity of diabetic retinopathy (P less than 0.025, trend test). The mean ratio of VIII:C/VIIIR:ag was lower in the diabetics with proliferative retinopathy than in the other groups of diabetics (P less than 0.05) or the controls (P less than 0.02). Concentrations of alpha 2 macroglobulin and alpha 1 antitrypsin were highest in diabetics with proliferative retinopathy (0.1 greater than P greater than 0.05, trend test) but mean prothrombin and activated partial thromboplastin times and mean concentrations of alpha 2 antiplasmin, plasminogen activator and antithrombin III were similar in all groups. Concentrations of the platelet-specific protein beta thromboglobulin, though higher in diabetics than controls (P less than 0.005), were not related to retinopathy. The plasma concentrations of coagulation factors did not correlate with creatinine clearance and there were no significant differences between groups in concentrations C-reactive protein; this suggests that the raised concentrations of coagulation factors in diabetics with retinopathy were not a result of associated nephropathy or an 'acute phase protein' response to diabetic tissue damage. Increased coagulation activity in diabetics may contribute to the development of retinopathy.


A 31P-NMR study on multilamellar liposomes formed from the lipids of a thermophilic bacterium.
The membrane lipids of a thermophilic bacterium, Thermus SPS11, isolated from thermal springs in São Pedro do Sul, Portugal, were fractionated by chromatography on silica gel. The total lipid extract was found to contain one major phospholipid (PL), which accounts for about 90% of the total lipid phosphorous, and one major glycolipid (GL), which accounts for about 95% of the total carbohydrate in the non-phospholipid fraction. The membranes also contain about 11% by weight of a complex mixture of carotenoids (CA). Multilamellar liposomes, in excess water, formed from PL and mixtures of PL with GL and CA in proportions found in the natural membrane were investigated by proton-decoupled 31P-nuclear magnetic resonance (NMR) spectroscopy and X-ray diffraction. All mixtures examined were found to be in a lamellar phase with disordered hydrophobic chains with no evidence for "non-bilayer structures" between 23 degrees and 85 degrees C. Compared to bilayers formed from pure PL or mixtures of PL and CA, significantly larger values for the chemical shift anisotropy of the 31P-NMR powder patterns were obtained from bilayers formed from mixtures of PL and GL, at temperatures above 75 degrees C, and mixtures of PL, GL and CA at all temperatures examined. These differences are interpreted in terms of changes in the order of the bilayer and/or changes in the orientation of the phosphate moiety of PL. The significance of these results to the thermophily of the bacterium is discussed.


Parallel quality assessment of emergency departments by European foundation for quality management model and Iranian national program for hospital evaluation.
European Foundation for Quality Management (EFQM) model is a widely used quality management system (QMS) worldwide, including Iran. Current study aims to verify the quality assessment results of Iranian National Program for Hospital Evaluation (INPHE) based on those of EFQM. This cross-sectional study was conducted in 2012 on a sample of emergency departments (EDs) affiliated with Tehran University of Medical Sciences (TUMS), Iran. The standard questionnaire of EFQM (V-2010) was used to gather appropriate data. The results were compared with those of INPHE. MS Excel was used to classify and display the findings. The average assessment score of the EDs based on the INPHE and EFQM model were largely different (i.e. 86.4% and 31%, respectively). In addition, the variation range among five EDs' scores according to each model was also considerable (22% for EFQM against 7% of INPHE), especially in the EDs with and without prior record of applying QMSs. The INPHE's assessment results were not confirmed by EFQM model. Moreover, the higher variation range among EDs' scores using EFQM model could allude to its more differentiation power in assessing the performance comparing with INPHE. Therefore, a need for improvement in the latter drawing on other QMSs' (such as EFQM) strengths, given the results emanated from its comparison with EFQM seems indispensable.


Cancer-testis and melanocyte-differentiation antigen expression in malignant glioma and meningioma.
Identification of well-defined glioma-specific antigens is a crucial and necessary step in developing immunotherapy for glioblastoma multiforme (GBM). In this study, we analyzed the composite expression of cancer-testis antigens (CTA) and melanocyte-differentiation antigens (MDA) in malignant glioma tissue and primary glioma cell lines and compared them with normal brain specimens and meningioma. CTA and MDA expression was assessed by the reverse transcription-polymerase chain reaction. The following primers were analyzed for CTA: LAGE-1, NY-ESO-1, MAGE-1, MAGE-3, MAGE-4, MAGE-10, CT-7, CT-10, HOM-MEL 40, BAGE, and SCP-1; and for MDA: tyrosinase, gp100, MELAN-A/MART-1, and TRP-2. The expression level was determined by ethidium bromide-stained agarose gel. Among malignant glioma tissue, the highest CTA and MDA expression rates were found for MAGE-3 (22%), MAGE-1 (16%), CT-7 (11%), gp100 (40%), and TRP-2 (29%). Among primary glioma cell lines, the highest levels of expression were: CT-10 (38%), gp100 (100%), and TRP-2 (31%). NY-ESO-1 was the only CTA demonstrated and seen in 12% of meningioma tissue specimens. TRP-2 and gp100 were expressed in 65% and 38% of meningioma tissue, respectively; gp100 and TRP-2 were expressed in 100% and 50% of meningioma cell lines. Of the nine normal brain specimens, all samples tested positive for TRP-2. All other CTA and MDA tested negative in normal brain. We conclude that CTA and MDA demonstrate low-to-variable levels of expression within GBM. However, two CTA (MAGE-1 and MAGE-3) and one MDA (gp100) may be considered candidate antigens based on their restricted expression in GBM. These results will greatly accelerate the development of novel, specific immunotherapeutic strategies.


Transmembrane Mucin Expression and Function in Embryo Implantation and Placentation.
Transmembrane mucins (TMs) are extremely large, complex glycoproteins that line the apical surfaces of simple epithelia including those of the female reproductive tract. TMs provide a physical barrier consistent with their role as part of the innate immune system. This barrier function must be overcome in the context of embryo implantation to permit blastocyst attachment. Three major TMs have been identified in uterine epithelia of multiple species: MUC1, MUC4, and MUC16. MUC1 has been found in all species studied to date, whereas expression of MUC4 and MUC16 have been less well studied and may be species specific. The strategies for removing mucins to permit embryo attachment also vary in a species-specific way and include both hormonal suppression of TM gene expression and membrane clearance via cell surface proteases. Studies emerging from the cancer literature indicate that TMs can modulate a surprisingly wide variety of signal transduction processes. Furthermore, various cell surface proteins have been identified that bind either the oligosaccharide or protein motifs of TMs suggesting that these molecules may support cell attachment in some contexts, including trophoblast interactions with cells of the immune system. The intimate association of TMs at sites of embryo-maternal interaction and the varied functions these complex molecules can play make them key players in embryo implantation and placentation processes.


Bone marrow-derived mesenchymal stem cells modulate BV2 microglia responses to lipopolysaccharide.
The immunoregulatory properties of mesenchymal stem cells (MSC) have been demonstrated on a wide range of cells. Here, we describe the modulatory effects of mouse bone marrow-derived MSC on BV2 microglia proliferation rate, nitric oxide (NO) production and CD40 expression. Mouse bone marrow MSC were co-cultured with BV2 cells at various seeding density ratios and activated with lipopolysaccharide (LPS). We show that MSC exert an anti-proliferative effect on microglia and are potent producers of NO when stimulated by soluble factors released by LPS-activated BV2. MSC suppressed proliferation of both untreated and LPS-treated microglia in a dose-dependent manner, significantly reducing BV2 proliferation at seeding density ratios of 1:0.2 and 1:0.1 (p<.05). Co-culturing MSC with BV2 cells at different ratios revealed interesting dynamics in NO production. A high number of MSC significantly increases NO in co-cultures whilst a lower number reduces NO. The increased NO levels in co-cultures may be MSC-derived, as we also show that activated BV2 cells stimulate MSC to produce NO. Cell-cell interaction is not a requirement for this effect as soluble factors released by activated BV2 cells alone do stimulate MSC to produce high levels of NO. Although NO is implicated as a mediator for T cell proliferation, it does not appear to play a major role in the suppression of microglia proliferation. Additionally, MSC reduced the expression of the microglial co-stimulator molecule, CD40. Collectively, these regulatory effects of MSC on microglia offer insight into the potential moderating properties of MSC on inflammatory responses within the CNS.


If a drug deemed 'safe' in nonclinical tests subsequently prolongs QT in phase 1 studies, how can its sponsor convince regulators to allow development to proceed?
New drugs are now routinely investigated for their QT-liability in nonclinical studies as well as in a formal Thorough QT Study in man. Data from these studies in man have provided better evidence of the benefits of defining concentration-QT effect relationship of a drug. Therefore, sponsors also frequently monitor electrocardiograms in early phase I clinical pharmacology studies. Although very rare, it is not inconceivable that a drug deemed safe in nonclinical studies may be found to have QT-liability in these early phase clinical studies. Regulatory authorities will no doubt seek a scientific explanation for this discrepancy and as long as the safety of subjects in later phase clinical trials is assured, are content to let the sponsor decide whether to continue or terminate the development of such drugs. Nevertheless, regulatory authorities are prepared provide advice at all the key stages on the optimal way forward so that regulatory concerns likely to arise at evaluation are addressed ahead of submission. Regulatory approval of a drug with QT-liability depends on the comparison of its overall risk/benefit analysis with alternatives available and the morbidity and mortality associated with the disease to be treated. Recent high profile withdrawal of drugs provides a clear signal that cardiac safety is high on the regulatory agenda. An additional regulatory concern is that although QT-related risk can be communicated by appropriate labeling, this may not be enough to mitigate the proarrhythmic risk in clinical practice. A major challenge is to ensure that such drugs are used appropriately.


Specific UV-absorbancy of pure rRNA isolated from trout liver as a standard for the quantification of ribonucleic acid from fish tissues.
1. Lyophilized crude rRNA from trout (Salmo gairdneri R.) liver was composed (w/w) of 2.9% protein, traces of DNA and glycogen, 13% water and 83% pure rRNA. The RNA content was derived from the discrepancy between effectively found (8.1%, w/w) and theoretical phosphorus content (9.6%, w/w). 2. The theoretical phosphorus content was calculated on the basis of the molar distribution of nucleotides in rRNA (UMP:GMP:AMP:CMP = 24.7%:30%:19.5%:25.8%), established upon cation exchange chromatography of alkali-degraded crude rRNA. 3. The extinction coefficient (corrected for moisture and none-ribonucleic acid contaminants) of pure rRNA in 0.2 N PCA after digestion in 0.3 N KOH at 37 degrees C for 90 min is 361 in terms of E1%260. That of undegraded, pure rRNA in water amounts to 279.


Thirty-Day Mortality Rate of Patients With Hip Fractures During the COVID-19 Pandemic: A Single Centre Prospective Study in the United Kingdom.
During the COVID-19 pandemic, the care of hip fracture patients remains a clinical priority. Our study aims to investigate the 30-day mortality rate of hip fracture patients during the first 30 days of the pandemic in the United Kingdom. A single-center, observational, prospective study of patients presenting with hip fractures. Data collection started from "day 0" of the COVID-19 pandemic in the United Kingdom and continued for 30 days. We collected data on time to surgery, Clinical Frailty Scale score, Nottingham Hip Fracture Score, COVID-19 infection status, 30-day mortality, and cause of death. For comparison, we collected retrospective data during the same 30-day period in 2018, 2019, and the previous 6 months (Control groups A, B, and C, respectively). Forty-three patients were included in the study. There was no difference in age or gender between the Study and Control groups. The 30-day mortality rate of the Study group was 16.3%, which was higher than Control groups A (P = 0.022), B (P = 0.003) and C (P = 0.001). The prevalence of COVID-19 infection in our Study group was 26%. Of the 7 mortalities recorded, 4 patients tested positive for COVID-19 infection. In our Study group, COVID-19 infection correlated significantly with 30-day mortality (P = 0.002, odds ratio 2.4). Our study demonstrated a significant increase in 30-day mortality among hip fracture patients during the first 30 days of the COVID-19 pandemic in the United Kingdom. A positive COVID-19 test result in patients with hip fractures is associated with a 2.4-fold increase in risk of 30-day mortality. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.


Considerations when introducing a new cardiac MDCT service. Avoiding the pitfalls.
The widespread introduction of multidetector computed tomography (MDCT) into mainstream imaging departments has enabled many centres to undertake cardiac MDCT and, in particular, MDCT coronary angiography. This review highlights the areas that need consideration when introducing a new cardiac MDCT service and covers both technical and non-technical aspects. This includes equipment requirements, personnel, training, patient selection and preparation, cardiac CT protocols and post-processing techniques, and potential pitfalls.


Beneficial effects of streptokinase on left ventricular function after myocardial reoxygenation and reperfusion following global ischemia in the isolated rabbit heart.
To determine the effect of streptokinase on the ischemic myocardium independent of its effects on the occluding thrombus, the isolated rabbit heart, perfused with Krebs-Henseleit solution, was subjected to a 45-min period of ischemia--83% reduction in myocardial (perfusion) flow--plus anoxia (95% N2 and 5% CO2), followed by restoration of perfusion and reoxygenation. Streptokinase, 75 or 150 IU/min, was infused starting 15 min before reperfusion and continuing for 30 min after reperfusion. Compared with the control group, streptokinase was associated during reperfusion with a significant dose-dependent greater restoration or smaller depression of ventricular function, dP/dt, and developed pressure. To determine if streptokinase effects were mediated during the ischemic or reperfusion phase, the high streptokinase dose was administered in either the last 30 min of the ischemia or the first 30 min of reperfusion. The improvement in recovery of left ventricular function was primarily in the group having streptokinase administered only during the ischemic period. Thus, streptokinase affects the ischemic myocardium so that there is an acceleration in the recovery of ventricular function or a reduction of the impairment in ventricular function during myocardial reperfusion.


Functional laser Doppler flowmetry of the optic nerve: physiological aspects and clinical applications.
The present paper reviews the methodology and clinical results of recording, by laser Doppler flowmetry, the hemodynamic response of the optic nerve head elicited by visual stimulation. The basic mechanism underlying this novel technique (which is called here functional laser Doppler flowmetry (FLDF)) is the coupling between visually evoked neural activity and vascular activity within the neural tissue of the optic nerve (neurovascular coupling). The blood flow responses elicited by various visual stimuli (luminance and chromatic flicker, focal and pattern stimulation) have been characterized in humans by FLDF. These responses are similar to those assessed by electrophysiological methods (flicker and pattern electroretinography) evoked by the same stimuli. In addition, a significant correlation has been demonstrated between the hemodynamic responses and the neural activity induced electrical signals arising from the inner retina, providing evidence in support of the presence of a neurovascular coupling in humans. The application of FLDF in patients with ocular hypertension and early glaucoma demonstrates that the visually evoked hyperemic responses are significantly depressed even when neural retinal activity may be still relatively preserved, suggesting that abnormal optic nerve head autoregulation in response to visual stimuli may be altered early in the disease process. FLDF may open new avenues of investigation in the field of glaucoma and other neuro-ophthalmic disorders, providing new pathophysiological data and outcome measures for potential neuro-protective treatments.


Preventive health behaviors among the middle-aged and elderly in China: Does social capital matter?
This study explores the status quo of preventive care use and social capital among middle-aged and elderly people (≥45 years old) in China, and employs a multi-level model to analyze whether social capital at different levels is associated with preventive care use. The data are derived from the 2018 China Health and Retirement Longitudinal Study (CHARLS), which includes 11,503 respondents and 450 communities. Preventive care use covers the utilization of routine physical examination services. Individual social capital is measured by the level of social network and social activities participation. Social network includes contacting with children or other people, for example, by phone, text message. Social activities participation is measured by the involvement in social activities, for example, playing mahjong, going to community club. Community social capital is evaluated by the richness of community facilities. Results reveals that the utilization of preventive care is 48.94% among middle-aged and elderly in China. The most used preventive service is routine blood test. The intra-class correlation (ICC) coefficient indicates that preventive health behaviors of the respondents are clustered at communities where they live. Multi-level regression shows that influence of social network is not significant to preventive care use (p > 0.05). Community facilities and individual social activities participation are significantly associated with preventive care use (p < 0.05). The association between social capital and preventive care use could be considered as an important factor when making policies to promote preventive care use.


Estimation of acute flurbiprofen and ketoprofen toxicity in rat gastric mucosa at therapy-relevant doses.
Since assessment of the acute gastrotoxicity of nonsteroidal antiinflammatory drugs (NSAIDs) in rats requires high doses of the drugs, we sought to establish an experimental model with which this adverse NSAID effect can be estimated at therapy-relevant doses. The study was performed with racemic flurbiprofen-trometamol (R/S-FBP), its pure enantiomers S-FBP and R-FBP, and racemic ketoprofen-trometamol (R/S-KP). Two hours after administration of FBP or KP to Sprague-Dawley rats, HCl (0.5 M, 10 ml/kg) was given intragastrically (IG), and the haemorrhagic lesion area in the gastric mucosa quantified 1 h post-HCI. FBP amplified gastric acid injury in a dose-related manner, the rank order of potency being S-FBP > R/S-FBP >> R-FBP. While less than 1 micromol/kg S-FBP and R/S-FBP aggravated acid injury, doses up to 50 micromol/kg failed to cause appreciable damage without subsequent HCl challenge. Similar observations were made with R/S-KP which at doses of > or = 1 micromol/kg aggravated gastric acid injury. There was no significant difference in the gastrotoxicity of FBP when the drug was administered subcutaneously or IG, whereas subcutaneously injected R/S-KP was slightly more toxic than IG R/S-KP. These data show that FBP- and KP-induced amplification of acid injury in the rat gastric mucosa is a sensitive assay whereby, with single drug dosing, the gastrotoxic potential of these and other NSAIDs may be estimated at therapy-relevant doses that in humans threaten mucosal integrity only following chronic use.


Cryo-EM of a heterogeneous biochemical fraction elucidates multiple protein complexes from a multicellular thermophilic eukaryote.
Biomolecular complexes and their interactions govern cellular structure and function. Understanding their architecture is a prerequisite for dissecting the cell's inner workings, but their higher-order assembly is often transient and challenging for structural analysis. Here, we performed cryo-EM on a single, highly heterogeneous biochemical fraction derived from Chaetomium thermophilum cell extracts to visualize the biomolecular content of the multicellular eukaryote. After cryo-EM single-particle image processing, results showed that a simultaneous three-dimensional structural characterization of multiple chemically diverse biomacromolecules is feasible. Namely, the thermophilic, eukaryotic complexes of (a) ATP citrate-lyase, (b) Hsp90, (c) 20S proteasome, (d) Hsp60 and (e) UDP-glucose pyrophosphorylase were characterized. In total, all five complexes have been structurally dissected in a thermophilic eukaryote in a total imaged sample area of 190.64 μm2, and two, in particular, 20S proteasome and Hsp60, exhibit side-chain resolution features. The C. thermophilum Hsp60 near-atomic model was resolved at 3.46 Å (FSC = 0.143) and shows a hinge-like conformational change of its equatorial domain, highly similar to the one previously shown for its bacterial orthologue, GroEL. This work demonstrates that cryo-EM of cell extracts will greatly accelerate the structural analysis of cellular complexes and provide unprecedented opportunities to annotate architectures of biomolecules in a holistic approach.


Response of human renal tubular cells to cyclosporine and sirolimus: a toxicogenomic study.
The molecular mechanisms involved in the potentially nephrotoxic response of tubular cells to immunosuppressive drugs remain poorly understood. Transcriptional profiles of human proximal tubular cells exposed to cyclosporine A (CsA), sirolimus (SRL) or their combination, were established using oligonucleotide microarrays. Hierarchical clustering of genes implicated in fibrotic processes showed a clear distinction between expression profiles with CsA and CsA+SRL treatments on the one hand and SRL treatment on the other. Functional analysis found that CsA and CsA+SRL treatments preferentially alter biological processes located at the cell membrane, such as ion transport or signal transduction, whereas SRL modifies biological processes within the nucleus and related to transcriptional activity. Genome wide expression analysis suggested that CsA may induce an endoplasmic reticulum (ER) stress in tubular cells in vitro. Moreover we found that CsA exposure in vivo is associated with the upregulation of the ER stress marker BIP in kidney transplant biopsies. In conclusion, this toxicogenomic study highlights the molecular interaction networks that may contribute to the tubular response to CsA and SRL. These results may also offer a new working hypothesis for future research in the field of CsA nephrotoxicity. Further studies are needed to evaluate if ER stress detection in tubular cells in human biopsies can predict CsA nephrotoxicity.


A review of computer aided detection in mammography.
Breast screening with mammography is widely recognized as the most effective method of detecting early breast cancer and has consistently demonstrated a 20-40% decrease in mortality among screened women. Despite this, the sensitivity of mammography ranges between 70 and 90%. Computer aided detection (CAD) is an artificial intelligence (AI) technique that utilizes pattern recognition to highlight suspicious features on imaging and marks them for the radiologist to review and interpret. It aims to decrease oversights made by interpreting radiologists. Here we review the efficacy of CAD and potential future directions.


Complete genome analysis of Pseudomonas furukawaii ZS1 isolated from grass carp (Ctenopharyngodon idellus) culture water.
Pseudomonas furukawaii ZS1, isolated from grass carp (Ctenopharyngodon idellus) culture water, exhibits efficient aerobic nitrate reduction without nitrite accumulation; however, the molecular pathway underlying this aerobic nitrate reduction remains unclear. In this study, we constructed a complete genome map of P. furukawaii ZS1 and performed a comparative genomic analysis with a reference strain. The results showed that P. furukawaii ZS1 genome was 6 026 050 bp in size and contained 5427 predicted protein-coding sequences. The genome contained all the necessary genes for the dissimilatory nitrate reduction to ammonia pathway but lacked those for the assimilatory nitrate reduction pathway; additionally, genes that convert ammonia to organic nitrogen were also identified. The presence of putative genes associated with the nitrogen and oxidative phosphorylation pathways implied that ZS1 can perform respiration and nitrate reduction simultaneously under aerobic conditions, so that nitrite is rapidly consumed for detoxication by denitrification. The aim of this study is to indicate the great potential of strain ZS1 for future full-scale applications in aquaculture. This work provided insights at the molecular level on the nitrogen metabolic pathways in Pseudomonas species. The understanding of nitrogen metabolic pathways also provides significant molecular information for further Pseudomonas species modification and development.


A novel alkaline keratinase from Bacillus subtilis DP1 with potential utility in cosmetic formulation.
The Bacillus subtilis DP1 was isolated from poultry farm soil at Anand district, India. The highest enzyme production (379.65U/ml) was obtained at pH 10.0, a temperature of 37°C and a growth period of 72h. The extracellular keratinase was purified by gel filtration chromatography with 27.98 purification fold. Purity was also confirmed by High-Performance Liquid Chromatography (HPLC) analysis, where a major peak having retention time of 2.5min was obtained on C18 column using photo diode array detector. Purified keratinase was stable in a broad range of pH (8-12) and temperature (20-50°C) with optimum at pH 10.0 and 37°C. The metallic ions, Ca(2+) and Mg(2+) enhance keratinase activity. Secondary structure from Circular Dichroism (CD) spectra implies that purified keratinase is largely β-pleated sheet rich protein. For preparation of dehairing cream formulation, compatibility studies of excipients were carried out. Fourier transform infrared spectroscopy (FTIR) spectra of sodium stearate, calcium carbonate and sodium lauryl sulphate shows no reactivity of functional groups and hence mixture was compatible for formulation of keratinase dehairing cream. Prepared biological depilatory was able to remove hair more efficiently compared to marketed formulations.


A novel mutation in the GAN gene causes an intermediate form of giant axonal neuropathy in an Arab-Israeli family.
Giant axonal neuropathy is a severe autosomal recessive neurodegenerative disorder of childhood that affects both the peripheral and central nervous systems. It is caused by mutations in the GAN gene linked to chromosome 16q24.1 At least 45 distinct disease-causing mutations have been identified throughout the gene in families of various ethnic origins, with different symptomatologies and different clinical courses. To date, no characteristic mutation or phenotype-genotype correlation has been established. We describe a novel missense mutation in four siblings born to consanguineous parents of Arab original with clinical and molecular features compatible with giant axonal neuropathy. The phenotype was characterized by a predominant motor and sensory peripheral neuropathies and severe skeletal deformities.


Emotional aspects of arm or leg amputation in children.
A clinical study of nine children between the ages of 4 and 15, who had undergone arm or leg amputation is presented. The emotional reactions of all those involved - the child, family, and the treatment team - are described. Amputation creates extreme stress in all participants in the procedure. Some similarities were found in the defensive mechanisms and stages experienced by the child, the family and the members of the treatment team.


Incidence and management of complications during posttraumatic early rehabilitation.
Early rehabilitation after traumatic brain injury has become a worldwide accepted interface between intensive care medicine and rehabilitation to aim for a better functional outcome of the surviving patients. So each chain can only be as strong as its weakest link, and there is still need for well defined quality standards depending on the medical demands during this period of treatment. Hence we were interested in quantifying the complications occurring until discharge to further rehabilitation with special regard on severe physical handicaps and organ failure necessitating surgical or intensive care therapy. Our results demonstrate that early rehabilitation is a part of intensive care medicine with enhanced approaches to preserve rehabilitation potential of the brain and for coma stimulation.


Hydroxyproline-rich glycopeptide signals in potato elicit signalling associated with defense against insects and pathogens.
HypSys peptides are 18-20 amino acids glycopeptide defense signal first discovered in tobacco and tomato that activate expression of defensive genes against insect-herbivores. Discovery of their orthologs in other Solanaceaous and nonsolanaceous plants demonstrated their possible ubiquitous nature and species specific functional diversity. In our continued search to establish the paradigm of defense signalling by HypSys peptides, we isolated a cDNA from potato leaves encoding putative analogs of tomato HypSys peptides flanked by conserved proteolytic cleavage sites. The gene encoding the cDNA was a member of a gene family in the tetraploid genome of potato and its expression was transcriptionally activated by wounding and methyl jasmonate. The deduced precursor protein contained a leader peptidase splice site and three putative HypSys peptides with conserved N- and C-termini along with central proline-rich motifs. In defense signalling, the three HypSys peptides elicit H₂O₂ generation in vivo and activate several antioxidant defensive enzymes in young potato leaves. Similar to potato systemin, the HypSys peptides activate the expression of octadecanoid pathway genes and protease inhibitors for insect defense. In addition, the HypSys peptides also activate the essential genes of the innate pathogen defense response in young potato leaves, acting as common elicitors of signalling associated with anti-herbivore and anti-pathogen defense in potato.


Phylogeny of lymphocyte heterogeneity: identification and separation of functionally distinct subpopulations of channel catfish lymphocytes with monoclonal antibodies.
The purpose of this study was to identify monoclonal antibodies reactive with channel catfish T cells. Since a variety of commercially available anti-human and mouse T cell reagents failed to react with channel catfish leucocytes, the development of anti-fish T cell monoclonal antibodies was undertaken. One of these reagents, designated mAb 13C10, reacted with channel catfish surface immunoglobulin negative, but not positive, lymphocytes. This reagent, when used in "panning" protocols, was able to isolate those channel catfish lymphocytes which provide helper activity for antibody synthesis to a thymus dependent antigen. In addition, this antibody was observed to react with most thymocytes, neutrophils, and thrombocytes, few hepatocytes, and with some brain cells (possibly neurons). It was concluded that this antibody reacts with relatively high molecular weight antigens on channel catfish T cells and that it may be a pan anti-T cell reagent (possibly akin to Thy-2) for this species.


Dual-emissive ratiometric fluorescent nanosensor based on multi-nanomaterials for Ag+ determination in lake water.
In this study, a sensitive ratiometric fluorescent nanosensor was constructed using a facile one-pot method by encapsulating carbon dots (CDs) and cadmium telluride quantum dots (CdTe QDs) into the pore cavities of a metal-organic framework (ZIF-8). In this nanosensor (CD/CdTe QD@ZIF-8), the fluorescence attributed to CdTe QDs was quenched by silver ions (Ag+), and the fluorescence intensity of CDs did not change. The introduction of ZIF-8 into the system can not only adsorb Ag+ but also easily separate CDs and CdTe QDs from the matrix. The developed CD/CdTe QD@ZIF-8 composite used as a ratiometric fluorescent probe exhibited high sensitivity and selectivity towards Ag+. The working linear range was 0.1-20 μM with a limit of detection (LOD) of 1.49 nM. Finally, the proposed nanosensor was applied to determine Ag+ in lake water with satisfactory results.


Oncolytic adenovirus that overproduces ADP and replicates selectively in tumors due to hTERT promoter-regulated E4 gene expression.
We have constructed a novel oncolytic adenovirus (Ad) vector, named VRX-011, in which the replication of the vector is targeted to cancer cells by the replacement of the wild-type Ad E4 promoter with the human telomerase reverse transcriptase (hTERT) promoter. Genes in the Ad E4 transcription unit are essential for Ad replication; therefore, VRX-011 will grow efficiently only in cells in which the hTERT promoter is active, that is, in a wide range of cancer and immortalized cells but not in most somatic cells. Consistent with these expectations, VRX-011 replicated efficiently in all cancer cell lines examined, while its growth was restricted in various primary and normal cells. VRX-011 overexpresses ADP (also known as E3-11.6K), an Ad protein required for efficient cell lysis and release of virions from cells at late stages of infection. This overexpression enhances cell-to-cell spread and could significantly increase antitumor efficacy. In a xenograft model in nude mice, both intratumoral and intravenous administration of VRX-011 effectively suppressed the growth of subcutaneous Hep3B human liver tumors. Also, intravenous delivery of VRX-011 greatly reduced the number and size of A549 human lung cancer cell nodules in a disseminated lung tumor model in nude mice. Importantly, tail vein administration of different doses of VRX-011 in C57BL/6 mice showed minimal liver toxicity. Considering its broad range of lytic replication in cancer cells, its attenuated phenotype in primary cells, its efficacy in suppressing xenografts, and its low toxicity in mouse liver, VRX-011 is a promising candidate for further evaluation as an anticancer therapeutic.


[Demonstration of a bile fistula caused by liver biopsy by way of endoscopic retrograde cholangiography (author's transl)].
ERP may be indicated in hepatic disease with or without cholestasis. A complete display of the bile duct system has to be achieved, if cysts or tumors are to be detected, by direct or indirect involvement of the bile ducts. A case is reported of a bile fistula caused by liver biopsy.


Etiopathogenic role of ERK5 signaling in sarcoma: prognostic and therapeutic implications.
Sarcomas constitute a heterogeneous group of rare and difficult-to-treat tumors that can affect people of all ages, representing one of the most common forms of cancer in childhood and adolescence. Little is known about the molecular entities involved in sarcomagenesis. Therefore, the identification of processes that lead to the development of the disease may uncover novel therapeutic opportunities. Here, we show that the MEK5/ERK5 signaling pathway plays a critical role in the pathogenesis of sarcomas. By developing a mouse model engineered to express a constitutively active form of MEK5, we demonstrate that the exclusive activation of the MEK5/ERK5 pathway can promote sarcomagenesis. Histopathological analyses identified these tumors as undifferentiated pleomorphic sarcomas. Bioinformatic studies revealed that sarcomas are the tumors in which ERK5 is most frequently amplified and overexpressed. Moreover, analysis of the impact of ERK5 protein expression on overall survival in patients diagnosed with different sarcoma types in our local hospital showed a 5-fold decrease in median survival in patients with elevated ERK5 expression compared with those with low expression. Pharmacological and genetic studies revealed that targeting the MEK5/ERK5 pathway drastically affects the proliferation of human sarcoma cells and tumor growth. Interestingly, sarcoma cells with knockout of ERK5 or MEK5 were unable to form tumors when engrafted into mice. Taken together, our results reveal a role of the MEK5/ERK5 pathway in sarcomagenesis and open a new scenario to be considered in the treatment of patients with sarcoma in which the ERK5 pathway is pathophysiologically involved.


Effect of intravenous dose on hydralazine kinetics after administration.
Six male hypertensive patients, three rapid and three slow acetylators, each received four different intravenous hydralazine doses by constant infusion over 100 sec. Two to four days elapsed between doses. Plasma or whole-blood hydralazine concentrations were measured by HPLC after each dose. There was no influence of acetylator phenotype on hydralazine kinetics after intravenous dosing. There also was no consistent effect of dose size on hydralazine clearance or volume of distribution at doses up to 0.45 mg (2.3 mumol/kg). One subject, who received doses up to 0.6 mg/kg (3.05 mumol), had an apparent decrease in clearance at the higher doses. These findings are consistent with the fact that hydralazine is converted intravascularly to hydralazine pyruvic acid hydrazone and the fact that potentially saturable hepatic metabolic pathways play only a modest role in systemic clearance.


Rapid differentiation of current infectious bronchitis virus vaccine strains and field isolates in Australia.
Rapid differentiation of vaccine strains of infectious bronchitis virus (IBV) from wild type strains would enhance investigations of disease outbreaks. This study aimed to develop a reverse transcription-polymerase chain reaction (RT-PCR) assay to differentiate between Australian vaccine strains of IBV and field isolates. A fragment of 6.5 kilobases that contains the S, M and N genes was amplified by RT-PCR from ten different IBV strains, including vaccine strains and field isolates, and then sequenced. Comparison of the sequences of these strains revealed a deletion of 58 bases in the 3' untranslated region (UTR) of IBV vaccine strains but not in the field isolates. Two primers were designed to amplify a fragment of the 3' UTR that differed in size between the vaccine strains and field isolates. RT-PCR was performed using these two primers to screen 20 IBV strains, including field isolates and the vaccine strains. All strains were correctly identified as either vaccine strains or field isolates. This procedure is a rapid, sensitive and inexpensive method for discrimination between most current Australian vaccine strains and field isolates of IBV.


Erratum for: "Gastrodin induced HO-1 and Nrf2 up-regulation to alleviate H2O2-induced oxidative stress in mouse liver sinusoidal endothelial cells through p38 MAPK phosphorylation" [Braz J Med Biol Res (2018) 51(10): e7439].
[This corrects the article doi: 10.1590/1414-431X20187439].


Selective Expression of Osteopontin in ALS-resistant Motor Neurons is a Critical Determinant of Late Phase Neurodegeneration Mediated by Matrix Metalloproteinase-9.
Differential vulnerability among motor neuron (MN) subtypes is a fundamental feature of amyotrophic lateral sclerosis (ALS): fast-fatigable (FF) MNs are more vulnerable than fast fatigue-resistant (FR) or slow (S) MNs. The reason for this selective vulnerability remains enigmatic. We report here that the extracellular matrix (ECM) protein osteopontin (OPN) is selectively expressed by FR and S MNs and ALS-resistant motor pools, whereas matrix metalloproteinase-9 (MMP-9) is selectively expressed by FF MNs. OPN is secreted and accumulated as extracellular granules in ECM in three ALS mouse models and a human ALS patient. In SOD1(G93A) mice, OPN/MMP-9 double positivity marks remodeled FR and S MNs destined to compensate for lost FF MNs before ultimately dying. Genetic ablation of OPN in SOD1(G93A) mice delayed disease onset but then accelerated disease progression. OPN induced MMP-9 up-regulation via αvβ3 integrin in ChAT-expressing Neuro2a cells, and also induced CD44-mediated astrocyte migration and microglial phagocytosis in a non-cell-autonomous manner. Our results demonstrate that OPN expressed by FR/S MNs is involved in the second-wave neurodegeneration by up-regulating MMP-9 through αvβ3 integrin in the mouse model of ALS. The differences in OPN/MMP-9 expression profiles in MN subsets partially explain the selective MN vulnerability in ALS.


An assessment of the economic burden of senile chronic diseases in China based on China Health and Retirement Longitudinal Survey.
This study assessed the economic burden of senile chronic diseases (SCD) in China. Based on China Health and Retirement Longitudinal Survey data, we used propensity score matching to compare the economic burden of SCD for families with and without members with SCD. We examined three aspects of economic burden: health service utilization, including health care utilization and expenditure, family daily consumption spending, and workforce participation of family members in labor markets. SCD-families showed a higher hospitalization rate and number of outpatient visits than the control group. SCD-families also consumed less per capita. Additionally, the negative influence of SCD on total family income may be partially offset by increasing the labor force participation rate of healthy family members. Finally, we also discussed the burden of SCD in different educational status. Relevant results may provide insight into formulating health and labor policies by the Chinese government. The study significance consists of the selection of matching variables and robustness, whereas study limitations include the omission of other important variables.


COVID-19 pneumonia: computer-aided quantification of healthy lung parenchyma, emphysema, ground glass and consolidation on chest computed tomography (CT).
To calculate by means of a computer-aided tool the volumes of healthy residual lung parenchyma, of emphysema, of ground glass opacity (GGO) and of consolidation on chest computed tomography (CT) in patients with suspected viral pneumonia by COVID-19. This study included 116 patients that for suspected COVID-19 infection were subjected to the reverse transcription real-time fluorescence polymerase chain reaction (RT-PCR) test. A computer-aided tool was used to calculate on chest CT images healthy residual lung parenchyma, emphysema, GGO and consolidation volumes for both right and left lung. Expert radiologists, in consensus, assessed the CT images using a structured report and attributed a radiological severity score at the disease pulmonary involvement using a scale of five levels. Nonparametric test was performed to assess differences statistically significant among groups. GGO was the most represented feature in suspected CT by COVID-19 infection; it is present in 102/109 (93.6%) patients with a volume percentage value of 19.50% and a median value of 0.64 L, while the emphysema and consolidation volumes were low (0.01 L and 0.03 L, respectively). Among quantified volume, only GGO volume had a difference statistically significant between the group of patients with suspected versus non-suspected CT for COVID-19 (p < < 0.01). There were differences statistically significant among the groups based on radiological severity score in terms of healthy residual parenchyma volume, of GGO volume and of consolidations volume (p < < 0.001). We demonstrated that, using a computer-aided tool, the COVID-19 pneumonia was mirrored with a percentage median value of GGO of 19.50% and that only GGO volume had a difference significant between the patients with suspected or non-suspected CT for COVID-19 infection.


A phase II multicenter trial of hyperCVAD MTX/Ara-C and rituximab in patients with previously untreated mantle cell lymphoma; SWOG 0213.
Rituximab-hyper-CVAD alternating with rituximab-high-dose methotrexate and cytarabine is a commonly utilized regimen in the United States for mantle cell lymphoma (MCL) based on phase II single institutional data. To confirm the clinical efficacy of this regimen and determine its feasibility in a multicenter study that includes both academic and community-based practices, a phase II study of this regimen was conducted by SWOG. Forty-nine patients with advanced stage, previously untreated MCL were eligible. The median age was 57.4 years (35-69.8 years). Nineteen patients (39%) did not complete the full scheduled course of treatment due to toxicity. There was one treatment-related death and two cases of secondary myelodysplastic syndrome (MDS). There were 10 episodes of grade 3 febrile neutropenia, 19 episodes of grade 3 and 1 episode of grade 4 infection. With a median follow-up of 4.8 years, the median progression-free survival was 4.8 years (5.5 years for those ≤ 65 years) and the median overall survival (OS) was 6.8 years. Although this regimen is toxic, it is active for patients ≤ 65 years of age and can be given both at academic centers and in experienced community centers.


Checklist of herpetofauna in the severely degraded ecosystem of Bidong Island, Peninsular Malaysia, South China Sea.
A herpetofaunal inventory was conducted on Bidong Island, Terengganu, Peninsular Malaysia. It incorporates data from a recent herpetological survey conducted from 1 to 3 April 2019 with reptile records from previous publications. Specimens were collected with drift-fenced pitfall traps and taxa were recorded with visual encounter surveys (VES). In total, 18 species of reptiles and amphibians were recorded, including three species of frogs, 12 species of lizards, and three species of snakes. Six species from the present survey are new records for the island.


The frontal bone skull post for image guided surgery of the nasopharynx.
To describe the use of the mastoid skull post of a surgical image guidance system for image guided surgery and intraoperative navigation of the nasopharynx. This adaptation overcomes the limitations of a headset frame or head clamp and can be applied to open and closed surgery of the nasal cavities, sinuses, orbits, midface and anterior skull base. A sterile mastoid skull post of a surgical image guidance system was securely screwed into the outer table of the frontal bone and a passive reference frame fixed to it. The position of the reference frame relative to the patient's head remained constant during surgery. Between August 2002 and November 2006, 22 patients underwent a surgical nasopharyngectomy using an image guidance system and frontal bone skull post. No surgical complications or complications of the frontal bone skull post occurred. Using the skull post of a surgical image guidance system anchored to the frontal bone to carry a passive reference frame provides real-time visual information about the relationship of relevant anatomy to the surgical field on a fully mobile head in open or closed procedures of the midface and anterior skull base while accuracy and sterility are maintained.


Endothelin-1 is associated with mortality that can be attenuated with high intensity statin therapy in patients with stable coronary artery disease.
All coronary artery disease (CAD) patients do not benefit equally of secondary prevention. Individualized intensity of drug therapy is currently implemented in guidelines for CAD and diabetes. Novel biomarkers are needed to identify patient subgroups potentially benefitting from individual therapy. This study aimed to investigate endothelin-1 (ET-1) as a biomarker for increased risk of adverse events and to evaluate if medication could alleviate the risks in patients with high ET-1. A prospective observational cohort study ARTEMIS included 1946 patients with angiographically documented CAD. Blood samples and baseline data were collected at enrollment and the patients were followed for 11 years. Multivariable Cox regression was used to assess the association between circulating ET-1 level and all-cause mortality, cardiovascular (CV) death, non-CV death and sudden cardiac death (SCD). Here we show an association of circulating ET-1 level with higher risk for all-cause mortality (HR: 2.06; 95% CI 1.5-2.83), CV death, non-CV death and SCD in patients with CAD. Importantly, high intensity statin therapy reduces the risk for all-cause mortality (adjusted HR: 0.05; 95% CI 0.01-0.38) and CV death (adjusted HR: 0.06; 95% CI 0.01-0.44) in patients with high ET-1, but not in patients with low ET-1. High intensity statin therapy does not associate with reduction of risk for non-CV death or SCD. Our data suggests a prognostic value for high circulating ET-1 in patients with stable CAD. High intensity statin therapy associates with reduction of risk for all-cause mortality and CV death in CAD patients with high ET-1.


Dry matter partitioning and root length/leaf area ratios in herbaceous perennial plants with diverse altitudinal distribution.
Partitioning patterns in 22 exclusively low and 27 exclusively high altitude perennial herbaceous species were examined in order to test the hypothesis that plants of high altitudes allocate more dry matter to below-ground parts and in particular to storage organs, than typical low altitude plants. Our results raise some doubts about the general validity of this hypothesis. The mean fractions of total dry matter allocated to green leaves (22±2% s.e. at low and 24±2% at high altitude) and special storage organs (28±4% at both altitudes) do not differ significantly among sites. The mean relative portions of total dry matter allocated to above-ground plant parts amount to 57±3% at low and 42±3% at high elevation (P=0.002) and differ less than often assumed. The greater below-ground fraction at high altitude results from reduced stem and proportionally increased fine root compartments. At high altitude specific root length is increased by 50% and mean individual rooting density is tripled. Fine root length per unit leaf area is 4.5 times greater (P<0.001). However, interspecific variation in all these quantities is considerable and species with quite contrasting partitioning patterns coexist at both elevations. This suggests that the success of perennial herbaceous plants at high elevations does not necessarily depend on a large below ground biomass fraction. The increased fine root length at high altitude may substitute for reduced mycorrhizal infection. Figure 1 provides a graphical summary.


Biologic activity of carotenoids related to distinct membrane physicochemical interactions.
Carotenoids are naturally occurring organic pigments that are believed to have therapeutic benefit in treating cardiovascular disease (CVD) because of their antioxidant properties. However, prospective randomized trials have failed to demonstrate a consistent benefit for the carotenoid beta-carotene in patients at risk for CVD. The basis for this apparent paradox is not well understood but may be attributed to the distinct antioxidant properties of various carotenoids resulting from their structure-dependent physicochemical interactions with biologic membranes. To test this hypothesis, we measured the effects of astaxanthin, zeaxanthin, lutein, beta-carotene, and lycopene on lipid peroxidation using model membranes enriched with polyunsaturated fatty acids. The correlative effects of these compounds on membrane structure were determined using small-angle x-ray diffraction approaches. The nonpolar carotenoids, lycopene and beta-carotene, disordered the membrane bilayer and stimulated membrane lipid peroxidation (>85% increase in lipid hydroperoxide levels), whereas astaxanthin (a polar carotenoid) preserved membrane structure and exhibited significant antioxidant activity (>40% decrease in lipid hydroperoxide levels). These results suggest that the antioxidant potential of carotenoids is dependent on their distinct membrane lipid interactions. This relation of structure and function may explain the differences in biologic activity reported for various carotenoids, with important therapeutic implications.


Muscle spindles as pain receptors.
Muscle membranes have a sensation of pain, but within the muscle tissue, the origin of pain is unclear. We present a hypothesis that the pain receptors of the muscle tissue are situated principally in the muscle spindles. A recent report reintroduced that 'end plate spikes' in needle electromyography (EMG) are fusimotor unit potentials of the intrafusal muscle fibres, and thus represent a marker of muscle spindles. We studied four relaxed muscles with 50 EMG needle insertions in each and mapped the appearance of pain and spontaneous EMG activity. Only 4.0% of the needle insertions in muscle tissue elicited pain. However, needle insertions in local active points showing 'end plate spikes' and, thus, fusimotor unit potentials of the muscle spindles elicited pain in 86% of the insertions, whereas needle insertions in points without 'end plate spikes' elicited pain in only 1.0% of the insertions (p<0.001). Muscle spindles have pain receptors. The extrafusal muscle tissue is practically pain-free for the needle insertions. This demonstrates a scarcity of extrafusal pain receptors. How this observation is put into perspective with the muscle pain syndromes was discussed.


Detection of the changes in protein distribution in rat serum after partial hepatectomy using two-dimensional electrophoresis under non-denaturing conditions.
The changes in rat serum protein distribution after partial hepatectomy were examined using two-dimensional electrophoresis, utilizing isoelectric focusing in polyacrylamide gel in the first dimension and pore gradient polyacrylamide gel electrophoresis in the second dimension. Drastic decreases in amount of protein were observed at more than twenty spot positions, and drastic increases in amount or newly appeared proteins were observed at eight spot positions. The amounts of albumin, immunoglobulin M and alpha 2-macroglobulin did not change relatively after hepatectomy. The time course of the changes was examined using a densitometer, and it was observed that almost all the serum proteins changed drastically at 24 h after hepatectomy.


A new lupane triterpene from Tetracera scandens L., xanthine oxidase inhibitor.
From the MeOH extract of the stem of Tetracera scandens L., a new nor-lupane triterpene, 28-O-β-D-glucopyranosyl ester of platanic acid (1), has been isolated together with six known compounds. Their structures were elucidated on the basis of spectroscopic data. Compounds 1-6 displayed significant xanthine oxidase inhibitory activity in a concentration-dependent manner, and compound 4 showed more potent inhibitory activity with an IC(50) value of 1.9 µM than that of a positive control allopurinol (IC(50) 2.5 µM).


Carbon dot reduced palladium nanoparticles as active catalysts for carbon-carbon bond formation.
Carbon dots were used as a reducing agent for the synthesis of Pd nanoparticles coated with ultrathin carbon dot shells of ca. 4 nm. The resulting composite nanoparticles showed high catalytic activity for the Heck and Suzuki coupling reactions.


Inhibition by azelastine of nonallergic histamine release from rat peritoneal mast cells.
The ability of azelastine and selected antiallergic drugs to inhibit compound 48/80-induced and PS-potentiated, Con A-induced histamine release from RPMC was investigated. Azelastine, ketotifen, theophylline, and DSCG added simultaneously with the secretagogues or preincubated with the RPMC for 10 min before the addition of secretagogues produced concentration-dependent inhibition of histamine release. In general, the relative order of potency at calculated IC50 level was as follows: azelastine greater than ketotifen greater than theophylline greater than DSCG. The preincubation of RPMC with azelastine for 10 min exerted 3.5 times greater inhibition of Con A plus PS-stimulated histamine release but did not influence the inhibitory activity on compound 48/80-induced release. The duration of preincubation did not influence the inhibitory effects of ketotifen with either secretagogue. Theophylline and DSCG exerted significantly greater inhibition when they were added simultaneously with Con A plus PS. The inhibitory activity of DSCG was also significantly improved upon simultaneous addition with compound 48/80. These data demonstrated that azelastine is the most potent inhibitor of nonallergic histamine release from RPMC among the four antiallergic drugs examined.


Routine evaluation of tonsillectomy specimens: a cross-sectional survey of Canadian Otolaryngology: Head and Neck Surgeons.
Tonsillectomy is a commonly performed procedure in Canada. The rate of occult malignancy is rare in adult and pediatric populations. At present, no guidelines exist surrounding the need for routine histopathological evaluation of tonsil specimens when no malignancy is suspected. We sent a confidential online survey to active members of the Canadian Society of Otolaryngology - Head and Neck Surgery (CSO-HNS) about their current tonsillectomy practice and beliefs surrounding the need for routine histopathological evaluation of tonsillectomy specimens when no malignancy is suspected. We used Opinio survey software for data collection and descriptive statistics. 95 participants completed our survey (response rate 19.3%). Most participants reported performing both adult and pediatric tonsillectomies. When no malignancy is suspected, participant responses were split between whether they send tonsil specimens in pediatrics only (4.2%), in adults only (31.6%), or not sending specimens (29.5%). Half of the participants reported that routinely sending specimens to rule out occult malignancy is an institutional policy. Approximately 75% of participants were in favour of removing this practice in both the pediatric and adult populations. Eliminating the practice of automatically sending tonsil specimens for histopathological evaluation when no malignancy is suspected was supported by the majority of study participants. This is in keeping with Choosing Wisely, a campaign designed to facilitate conversations about unnecessary medical tests and procedures. Institutional change is likely required in order to alter this practice.


Primary abdominal pregnancy: can artificial abortion, endometriosis and IUD be etiological factors?
Primary abdominal pregnancy is a very rare condition, accompanied by high rates of perinatal and maternal mortality. The etiology of this condition is not clear; nevertheless several theories have been proposed. We have reported three cases in whom the etiological factors may have been the presence of an IUD, and patches of endometriosis adjacent to the site of the pregnancy in two cases. It is suggested that in cases suspected of ectopic pregnancy, in the presence of IUD or other pelvic pathology, it should first be determined whether it is the dangerous condition of abdominal pregnancy, in view of the high mortality rates.


Rainfall reductions over Southern Hemisphere semi-arid regions: the role of subtropical dry zone expansion.
Since the late 1970s, Southern Hemisphere semi-arid regions such as southern-coastal Chile, southern Africa, and southeastern Australia have experienced a drying trend in austral autumn, predominantly during April and May. The rainfall reduction coincides with a poleward expansion of the tropical belt and subtropical dry zone by around 2°-3° in the same season. This has raised questions as to whether the regional rainfall reductions are attributable to this poleward expansion. Here we show that the impact of the poleward subtropical dry-zone shift is not longitudinally uniform: a clear shift occurs south of Africa and across southern Australia, but there is no evidence of a poleward shift in the southern Chilean sector. As such, a poleward shift of climatological April-May rainfall can explain most of the southeastern Australia rainfall decline, a small portion of the southern Africa rainfall trend, but not the autumn drying over southern Chile.


Chiral recognition of ephedrine: Hydrophilic polymers bearing β-cyclodextrin moieties as chiral sensitive host molecules.
In this work we demonstrate chiral recognition of (+)- and (-)-ephedrine using a cyclodextrin-containing polymer. The supramolecular structures obtained by complexation of ephedrine and cyclodextrin were verified by 2-D ROESY NMR measurements. Dynamic light scattering showed clear differences in the mean coil size.


Role of bradykinin in acid-induced mesenteric hyperemia and duodenal villous damage.
Intestinal mucosal capsaicin-sensitive afferent nerves mediate, in part, the mesenteric hyperemia after intraduodenal acidification. The hyperemia plays a role in protecting the duodenal mucosa against acid damage. We tested the hypothesis that bradykinin contributes to this protective hyperemia. A specific antagonist of bradykinin will attenuate the hyperemia and exacerbate duodenal villous damage induced by acid. Study 1: Intravenous vehicle, or the specific bradykinin B2 receptor antagonist (HOE 140) was administered to anesthetized rats. This was followed by intraduodenal bolus administration of 160 microM capsaicin or 0.1 N HCl, and then intravenous bradykinin. Study 2: Intravenous administration of vehicle or HOE 140 was followed by duodenal perfusion with 0.1 N HCl. Superior mesenteric artery blood flow (pulsed Doppler flowmetry) (Study 1) and duodenal villous damage (histology) (Study 2) were recorded. HOE 140 significantly reduced the hyperemia induced by bradykinin and intraduodenal capsaicin or acid. Deep villous injury was significantly increased after treatment with HOE 140. These findings support the hypothesis that acid-induced and afferent nerve-mediated mesenteric hyperemia is modulated by a mechanism that involves bradykinin B2 receptor. Antagonism of bradykinin B2 receptor also increased acid-induced deep duodenal villous damage. Thus, maintenance of bradykinin-mediated mesenteric hyperemia, is a previous unrecognized mechanism associated with protection of the rat duodenal mucosa against acid-induced damage.


Identification of tyrosinase inhibitors from traditional Chinese medicines for the management of hyperpigmentation.
The inhibition of tyrosinase is the most effective method to decrease melanin synthesis during the process of pigmentation. We aimed to find compounds from traditional Chinese medicines (TCM) that are more effective than the most commonly used tyrosinase inhibitor, arbutin. First, we employed homology modeling to construct a tyrosinase-modeled structure, and structure-based virtual screening to screen from 61,000 TCM compounds. We also adopted the following quantitative structure-activity relationship (QSAR) models for ligand-based validation: support vector machine, multiple linear regression, and Bayesian network. Molecular dynamics (MD) simulation was used to confirm the stability of ligand binding. We found that merresectine C might more effectively bind and inhibit the activity of tyrosinase than arbutin. This study provides useful evidence for the potential development of a novel non-toxic bleaching or whitening ingredient.


Differences in prosthodontic treatment needs assessments between the standard normative and sociodental approach.
To assess and compare prosthodontic treatment needs and the related manpower requirements using the normative and sociodental needs approaches for adult Koreans aged 30 to 64 years. Data were obtained from 1,029 30- to 64-year-old adults who were a subsample of the 2003 Korean National Oral Health Survey. Subjects were clinically examined for normative needs and interviewed using an oral health-related quality of life (OHRQoL) measure, the Oral Impacts on Daily Performance. Their oral health behaviors were also assessed. The sociodental approach includes impact-related needs, in which normative needs are integrated with OHRQoL, and propensity-related needs, in which oral health behaviors are used to determine appropriate treatments. Prosthodontic treatment needs and number of clinicians needed to treat those needs were estimated using normative needs, impact-related needs, and propensity-related needs. Compared to normative needs, significant decreases of 74.1% to 78.5% were found for prosthodontic treatment needs using impact-related needs and propensity-related needs, respectively. Differences in manpower requirements to deal with prosthodontic treatment were large; per 100,000 people, 86.5 dental clinicians would be needed using normative needs, compared to 22.4 clinicians using impact-related needs and 18.6 clinicians using propensity-related needs. The sociodental approach for assessing dental needs for prosthodontic treatment indicated much lower levels of treatment needs than the normative approach. The sociodental approach should be applied to dental workforce planning.


Cervico-facial pain associated with Eagle's syndrome misdiagnosed as cranio-mandibular disorders. A retrospective study.
a retrospective study was done to assess symptoms correlated with and responsible for the misdiagnosis of Eagle's syndrome with Cranio-Mandibular Disorders. Our study comprised patients suffering from vague craniofacial pain resulting from elongated styloid processes, presented to the outpatient clinic of the oral and maxillofacial surgery department, October 6 University Hospital. The length of styloid processes was measured on 3D-CT X-rays. All our patients were operated by surgical treatment in the form of shortening of the styloid process (styloidectomy) under general anaesthesia and followed up clinically as well as radiographically for 12 months. Patients were assessed preoperatively as well as postoperatively throughout the following scheduled regular follow up intervals at 1 week and at 1,3,6 and 12 months postoperatively for the following parameters. VAS pain score gradually decreased from a median of 9, with a minimum of 7 and a maximum of 10 pre-operatively to a median of 1.5, with a minimum of 0 and a maximum of 3 at twelve months. Freidman test revealed a statistically significant difference by time. Maximum unassisted mouth opening was assessed. Mouth opening significantly decreased from 30.23 ± 3.28 pre-operatively to 26.08 ± 2.83 after one week, then gradually increased to reach its highest level (43.56 ± 0.72) at twelve months. When dealing with cases of vague craniofacial pain, possibility of Eagle syndrome should be considered.


Proposed Requirements for Cardiovascular Imaging-Related Machine Learning Evaluation (PRIME): A Checklist: Reviewed by the American College of Cardiology Healthcare Innovation Council.
Machine learning (ML) has been increasingly used within cardiology, particularly in the domain of cardiovascular imaging. Due to the inherent complexity and flexibility of ML algorithms, inconsistencies in the model performance and interpretation may occur. Several review articles have been recently published that introduce the fundamental principles and clinical application of ML for cardiologists. This paper builds on these introductory principles and outlines a more comprehensive list of crucial responsibilities that need to be completed when developing ML models. This paper aims to serve as a scientific foundation to aid investigators, data scientists, authors, editors, and reviewers involved in machine learning research with the intent of uniform reporting of ML investigations. An independent multidisciplinary panel of ML experts, clinicians, and statisticians worked together to review the theoretical rationale underlying 7 sets of requirements that may reduce algorithmic errors and biases. Finally, the paper summarizes a list of reporting items as an itemized checklist that highlights steps for ensuring correct application of ML models and the consistent reporting of model specifications and results. It is expected that the rapid pace of research and development and the increased availability of real-world evidence may require periodic updates to the checklist.


Decreased plasma gelsolin is associated with 1-year outcome in patients with traumatic brain injury.
Decreased plasma gelsolin level has been associated with 1-month mortality after traumatic brain injury (TBI). Thus, we investigated the ability of gelsolin to predict 1-year mortality and functional outcome in these patients. One hundred fourteen healthy controls and 114 patients with acute severe TBI were included in this study. Plasma gelsolin concentration on admission was measured by ELISA. Fifty-five patients (48.2%) had unfavorable outcome (Glasgow Outcome Scale score of 1-3) and 38 patients (33.3%) died in 1 year after TBI. Upon admission, plasma gelsolin level in patients was substantially lower than that in healthy controls. A multivariate analysis selected plasma gelsolin level as an independent predictor for 1-year unfavorable outcome and mortality of patients. A receiver operating characteristic curve analysis showed plasma gelsolin level predicted 1-year unfavorable outcome and mortality statistically significantly. The predictive value of the gelsolin concentration was thus similar to that of Glasgow Coma Scale (GCS) score. In a combined logistic-regression model, gelsolin did not statistically significantly improve the area under curve of GCS score. Plasma gelsolin level is a useful, complementary tool to predict functional outcome and mortality 1 year after TBI.


Psychotic-like experiences in patients with insomnia or sleep apnea: associations with sleep parameters.
There are strong links between sleep and psychotic-like experiences (PLE), such as magical ideations or persecutory ideas. Sleep disturbances seem to play an important role in the occurrence of such symptoms, but studies investigating PLE in patients with sleep disorders are lacking. We studied 24 subjects with insomnia disorder (41 ± 13 years) and 47 participants with obstructive sleep apnea (OSA, 47 ± 11 years) in the sleep laboratory and 33 healthy controls. Sleep in patients with sleep disorders was recorded and scored according to standard criteria of the American Academy of Sleep Medicine. PLE were measured by the Magical Ideation Scale (MIS, short form with 10 items) and by the Peters et al., Delusions Inventory (PDI, 21 items). Additionally, cognitive tests and further psychological self-rating tests such as the Beck Depression Inventory (BDI) and the Pittsburgh Sleep Quality Index (PSQI) were administered. Patients with insomnia had significantly higher scores of magical and delusional ideations compared to healthy controls. Sleep apnea patients showed a tendency of a higher score of delusional beliefs in comparison to controls. Magical ideations in insomnia subjects were significantly negatively correlated with the number of sleep spindles. In a subgroup of insomnia patients without antidepressants, delusional beliefs were negatively associated with rapid eye movement (REM)-sleep. As there are indications that diminutions of sleep spindles are a biomarker for dysfunctional thalamo-cortical circuits underlying the neuropathology of psychosis, we conclude that there might be a sub-group of insomnia patients with fewer sleep spindles which is more vulnerable to developing a psychotic disorder in the future.


HIV-1 group O infection in Cameroon from 2006 to 2013: Prevalence, genetic diversity, evolution and public health challenges.
The human immunodeficiency virus, HIV, is characterized by a tremendously high genetic diversity, leading to the currently known circulating HIV types, groups, subtypes, and recombinant forms. HIV-1 group O is one of the most diverse forms of HIV-1 and has been so far related to Cameroon or individuals originating from Cameroon. In this study, we investigated in Cameroon, the evolution of this viral group from 2006 to 2013, in terms of prevalence, genetic diversity and public health implications. Our results confirmed the predominance of HIV-1 group M (98.5%), a very low prevalence (<0.02%) for HIV-1 group N and P, and HIV-2 in this country. HIV-1 group O was found at around 0.6% (95% confidence interval: 0.4-0.8%), indicating that the frequency of this virus in Cameroon has remained stable over the last decades. However, we found an extensive high genetic diversity within this HIV-1 group, that resulted from previous steady increase on the effective number of HIV-1 group O infections through time, and the current distribution of the circulating viral strains still does not allow classification as subtypes. The frequency of dual infections with HIV-1 group M and group O was 0.8% (95% confidence interval: 0.6-1.0%), but we found no recombinant forms in co-infected patients. Natural resistance to integrase inhibitors was not identified, although we found several mutations considered as natural polymorphisms. Our study shows that infections with HIV-1 group O can be adequately managed in countries where the virus circulates, but this complex virus still represents a challenge for diagnostics and monitoring strategies.


Youngest netherton patient with infantile asthma.
Netherton syndrome is a very rare disorder characterized with icthyosis, atopy, bamboo hair and intermittant aminoaciduria. The specifity of clinical and histopathological features of netherton syndrome is low in neonates and young infants who presents with predominating erythrodermia. Being the youngest infant presenting with the symptoms of infantile asthma we found it worth to report a six months old girl presenting with the feature of severe respiratory distress, generalized erythrodermia, and brittle hair.


Enzalutamide Reduces Oxycodone Exposure in Men with Prostate Cancer.
Up to 90% of patients with castration-resistant prostate cancer (CRPC) will develop symptomatic bone metastases requiring pain medication, with opioids being the mainstay of therapy in treating moderate and severe pain. Enzalutamide is an androgen receptor antagonist for the treatment of CRPC and a strong inducer of cytochrome P450 (CYP)3A4. Hereby, enzalutamide potentially reduces the exposure of oxycodone, an opioid metabolized by CYP3A4 and CYP2D6. Our objective was to evaluate the potential drug-drug interaction of enzalutamide and oxycodone. A prospective, nonrandomized, open-label, two-arm parallel study was performed. All patients received a single dose of 15 mg normal-release oxycodone. Patients in the enzalutamide arm (ENZ-arm) received enzalutamide 160 mg once daily. Plasma concentrations of oxycodone and its metabolites were quantified using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Twenty-six patients (13 ENZ-arm; 13 control arm) were enrolled in the study. Enzalutamide decreased the mean AUC0-8 h and Cmax of oxycodone with, respectively, 44.7% (p < 0.001) and 35.5% (p = 0.004) compared with the control arm. The AUC0-8 h and Cmax of the active metabolite oxymorphone were 74.2% (p < 0.001) and 56.0% (p = 0.001) lower in the ENZ-arm compared with the control arm. In contrast, AUC0-8 h and Cmax of the inactive metabolites noroxycodone and noroxymorphone were significantly increased by enzalutamide. Co-administration of enzalutamide significantly reduced exposure to oxycodone and its active metabolite oxymorphone in men with prostate cancer. This should be taken into account when prescribing enzalutamide combined with oxycodone.


Structural basis of transcription reduction by a promoter-proximal +1 nucleosome.
At active human genes, the +1 nucleosome is located downstream of the RNA polymerase II (RNA Pol II) pre-initiation complex (PIC). However, at inactive genes, the +1 nucleosome is found further upstream, at a promoter-proximal location. Here, we establish a model system to show that a promoter-proximal +1 nucleosome can reduce RNA synthesis in vivo and in vitro, and we analyze its structural basis. We find that the PIC assembles normally when the edge of the +1 nucleosome is located 18 base pairs (bp) downstream of the transcription start site (TSS). However, when the nucleosome edge is located further upstream, only 10 bp downstream of the TSS, the PIC adopts an inhibited state. The transcription factor IIH (TFIIH) shows a closed conformation and its subunit XPB contacts DNA with only one of its two ATPase lobes, inconsistent with DNA opening. These results provide a mechanism for nucleosome-dependent regulation of transcription initiation.


The cat lumbar spinal cord somatotopic map is unchanged after peripheral nerve crush and regeneration.
Microelectrode recordings have been made of the activity of neurons in the left dorsal horn of the lumbar enlargement of cats in which the left sciatic and saphenous nerves had been crushed 9 months earlier. In normal animals the receptive fields of neurons in this part of the spinal cord excited by gentle mechanical stimulation of the leg are somatotopically organized in such a way that they provide a map of the hind-leg skin. Previous experiments have shown that 9 months after cutting the nerves supplying the lower half of the hind-leg this somatotopic map is lost. The present experiments show that 9 months after nerve crush the somatotopic map is restored and indistinguishable from that seen in normal animals.


GCNF-dependent repression of BMP-15 and GDF-9 mediates gamete regulation of female fertility.
To determine the function of germ cell nuclear factor (GCNF) in female reproduction, we generated an oocyte-specific GCNF knockout mouse model (GCNF(fl/fl)Zp3Cre(+)). These mice displayed hypofertility due to prolonged diestrus phase of the estrous cycle and aberrant steroidogenesis. These reproductive defects were secondary to a primary defect in the oocytes, in which expression of the paracrine transforming growth factor-beta signaling molecules, bone morphogenetic protein 15 (BMP-15) and growth differentiation factor 9 (GDF-9), were up-regulated in GCNF(fl/fl)Zp3Cre(+) females at diestrus. This was a direct effect of GCNF, as molecular studies showed that GCNF bound to DR0 elements within the BMP-15 and GDF-9 gene promoters and repressed their reporter activities. Consistent with these findings, abnormal double-oocyte follicles, indicative of aberrant BMP-15/GDF-9 expression, were observed in GCNF(fl/fl)Zp3Cre(+) females. The Cre/loxP knockout of GCNF in the oocyte has uncovered a new regulatory pathway in ovarian function. Our results show that GCNF directly regulates paracrine communication between the oocyte and somatic cells by regulating the expression of BMP-15 and GDF-9, to affect female fertility.


Participatory action research in the implementing process of evidence-based intervention to prevent childhood obesity: project design of the "Healthy Future" study.
To describe the design of the developmental project Healthy Future that aims to implement a new evidence-based program for the prevention of childhood obesity and collaboration and sharing of work between specialist and community health care professionals in parts of a county in western Norway. Comprehensive participatory planning and evaluation (CPPE) process as an action-oriented research approach was chosen, using mixed data sources, mixed methods, and triangulation. A bottom-up approach might decrease the barriers when new evidence-based childhood prevention interventions are going to be implemented. It is crucial not only to build partnership and shared understanding, motivation, and vision, but also to consider the frames of the organizations, such as competencies, and time to carry out the interventions at the right level of health care service and adapt to the overweight children and their families needs. The developmental process of new health care programs is complex and multileveled and requires a framework to guide the process. By CPPE approach evidence-based health care practice can be delivered based on research, user knowledge, and provider knowledge in the field of childhood overweight and obesity in a certain context.


Clinicals And Upper Airway Characteristics in Obese Children with Obstructive Sleep Apnea.
Obesity is a factor that is strongly related to the occurrence of obstructive sleep apnea (OSA) in adults, although this association remains controversial for children. The aim of this study was to compare the clinical and upper airway charactheristics, obtained by questionnaires, physical examination and laboratory tests, among obese children with and without OSA. This was aprospective cohort study. 44 obese children (body mass index above the 95th percentile) were included in the study. Questionnaires, physical examination of the upper airway, nasofibrolaryngoscopy, polysomnography, and laboratory allergic tests were performed. There were 22 male patients (50%), and the mean age was 7.6±2.5 years. OSA was present in 19 (43%) patients. There were no statistically significant differences between the groups with and without OSA, in relation to clinical or laboratory allergic parameters. For the upper airway assessments, hypertrophy of the pharyngeal (p=0.001) and palatine (p=0.049) tonsils were the only parameters associated with OSA, and a modified Mallampati index of class III/IV also demonstrated a tendency towards being statistically associated with OSA (p=0.081). Moreover, these findings were confirmed to be factors associated with OSA in this group of children according to a logistic regression analysis. The occurrence rate of OSA in this obese pediatric population was high. Adenotonsillar hypertrophy and a modified Mallampati index of class III/IV were the factors associated with OSA.


Acute cardiac impairment associated with concurrent chemoradiotherapy for esophageal cancer: magnetic resonance evaluation.
To evaluate acute cardiac effects of concurrent chemoradiotherapy (CCRT) for esophageal cancer. This prospective study was approved by the institutional review board, and written informed consent was obtained from all participants. The left ventricular function (LVF) of 31 patients with esophageal cancer who received cisplatin and 5-fluorouracil-based CCRT was evaluated using cardiac cine magnetic resonance imaging. The patients were classified into two groups according to mean LV dose. The parameters related to LVF were compared between before and during (40 Gy) or between before and after CCRT using a Wilcoxon matched-pairs single rank test, and parameter ratios (during/before CCRT, after/before CCRT) were also compared between the groups with a t test. Data were expressed as mean ± SE. In the low LV-dose group (n = 10; mean LV dose <0.6 Gy), LV ejection fraction decreased significantly (before vs. during vs. after CCRT; 62.7% ± 2.98% vs. 59.8% ± 2.56% vs. 60.6% ± 3.89%; p < 0.05). In the high LV-dose group (n = 21; mean LV dose of 3.6-41.2 Gy), LV end-diastolic volume index (before vs. after CCRT; 69.1 ± 2.93 vs. 57.0 ± 3.23 mL/m(2)), LV stroke volume index (38.6 ± 1.56 vs. 29.9 ± 1.60 mL/m(2)), and LV ejection fraction (56.9% ± 1.79% vs. 52.8% ± 1.15%) decreased significantly (p < 0.05) after CCRT. Heart rate increased significantly (before vs. during vs. after CCRT; 66.8 ± 3.05 vs. 72.4 ± 4.04 vs. 85.4 ± 3.75 beats per minute, p < 0.01). Left ventricle wall motion decreased significantly (p < 0.05) in segments 8 (before vs. during vs. after CCRT; 6.64 ± 0.54 vs. 4.78 ± 0.43 vs. 4.79 ± 0.50 mm), 9 (6.88 ± 0.45 vs. 5.04 ± 0.38 vs. 5.27 ± 0.47 mm), and 10 (9.22 ± 0.48 vs. 8.08 ± 0.34 vs. 8.19 ± 0.56 mm). The parameter ratios of LV end-diastolic volume index, stroke volume index, wall motion in segment 9, and heart rate showed significant difference (p < 0.05) after CCRT between the groups. Concurrent chemoradiotherapy for esophageal cancer impairs LVF from an early treatment stage. This impairment is prominent in patients with high LV dose.


Seeing sounds: visual and auditory interactions in the brain.
Objects and events can often be detected by more than one sensory system. Interactions between sensory systems can offer numerous benefits for the accuracy and completeness of the perception. Recent studies involving visual-auditory interactions have highlighted the perceptual advantages of combining information from these two modalities and have suggested that predominantly unimodal brain regions play a role in multisensory processing.